The ,Health Benefits of SMOKING CESSATION a report of the Surgeon General 1990 U.S. DEPARTMENT OF HEALTH AND HCIMAN SERVICES Public Health Service Centen for Disease Control Center for Chrome Disease Prevention and Health Promorwn CDC CENTERS FOR DGEASE CONTROL Office on Smoking and Health Rockvllle. Maryland 20857 U.S. Department of Health and Human Ser\ ice\. 7%1> filwlllr Rlvrcytr\ /!f .S/?i,JX- /~,q L`c~c.wfio/~. U.S. Department of Health and Human St'r\~ices. Public Health Service. Center3 for Diwaw Control. Center for Chronic Die;Le Pre\ ention and Health Promotion. Ofke on Smohing and Health. DHHS Publication No. (CDC) YO-K-116. 1990. The Honorable Thomas S. Foley Speaker of the House of -RSpreSSlltSti"eS Washingcon, D.C. 20515 Dear nr. Speaker: It is my pleasure to transmit to the Congress the 1990 Surgeon General's Report on the health consequences of smoking as mandated by Section E(a) of the Public Health Cigarette Smoking Act of 1969 (Pub. L. 91-222). The report YSS prepared by the Centers for Disease Control's Office on Smoking and Health. This report, entitled The Health Benefits of Smoking Cessation, examines hov an individual's risk of smoking-related diseases declines after quittins smoking. The evidence is overvhelming that smoking cessation has major and inmediate health benefits for me" and women of all ages. Smoking cessation increases overall life expectancy and reduces the risk of lung ca"cer, other cancers. heart attack. stroke. and chronic 1"~ disease such as emphysema. The health benefits of smoking cessation far e;ceed any risks from the average S-pound weight gain or any adverse psychological effects that may follov quitting. Cigsrette smoking is the most important preventable cause of death in our sWC.i.Sty. It is responsible for approximately 390,000 deaths each year in the United States, or more than one of every six deaths. We must dl, Sll YP can to prevent young people from taking up this deadly addiction, and ve m"st help smckers quit. Give" the enormous benefits of smoking cessation, and the fact that good smoking cessation programs can achieve abstinence rates of 20 to 40 percent at one-year follovup, these programs are likely to be extremely cost-effective compared with other preventive or curative services. Therefore. I would encourage health insurers to provide psyment for smoking cessation treatments that arc show" to be effective. At a minimum, the treatment of nicotine addiction should be considered as favorably by third-party payers as treatment of alcoholism and ill!clt drug addiction This report should help convince all smokers of the compelling need to quit smoking. Sincerely, Louis W. Sullivan, U.D. SWXetFlLY Enclosure The Honorable Dan Quayle President of the Senate Washington, D.C. 20515 Dear Mr. President: It is my pleasure to transmit co the Congress the 1990 Surgeon General's Report on the health consequences of smoking as mandated by Section g(a) of the Public Health Cigarette Smoking Act of 1969 (Pub. L. 91-222). The report was prepared by the Centers for Disease Control's Office 0" Smoking and Health. This report, entitled The Health Benefits of Smokinn Cessation, examines how a" individual's risk of smoking-related diseases declines after quitting smoking. The evidence is overwhelming that smoking cessation has major and immediate health benefits for me" and wme" of all ages. Smoking cessation increases overall life expectancy and reduces the risk of lung cancer, other cancers, heart attack, stroke, and chronic lung disease such as emphysema. The health benefits of smoking cessation far exceed any risks from the average S-pound weight gain or any adverse psychological effects that may follow quitting. Cigarette smoking is the most important preventable cause of death in our SOCiStY. It is responsible for approximately 390,000 deaths each year in the United Stares, or more than one of every six deaths. We must do all ue can to prevent young people from taking up this deadly addiction, and "e must help smokers quit. Given the enormous benefits of smoking cessation, and the fact that good smoking cessation programs can achieve abstinence rates of 20 to 40 percent at one-year followup. these programs are likely to be extremely &at-effective eonpared withother preventive or curative services. Therefore, I would encourage health insurers to provide payment for smoking cessation treatments that are show" to be effective. At a minimum, the treatment of nicotine addiction should be considered as favorably by third-party psyors as treatment of slcoholism and illicit drug addiction. This report should help convince all smokers of the compelling need to quit smoking. Sincerely, ~&&j,&&& LOUiS w. Sullivan, M.D. secretary Enclosure FOREWORD More than 38 million Americans have quit smoking cigarette\. and nearI> half of all living adults who ever smoked have quit. Unfortunately. \ome SO million American\ continue to smoke cigarettes. despite the many health education programs and anti- smoking campaigns that have been conducted during the past quarter century. despite the declining social acceptability of smoking, and despite the consequences of \mohing to their health. Twenty previous report\ of the Surgeon General have reviewed the health effect\ of smoking. Scientific data are now available on the consequences of smohing ce\\ation for most smoking-related disease\. Previous reports have considered \ome of thece data. but this Report is the first to provide a comprehensive and unified re\,ieu of [hi\ topic. The major conclusions of this volume are: I. Smoking cessation has major and immediate health benefits for men and w-omen of all ages. Benefits apply to persons with and without smoking-related disease. 2. Former smokers live longer than continuing smokers. For example, persons who quit smoking before age 50 have one-half the risk of dying in the next 15 years compared with continuing smokers. 3. Smoking cessation decreases the risk of lung cancer, other cancers, heart attack, stroke, and chronic lung disease. 1. Women who stop smoking before pregnancy or during the first 3 to 4 months of pregnancy reduce their risk of having a low hirthweight baby to that of women who never smoked. 5. The health benefits of smoking cessation far exceed any risks from the average 5pound (2.3-kg) weight gain or any adverse psychological effects that ma! follow quitting. With the long-standing evidence that smoking is extremely harmful to health and the mounting evidence that smoking cessation confers major health benefits. we remain faced with the task of developing effective strategies to curtail the use of tobacco. Two broad categories of intervention are available: prevention of smoking initiation among youth and smoking cessation. Resources for tobacco control are limited. and policymakers must decide how best to allocate those resource\ to smohing prevention and cessation. The goal of public health i\ to intervene a\ earl! a\ pos\iblc to prc`\`ent di\ea\c. disability. and premature death. From that standpoint. prevention of~mokin~ initiation should he a maior priorit!. More than 3.000 tecnafer\ become regular w~oker~ (`UC /I tltr~, in the United State\. Becauw of the strength of nicotine addiction. wme have argued that public health effort\ should focu\ on smohing prevention rather than wioking cessation. Houevcr. thi\ need not be an "either-or" Gtuation. Public health practitioners have categorized interwntion\ into primary. secondnr!. and tertiary prevention. Primary prevention generally refer\ to the elimination of ri\h factors for di\ea\e in asymptomatic persons. Secondary prevention i\ defined a\ the early detection and treatment ofdi\ease. and is practiced using toots wch 3s Pup smear\ and blood pressure \creenin_r. Tertiary prevention con\i\ts of measures to reduce impairment, diaabilit),. and suffering in people I$ ith existing disease. Smoking cessation fall> under the catepor\' of primary prevention a\ does the prevention of smoking initiation. Smoking cessation meets the definition of primq prevention by reducing the rich of morbidity and premature mortality in asymptomatic people. In addition. parent\ who quit smohing reduce or eliminate the rish ofpa~ive- smoking-related disease among their children and reduce the probability that their children will become smoher\. Thu\. there should be no debate about the need for smoking prevention versw cessation-both are important. Public awareness of the health effect\ of smoking ha\ increased substantialI!, through the years. Neverthelcah. important gaps in public hnowledge still exist. Some \moher\ may have failed to quit hecawe of a lath of appreciation of the health hazards of smoking and the benefits of quitting. In the 1987 National Health Intervie% Survey ot Cancer Epidemiology and Control. rehpondentz were asked whether making increases the risk of variou\ disease:, (lung cancer. cancer of the mouth and throat. heart disease. emphysema. and chronic bronchitis) and uhethrr mohing ceaation reduces the rish. Thirty to forty percent of smoker\ either did not believe that \mohiry increases thew risks or did not beliebe that cessation reduces these ri\hs. The\e proportion\ correspond to IS to 20 million smohen in the United State\. Clearly. our efforts to educate the public on the health haLard\ ofmohing and the benefits ofquitting are not yet complete. As we continue and intensit) our efforts to inform the public of thehe finding\. we must make available wwhing cc\sation programs and ser\ ices to those Q ho need them. Although 90 percent of former \moher\ quit without using smoking ce\Mion program\. counseling. or nicotine pm. smoher\ Mho do need this asistancc should ha\e it available. WC endorw the vie\\ rxprewxi in the Preface to the Ic)XX Surgeon General'\ Report that treatment of nicotine addiction should be con\idrred at least ;I\ fa\orabl! by third-part) ptiyor\ ;I\ treatment of atcoholim anti illicit drug addiction. Good smohing cessation trcatmt'nt\ C;III xhie\e :rh\tinencc rate\ of 20 to 40 percent at I -\car followup. Those SLICLYS\ rate\. combined with the enormou\ health benefits ofmokinf cessation. would libel) mahc pa! IIICIII for WIIIC wlohln, (I ce4ation tre3tments cwt- beneficial. For example. research b! the Center\ for Diwazc Control suggests that a smoking cessation program offered to all pregnant \mohers could sa\`e $5 for e\er!, dollar spent b> prz\entin, 0 tow hirthuttiflit-3s~oc~icltt`tl nrc~natul intt`n\i\ e cure and long-term cure. ii This Report should galvanize the health community, to stres\ repeatedly at every opportunity the value of smoking cessation to the 50 million American\ who continue to smoke. James 0. Mason. M.D.. Dr.P.H. William L. Roper. M.D. Assistant Secretaq for Health Director Public Health Service Centers for Disease Control lil PREFACE This Report of the Surgeon General is the 2lst Report of the U.S. Public Health Service on the health consequences of smoking and the first issued during my tenure as Surgeon General. Whereas previous reports have focused on the health effects ot smoking. this Report is devoted to the benefits of smoking cessation. The public health impact of smoking is enormous. As documented in the 1989 Surgeon General's Report. an estimated 390.000 Americans die each year from diseases caused by smoking. This toll includes 1 IS.000 death\ from heart disease: 106.000 from lung cancer: 31.600 from other cancers; 57,000 from chronic obstructive pulmonary disease; 27,500 from stroke: and 52.900 from other conditions related to smoking. More than one of every six deaths in the United States are caused by smoking. For more than a decade the Public Health Service has identified cigarette smoking as the most important preventable cause of death in our society. It is clear, then, that the elimination of smoking would yield substantial benefits for public health. What are the benefits. however, for the individual smoker who quits'? A large body of evidence has accumulated to address that question and derives from cohort and case-control studies, cross-sectional surveys, and clinical trials. In studies of the health effects of smoking cessation. persons classified as former smokers may include some current smokers; this misclassification is likely to cause an underestimation of the health benefits of quitting. Taken together. the evidence clearly indicates that smoking cessation has major and immediate health benefits for men and w'omen of all ages. Overall Benefits of Smoking Cessation People who quit smoking live longer than those who continue to smoke. To what extent is a smoker's risk of premature death reduced after quitting smoking'? The answer depends on several factors, including the number of years of smoking. the number of cigarettes smoked per day, and the presence or absence of disease at the time of quitting. Data from the American Cancer Society's Cancer Prevention Study II (CPS-II) were analyzed in this Report to estimate the risk of premature death in ex-smokers versus current smokers. These data show, for example. that persons who quit smoking before age 50 have one-half the risk of dying in the next IS years compared with continuing smokers. Smoking cessation increases life expectancy because it reduces the risk of dying from specific smoking-related diseases. One such disease is lung cancer, the most common cause of cancer death in both men and women. The risk of dying from lung cancer is 22 times hitcher among male smohers and 12 times higher among female smokers L compared with people u ho have never smoked.The risk of lung cancer declines steadil) in people who quit smoking; after IO years of abstinence, the risk of lung cancer is about 3) to 50 percent of the risk for continuing smokers,. Smoking cessation also reduces the risk of cancers of the larynx. oral cavity. esophagus. pancreas. and urinary bladder. Coronary heart disease (CHD) is the leading cause of death in the United States. Smokers have about twice the risk of dying from CHD compared with lifetime nonsmokers. This excess risk is reduced by about half among ex-smokers after only 1 year of smoking abstinence and declines gradually thereafter. After 15 years ot abstinence the risk of CHD is similar to that of persons who have never smoked. Compared with lifetime nonsmokers. smokers have about twice the risk ofdying from stroke, the third leading cause of death in the United States. After quitting smoking. the risk of stroke returns to the level of people who have never smoked: in some studies this reduction in risk has occurred within 5 years. but in others as long as IS years of abstinence were required. Cigarette smoking is the ma.jor cause of chronic obstructive pulmonary disease (COPD). the fifth leading cause of death in the United States. Smoking increases the risk of COPD by accelerating the ape-related decline in lung function. With sustained abstinence from smoking. the rate of decline in lung function among former smokers returns to that of never smokers. thus reducing the risk of developing COPD. Influenza and pneumonia represent the sixth leading cause of death in the United States. Cigarette smohing increases the risk of respiratory infections such as intluenla. pneumonia. and bronchitis. and smoking cessation reduces the rish. Cigarette smohing is a major cause of peripheral artery occlusive disease. This condition causes substantial mortality and morbidity: complications may include inter- mittent claudication. tissue ischemiu and gangrene. and ultimately. loss of limb. Smoking cessation substantially reduces the risk of peripheral arter) occlusive disease compared with continued smoking. The mortalit> rate from abdominal aortic aneurysm is two to fi\,e times higher in current smokers than in never smohers. Former smohers ha\e half the excess rish of dying from this condition relative to current smohcrs. About 20 million Americans currently ha\,e. or ha\c had. an ulcer of the stomach 01 duodenum. Smohers have an increased rish of developin g gastric or duodenal ulcers. and this increased rish is reduced h> quitting smohing. Benefits at All Ages According to a I YXY Gallup survq. the proportion of smohers 14 ho say they would lihc to give up smohing is loL\er for smokers aged 50 and older (57 percent) than for smokers aged I X-24, (6X percent) and 3019 (67 percent ). Older smokers ma)' be less motivated to quit smohin g because the highly motivated may have quit already at younger ages. leaving a relatively "hard-core" group of older smohers. But man> long-term smohers may Iach motivation to quit for other reasons. Some may believe they are no longer at risk of smohing-related diseases because they have alread) survived smohing for man)' j'ears. Others ma> believe that an) damage that may ha\,e vi been caused by smoking is irreversible after decades of smohing. For similar reasons. many physicians may be less likeI) to counsel their older patients to quit. CPS-II data were used to estimate the effects of quittin, (7 smoking at various ases on the cumulative risk of death during a fixed interval after cessation. The results she\+ that the benefits of cessation extend to quitting at older ages. For example. a health! man aged 60-63 u ho smohes I pack of cigarettes or more per da\ reduces his rish of dying during the next IS learx by IO percent if he quits smoking. These findings support the recommendations of the Surgeon General's I'SXX Workshop on Health Promotion and Aging for the de\~elopmrnt and dissemination of smoking cessation messages and interventions to older persons. I am pleased that a coalition oforganirations and agencies is now worhing toward implementation of those recommendations. including the Centers for Disease Control; the Nut~onal Cancer Institute: the National Heart. Lun g. and Blood Institute: the Administration on Aging: the Department of Veterans Affairs: the Office of Disease Pre\,ention and Health Promotion: the American Association of Retired Persons: ;md the Fox Chase Cancer Center. The major mcssafc of this campaign bill be that it is nc\cr too late to quit smoking. Two facts point to the urgent need for a strong smohing cessation campaign targetin? older Americans: ( I ) 7 million smohers are aged 60 or older: and (2) smoking is :I ma,ior rish FActor for 6 of the I3 leading causes of death among those aged 60 and older. and is a complicating factor for 3 others. Benefits for Smokers with Existing Disease Many smokers who have already developed smoking-related disease or symptoms may be less motivated to quit because of a belief that the damage is already done. For the same reason, physicians may be less motivated to advise these patients to quit. However, the evidence reviewed in this Report shows that smoking cessation yields important health benefits to thoe who already suffer from smoking-related illness. Among persons with diagnosed CHD, smoking cessation markedly reduces the risk of recurrent heart attack and cardiovascular death. In many studies. this reduction in risk has been 50 percent or more. Smoking cessation is the most important intervention in the management of peripheral artery occlusive disease: for patients with this condi- tion, quitting smoking improves exercise tolerance, reduces the risk of amputation after peripheral artery surgery, and increases overall survival. Patients with gastric and duodenal ulcers who stop smoking improve their clinical course relative to smokers who continue to smoke. Although the benefits of smoking cessation among stroke patients have not been studied. it is reasonable to assume that quitting smoking reduces the risk of recurrent stroke just as it reduces the risk of recurrence of othercardiovascular events. Even smokers who have already developed cancer may benefit from smoking cessation. A few studies have shown that persons who stopped smoking after diagnosis of cancer had a reduced risk of acquiring a second primary cancer compared with persons who continued to smoke. Although relevant data are sparse. longer survival might be expected among smokers with cancer or other serious illnesses if they stop smoking. Smoking cessation reduces the rihk of respiratory infection\ such as pneumonia. w,hich are often the immediate causes of death in patient5 with an under- lying chronic disease. The important role of health care providers in counseling patients to quit smoking is well recognized. Health care providers should give smoking cessation advice and assistance to all patients v. ho smohe. including those uith existing illness. Benefits for the Fetus Maternal smoking is associated with several complications of pregnancy including abruptio placentae. placenta previa. bleeding during pregnancy. premature and prolonged rupture of the membranes. and preterm delivery. Maternal smoking retards fetal growth. causes an average reduction in birthweight of 100 g, and doublej the risk of having a low birthueight baby. Studies have shown a 25- to S0-percent higher rate of fetal and infant death\ among women who smoke during pregnancy compared with those wsho do not. Women who stop smohing before becoming pregnant have infants of the \ame birthweight ah those born to women who have never smoked. The same benefit accrue5 to women who quit smoking in the first 3 to 4 month\ of pregnancy and who remain abstinent throughout the remainder of pregnancy. Women who quit smoking at later stages of pregnancy. up to the 30th weeh of gestation. have int'ants with higher birthueight than do women who smoke throughout pregnancy. Smoking is probably the most important modifiable cause of poor pregnanq Cutcome among women in the United State\. Recent estimate\ suggest that the elimination of smoking during pregnancy could prevent about 5 percent of perinatal death\. about 20 percent of low birthweight births. and about 8 percent of preterm deliveries in the United State\. In groups with a high prevalence of smohin, 0 (e.g.. women who have not completed high school I. the elimination of smohing during prepnanq could prevent about IO percent of perinatal death\. about 35 percent of low birth\\eight birth\. and about IS percent of preterm deliverie\. The prevalence of mohing during pregnancy haj declined over time but remain\ unacceptabl!, hi2h. ApproximateI! 30 percent of U.S. women L\ ho are cigarette smokers quit after recognition of pregnancy. and other\ quit later in preganq. However. about 25 percent of pregnant \\omen in the United State\ \mohe throughout preynanc\. A \hoching \tatlstic i\ that half of pregnant uomcn who ha\,e not completed 2 high school smoke throughout prqnanc!. .Van) Momen N ho do not quit mohing during pregnanq reduce their dail? ci garettc consumption: however. reduced con- sumption without quitttng ma> have little or no benetit for hlrthuerfht. Of the ltomen who quit smoking during prepnanc!. 70 percent re\umt' \mohing within t >ear of deliver). Initiatives ha1.e been launched In the public and pri\ate sector\ to reduce smohing during pregxmc!. The\e pqrams should lx expanded. and le\\ educated pregnant women should be a \peciat target of these et'fort\. Strategic\ need to be developed to address the problem of relapse after deli\ er! Benefits for Infants and Children As a pediatrician. 1 am particularly concerned about the effects of parental smohing on infants andchildren. Evidence re\ ieued in the 1986 Surgeon General's Report. 7`1~ HW/I/I Co//.\(,y~rc,/r(.f,.\ c!f'/l/l.~/lllltu~.\, SINI&III~~. indicates that the children of parents who smoke, compared with the children of nonsmohinf parents. have an increased frequency of respiratoq infections 4uch as pneumonia and bronchitis. Man>, studies have found a dose-response relationship between respiratory illness in children and their level of tobacco smoke exposure. Several studies have shown that children exposed to IO~XILXXI smohe in the home are more libel) to develop acute otitis media and persistent middle ear effu\ions. Middle ear disease imposes a substantial burden on the health care system. Otitis media is the most frequent diagnosis made by physicians who care for children. The m> ringotom> and-tube procedure. used to treat otitis media in more than 1 million American children each year. is the most common minor surgical operation performed under general anesthesia. The impact of smoking cessation during or after prepnancq on these associations has not been studied. Hotiever. the dose-response relationship between parental smohing and frequency of childhood respirator), infection{ suggests that smohing cessation during pregnancy and abstinence after delivery would eliminate most ora1 I of the excess risk by eliminating mo\t or all of the exposure. If parents are unwilling to quit smoking for their own sake. I hould urge them to quit for the sake of their children. Passive-smohing-induced infections in infants and )`oung children can cause serious and even fatal illness. .Moreo\,er. children whose parents smoke are much more likely to become smokers themselves. Smoking Cessation and Weight Gain The fear of postcessation weight gain may discourage man) smoher\ from trying to quit. The fear or occurrence of height gain may precipitate relapse among many of those who already have quit. In the I%% Adult Use ofTobacco Survey. current smokers who had tried to quit were asked to judge the importance of several possible reasons for their return to smoking. Twenty-seven percent reported that "actual weight pain" was a "very important" or "somewhat important" reason why they resumed smoking: 22 percent said that "the possibility of gaining weight" was an important reason for their relapse. Forty-seven percent of current smokers and 48 percent of former smohers agreed with the statement that "smoking helps control weight." Fifteen studies involving a total of 20.000 persons were reviewed in this Report to determine the likelihood of gaining weight and the average height gain after quitting. Although four-fifths of smokers who quit gained weight after cessation. the average weight gain was only 5 pounds (2.3 kg). The average weight gain among subjects who continued to smoke was I pound. Thus, smoking cessation produce< a£ greater weight gain than that associated with continued smoking. This weight gain poses a minimal health risk. Moreover. evidence suggests that this small weight pain is accompanied by favorable changes in lipid profiles and in body fat distribution. i\ Smoking cessation programs and messages should emphasize that weight gain after quitting is small on average. Not onI\, is the average postcessation weight gain small. but the risk of large weight gain after quitting is extremely low. Less than -4 percent of those who quit smoking gain more than 20 pounds. Nevertheless. special advice and assistance should be available to the rare person who does gain considerable weight after quitting. For these individuals. the health benefits of cessation still occur. and weight control programs rather than smoking relapse should be implemented. Increases in food intake and decreases in resting energy expenditure are largely responsible for postcessation weight gain. Thus. dietary advice and exercise should be helpful in prevaentinp or reducing postcessation weight pain. Unfortunately. minor weight control modifications to smoking cessation programs do not generally yield beneficial effects in terms of reducing weight gain or increasing cessation rates. A few studies have investigated pharmacologic approaches to postcessation weight control: preliminary results are encouraging but more research is needed. High priority should be given to the development and evaluation of effective weight control programs that can be targeted in a cost-effective manner to those at greatest need of assistance. Psychological and Behavioral Consequences of Smoking Cessation Nicotine withdrawal symptoms include anxiety. irritability. frustration, anger. dif- ficulty concentrating. increased appetite. and urses to smohe. With the possible exception of urges to smohe and increased appetite. these effects soon disappear. Nicotine withdrav~al peaks in the first I to 7 days following cessation and subsides rapidly during the following weeks. With long-term abstinence. former smokers are likely to en.job favorable psychological changes such as enhanced self-esteem and increased iense of self-control. Although most nicotine withdrawal symptoms are short-lived. thej, often exert a strong influence on smokers ability to quit and maintain abstinence. Yicotine withdrawal may discourage many smohers from tr>inF to quit and may precipitate relapse among those who have recently quit. In the I%6 Adult U\e ofTobacco Survey. 39 percent of current smokers reported that irritability was a "very important" or "somew hat important" reason M hy the, resumed smoking after a previous quit attempt. Smokers and ex-smohcrs should be counseled that adverse psychological effects of smohing subside rapid]! over time. Smohing cessation materials and programs. nicotine replacement. exercise. \tre\s management. and dietary counseling can help smohers cope with these symptoms until the!, abate. after LI hich favorable psyhologi- cal changes are likeI> to occur. Support for a Causal Association Between Smoking and Disease Ten> of thousands of studies have documented the associations between cigarette smoking and a Iaye number of serious disease?;. It is safe to say that smoking represents the most extensively documented cause of disease ever investigted in the history of biomedical research. Previous Surgeon General's reports. in particular the landmarh 1964 Report of the Surgeon General's Advisory Committee on Smokin, L 0 ,tnd Health and the I982 Surgeon General's Report on smoking and cancer, examined these associations with respect to the epidemiologic criteria forcausality. These criteria include the consistent>. strength. specificity. coherence. and temporal relationship of the association. Based on these criteria. previous reports have recognired a causal association betueen smohing and cancers of the lung. larynx. esophagus. and oral cavity: heart disease: strobe: peripheral artery occlusive disease: chronic obstructive pulmonary disease: and intrauterine growth retardation. This Surgeon General's Report is the first to conclude that the evidence is now sufficient to identify cigarette smohin, (7 as a cause of cancer of the urinary bladder: the 1983 Report concluded that cigarette smohing is a contributing factor in the development of bladder cancer. The causal nature of most of these associations was v.ell established long before publication of this Report. Nevertheless. it is worth notin, ~7 that the findings of thi\ Report add even more weight to the evidence that these associations are causal. The criterion of coherence requires that deacriptibc epidemiologic findings on disease occurrence correlate with measures of exposure to the suspected agent. Coherence would predict that the increased risk of disease associated with an exposure Lvould diminish or disappear after cessation of exposure. As this Report shows in great detail. the risks of most smoking-related diseases decrease after cessation and with increasing duration of abstinence. Evidence on the risk of disease after smoking cessation is especially important for the understanding of smoking-and-disease associations of unclear causality. For ex- ample, cigarette smoking is associated with cancer of the uterine cervix. but this association is potentially confounded by unidentified factors (in particularby a sexually transmitted etiologic agent). The evidence reviewed in this Report indicates that former smokers experience a lower risk of cervical cancer than current smokers. even after adjusting for the social correlates of smoking and risk of sexually acquired infections. This diminution of risk after smoking cessation supports the hypothesis that smoking is a contributing cause of cervical cancer. Conclusion The Comprehensive Smoking Education Act of 1983 (Public Law 98473) requires the rotation of four health warnings on cigarette packages and advertisements, One of those warnings reads. "SURGEON GENERAL'S WARNING: Quitting Smoking Now Greatly Reduces Serious Risks to Your Health." The evidence reviewed in this Report confirms and expands that advice. The health benefits of quitting smoking are immediate and substantial. They far exceed any risks from the average S-pound weight gain or any adverse psychological effects that may follow quitting. The benefits extend to men and women. to the young and the old. to those who are sick and to those who are well. Smoking cessation represents the single most important \tep that smokers can take to enhance the length and quality of their lives. xi Public opinion poll\ tell u\ that mat smoker\ &ant to quit. This Report provides smokers with new and more pouerf-ul motivation to give up thi\ self-destructive beha\ ior. Antonia C. Novello. M.D.. M.P.H Surgeon General xii ACKNOWLEDGMENTS This Report was prepared by the Department of Health and Human Serv,ices under the general editorship of the Office on Smoking and Health. Ronald M. Davis. M.D.. Director. The Managing Editor wa\ Susan A. Hawk. Ed.M.. MS. Jonathan M. Samet. M.D. (Senior Scientific Editor). Professor of Medicine and Chief. Pulmonary Division. Department of Medicine and the New MexicoTumor Registry. Cancer Center. University of New Mexico, Albuquerque. New Mexico Ronald M. Davis, M.D., Director. Office on Smoking and Health, Center for Chronic Disease Prevention and Health Promotion (CCDPHP), Centers for Disease Control (CDC), Rockville, Maryland Neil E. Grunberg, Ph.D., Professor. Department of Medical Psychology. Uniformed Services University of the Health Sciences. Bethesda, Maryland Judith K. Ockene. Ph.D.. Professor of Medicine, and Director, Division of Preventive and Behavioral Medicine. Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts Diana B. Petitti, M.D., M.P.H., Associate Professor, Department of Family and Com- munity Medicine, University of California at San Francisco, School of Medicine. San Francisco, California Walter C. Willett, M.D.. Dr.P.H.. Professor of Epidemiology and Nutrition. Harvard School of Public Health, and The Channing Laboratory, Department of Medicine. Harvard Medical School and Brigham and Women's Hospital. Boston. Mas- sachusetts Robert Anda. M.D., Epidemiologist. Office of Surveillance and Analysis, CCDPHP. CDC. Atlanta, Georgia John Baron, M.D., Associate Professor of Medicine. Department of Medicine. Dartmouth Medical School, Hanover, New Hampshire Tim Byers. M.D.. M.P.H., Chief, Epidemiology Branch. Division of Nutrition. CCDPHP. CDC, Atlanta. Georgia Arden G. Christen, D.D.S., M.S.D., M.A.. Chairman. Professor, Department of Preven- tive and Community Dentistry, Indiana University School of Dentistry. Indianapolis. Indiana Graham Colditz. Dr.P.H., Assistant Professor of Medicine. Harvard School of Public Health, and the Channing Laboratory, Department of Medicine. Harvard Medical School and Brigham and Women's Hospital. Boston. Massachusetts Carlo C. DiCiemente. Ph.D.. Associate Professor. Department of Psychology. Univer- sity of Houston. Houston, Texas Douglas W. Docket-y, Sc.D.. Associate Professor. Department of Environmental Health. Environmental Epidemiology Program. Harvard School of Public Health. Boston, Massachusetts Gary A. Giovino. Ph.D.. Acting Chief. Epidemiology Branch. Office on Smoking and Health. CCDPHP. CDC. Rockville. Maryland Deborah Grady, M.D., Assistant Professor. Departments of Epidemiology and Medicine, University, of California at San Francisco. School of Medicine. San Francisco. California Neil E. Grunberg. Ph.D.. Professor, Department of Medical Psychology. Uniformed Services University of the Health Sciences. Bethesda, Maryland John R. Hughes. M.D., Associate Professor. Human Behavioral Pharmacology Laboratory, Departments of Psychiatry. Psychology. and Family Practice. University, of Vermont. Burlington. Vermont Robert W. Jeffery. Ph.D., Professor, Division of Epidemiology. School of Public Health. University of Minnesota, Minneapolis, Minnesota LTC James W. Kikendall, M.D.. Assistant Chief. Gastroenterology Section. Walter Reed Army Medical Center, Washington. D.C. Robert Klesges. Ph.D.. Associate Professor. Department of Psychology. Memphis State University, Memphis, Tennessee Lynn Kozlowski. Ph.D.. Head, Behavioral Tobacco Research. Socio-behavioral Re- search Department, Addiction Research Foundation, Toronto. Ontario. Canada Stephen Marcus. Ph.D.. Epidemiologist. Office on Smoking and Health. CCDPHP. CDC. Rockville, Maryland James L. McDonald. Jr.. Ph.D.. Assistant Chairman. Professor. Department of Preven- tive and Community Dentistry. Indiana University School of Dentistry. Indianapolis. Indiana Sherry L. Mills, M.D.. M.P.H.. Medical Officer. Office on Smoking and Health. CCDPHP. CDC. Rockville. Maryland Judith K. Ockene. Ph.D.. Profeswr of Medicine. and Director. Division of Preventive and Behavioral Medtctne. Department of Medicine. Univjersity of Massachusetts Medical School. Worcester. Massachusett\ Carolr Tracy Orleans. Ph.D.. Director. Smohing Cc\sation Srrv,ice\. Fox Chaw Cancer Center. Cheltenham. Pennsylvania Diana B. Pctitti. M.D.. M.P.H.. .Aswciatc Professor. Department of Family and Com- munity, Medtctne. University ofCalifomiaat San Franciwo. School of Medicine, San Franci\co. California John P. Pierce. Ph.D.. Associate Professor. Director. Population Studies and Cancer Prevention. Tobacco Control Pro.icct. University of California. San Diego Cancer Center. San Diego. California Paul R. Pomrehn. Ph.D.. M.S.. Associate Profe\wr. Department of Preventive Medicine and Environmental Health. University of Iowa College of Medicine. Iowa City. Iowa James 0. Procha\ka. Ph.D.. Professor. Director. Cancer Prevention Research Unit. Department of Psychology. Liniversity of Rhode Island. Kirqston. Rhode Island xiv Barbara Rimer. Dr.P.H.. Director, Beha\ ioral Research. Fox Chase Cancer Center. Philadelphia. Pennsylvania Mary Ann Salmon. Ph.D.. Research Specialrst. School of Social Worh. C.A.R.E.S.. University of' North Carolina. Chapel Hill. North Carolina Jonathan M. Samet. M.D. (Senior Scientific Editor). Profehsor of Medicine and Chief. Pulmonary Division. Department of Medicine and the Nea Mexico Tumor Registry. Cancer Center. University of New Mexico. Albuquerque. New Mexico David Savitz. Ph.D.. Associate Professor. Department of Epidemiolog>. School oi Public Health. University of North Carolina. Chapel Hill. North Carolina Charles B. Sherman, M.D.. Director. Pulmonar! Division. Miriam Hospital. Providence. Rhode Island Meir Stampfer. M.D.. Dr.P.H.. Associate Professor of Epidemiolog! Har\ ard School of Public Health. and The Charming Laboratory. Department of Medicine. Harvard Medical School and Brigham and Womm's Hospital. Boston. Massachusetts Wayne F. Velicier. Ph.D.. Professor. Co-Director. Cancer Prclention Research Unit. Department of Psychology. Cnivcrsity of Rhode Island. Kingston. Rhode Island Thomas Vogt. Ph.D., Principle Investigator. Center for Health Research. Portland. Oregon Scott T. Weiss. M.D.. Associate Professor. Harvard School of Public Health. and The Charming Laboratory. Department of Medicine. Harvard Medical School and Brigham and Women's Hospital. Boston. Massachusetts Anna H. Wu-Williams. Ph.D.. Associate Professor. Department of Preventive Medicine. University of Southern California. Los Angeles. California David B. Abrams, Ph.D., Director. Division of Behavioral Medicine. The Miriam Hospital. Associate Professor, Psychiatry and Human Behavior. Brown Universit) Program in Medicine, Providence. Rhode Island Duane Alexander, M.D.. Director. National Institute of Child Health and Human Development. National Institutes of Health. Bethesda. Maryland David Bates. M.D.. FRCP, FRCPC. FACP. FRSC, Professor Emeritus of Medicine. Department of Health Care. University of British Columbia. Vancouver. British Columbia James S. Benson, Acting Commissioner. Food and Drug Administration. Rockville. Maryland Trudy S. Berkowitz, Ph.D.. Associate Professor. Department of Obstetrics. Gynecol- ogy. and Reproductive Science, Mount Sinai School of Medicine. New York. New York Ruth Bonita, M.P.H., Ph.D., Masonic Senior Research Fellow. Geriatric Unit. Univer- sity of Auckland. Auckland 9. New Zealand Lester Breslow, M.D.. M.P.H.. Professorof Public Health and Director. Health Services Research. Division of Cancer Control, Jonsson Comprehensive Cancer Center. University of California. Los Angele\. Los Angeles. California Samuel Broder. M.D.. Director, National Cancer Institute. National Imtitutes of Health. Bethesda, Maryland David Bums. M.D.. Associate Professor. Pulmonary Division. Division of Pulmonary Medicine and Critical Care, University of California at San Diego Medical Center, San Diego, California Benjamin Burrows. M.D.. Director, Division of Respiratory Sciences. University of Arizona Health Sciences Center. University of Arizona School of Medicine, Tucson, Arizona Jane Cauley. Dr.P.H.. Assistant Professor of Epidemiology. Department of Epidemiol- ogy. University of Pittsburgh. Pittsburgh. Pennsylvania Gregory N. Connolly, D.M.D., M.P.H.. Director, Office on Nonsmoking and Health. Massachusetts Department of Public Health. Boston. Massachusetts Thomas M. Cooper, D.D.S.. Professor. University of Kentucky Medical Center. Col- lege of Dentistry. Lexington. Kentucky Stephen Corbin. D.D.S.. M.P.H., Policy Analyst, Disease Prevention. Center for Preventive Services (CPS). CDC. Bethesda, Maryland K. Michael Cummings. Ph.D.. M.P.H.. Cancer Control and Epidemiology. Roswell Park Cancer Institute. Buffalo, New York Joseph W. Cullen. Ph.D.. Director. AMC Cancer Research Center, Denver. Colorado Sir Richard Doll. ICRF Cancer Studies Unit. Oxford. United Kingdom Virginia Ernster. Ph.D.. Professor of Epidemiology. Department of Epidemiology and International Health. University of California. San Francisco. San Francisco. California Jonathan E. Fielding. M.D.. M.P.H.. Vice President and Health Director. Johnson and Johnson Health Management. Inc.. Santa Monica. California Gary D. Friedman. M.D.. M.S.. Division of Research. Kaiser Permanente Medical Care Program. Northern California Region. Oakland. California William Foege. M.D., Executive Director. The Carter Center of Emory University. Atlanta. Georgia Lawrence J. Furman. D.D.S.. M.P.H.. Chief. Dental Disease Prevention Activity. CPS. CDC, Atlanta. Georgia LawrenceGarfinkel. Vice President for Epidemiolog) and Statistic>. DirectorofCanccr Prevention, American Cancer Society. Inc.. New York. New York Barbara A. Gilchrest. M.D.. Professor and Chairman. Department of Dermatolog . Boston University Medical Center. Boston. Mahjachu\ett\ Frederick K. Goodwin. M.D.. Administrator. Alcohol. Drug Abuse. and Mental Health Administration. Rochville. Maryland Robert 0. Greer. Jr.. D.D.S.. Sc.D.. Profes5orand Chairman. Division ofOral Patholog and Oncology. Department of Diagnostic and Biological Sciences. School of Den- tistry. University of Colorado Health Sciences Center. Boulder. Colorado Ellen Gritz. Ph.D.. Director. Division of Cancer Control. Jon\\on Comprehensive Cancer Center. University of California. Lo\ Angele\. Los Angeleh. California xvi Nanq J. Haley. Ph.D.. Associate Chief. Division of Nutrition and Endocrinology. American Health Foundation, Valhalla, New> York Sharon M. Hall. Ph.D.. Professor of Medical Psychology. Department of Psychiatry. University of California. San Francisco. San Francisco Veterans Administration Medical Center. San Francisco. California Robert Harmon. M.D.. Administrator. Health Resources and Services Administration, Rockville. Maryland Jeffrey E. Harris. M.D.. Ph.D.. Associate Professor. Department of Economics. Ma\- sachusetts Institute of Technology. Cambridge. Massachusett\. Clinical Associate. Medical Services. Massachusetts General Hospital. Boston. Massachusetts Norman 0. Harris, D.D.S.. M.S.. University of Texas Health Science Center. San Antonio. Texas Jack Henningfield. Ph.D.. Chief. Clinical Pharmacology Branch. National Institute on Drug Abuse Addiction Research Center, National Institutes of Health. Baltimore. Maryland Robert A. Hiatt. M.D.. Ph.D.. Senior Epidemiologist. Division of Research. Kaiser Permanente Medical Care Program. Oakland California Millicent Higgins. M.D.. Associate Director. Epidemiology and Biometry Program. Division of Epidemiology and Clinical Applications. National Heart. Lung. and Blood Institute. National Institutes of Health. Bethesda. Maryland Carol Hogue. Ph.D., M.P.H.. Director, Division of Reproductive Health. CCDPHP. CDC. Atlanta. Georgia John Holbrook. M.D.. Professorof Internal Medicine. Department of Internal Medicine. University of Utah School of Medicine. Salt Lake City. Utah Richard Hunt. M.D.. Division of Gastroenterology. McMaster University Medical Center. Hamilton, Ontario, Canada Dwight Janerich. D.D.S.. M.P.H.. Professor of Epidemiology. Department of Epidemiology and Public Health. Yale University School of Medicine, New Haven. Connecticut William Kannel. M.D., Professor of Medicine. Department of Preventive Medicine. Boston University School of Medicine, Boston, Massachusetts LTC James W. Kikendall. M.D., Assistant Chief, Gastroenterology Section. Walter Reed Army Medical Center, Washington. D.C. Dushanka V. Kleinman. D.D.S.. M.Sc.D., Section Chief. National Institute on Dental Research. National Institutes of Health. Bethesda, Maryland C. Everett Koop. M.D.. Sc.D., U.S. Surgeon General, I98 i-89. Bethesda. Maryland Jeffrey P. Koplan, M.D.. M.P.H., Director, CCDPHP, CDC. Atlanta. Georgia Lewis H. Kuller, M.D.. Dr.P.H., Professor and Chairperson. Department of Epidemiol- ogy, University of Pittsburgh Graduate School of Public Health. Pittsburgh. Pennsyl- vania Charles L. LeMaistre. M.D., President, The University of Texas M.D. Anderson Cancer Center. Houston. Texas Claude Lenfant, M.D., Director. National Heart, Lung. and Blood Institute. National Institutes of Health, Bethesda, Maryland Richard J. Levine. M.D.. M.S.. M.P.H., Chief Epidemiologist. Chemical Industr! Institute of Toxicology. Research Triangle Park. North Carolina Edward Lichtensrein. Ph.D.. Research Scientist. Oregon Research Institute. Eugene. Oregon Jay H. Luhin. Ph.D.. National Cancer Institute. National Institutes of Health. Rockville. Maryland Alfred C. Marcus, Ph.D., Director. Community Research and Applications. AMC Cancer Research Center. Denver. Colorado Denis M. McCarthy. M.D.. MSc.. Chief. Division of Gastroenterology. University of New Mexico. Department of Medicine. Veterans Administration Medical Center. Albuquerque. New Mexico J. Michael McGinnis. M.D.. Deputy Assistant Secretary for Health. Disease Prevention and Health Promotion. Department of Health Human Services. Washington. D.C. Sonja M. McKinlay. Ph.D.. M.Sc.. M.A.. B.A.. ASA. APHA. AER. SCt. Biometrics Society. Institute of Mathematical Statistics. International Menopause Society. American Association for the Advancement of Science. President. New England Research Institute. Inc.. Watertown. Massachusetts Robert E. Mecklenberg. D.D.S.. M.P.H.. Potomac. Maryland L. Joseph Melton. III. M.D.. Head. Section of Clinical Epidemiology. Department of Health Sciences Research. Mayo Clinic and Foundation. Rochester. Minnesota Anthony Miller. B.A., M.B.B.. M.R.C.P.. M.F.C.M.. F.R.C.P.C.. Professor. Depart- ment of Preventive Medicine and Biostatistics. University of Toronto. Toronto. Ontario, Canada Gregory Morosco. Ph.D.. M.P.H.. Chief. Health Education Branch and Coordinator. Smoking Education Program. National Heart. Lung. and Blood Institute. National Institutes of Health. Bethesda. Maryland Richard L. Naeye. M.D.. Professor and Chairman. Department of Pathology. Pennsyl- vania State University School of Medicine. Hershey. Pennsylvania Thomas A. Pearson. M.D.. M.P.H.. Ph.D.. Director. Mary lmogene Bassett Research Institute,Cooperstown. New York. ProfessorofPuhlic Health in Medicine. Columbia University. New Yorh. New Yorh Terry Pechaceh. Ph.D.. Acting Chief. Smohing. Tobacco, and Cancer Branch. Nation;tI Cancer Institute. National Institutes of Health. Bethesda. Maryland Michael G. Perri. Ph.D.. Professor and Deputy Chairman. Psychology Department. Fairleigh Dichinson University. Teanech. New Jersey Richard Peto. FRS. ICRF Cancer Studies Unit. Oxford. United Kingdom John M. Pinney,. Executive Director. Institute for the Study, of Smohing Brhav ior and Policy. John F. Kennedy School of Government. Harvard University. Cambridge. Massachusetts William F. Raub. Ph.D.. Acting Director. National Institute\ of Health. Bethesda. Maryland Patrick L. Remington. M.D.. Bureau of Community Health Prevention. Wisconsin Division of Health. Madison. Wisconsin Everett R. Rhoades. M.D.. Director. Indian Health Service. Rocbville. Maryland Julius Richmond. M.D.. John D. MacArthur Professor of Health Policy. Emeritus. Division of Health Policy. Research. and Education. Harvard Cniuersity. Boston. Massachusetts XVIII Williatn A. Robinson, M.D.. M.P.H.. Director. Office ot'\linorit! Health. Department of Health and Human Service\. Washington. D.C. William L. Roper. M.D.. M.P.H.. Director. CDC. Atl;rn~~. Georgia Richard B. Rothcnhq. M.D.. A\si\Iant Director for Science. CCDPHP. CDC. Atlanta. Georgia Thomas C. Schelling. Ph.D.. Director. Iwtitute t'or the Stud\ of Smoking Behavior and Policy. Lucius Iv. Littauer Professor of' Political Econotii~, tlar\ard L'ni\,ersit>. Cambridge. Massachusetts Marc B. Schenker. M.D.. M.P.H.. Associate Professor ;md Di\ i\ion Chief. Occupation- al and Environmental Medicine. University of California. Da\ i\. Da\ i\. California Da\,id Schottenfeld. M.D.. Professor and Chairman. Department of Epidetniolog . University of Michigan School of Public Health. Ann Arbor. hlichigan Kathleen L. Schroeder, D.D.S., M.Sc.. Assistant Professor. Section of Oral Biology. The Ohio State University College ot`Dentistr\,. Columbus. Ohto Mary J. Sexton. Ph.D.. M.P.H.. Professor. Department ofEl-7idrmiolo~! and Ptwentive Medicine. University of Maryland School of` Medtcine. Baltimore. Mar! land Saul Shiffman. Ph.D.. Associate Professor. Department of Psychology. L'niwrsit>, ot Pittsburgh. Pittshurgh. Pennsylvania Donald Shopland. Smoking. Tobacco. and Cancer Branch. 2iational Cancer Institute. National Institutes of Health. Bethesda. blur> land Amnon Sonnenberg. M.D.. Associate Professor. Gastroentet.olof! Section. Medical College of Wisconsin. Veterans Administration Medical Center. Milwaukee. Wis- consin Frank E. SpeiLer. M.D.. Professor of Medicine, Harvard Medical School. Professor of Environmental Epidemiology. Harvard School of Public Health. Co-Director. The Channing Laboratory. Department of Medicine. Brigham and Women's Hospital. Boston. Massachusetts Jesse Steinfeld. M.D., San Diego. California Steven D. Stelltnan. Ph.D.. Assistant Commissioner. New Yorh Cit>, Department of Health. New York. Neu York Ira B. Tager, M.D.. M.P.H., Associate Professor of Medicine and Epidemiology and Biostatistics, University ofcalifornia. San Francisco. Veterans Administration Medi- cal Center, San Francisco, San Francisco. California Kenneth Warner. Ph.D.. Senior Fellow. Institute of Gerontology. University, of Michigan. Ann Arbor. Michigan Jonathan S. Weiss. M.D.. Assistant Professorof Dertnatologz. Section of Dertnatology. Emory Clinic, Atlanta. Georgia Noel S. Weiss. M.D., Dr.P.H.. Professor and Chairman. Department of Epidemiology. University of Washington. Seattle, Washington Gail R. Wilensky. Ph.D., Administrator. Health Care Financing .4dministr:ttion. Washington. DC Deborah Winn. Ph.D.. Deputy Director. Division of Health Interview Stati\lics. Na- tional Center for Health Statistics. CDC. Hyattsvillc. Mqland Philip A. Wolf, M.D.. Professor of Neurology. Department of Neurology. Boston University School of Medicine. Boston, Massachusetts Ernst L. Wynder. M.D.. President. American ffcalth Foundation. Neu Yorh. Ur\\ Yorh \i\ Cxnwn Aguirrr. Secretq. Officeon Smohtng and He;~l~h. C'CDPHP. (`DC`. Roc,h\ 111~`. hlar! land Andrea Anderwn. Student Intern. Of`t~ice on Smohln $! ~11111 tic~lltll. C`C`DPI it'. (`I)(`. Rochville. Marylnnd Mxgaret Anglin. Secretq. Oft'icr on Smohin, `7 and Health. CCDPHP. (`DC`. Koch- ville. Maryland Cathy Arney. Graphic Artist. The Circle. Inc.. MCLC;III. Virginia John Arti>. Courier. The Circle. Inc.. McLean. Virgini; Michele Awael. Confrrenctr Coordinator. The C'il-ck. Inc... ZlcLcan. 1'11.21111s John L. Bqrwhy. A\wciate Director for Progr;lm C>pcl-ation\. Ol'l.ic~ on Snlohlns ;111d Health. CCDPHP. CDC. Roch\~ille. Mql;~nd Sonia Bslahirsky. Srcrctary. Office on Snlohin, $1 and Hcal~h. (`(`DPHP. C`D(`. Roc,h- ville. Maryland Barbara Barme\. Admini\tratiw A\\istant. The Circle. Inc.. \lc,l.c;~n. L'Irglnl;l Carol A. Bean. Ph.D.. Acting 2l;ulaging Editor. ..Irtcntl\ Tcc~hnol~~gic~. IIIC... Springfield. Virginia Mari\sa A. Bernctrin. Editor. The Circle. Inc.. IllcLean. L'irslnia Em' Ria Brikcoe. Cont'erencr Coordinator. The Circk. Inc.. \lcl~can. \`irglni.r Karen Broder. Public Information Spwiali\t. Ot't`icc on Smohing a~ld ticalrh. (`CDPtt P. CDC. Rochville. Mar> INKI Barbara M. Broun. Editowl h\\l\t;unt. 00'~ cw Smoking ;untl Health. Rc)ch\ 111~~. h4aryland Catherine E. Burchhardt. Public Int'ormation Speci,llist. Ol't'iw on Srnc\hlns and ticL\l\ll. CCDPHP. CDC. Roth\ ilk. Mar! land Ltx Chapell. Courier. The Circle. Inc.. McLtxn. Virginia Won Choi. Revarch A\\l\tant. Ot't`iw m Smohing and Health. CCDPI IP. C'DC`. Roch\,ilk. Mar> Im~d Trihh Da\.itlwn. Studtxt Intam. Ot't`icc on Smohlng and Health. C`C`DPtiP. C`tX`. Rochville. Maryland Susan E. Da!. Sawtar!. Office OII Snlohln, cr and Health. CCDPHP. C-LX`. Roi,h\ 111~`. hlaryiand Karen M. Dtxs~. .-I\soci;nc Dirt'ctot- I'oI- PoIIc,!. Ott~c~ OH Smohir); and tlcalttj. CCDPHP. CDC'. Roth\ ilk. 3l;rr> land June DOM. Public Health Scr\ 1c.c Congrcs\ionaI Rcpol-t\ (`c)c)rdiii;ltor. Ot`tlce ot'llcattl~ Planning UKI E\~;rluation. Ot`t`icc ot`thc .\\xl\t;tnt Sec~rctar-\ i(v tfcal~ll. M';l\llingtcw. D.C. Joanna Ebling. \+`or-d Proc~c\\lns S~LTI;I~I\~. 7`1~ CirL,Ic. Inc.. \l~~Lean. l'lrglnia Pam Edward\. S!\tem Xdministrator. %lS;\. Inc.. Roth\ 111~. \lar- I;t~~cl Rita Elliott. Technical Editor-. \c\r hlz\ico Tunior Rc:i\tl-! I ni\cl-\lt> rjt' \c\\ Mexico. Albuquerque. NW Xlc\icc) Seth Errwnt. Ph.D.. Epidemic Intelllgcnce Ser\ ice Ot't'lca. 0t'l'lc.c on Smohtll~ ;111d Health. CCDPHP. CDC. Roch\ille. \lar\l;~nd Sharon K. Faupel, Staff Assistant, Office on Smoking and Health. CCDPHP. CDC. Rockville, Maryland Leanna Fernando, Administrative Assistant, New Mexico Tumor Registry, University of New Mexico, Albuquerque, New Mexico David Fry. Editor, The Circle, Inc., McLean, Virginia Lynn Funkhauser, Word Processing Specialist, The Circle, Inc.. McLean, Virginia Amy Carson, Student Intern, Office on Smoking and Health. CCDPHP. CDC. Rock- ville, Maryland Mary Graber. Secretary, University of California at San Francisco, School of Medicine. Department of Family and Community Medicine, San Francisco. California Gwen Harvey, Program Analyst, CCDPHP. CDC. Atlanta. Georgia Patricia Healy, Technical Information Specialist. Office on Smoking and Health. CCDPHP. CDC. Rockville, Maryland Phyllis E. Hechtman. Editorial Assistant. The Circle, Inc.. McLean, Virginia Timothy K. Hensley. Technical Publications Writer-Editor, Office on Smoking and Health, CCDPHP. CDC, Rockville. Maryland Julian Hudson, Courier. The Circle, Inc.. McLean. Virginia Beth Jacobsen, Student Intern, Office on Smoking and Health. CCDPHP. CDC. Rockville. Maryland Renee Kolbe, Program Specialist. Office on Smoking and Health, CCDPHP. CDC. Rockville, Maryland Matt Kreuter, Public Information Specialist, Office on Smoking and Health, CCDPHP. CDC. Rockville, Maryland Peggy Lytton, Editor, The Circle, Inc., McLean, Virginia Diana Lord, Research Psychologist, Department of Medical Psychology. Uniformed Services University of the Health Sciences. Bethesda. Maryland Daniel F. McLaughlin, Editor, The Circle, Inc., McLean. Virginia Jackie L. Meador, Desktop Publishing/Word Processing Specialist. The Circle. Inc.. McLean, Virginia Elaine Medoff-McGovern, Medical Secretary. Division of Preventive and Behavioral Medicine, Department of Medicine. University of Massachusetts Medical School. Worcester, Massachusetts Nancy A. Miltenberger, M.A., Production Editor, The Circle. Inc.. McLean. Virginia Rebecca Mosher, Staff Assistant, New Mexico Tumor Registry. University of New Mexico, Albuquerque, New Mexico Millie R. Naquin, Research Assistant. Office on Smoking and Health, CCDPHP. CDC. Rockville. Maryland Thomas E. Novotny, M.D., Chief, Program Services Activity. Office on Smoking and Health, CCDPHP, CDC, Rockville, Maryland Cathie M. O'Donnell. Project Director, The Circle. Inc., McLean, Virginia Christine Pappas, Editorial Research Assistant, The Channing Laboratory, Harvard School of Public Health. Boston, Massachusetts Stacey M. Parcover, Secretary, Office on Smoking and Health, CCDPHP. CDC, Rockville. Maryland Lida Peterson, Computer Systems Manager. The Circle. Inc., McLean. Virginia Renate J. Phillip\. Graphic .Arti\t. D&top Puhli\hln 2 Desipnrr. The Circle. Iric.. McLean. Vir~~ini~t ` Margaret E. Pickerel. Public Int'ormation and PubIicatlons SpeciaIi\t. ~t`t`icc 011 SIII~~- ing and Health. CCDPHP. CDC. Rochville. Mq land EliAmh Precup. Student Intern. Office on Smohtng and Health. CCDPHP. CDC. Rochville. Maryland Cary R. Prince. Editor. The Circle. Inc.. McLean. Virginia Dick Ray. Director of Computer Sm ice\. The Circle. Inc.. IlcLean. Virginia Nancy J. Rhodes. Editor. The Circle. Inc.. McLean. Virginia Rose Mary Romano. Chiet`. Public Int'orm;Ltion Branch. Oft`icr m Snlohing and Health. CCDPHP. CDC. Rocl\\.ille. Mar! land Lisa Phelph. Computer S>3tern\ Anal! \t. The Circle. Inc.. hlclcan. \`irginia Sel Semler. Sccreta~-1. Oi`ficc on Swrhing and Halth. CCDPHP. CDC. Roth\ 111e. Maryland Jane\ S1in.a. Student Intern. Otl`ice on Smohin 2 imi Health. CCDPHP. CDC. Roch- ville. Marshland Mattie Smith. Srcrrtar!, . CCDPHP. CDC. Roch\,ille. hl;rr> Ixnd Linda R. Spiegrhmn. Administrative Oft`iccr. Office on Smohin: and Health. CCDPHP. CDC. Roth\ ilk. Mar> Imd Traion C. Stallinys. Project Sectmar>. The Circle. Inc.. McLean. C'irsinla Sophia Stewart. Student Intern. Ofl`icr on Smohing and Htxtlth. CCDPHP. CDC. Rock\~illr. Maryland D:tniel R. Tich. Director of Publications. The Circ~lc. II~c~.. LlcLean. \`iyinia Anne Trontell. M.D.. Epidemic Int~lligencr Stm ice Otfiwr. Ot`t`icc on Smohing and Health. CCDPHP. CDC. Roth\ ilk. Mar! land Karen T\,lrr. Cont'erenct` Coordinator. The Circle. Inc.. ZlcLwt. I'tt-ginta Godfrey R. Vw. h1.D.. Student Intern. Ot`ficc on Smohing and Hcal~h. CCDPHP. CDC'. Rock\ ilk. Mar> land Su~n Von Bratmberg. Ini'ormaticm Speci;tli\t. The Circle. lw.. \lcLcarl. Virginl;r Elyse Watwn. Adminiaxtt~c :\\\imnt. Nrn ?,le\ico TUII~~I- RcFi\tr>. L.ni\cr\lt! ot New Mexico. Albuquaque. UC\+ Llcxico Michael F. White. .A \sociate Dirt`ctor for Progr-am De\ ~~lopncn~. C`C`DPHf'. C`DC. Roth\ ilk. Rlx~ land Chxlex WIggin\. Xl.S.P.11.. E~~l~l~~liiologl\t. Xc\\ \lc\~co 1~t11iior RC~I\II-!. I 11i\ C`I.\II\ Of Neu Rle-ilco. .~lhlK~llmp'. Kl?\\ l\tc\tcr, Louiw G. Wist`nxtn. TcchnicA Information Specul~s~. Ott`icc on Snlohlng and tlcalth. CCDPHP. CDC`. Koch\ tllc. \l;rr> I;mcI Rebecca B. b'olt'. Progrm .Inal! st. 0t`t'ic.c ot` Progrant Planning ,~nd I!\ ;rlu,ltioll. C`D(`. Attanta. Gccwgia S. Tannc~- Wra!. Technical Inter-matioll Spcclall\t. Ot't~cc 011 Snlohlng ad llcalth. CCDPHP. CDC. Rtrch\ilk. IlarylmA TABLE OF CONTENTS Foreuord ........................................................... i Preface ............................................................. I Acknowledgments .................................................. xiii ListofTables .................................................... ..xx v ListofFigur& .................................................... xxxi 1. Introduction. Overview, and Conclusions ............................. I 2. Assessing Smoking Cessation and Its Health Consequences .............. 17 3. Smoking Cessation and Overall Mortality and Morbidity ................ 7 1 4. Smoking Cessation and Respiratory Cancer-5 ......................... IO3 5. Smoking Cessation and Nonrespiratory Cancers ...................... I43 6. Smoking Cessation and Cardiovascular Disease ...................... 1 X7 7. Smoking Cessation and Nonmalignant Respiratory Diseases ............ 175 8. Smoking Cessation and Reproduction .............................. 367 9. Smoking, Smoking Cessation, and Other Nonmalignant Diseases ........ 425 10. Smoking Cessation and Body Weight Change ........................ 469 1 I. Psychological and Behavioral Consequences and Correlates of Smoking Cessation ............................................. 5 I7 Volume Appendix. National Trends in Smoking Cessation ................ 579 Glossary ........................................................ ..617 lndex.............................................................61 9 Xklll LIST OF TABLES Chapter 2 Table 1. Measures of false reports of not smoking from studies using nicotine and cotinine as a marker . . 3X Table 2. Measures of false reports from studies using CO as a marker 1 I Table 3. Examples of potential methodologic problems in investigating the health consequences of smoking cessation 17 Chapter 3 Table 1. Summary of longitudinal studies of overall mortality ratios relative to never smokers among male current and former smokers according to duration of abstinence (when reported I 76 Table 2. Overall mortality ratios among current and former smohers. relative to never smokers. by sex and duration of abstinence at date of enrollment. ACS CPS-II . . . . . . . . . . , 7x Table 3. Estimated probability of dying in the next 165year interval for quitting at various ages compared with never smohing and continuing to smoke. by amount smoked and sex . . . x3 Table 4. Summary of overall mortality ratios in intervention studies in which smoking cessation was a component . . . , . 8-t Table 5. Summary of studies of medical care utilization among smokers andformersmokers . . . . .._.................................. Table 6. Relation of smoking cessation to various measures of general health status . . . . . . . . . . . .._.................................. Table 7. Age- and sex-specific mortality rates among never smokers. continuing smokers. and former smokers by amount smoked and duration of abstinence at time of enrollment for subjects in ACS CPS-II study who did not have a history of cancer. heart disease. or stroke and were not sick at enrollment . . . , . . Table 8. Estimated probability of dying in the next 165year interval (95% Cl) for quitting at various apes compared with never smohing and continuing to smoke. by amount smohed and sex . xx 90 . 95 97 \\\ Chapter 4 Table I. Histologic changes (?/ ) in bronchial epithelium by smoking status .___.____.___.,,....._.__,.._._._...,.._.,....,..._._ Table 2. Relative rishs of lung cancer among never, fomter. and current smokers in selected epidemiologic studies . . Table 3. Lung cancer mortality ratios among never. current. and former smokers by number of years since stopped smoking (relative to never smokers). prospective studies . . . . . . . Table 4. Relative risks of lung cancer among former smokers. by number of years since stopped smoking. and current smokers. from selected case ratio\ for COPD among current and former smoher\ hrohen down h) y;Lr\ of ah5tinence . Chapter 8 Table 1, Possible mechanisms for effect of smohing on pregnant!' and pregnancy outcome ,......._........................., . . . Table 2. Summary of studie\ of fertility among smokers and former smoker\ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 3. Summary of studies of perinatal and neonatal mortality in smokers and nonsmoker\ during pregnanq . . Table 3. Estimated relative risk of fetal plu\ infant mortality for maternal smoking in several birthweight groups. adjusting for maternal marital statu\. education. age. and parity . . . Table 5. Summary of studies of perinatal mortality in wloher\ throughout pregnancy. smohers who quit in the early month\ of pregnancy. and nonsmokers during pregnancy Table 6. Summary of studieh of mean birthweight. b>, smoking statuh . Table 7. Summar\, of nonexperimental studie\ of smoking cewttion after conception. mean increase (+) or decrease (6) in birthueight (g) according to timing of cessation Table 8. Summary of nonexperimental studies of relative risk of IOU birthweight for smoking ceaation after conception Table 9. Summary of birthweight outcome in randomized trials ot smohing cessation in pregnancy . . . . Table IO. Smoking and smoking! cehation during pregnancy. summq of results of two wrveys of national probability \ample\ Table I I. Patterns of smoking cessation during pregnarq among selected population4 . . . Table 12. Summary of \tudit`s that estimated relative rish of \ariou~ pregnancy outcome\ for \mohing based on ;t "SJ nthe\ih" of the literature. and attributable risk percent based on several estimate\ of the prevalence of smohing during pregnancy . 3% Table 13. Summary of studies reporting relationship of cigarette smoking and age at natural menopause . . . 3'97 Table II. Summary of studit`\ of age of natural menopause among former smoker5 . . . . . . . . . 399 Table 15. Sexual performance among male former smoher\ 104 Table 16. Sperm quality among smokers and nonsmokers 406 xxviii Table 17. Estimated relative risk of azoospermia or oligospermia among smokers versus nonsmokers or never smokers . . . . . . . . 408 Table 18. Sperm quality among former smokers . . . . . 409 Chapter 9 Table I. Percentage of healed duodenal ulcers among smoking and nonsmokingpatients . . . . . . . . . . . . . . . . . .._..._...._..._........_ 433 Table 2. Results of statistical analysis of pooled data from Table I . 437 Table 3. Recurrences of duodenal ulcer in smokers and nonsmoker\ in clinical trials _ ~. . . . . . . . . . . . . . . . 43X Table 4. Recurrences of gastric ulcer in smokers and nonsmokers in clinical trials . . . . . . . . . . . . . . . . . 442 Table 5. Summary of studies of smoking and bone ma\< . . 445 Table 6. Summary of casernsu\ conference defined relapse as at least one puff per day for 7 da! 4 and recommended that this definition be applied uniformly (Shumaker and Grunbt'rs 19X61: however. thi\ definition is not used in all studies. Any return to \mokin~ that i\ Ic\s than the criterion for relapse is considered a "lapse" or a "slip." n,hich may or may not C;ILI~ a return 10 regular smoking (Brownell et al. 19X6: Marlatt. Curry. Gordon. 19Xx1. Although 75 to X0 percent of relapse occur> at 6 month Y and before (Hunt. Barnett. Branch 1971: Hunt and Bespalec 1973: Hughes ct al. 19X1: Gar\c\. Hcinold. Rohncr 1989). individuals who maintain abstinence for 6 montll\ continue IO rclap~ b\ 12 months and beyond. For example. in a re\,ieu of IO ctudies III u hich minimal or no intervention occurred (i.e.. \elf-change htudieb). relap~c' rate\ at 12 rnontl~~ i'or wmhw who had previously maintained abstinence t'or ;II 1~41 6 mcmth\ ranged t`rom 7 to 35 percent (Cohen et al. 1989). Data from the National lical~h and Nutrition t!\;tmin;111011 Survey I (NHANES-I) Epidemiologic Follouup Stud) demonstrate that even after I year of prolonged abstinence. relapse continues to occur 111 about one-third of former smokers. Relapse continues to occur at a much lovver rate after 2 years (Volume Appendix). In the Multiple Rirh Factor Intervention Trial (MRFIT). a multifact~~t intensive intervention study, Ochene and colleagues (19x2) found that among smokers who had stopped with the aid of intensive intervention. relapse continued to occur throughout the 6 years offollowup. However. relapse has at a much higher rate in the first year than in years two through six. Kirscht and colleagues ( lYX7) reported that Y.5 percent of adults who had been abstinent for 2-l to I I9 monthsreported smohing again in a followup survey. Even after I10 months. 1.3 percent of fomrer smokers reported smoking again. Research would be simplified if the probabilrty of remaining a former smoker were 100 percent after a prolonged period of abstinence. If this were the case. then there would be no concern about future misclassification of these confirmed former smokers. However. the continuous nature of the relapse process and the curv'es that represent this process indicate that the probability of maintained cessation u ill never be I00 percent. The available data (Garvey. Heinold. Rosner 19X9: Ochene et al. 19X2: Cohen et al. 1989: Volume Appendix) suggest that for most research purposes. 2-l months of continuous abstinence can be used as a practical criterion for categorizing individuals as confirmed former smokers. However. use of this timeframe is often not feasible or applicable in many research studies, and as a general fuideline for interpreting out- comes-the longer the duration of continuous abstinence. the greater the probability that individuals will remain former smokers. Cessation is a cyclical. not linear. process: smokers cm enter or leave the process at any point (Prochaska and DiClemente 1983: Prochasha et al.. in press) (Figure I). Research on self-change approaches to smoking cessation suggests that the average smoker cycles three to four times through the stages before attaining long-term continuous abstinence and becoming a confirmed former smoher (Prochasha and DiClemente 19X4. 1986: Marlatt. Curry. Gordon I YXX; Schachter 19X2). In a review of self-change studies. Cohen and colleagues ( 19x9) found that onI> -l.3 percent of the participants in the rev iewed studies shifted immedtately, from current smokers to former smokers without experiencing any lapsesor relapses. Most smokers M ho relapse return to a point where they think about stopping again. that is. the contemplation stage. A smaller proportion lose their motivation to change and regress back to the pre- contemplation stage (Prochaska and DiClemente 19X-l). In summary, because of the dynamic nature of change in smohing behavior. an> categorization of smoking status at a single point in time becomes a simplification. A group of former smokers aill include individuals who have stopped recently or who have been abstinent for varyin g lengths of time; some bill maintain abstinence. and some will relapse. Knowledge of the dynamics ofsmohinp cessation and its usual time course can help invtestigators minimize misclassification by choosing the most ap- propriate methods for assessing smoking behavior and the appropriate sampling pro- cedures (e.g. number of measurements made and time betueen repeated measures ot smoking status). Behavioral Measures Self-Report: Questionnaires and Interviews For health research purposes. smoking status is usually assessed by using self- administered questionnaires or interviews. However, other behavioral methods. sur- rogate assessments, and nonbehavioral methods such as biochemical assessments are also used as sources of smoking data. These other sources will be reviewed in subsequent sections. (See also rev,iews by Pechacek. Fox et al. lYX3 and Marsh et al. IYXX.) Questionnaires and interviews may include information concerning smohing at the timeoftheassessmentorconcernin~acompleteorpartial retrospective lifetime history,. Assessment can be made once or serially over time, thus providing more valid data regarding cessation and possible relapse. Infortnation gathered from an intervieu or questionnaire about smoking categorizes respondents as never. current. or former smokers. Two standard items used in the National Health lntetvieu Survey (Volume Appendix) to classify smoking status are "Have you smoked at least 100 cigarettes in your entire life?" and "Do you smoke cigarettes now?" Someone responding "yes" to the first question and "no" to the second would be classified as a former smoker. Such a broad definition for former smokers combines persons who experimented with smoking enough to have smoked lOOcigarettes with individuals who may have smoked during their entire adult life and quit in the week prior to being interviewed. The commonly used item. "Have you smoked at least 100 cigarettes in your entire life?" has an advantage of counting as never smokers those individuals who experi- mented with 1, 2. or quite a few cigarettes. Only those who have smoked at least 5 packs of cigarettes in their lifetime are counted as ever smokers. The arbitrariness of this definition reflects the lack of accepted and standardized definitions for ev'er smokers and never smokers. A definition of never smokers that requires only minimal or no use of tobacco may result in many individuals with extremely low exposure to cigarettes being classified as former smokers. which in general would not be biologi- cally appropriate. Another commonly used type of item. as in the Medical Research Council (MRC) National Survey of Health and Dev,elopment (Britten 19X8). for defining ever smokers is "Have you ever smoked as much as 1 cigarette a day for as long as I year'?" This item is used by the American Thoracic Society. Division of Lung Disease in its Adult Respiratory questionnaire: however. two other choices are added- "or 20 packs of cigarettes" or "12 ounces of tobacco" (Ferris 1978). A comparable questions is "Have you ever smoked at least 5 cigarettes per week. almost every week for at least I year'?" (Petitti. Friedman. Kahn 19X I ). These items that are used to classify ever smokers are based on a combination of the amount of cigarettes smoked (e.g.. 365) and the duration of smoking (e.g.. at least 6 or I3 months). The particular question used to differentiate between ever smokers and never smokers can directly affect categorization of individuals. For example. Petitti. Friedman. and Kahn ( 19X I ) found that with a more specifically defined question such as "Have you ever smoked at least 5 cigarettes per weeh almost every week for at least I year'!" M hich require\ wme period 0f"re~ular" smoking for an individual to be clawificd as an t`ver maker. 12% of?i:! individuals reported being neler smoker\. However. when assessed concurrently ti ith another questionnaire in which regular smoking was not defined and the respondent self-defined waking. 7 percent fewer subjects t II9 of 252) reported being never smokers. Thus, the use of more clearly defined questions. wch as specifying 100 cigarettes in ;1 lifetime. or 1 cigarette per day for I year. or 5 ci_rarettes per week for I year. Mill reduce misclaGtIcatlon. However. some misclassification will still occur for thaw individuals who hmohed for relatively brief periods during their lives but cannot accurately remember hou long they smoked or accurately estimate the number of cigarettes they smoked. Attention also must be paid to defining current or former smokers. Some studies. such as the Cancer Prevention Study I (CPS-1) (Hammond and Garfinkel 1969). define current smokers as those who respond affirmatively to the question "Have you smoked within the past year?" Other studies u$e smoking in the past 6 months as the guideline for current smokers (Coultas et al. 1988). The criteria for questions identifying current smoker\ can range from having smoked in the past year. to the past 6 months. to the past week. or to an unspecified period. A few additional questions will enhance the specificity of the definitions of current smokers and former smokers. These items. or comparable ones. have been used in previous surveys. for example. the 198X Baseline Prevalence Survey for the Community Intervention Trial for Smoking Cessation. funded by the National Cancer Institute: `.At what age did you start smoking on a regular basis?": "On the average. about hou many cigarettes did you smoke per day during the lact I?. months you smohed?": and for former smokers. "When did you quit smoking cigarettes'?" (recorded to exact date if possible). These item\ provide udd- tional information for defining ever smohers. or stratifying by levels of exposure. and for determining the period of abstinence. The dynamic nature of smoking ce\\ation highllghts the importance of being aware that any categorical definition of former smoker in relation to the health effects of smohing cessation will include former woher\ who h:r\,e been abstinent for \,arying period\ of time. Optimally. questions on smohin, ~7 historv should ascertain the duration _ of abstinence for former \moher\. and if possible. abstinence period\ should be treated aj continuous or categorized vuriablc\ in an anal>si\. thus avoidins the problem ot treating former smoher\ ;IS ;1 single group. Howewr. benefit\ of ce\\ation are still clearly observed in spite of the limitation\ of using categorical data. The mo\t common minimum period\ ofabstinencc u$ed for defining former smoking statu\ are 2-l hours. 7 days. and 30 da\\. The National Interagency Council on Smoking and Health ( 1973) recommended using ;I minimum of 7 da> s ofab\tinence for defining cessation. However. becuuw of the nature of mokin g. usin_r ;t short abstinence period to define former smoher\ i\ not optimal in epidemiologic studies. The degree of misclassification of former smoker\ M ill depend on the minimum duration of abstinence u\ed to define former smokers and the criterion wed to consider determine relapse. Many studie\ do not specify a minimum duration of abstinence for indi\,idual\ classified 3s former smohers at ;I particular point in time. Data from such \tudie\ on the aswciation of smohin, 17 ce\\ation L+ ith health and disease outcome\ mu\t bc interpreted cautiously. For example. in the reports of the Whitehall Civil Servants Study (Rose and Hamilton 197X; Rose et al. 1982). the criterion used to define abstinence is not indicated. The only information provided is that the smokers reported that "they were then smoking no cigarettes at all" (Rose and Hamilton 1978). Regardless of the criteria used to define abstinence. the methodology for assessing smoking status, including questionnaire items. needs to be carefully described by investigators. Optimally these items should enhance the process of obtaining informa- tion regarding the duration of abstinence. making it possible to fully determine the relationship of smoking cessation to health and disease outcomes. When reviewing studies of the health effects f smoking, the definition of the former smoker must be carefully assessed, and the effect of the definition on the findings must be carefully examined. Temporal and Frequency Issues Studies vary according to whether smoking is assessed retrospectively or prospec- tively and whether a single assessment or a series of assessments is used. The category of never smokers can be assessed retrospectively. usually relying on a single assess- ment. Requiring subjects to reconstruct more detailed smoking histories can be very demanding. Nevertheless, simply classifying individuals as former smokers or current srnl i reveals very little about the amount of smoking exposure experienced. More pen. .Lnt questions regarding exposure include "How) long have you been abstinent from cigarettes`?`: "At what age did you start smoking`?": "How many cigarettes did you smoke during different periods of your life'?": "How many times did you stop smoking'?"; and "How long did you remain abstinent during each of these occasions'?" A series of repeated assessments can result in inconsistencies such as some in- dividuals reporting smoking at one assessment and later reporting that they never smoked. In a followup study in England. for example, Britten (198X) found 1.296 participants aged 36 who claimed that they had never smoked. Of these. 232 ( IX.7 percent) previously had reported smoking less than I cigarette per day, and 102 (7.9 percent) previously had reported smoking at least I cigarette per day for at least I year. Of the 102 who reported previously that they had been regular smokers, 93 percent reported that the last time they had smoked was at least IO years prior to the survey. If the Britten study had used only one retrospective assessment of the subjects at age 36.323 percent of the 1,296 subjects would have been classified as never smokers and 32.6 percent as former smokers. Assuming that reports at a young age were more accurate because memory bias was less likely to occur, the serial assessment indicates that a more accurate categorization would be 29. I percent for never smokers and 36.5 percent for former smokers. Britten (1988) estimated that misclassification of this magnitude, when applied to a study by Friedman and colleagues ( 1979). would result in only a S-percent increase from 2.41 to 2.53 in relative risks of death for former smokers compared with never smokers. Krall and colleagues ( 1989) found that of 87 middle-aged adults. X7 percent accurate- ly recalled their smoking status of 20 years earlier. but only 71 percent accurately recalled the amount that they had smoked. Furthermore. underestimation of the amount -77 smoked was tu ice as common for 20 years earlier ( I7 vs. 9 percent) and six times more common for 32 years previously (37 vs. 6 percent). Persson and Norell (1989) found that in a random sample of 9.394 individuals in Sweden. retrospective information obtained 6 years later resulted in a strong tendency to overestimate previous cigarette consumption among individuals who had increased their smoking (69 percent over- estimated) and to underestimate among individuals who had decreased their smoking (39 percent underestimated). Subjects with unchanged cigarette consumption showed the highest levels of agreement (X9 percent) between original and retrospective infor- mation. Rather than reconstructing full smoking cessation histories that are subject to biased reporting. many retrospective studies rely on more limited categorization such as never. former, and current smokers. Retrospective studies enable researchers to assess long periods of smoking abstinence without the need to observe the subjects over a long period of time. as would be necessary in prospective studies. Case+zontrol studies. for example. can compare cases with smoking-related diseases with controls with histories of being abstinent for IO to 20 years: in a prospective study. it may be impractical or impossible to study health consequences of cessation with more than IO to 20 years of abstinence (Chapter 2. Part II). Prospective studies have the potential for more reliable and valid measures of smoking status over time. especially when using a series of assessments, than do retrospective studies. In intervention trials, for example. all subjects enter the trial as current smokers. Following intensive intervention. subjects are identified as continuing smokers or former smokers (abstinent). By assessing subjects at specified intervals such as every 1 or 6 month\ over a series of years. especially when paired with biochemical verification (Chapter _. ' see section on Biochemical Markers). researchers can reduce the measurement bias and he more confident in the reliability and validity of measures classifying continuing and former smokers and specifying length of abstinence for former smohers. In MRFIT (Ockene et al. 1990) for example. a series of4month followups over 6 year\ enabled researchers toclassify participants into three categories: persistent quitters (continuous abstainers since the initial intervention). intermittent quitters (abstinent for periods of time since the initial intervention). and continuous smoherx (not abstinent during any of the followup periods). Such precision in measurement is generally not possible or necessary in epidemiologic studies. Prospective stud& may use 3 single assessment to categorize current. former. and never smokers. These studies then prospectively, examine the categories to detect differential rates of morbidity~ and mortality.. As discussed above. the assumption that individuals vvill not change their smoking status maybe a tlavv, with \uch single as\es\ments. Improving Self-Report Measures Ideally. assessments of smoking statu\ need to include standardized questions to determine smoking status. that is never. current. and former smokers. For example. to be categorized as a never smoker. the necessary response bould be "no" to a standard question such as. "Have you ever \mohed at least I cigarette per day for at least I year?" 28 Whenever possible. questions should be used that allow continuous rather than dichotomous scales for rejpon$e. A question such as "Do you smoke regularly?" results in a dichotomous response scale. This scale provides much less information than does a continuous scale. such as the question. "On the average. how many cigarettes do you smoke per day`?" which can range from 0 to 20. 40. 60. or more. Multiple questions such as. `* Have you smoked even a puff of a cigarette in the past 7 days?": "How many cigarette% do you typically smoke each da),`?": and "How many cigarettes do you typically smohc each weeh'l" can be used to refine a category such as current smokers. Inclusion of other indices. such as biochemical markers of smoking (e.g.. sali\,acotinine levels). can also be used to describe smoking statu\. In a followup study. measures of smoking status optimally should be repeated over multiple occasions. especially for dynamic categories lihe current smokers and former smokers. which are open to change over time. Repeated measure\ over a series of occasions provide further reliability and validity for assessments and alw provide greater statistical power for detectin g differences betueen groups. Nevertheless. studies with only a single or a few assessments of smohing behavior have been extremely informative. Alternative BehaGral Measures As a measure of smoking, self-report by questionnaires and interviews is the most common. the least expensive. the easiest to use. and the most feasible in epidemiologic studies (Frederiksen. Martin. Webster lY7Y: Pechacek. Fox et al. 1983). However. other behavioral measures have also been used in clinical studies. Because these measures are generally not used in large-scale epidemiologic studies. they w*ill be presented only briefly m this Chapter. Self-monitoring by the smoker. a measure of smoking commonly used in intervention studies. involves recording by paper. pencil. and mechanical counters each cigarette as it is smoked. The monitoring itself may be a reactive measure and alter the behavior. depending on the nature of the monitored behavior and motivation (Abrams and Wilson 1979: Frederiksen. Martin. Webster 1979; Lipinski et al. 1973: McFall 1978: Orlean\ and Shipley 1982). It is an intrusive measure that is normally restricted to small \tudie\ of high intensity. Other behavioral measures, such as direct observation. collecting and counting cigarette butts (McFall lY78). and measurin f their length (Auger. Wright. Simpson 1979). are even more costly and intrusive and less appropriate for epidemiologic and large intervention studies. Alternative types of behavioral reports for validation of smoking status include verification by an informant (Shipley I981 J. by self-report measure\ tising multiple questions about smoking behavior or status as part of the same interview or question- naire (see above). and by samplin 2 on multiple occasion\. Examples of the latter usually involve long periods of time and often rc\ult in multiple sources of di\- crepancy. (See Lee I9XX for summary.) Surrogate Assessments In some circumstances researchers may need to obtain information from sources other than the index subjects. With some study designs, for example a casen smoking histories vvhile alive. They found that of 77 uiv,es of current smokers, all supplied information about the cases' cigarette smoking status (ever/never) that was in perfect agreement with the information supplied by the cases themselves. Sixty-six (X6 percent) w'ere able to supply complete responses about their husbands' smoking behavior. For those who responded. however. mean values reported by cases and their wives were not significantly different for age at which cases started smoking. years smoked. or average number of cigarettes smoked per day. Wives tended to report 20 cigarettes smoked daily even when their husbands smoked substantially more or fess. Pershagen and Axelson (1982) also reported perfect agreement regarding smoker/nonsmoker status when information was obtained from a close relative (parent. wife. or child) for I4 lung cancer cases compared with information that had previously been obtained from the cases by the physician. Blot. Akiba. and Kato (19X4) also interviewed next of kin in a case, helo\{ IO ng/mL. When nonmohers are aaeshed. the\ rarely have any detectable cotininc' (Benowit~ IYXi: Hale!. Axelrad. Tilton IYX3: Sepkovic and Hale) IYX.5: Zeidenbers et al. 19771. In comparative studieb of different biochemical measures of smoking. cotinine ha3 emerged a$ the measure of choice (Abram\ et al. lYX7: Hale). .4xelrad. Tilton 19X3: Jarvis et al. IYX-I. 19X7: Knight et al. 19X5: Pojer et al. 1YX-l) because of itz superior senGtivity and specificit!. However. it i\ more expensive and more analytically complex than the other biochemical measure\. The value of biochemical meaures is limited to short-term abstinence and cannot be used to document continuous abstinence in long-term \tudie\. CO. with a half-life of 3 to 5 hours. can validate self-reports of not having smoked in the pact 23 to 3X hour> (Benowitz 19x3). Cotinine. with a half-life of I5 to 40 hours. would have limited application for validation beyond a few day\. SCN-. ivith a half-life of 10 to l-1 day\. 36 has been used to validate self-reports of not having smoked in the past 7 days and may be useful to validate up to 3 to 4 weeks. However. specificity of this measure is low compared with cotinine and CO. Bogus Pipeline The bogus pipeline, an assertion to subjects that biochemical assessments will be used to assess smoking status when they will actually only be collected but not evaluated. is used mostly in research with adolescents. One of the reasons given by researchers for continuing to use biochemical verification for at least some proportion of the total subjects is the assertion that if the subjects believ,e biochemical validation will occur. they will be more likely to provide valid responses to self-report measures. This "bogus pipeline effect" was first presented by Evans. Hansen. and Mittelmark ( 1977) from the work of Jones and Sigall ( I97 I ) concerning smoking among adolescents. It is believed that there is great pressure among adolescents to misreport smoking activities, Murray and coworkers ( 1987) provided an estensiv#e review of this aspect. Murray and Perry (1987) attempted to determine the conditions under which a bogus pipeline will be effective by manipulating conditions ofanonymity. They demonstrated that a bogus pipeline for adolescents is more likely to have an effect if there is an expectation that subjects would otherwise perceive large amounts of pressure to report not smoking and there is a credible pipeline message. However, their findings suggest that an effective procedure to ensure anonymity can reduce this pressure and likewise reduce the need for the pipeline. Contextual Issues Affecting Biochemical Assessment The accuracy of self-report measures, the desirability for behavioral or biochemical validation of self-report. and the type of assessment needed are issues that need to be considered in the context of the type of study. the nature and size of the study sample. and possible refusal problems. The nature of the subject sample can affect the likelihood of misreporting and therefore the desirability of validation by biochemical assessment. In Table I. studies demonstrating misreporting rates for individuals who report cessation but who are assessed to be smokers by cotinine or nicotine measurement are classified into three types of subjects: untreated volunteer samples. intervention samples, and high-risk for disease and/or medical patients. Table 2 presents a similar classification of studies demonstrating misreporting with CO validation. The tables are adapted from Lee's work (1988) with the inclusion of additional studies. In cases where multiple cutoff criteria are recorded, the values closest to the optimal cutoff are reported. Several studies should be viewed as outliers and are noted in the tables,. These studies reported unusually high rates of individuals who reported not smoking but were above the cutpoint and also employed cutoff criteria far below optimum cutpoints (Cummings and Richard 198X). For untreated volunteer samples. the mode for individuals classified as smokers by biochemical assessment who reported not smoking is zero, and no sample exceeds 5 37 TABLE I.-Measures of false reports of not smoking from studies using nicotine and cotinine as a marker Wllll;nrl\ 1'1 d I lY7Y 1 H;tlcy. AxclwJ. TlllWl ( IYX3) WaltI c, aI , I YXJ) Nm )l und l.a&ncc ( I'JXX) I'icrce cl ill. ( I YX7 J 0 (O/27) 2 (2/0X) 0 (O/IX) 0.`) (2/Z I ) I .3 ty2.32, 2.1 (S/2.32, 2.2 (33/1,?60) 2.5 (20/X0X, 1.2 (34/X()X) 0 (O/43, 1.0(3/h?.!) TABLE I.--Continued Kwwll et al c I')X7? Stoohq 111 al. ,19X7) Saltvary nIcoIine 7.1 (l/13) Ilrtnary nlcotme II=?. Nnn. Gruder. Chicago Lung Awxxttion Jqxr\hl ( I'MI ce\\i111011 wiy Part 111. titFh-rt\h/mc~lic;tl patient\ Told to Criterion for titlw pivz up reports of not vllohirtg Some group\ 7 ppm co YC\ IO ppm (`0 Ye\ I 2 ppm tconfoundmg exaggerate the apparent benefit\ 01 hia\) ceaatmn Smoking practtce\ and the presence of smoking-related direases affect panicipntton in btudtes (selection hias) .4pperent benefit\ of cr\wtlon ma) hr mcreawd or decrrawd Small number of wbject\ in a stud) A heneficlal effect ofcrsttion may not reach sttisttcal stgntficancr Ecologic Studies Ecologic studies represent a descriptive approach for examining the relation between risk factors and disease. Groups, rather than individuals, are the unit of analysis in ecologic studies. For example, changes in lung cancer mortality rates for selected countries have been examined for correlation with changes in measures of smoking for those countries. such as the percentage of smokers or per capita cigarette consumption (US PHS 1964; Cairns 1975: Cummings 1984; Doll and Peto I98 I ). Ecologic studies often have the advantage of being performed inexpensively and feasibly by using already available data. This design has well-described limitations related to the estimation of exposure and control of confounding, and may yield seriously biased data on exposuredisease relationships (Kleinbaum, Kupper, Morgenstern 1982: Rothman 1986). Cross-Sectional Studies In a cross-sectional or prevalence study, exposure and outcome are assessed at the same point in time among individuals in a population. Because cross-sectional studies measure exposure and outcome variables simultaneously. the true temporal relation between exposure and disease may be obscured (Rothman 1986). However. cross- sectional studies can be readily performed and have supplied much of the evidence on smoking cessation and nonmalignant respiratory diseases (Chapter 7). 47 Cross-sectional studies may be affected by selection hia\. Because cigarette smoking is a strong cause of disease and death. groups studied cross-sectionally may not accurately reflect the natural history of smoking. smoking cessation. and the develop- ment of smoking-related illness. The proportion of heav ier smokers and more suscep- tible smokers may be reduced compared with the original birth cohorts giving rise to the cross-sectional study population (McLaughlin et al. 1987). Former smokers who stopped because ofthe development ofdisease may be underrepresented. whereas those who stopped to reduce the rish of illness may be overrepresented. Information bias is also of potential importance in cross-sectional studies. Pre- existing conditions in survey participants may affect recall of past smoking or may alter the approach used by interviewers to gather smoking information. However. as summarized in Tables I and 7. cross-sectional surveys generally demonstrate low rates of misreporting of smoking status when compared with cotinine and CO levels. As mentioned previously. a single observation on smohing behavior may lead to misclassification of smokers because of the dynamic nature of smoking behavior. Former smokers are typically a heterogeneous group with periods of abstinence ranging from days to years. For example, in the 1986 Adult Use of Tobacco Survey (US DHHS 1989). the subjects' responses were classified in IO categories. -l of which included former smokers. Of the former smokers. 12.5 percent had quit within the past 3 months. 7.X percent had quit in the past 3 to 12 months . 77.3 percent had quit in the past I to 5 years. and 57.4 percent had quit 5 or more y'ears earlier. Cohort Studies In a cohort study. the \ubjrcts are selected on the basis of exposure status (e.g.. smoking behavior) and observed for de\.elopment of disease. Observation may be forward in time (prospective). backward in time (historical or retrospective). or both. Correct conclusions can usually be made about the temporal relation between exposure (smoking cessation) and outcome (reduction of morbidity, or mortality). With the cohort design. multiple health outcomes can be considered simultaneously. For ex- ample, the CPS-I and CPS-II conducted by the American Cancer Society (ACS) examined the effect of smohing bells\ ior on total mortality and specific causes of death. In a study of \mohing cessation. selection bias could affect the findings of cohort studies if subjects lost to observation were more or less lihely to benefit from smoking cessation than subjects remaining under observation (Greenland 1977). For inten,en- tion studies and cohort studies. the rate of sub,ject loss provides an index of the potential selection bias. In a cohort study of smohin, 0 ccs\ation. some Ini\cla\zification of exposure may be introduced if the classification of smoking status is based on a single assessment. Although the categorization of smohing status may' be correct at the time the informa- tion is collected. inevitably some former smoker\ will resume smoking and some current smokers will stop. The extent of the resulting error will increase with the duration of followup. The resulting misclassification will tend to underestimate the effects of quitting because those who relapse to become current smoker\ would not be expected to experience beneficial effects attributable to quitting. 48 For example. in ACS CPS-I involving nearly I million people. Hammond and Garfinkel ( 1969) studied changes in smoking status over a Z-year period. Male former cigarette smokers in 1959-60 who reported that they were smoking in 196142 varied according to duration of prolonged abstinence reported in the lYS9-60 survey. For respondents abstinent le5s than I year in 1959-W. 37.3 percent reported smoking 2 years later; of those reporting abstinence for I to 2 years. 19.1 percent were smohing :! years later; and of those reporting abstinence of more than 2 years. 1.6 percent were smoking 3 years later. For all males who were former smohers in 1959~60. I I .3 percent reported smoking 2 years later. For all female former smoker\ in 195Y-60. 6 percent reported smoking 2 vears later. In the U.S. Veterans Study (Roget and Murq IYXO: Kahn 1966). male veterans itt a cohort of 23X.X16 were classified based on responses to questionnaires administered in 1954 or in 1957 (if the 1951 questionnaire was not returned) and then folloued for 16 years to determine the relationship betbeen tobacco use and mortality. Undoubtedly, many of the original current smokers became former smokers as a result of the strong trend of smoking cessation among U.S. males durin_g the followup period (US DHHS lYX9). Repeated assessment of smoking status in a cohort stud) can mitigate misclassifica- tion due tochanges in smoking status over time (Chapter 2. Part I). Repeated measures are often feasibly made in cohort studies to minimiLe the effects of misclassification. Alternatively. validation substudies can be conducted within the cohort to quantify misclassification errors (Greenland I9XX). Case-Control Studies Casexontrol studies involve selection of study suqjects based on the presence (cases) or absence (controls) of a disease. Exposure and other attributes of cases and controls (e.g.. smoking status or lifetime cigarette consumption) are then measured. The groups are compared with respect to the proportion having the attribute of interest to calculate the exposure odds ratio. which estimates the relative risk associated with exposure. Case-control studies can generally be conducted in les\ time than cohort studies or intervention studies and are less expensive to perform. Case+ontrol studies are well suited for evaluation of disease\ with low incidence rates. Case+zontrol analyses may be affected by information bias and selection bias. Case+ontrol studies are prone to information bias if lifetime exposure histories are collected by interview (Schlesselntan 19x21. Retrospective lifetime histories of smoh- ing or other exposures obtained from ill or elderly sub.jecth may introduce misclassifica- tion. SimilarI\.. studies that rel\, on reports from surrogate\ to assess smohing ma). misclassify exposure. If individuals classified as cases recall more accurately or less accurately than those classified as controls, differential misclassification result\ (Gordix 1982). Differential misclassification may also be introduced ifre\pondent~ deliberateI> falsify answers or if interviewers differentialI> gather information from cases and controls (interviewer bias): interviewer\ not blinded to case-control \tatu\ may probe more intensely for a putative causal exposure in cases than in controls (Sachett I Y79). Blinding is often not feasible. and meticulous attention must be directed to training interviewers and to designing questionnaire\ to rcmovc the po\\ibilit!, of intervieuer bias. Although selection bias may affect any case-control study that is not population based. it is unlikely to be of particular importance in most casexontrol studies of smoking cessation. Intervention Trials Intervention trials are designed to test a hypothesized cause-effect relationship or the benefits of a preventive program by modifying the putative causal or preventive factor and measuring the effect on relevant outcome measures. Intervention trials may be directed at individuals or groups. such as communities. Regardless of the unit of observation. the trials may be conducted wsith (e.g.. a clinical trial) or without ran- domization to the intervention. Clinical trials are most commonly used to assess therapeutic interventions. but this design has also been used to evaluate preventive interv,entions. such as smoking cessation. A clinical trial includes one or more comparison groups in which subjects receive the control intervention: subjects are randomly assigned to the treatment and comparison groups to ensure that the groups are comparable with respect to charuc- teristics potentially affecting the outcomes of interest. Individuals or groups such as communities can be the units of randomization. Within the limits of chance. random assignment makes the intervention and control groups similar at the onset of study. Although widely used to test smoking cessation methods. clinical trials have been used infrequently to assess the health benefits of smokin, 0 cessation. In comparison with observation studies. the clinical trial design offers the potential for eliminating or more tightly controlling bias from the selection of subjects and from confounding. However. for many health outcomes, both a large sample size and a lengthy followup period may be needed to have sufficient statistical pow'er. Moreover. in a study of smoking cessation. the power of the trial also depends on the extent of the reduction in smoking in the intervention group. in comparison with the control group. In the reported smoking intervention trials. only ;I minority of participants attained continuous or prolonged abstinence following most cessation interventions (Hunt. Barnett. Branch 1971: Hunt and Bespalec lY73: Ockene et al. 1990). Even with intensiv,e. prolonged inten entions. as in MRFIT. only 42 percent of smokers within the special intervention group were not sntohing at h-scar follow up. and only 76 percent of baseline smobers 2 had been continuously abstinent from cigarettes over this prolonged period (Ockene et al. IYYO). Only a few clinical trials provide information relevant to the health benefits of cessation (Chapter 3). In the Whitehall Civil Servants Study, (Rose et al. 19821. the investigators randomly intervened in smoking with advice from a phy,sician in a group of men at high rish for cardiopulmonary disease. In MRFIT. smoking intervention w'as one component of the rish factor intervention program directed at the special interven- tion group (MRFIT Research Group IYX3). In tnost clinical trials that assess the effect of cessation on disease outcomes. such as the Whitehall Civil Servants Study (Rose et al. 1982). the tn\,estigators did not monitor longitudinally the persistence of quitting or levels of biochemical markers. The only clinical trial that has provided these measures is MRFIT (Ochene et al. lY90). Although SO maintained cessation rates were significantly greater in the special intervention than in the usual care group, to date the difference has not been large enough to provide adequate statistical power to assess the effect of smoking cessation alone on differences in morbidity and mortality between the intervention and control groups (Chapter 3). However, MRFIT was designed as a multifactor trial and did not assess the impact of smoking cessation alone. Because MRFIT results indicated the greatest difference in smoking cessation between special intervention and usual care subjects compared with any other clinical trial and still lacked the power to detect outcome differences from smoking cessation. it is unlikely that smaller trials would have sufficient power to demonstrate an effect of cessation on morbidity and mortality (Chapter 3) (US DHHS 198.3). Compared with observational studies which place few demands directly on subjects. the use of interventions for smoking cessation in clinical trials increases the probability of misreporting smoking status at postintervention followup because of the expectations of the participants and the investigators. Typical periodic followup in clinical trials. however, reduces the chances of misclassification related to relapses or to delayed action to quit smoking-phenomena that are often not adequately recorded in observa- tional studies. Routine followup also allows for more accurate measurements of the duration of prolonged or continuous abstinence and the opportunity to validate with biochemical testing. Intervention trials other than clinical trials also provide information on the health consequences of smoking cessation. A number of studies are in progress involving interventions of varying intensity within a community. The North Karelia project conducted in Finland is such a community trial: a comprehensive, community-based intervention program was conducted to reduce cardiovascular disease (CVD) (Tuomilehto et al. 1986). Mortality rates in North Karelia were compared with those in other areas of Finland. Methodologic Issues Introduction Epidemiologic studies have been the principal source of information on the health benefits of smoking cessation. Although the resulting data have provided strong evidence for the benefits of cessation, the data need to be interpreted with consideration of potential sources of bias and of other methodologic issues. This Section considers the methodologic issues potentially affecting interpretation of studies of the health consequences of smoking ceshation. The criteria for causality have served as a basis for evaluating all of the evidence relevant to a particular association (US PHS 1963: US DHHS 1981. 1989). However. associations found in individual studies must also be assessed carefully. In any epidemiologic or clinical study. association may result by chance, as the result of bias. or through a causal mechanism. Thus. this Section presents an overview of statistical considerations relevant to studies of smoking cessation and the most prominent sources of bias in such studies-information bias and confounding hia\. It also considers the potentially complex problem ofanal!~ing data on the effects of smohing cessation. Statistical Considerations Statistical significance testing addresses the likelihood that an observed association has occurred by chance if. in fact. exposure and disease are unassociated (the null hypothesis). By convention. probability (p) L alues less than 0.05 are generally accepted as "statistically significant"; that is. chance is considered an unlikely explanation for the association. For example. if the p value is less than 0.05. the probability that chance explains the association is less than 5 percent. Confidence intervals describe the range of effects compatible with the data at some specified level of probability. for example 95 percent. Some studies find associations that do not attain statistical significance. "Negative" investigations must be interpreted in the context of an investigation's sample size: a small sample size may not provide sufficient information to test associations in the range of interest. Such small sample sizes often provide inadequate statistical power to test for the anticipated effects of smoking cessation. and such studies are uninforma- tive as a result. In interpreting associations not achieving statistical significance. confidence limits describe the range of effect compatible with the data. Bias In an)' epidemiologic study. associations may be affected h> bias. Biases from misclassification and from confounding need to he considered in interpreting the findings of studies of the consequences of smoking cessation. This Section focuses on the effects of these biases in studies of smohing cessation. Categorizing the dynamic process ofsmohing cessation poses ;I substantial challenge to epidemiologic researchers (Chapter 2. Part I ). hlorrovcr. subject report their o\\ n sniokin, 17 beha\,ior. and reliance on surrogate sources of information on smohing. LIS ma\ bt~ nc:ccssar!. in casc`+control studIt`\. ma\ also introduce error. The c~~scqucnces of misclassi~c~~tion in obser\ ation studies ha\,c recei\ 4 substall- tialcon~ideratic,n in the rpidcmiolog~c litt'rature (Copeland et al. 1977: Greenland 19X0: Fleiss 1% I: Klcinhaum. Kuppcr. I\lor~enstcrn 19X2: Schlc~sclman 19X7: Kothm;r~~ 19X6). Misclassiticatiorl c;m oc`c~ir in classif! in; either e\pc)surc` or outcome. Onl! exposure inisclllssific~ltic~il. that is smohing \t;ltus. will he considered in this Section (Chapter 2, Part I ). Miscl~!s\it`ic~ltiorl nl;~> be cla\sified ;I\ nondifferential (or random) or 215 differential: both types of miscl~rssit'ic~ltion ;!I-e potentialI> relet ant to studies of \mohing cessation. ~0ndit`ferentiA misclasslfic~ition occurs r:uidonil\ In relation to disease or ourcome status. \rhercas diffcrcntial iiiiscl3\sificati(,n al`fects exposure information in a pattern that varies u ith outcome status. For c\;unple, differential ini\classification \roulJ occur in a case+control stud! of lung cancer if cast`s tended to minimize the extent of past smohing in compari\on u ith the information 5 "ii en h\ controls: elderI\ cases and _ controls might introduce nondifferential misclassification from errors in recall of past smoking. The consequences of nondifferential and differential misclassification have been addressed in the epidemiologic literature. Brass ( 1954) is credited with demonstrating that random misclassification in a 2x2 contingency table diminishes an association that exists between two variables: in general for such cross-classified data. nondifferential misclassification of exposure biases toward the null value. indicating no effect of eposure (Rothman 1986). For exposures classified into three or more levels. the consequencs of nondifferential misclassification are not exclusively directed toward reducing the degree of association. Differential misclassification may either strengthen or weaken associations. depending on the direction of the bias in reporting exposure (Kleinbaum, Kupper, Morgenstern 1982: Rothman 1986). The information presented in prior sections of this Chapter describes the directions that bias may take and allows some generalizations. First, some degree of nondifferen- tial misclassification may affect studies of active smoking and of smohing cessation: the extent of misclassification depends on the type of information collected. the choice of respondents (index subject or surrogate). and the health and age of the respondents. Second. because disease is present at the time of interview. nondifferential mis- classification is particularly likely to affect exposure information collected in cross- sectional studies and case/ 2tXS50~: 1376-l 380, December 13. 19X6. COPELAND, K.T.. CHECKOWAY. H.. MCMICHAEL. A.J.. HOLBROOK. R.H. Bias due to misclascification in the estimation of relative ri$h. hro-rc~u/~ Jorrrwl of` ~/`iclc~n~r(~lc~,~~~ 1OS(S):3883YS. May 1977. CORNONI-HUNTLY. J.. BARBANO. H.E.. BRODY. J.A.. COHEN. B.. FELDMAN. J.J.. KLEINMAN. J.C.. MADANS. J. National Health and Nutrition Examtnation 1 Epidemio- ofy Follow~p Survey. P rthlic Hculrlt Rcpm YX:315%25 I. I YX?. COULTAS. D.B.. HOWARD. C.A.. PEAKE. G.T.. 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Con7prd7c~~7- si1.e Ps~c~Aiurr-~ I 8( I ):93- 101, January-February 1977. 69 CHAPTER 3 SMOKING CESSATION AND OVERALL MORTALITY AND MORBIDITY CONTENTS Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...75 Smoking Cessation and Overall Mortality in Cohort Studies . . . . . . . 75 Smoking Cessation and Overall Mortality in Intervention Studies .............. 8-I Smoking Cessation and Medical Care Utilization ........................... X7 Population Projections .............................................. X7 Observational Studies ............................................... X7 Smoking Cessation and Health Status .................................... X7 Conclusions ........................................................ 92 Chapter3 Appendix .................................................. 93 References . . . . . .._................................................. 90 73 INTRODUCTION The overall risk of mortality among smokers has been discussed in several prior reports of the Surgeon General (US PHS 1964. 1969; US DHEW 1979: US DHHS I989 ). The 1989 Report estimated that approximately 390.000 Americans died in I985 from diseases attributable to smoking (US DHHS 1989). Another source (Mattson. Pollack. Cullen 1987) estimated that 36 percent of heavy smokers aged 35 will die before age 85. and 2X percent before age 75. from a disease caused by smoking. Prior reports of the Surgeon General (L'S PHS 196X; US DHEW 1979: US DHHS 19X9) have reviewed the association of smoking with overall morbidity. concluding that ov,erall morbidity is increased among smokers. Quantitative estimates of the amount of morbidity attributable to smoking vary because of differences in the measures of morbidity used. Data from the aggregate of studies of overall mortality and morbidity among \mohers and former smokers show that smoking causes increased risk of morbidity and mor- tality. However. the temporal pattern of the reduced all-cause mortality after quitting and the effects on mortality risk of quitting at variou\ ages have not been fully described. In addition, questions about the benefits of smoking cessation for mortality have arisen because of the results of studies involving interventions to promote smoking cessation. The association of smoking with medical care utilization is a topic that has not been addressed in detail in previous reports of the Surgeon General. This Chapter reviews studies of overall mortality among former smokers, with particular attention to the temporal pattern of decline in mortality after quitting and the association of age at quitting with decline in mortality. Overall mortality in intervention studies that include smoking cessation is discussed with attention to problems of inferring the benefits of smoking cessation for the individual from these studies. Studie\ of medical care utilization by and health status of former smokers are described. SMOKING CESSATION AND OVERALL MORTALITY IN COHORT STUDIES Table I summarizes the results of major cohort studies comparing overall mortality among never, current, and former smokers. The studies consistently showed a substan- tially lower risk of mortality among former smokers in comparison with continuing smokers. Compared with continuing smokers. former smokers had a progressive decline in mortality risk as duration of abstinence increased. although risk in some studies was increased for I to 3 years after cessation, almost certainly because some people quit due to ill health (Chapter 2). The durations of abstinence required for former smokers to reach the mortality risk of never smokers differ among studies. The American Cancer Society (ACS) study of I million American volunteers (Hammond 1966). also known as the 2S-State Study and as the Cancer Prevention Study I (ACS CPS-I). found that after IO years, mortality rates among former smokers of fewer than 20 cigarettes per day reached levels equivalent to those of never smokers. Among former smokers of 30 cigarettes or more per day. 7s TABLE I.--Summary of longitudinal studies of overall mortality ratios relative to never smokers among male current and former smokers according to duration of abstinence (when reported) All I ox Former smoker\ Duration ot ah\tinencc (yr ) s-9 IO-15 >I5 I.5 I.3 I I 1.34 I.01 1.3X I.31 1.x7 I.24 I 47 7.0x 1 .xx I .72 I .hO I.55 I .5x 0.x-l 0.93 0.90 0 91 TABLE I.-Continued Former wwhers All tlurarion\ Study Current smokerc Pcr\i\lent uuIUcr\ California HMO' (Friedman et al. 1981) I .x2 I Sl I.13 mortality risk was still higher than that of never smokers even after IO years of abstinence. The more recent ACS study. ACS CPS-II. is designed similarly to CPS-I. Re- searchers enlisted 77.000 volunteers. who then solicited their friends. neighbors, and relatives to participate in the study. Those enrolled completed a four-page confidential questionnaire on medical history. health behaviors. medication use, and occupational exposures (Stellman and Garfinkel 1986: Garfinkel and Stellman 1988). A total of 52 1,555 men and 658.748 women were enrolled: 4-year followup data ( 1982-86) on the cohort were included in the 1989 Surgeon General's Report (US DHHS 1989). In this Report, mortality rates for all causes of death from the ACS CPS-II were calculated using updated data for the same 4-year followup period (Table 2). Rates were calculated by gender in S-year age groups for current and former smokers according to level of cigarette consumption ( l-20 cig/day, 22 I cig/day for males: I -I 9 cig/day, 220 cig/day for females). Rates for former smokers were further stratified by years since smoking cessation (I! I cig/day Female\ I-IO q/da> 20 Ih Male\ I-20 q/da\ 22 I cig/da> Female\ I-IY cigiday X0 q/da! 2.31 2.Oh 2.M I .x9 I .4x 1.2') I .o I 7.73 I x5 2 IS I .YO 1.77 I fl.5 1.1') I .x7 0.76 I.26 I .J2 I .OI I .09 I .Oo Z.Jh 7.33 2.15 I .-II I 46 I.IX 0 YS In this analysis, subjects who had quit smoking were assigned to the duration of abstinence category appropriate for when they enrolled in the study. This method of assignment tends to blunt the rate of decline of mortality risk according to duration of abstinence when compared with never smokers because former smokers do not change categories as duration of abstinence lengthens. No attempt was made in this study to determine smoking status after enrollment. and persons who had quit at enrollment but had resumed smoking were still considered former smokers. Likewise. persons who smoked at enrollment but subsequently quit remain assigned to the current smoker category. This probably leads to some degree of misclassitication and affects relative risk estimates (Chapter 2). Like AC3 CPS-I and other cohort studies. mortality ratios were substantially lower among former smokers than continuing smokers for all durations of abstinence except that of I to 3 years. With the exclusion of those subjects who had a history of cancer. heart disease, or stroke and those who said they were "sick" at the time of recruitment. mortality ratios were lower among former than continuing smokers for all durations of abstinence, among males at all prior levels of cigarette consumption. and among females who smoked fewer than 20 cigarettes per day before they quit. The difference in the pattern of decline in overall mortality between all subjects and the subset of subjects who were healthy at recruitment provides strong evidence that recent quitters disproportionately include those who have quit because they are ill. In contrast with ACS CPS-I. which was conducted in the early 1960s. mortality ratios among both heavy and light smokers in ACS CPS-II remained substantially elevated in comparison with those of never smokers IO years after quitting. This increase was evident in all subjects and in the subset of subjects who did not have a history of cancer, heart disease, or stroke and who did not state that they were "sick" when recruited. Sixteen years after quitting, the mortality risk among male former smokers of fewer than 2 I cigarettes reached that of never smokers but remained elevated among former smokers of 21 cigarettes or more. Among female former smokers in both categories, mortality was comparable with that of never smokers after 16 years of abstinence. The results of ACS CPS-II are broadly in agreement with those of the British Physicians Study (Doll and Peto 1976; Doll and Hill 1964a,b) and the U.S. Veterans Study (Kahn 1966; Rogot and Murray 1980). In both, the overall mortality risk among former smokers remained elevated in comparison with that of never smokers up to 15 years after quitting, although the risk was substantially less than among continuing smokers. An Australian study of petrochemical workers (Christie et al. 1987) appears to differ from the other cohort studies in finding that overall mortality risk among former smokers reached that of never smokers 5 years after quitting. This study is unique in that subjects classified as former smokers were all persistent abstainers. The differences among other studies in estimates of the duration of abstinence needed for a former smoker to have the same overall mortality risk as a never smoker are likely to be due to other smoking-related factors, such as age at smoking initiation, that differ among study populations and over time (Chapter 2). Irrespective of the duration of abstinence needed to reach the mortality risk of never smokers, former smokers have substantially lower mortality when compared with continuing smokers. For three reprc\entative age groups (NJ--54.60-64, and 70-74 yr). Figure I shows the relative risk of death among current and former smokers compared with never smokers based on recent ACS CPS-II data for the subjects who did not have cancer, heart disease. or stroke and were not "sick" at recruitment. Complete data from ACS CPS-II on mortality in current. former. and never smokers aged 50-74 years are presented in Table 7 of the Chapter Appendix. Data are not presented for those aged less than 45 years and greater than X0 years because there were fewer than IO deaths in almost all of the categories of former smokers. In each of the age subgroups shown in Figure I. among both sexes and among former light and heavy smokers, mortality risk relative to continuing smokers decreased with increasing duration of abstinence. Using a method described by Kleinbaum, Kupper. and Morgenstern (1982). the data from ACS CPS-II were also used to estimate the effects of quitting at various ages on the cumulative risk of total mortality in a fixed interval after cessation. Several assumptions have been made in conjunction with CPS-II age-specific mortality data in order to estimate as many as 16.5 years' risk of death from all causes for individuals who continue to smoke and those who stop smoking. The first assumption is that age-specific mortality mtes measured from 1982-86 CPS-II data remain constant for the next 16.5 years. The first category of smoking cessation is l-2 years: that is. the individual gave up smoking I to 2 years ago. It is assumed that. on average. respondents in the I-2-year category pave up smoking I .5 years ago. Similarly. for the cessation categories 3-S. 6-l 0, and I l-l 5 years, the average durations of abstinence are 1. X. and 13 years, respectively. It is further assumed that respondents are exposed to the age-specific mortality rates of the age interval in which quitting occurs for I .5 years and to each of the next three age intervals for 5 years each, making a total of 16.5 years. For example. a quitter of the -IO-&-year interval would be exposed to the age-specific mortality rates of the 301-t-year-olds for I .S years. to those of 4539-year-old\ for 5 years, to those of SG%-year-old\ for 5 years. and to 5%59.year-olds for 5 years. The results of thi5 analysis. presented in Table 3 and in greater detail in Table X of the Chapter Appendix. \how that the benefits of cessation for total mortality extend to quitting at older age<. For example. a healthy man aged 60-63 years who smokes 21 cigarettes or more per day is estimated to have a chance of dying in the next 16.5 \`ears of 56 percent if he continues to smoke and 5 I percent if he quits. Quitting smoking at younger ages confers even greater proportionate increasej in survival (\ee Figure 7 of the Chapter Appendix ). Framingham investigator\ recentI!, analyred data from their cohort (D'Ago\tino et al. 19X9) and aI\0 found that the benefit\ of quitting apply to those who quit at more advanced age\. These researchers estimated that mean additional life expectancy for those who quit at ages 35 to 39 wah 5. I years for males and 3.2 years for females. For those who quit at ages AS to 69. additional life expectancy was estimated to be I .3 years for males and I .O year for females. As discussed in detail in Chapter _ 7 and other chapters. smokers differ from non- smokers in a variety of social. behavioral. and psychological characteristics. and successful quitters differ from those who continue to smoke (Rode. Ross. Shephard 1972: Blair et al. 19x0: Haines. Imeson. Meade 19X0: McManus and Weeks 1982: Billings and Moos 19X3: Gottlieb 19X3: Brod and Hall 19X-l: Seltzer and Oechsli 19X5: X0 MALES Aged XL54 Current Smokers amount smoked and duration of abstinence x2 TABLE 3.-Estimated probability of dying in the next 16.5year interval for quitting at various ages compared with never smoking and continuing to smoke, by amount smoked and sex Age at quitting or at 51art of interv31 Female\ Age at qutttmg or at \tart of interval Never \moher\ x!o q/da\ Contmumg Former mohrr\ smoker\ 1&`&l 0.03 0.06 0.03 (I ox 0.0-l 4519 0.04 0.0') 0.06 0.1 3 0.0 SO&S-l 0.07 0. l-l 0.07 0.14 (l.OY 55-s') 0.1 I 0.2 I 0. 12 0.27 (I. IS 60-64 0.1 x 0.30 0. I Y (I.38 0.3' 65-6') 0.30 0.46 0.3Y 0.52 (I.32 70-7-1" 0.26 0.4 I 0.77 0.4S (I.3 I Kaprio and Koskenvuo 1988). These differences may exist among adolescents prior to initiation of smoking (Seltzer and Oechsli 1985). For these reasons, interpretations of studies comparing these self-selected groups (never smokers. smokers, and quitters) must consider the problem of confounding (Chapter 2). Misclassification. which is discussed in detail in Chapter A. 7 also must be considered. However, studies of smoking cessation predominantly misclassify persons who are still smoking cigarettes as former smokers, and this would tend to obscure the benefits of cessation in comparison with continued smoking. Further. although the possibility of uncontrolled confounding needs to be considered in epidemiologic studies of smokin, 0 cessation and mortality. the totality of data must be interpreted with consideration of its consistency. To account for the evidence of a benefit of quitting that derives from nonexperimental cohort studies, confounders would need to be distributed quite differently among current and x3 former smokers and would need to be strong predictors of mortality. There is no substantial evidence that thih is the tax. SMOKING CESSATION AND OVERALL MORTALITY IN INTERVENTION STUDIES Five studies. four of which were randombed triak evaluated overall mortality in relation to interventions that included smoking cessation 3s a component. The results of these studies are aummurired in Table 1. TABLE 4.-Summary of overall mortality ratios in intervention studies in which smoking cessation was a component Otil!~ one stud! cxaminccl wlohin g inter\ c'ntion alone t Rwc and Hamilton 197X: Rose et al. 19X2). Of I .145 IIMIC` mwk~~. aged 10 to 59 and at hish ri\h of coronaq heart diNe;Iw (CHDI or chrotttc hronchttis. 7 t-I \+erc randomt~ a\\iyed to a11 interLen- tion group and 73 I to ;I norm;tl cat-c group. hlcn in the inter\ ention group wcrc fi\ en individual ad\ ice to quit \mohing. and if intereaxi III quittins. up to four additional vi5it4 over 12 month\. AI the c)-!car follow up. 55 pcrccnt of responder5 in the intervention reported abbtincnce compared I+ itli 1 I percent in the normal care group. After IO !eat-\ of 1'~~llo~~ up. there \\crc 123 death\ III the inter\,ention group and 1% in the normal care group. The proportionatt' diffcrcnce in total mort;rlit! hewecn the intervention group anti normal cxc group I-2 percent) \\a not \t;iti4icall\ stgnitkxnt. but the confidence inter\;tl \\;I\ u I& 1-12 percent to +23 percent). There \\t're XI X-l smoking-related deaths in the intervention group and Y2 in the normal care group. The proportionate difference in smohing-related deaths has -Y percent. Again the con- fidence interval was wide (-31 percent to +20 percent). Twenty percent of the men in the intervention group who quit smohing cigarettes tooh up pipe or cigar smohing compared with 3 percent of the men in the normal care group. and to the extent that pipe and cigar smoking are mortalit) rish factors. any benefit of cessation of cigarette smohing is obscured. This trial is largely uninformative as to the benefit or lack of benefit of smoking cessation for total mortality because of the small number of subjects. The trial uas further compromised by the relatively poor compliance of the subjects with the intervention: the net reduction in mean cigarette consumption over the IO years of the followup among the intervention group compared ti ith the normal care group was onI\ 7.6 cigarettes per day. Other intervention studies that allow assessment of the relation ofsmohing cessation to overall mortality have involved multiple interventions aimed at reducing several different factors for CHD. The ability to draw conclusions about the effect of smoking cessation on overall mortality from these studies is quite limited for this reason. The North Karelia study targeted a region of Finland that had the world's highest CHD death rate at the time of the study's initiation (Tuomilehto et al. 19X6) and was aimed at modifying smohing. cholesterol levels. and blood pressure. The rest of Finland was used for comparison. In the IO years after initiation of an aggressive risk reduction program. there was a 35percent decrease in smohing in North Karelia compared with a I-percent reduction in the rest of Finland (Salonen et al. IYXY). Blood pressure and cholesterol levels did not change significantly in the intervention area compared u ith the rest of Finland. Total mortality in the intervention area in the IO years after the start of the study declined more rapidly than in the rest of Finland. although the difference in the rate of decline in overall mortality was not statistically significant. For at least two reasons, interpretation of the North Karelis study is problematic with respect to the effect of smoking cessation on overall mortality. First. the study was nonexperimental. with conclusions based on a comparison of total mortalit\, in the stud) area with that of Finland. During the study period. overall mortalit) also declined in the rest of Finland, perhaps because of secular changes in other factors related to mortality and to changes in medical care (Salonen et al. 19X9). Second. the study was not designed to investigate smoking cessation alone. Because of the mixing of inter- ventions for three CHD rish factors, it was difficult to isolate the impact of the smoking cessation component. The Oslo study (Hjermann 19X0: Hjermann et al. 1981; Holme 1982) involved 1.237 normotensive men at high risk for CHD because of their smoking behavior and cholesterol levels. The men were randomly assigned either to recei\,e interventions aimed at reducing both CHD risk factors or to a control group. Tobacco consumption. including pipe and cigar smoking. fell 45 percent more in the intervention group than in the control group. There was also a mean difference of I3 percent in serum cholesterol between the intervention and control groups over 5 years (Hjermann et al. IYX I ). The stud!, was small. and it was not designed toexamine total mortality endpoints; only 42 deaths were X5 observed. Nevertheless. the mortality rate in the intervention group was one-third lower than in the control group (one-sided p value=O. 13). Because there were changes in both smoking and cholesterol levels. the difference in mortality cannot be attributed entirely to smoking cessation. The World Health Organization (WHO) European Collaborative Group conducted an intervention study in factories in four European countries (WHO European Col- laborative Group 1983). The study involved random allocation of 66 factories that employed 49,781 men aged 40 to 59 to an intervention program targeting smoking. cholesterol level. and blood pressure or to a control group. After 4 years. the net reduction in mean cigarettes perday in the intervention factories was X.9 percent (WHO European Collaborative Group 1983). At 6 years. overall mortality in the intervention factories was 3.04 percent: in the control factories. it was 4. IS. The difference was not statistically significant. The Multiple Risk Factor Intervention Trial (MRFIT) was a randomized study of more than 12.000 American men. aged 35 to 57 at entry. who were at high risk for CHD on the basis of their smoking behavior. blood pressure. and cholesterol levels (MRFIT Research Group 1981). Men in the special intervention group received an intensive intervention aimed at reducing hlood pressure and cholesterol and encouraging smok- ing cessation. Men in the usual care group were referred to their physicians and examined annually. The interventions continued over the entire course of the study. At 6 years. q-l.3 percent of special intervention smokers and 3.X percent of the usual care smokers reported cessation. In the 7-year followup data reported in IYXZ. there was no difference in total mortality between the special intervention and usual care groups (MRFIT Research Group lYX3). However. in the 10.5-year follow up data of MRFIT participants. overall mortality for the special intervention participants was 7.7 percent lower than for the usual care group (one-sided p value=O. IO: YO-percent confidence interval (Cl). -16.6 to +7.3) (MRFIT Research Group IYYO). A subgroup of MRFIT special intervention participants. who were hypertensive. had resting electrocurdiograrll abnormalities. and comprised 31 percent of the special intervention group. may have suffered excess mortality as a result of an unanticipated adv,erse effect of one of the antihy~pertcnsive drugs (Cutler. MacMahon. Furberg 19X9). This has recently been sugested as an explanation for the absence of an overall difference in mortality~ between the special intervention and usual care groups at the 7-year follow LIP (MRFIT Research Group. submitted for publication I. Furthermore. Ockene and coworhers ( 1900) recently reported that at IO.5 years. MRFIT participants who quit smohing had significantI\ lower death rates than those who continued to smohe in both special inter\ cntion and usual care groups. Mo5t important. like the other multifactor intervention trials. it is difficult to infer a benefit or a lath of benefit ot smoking cessation for total mortality from this study. In summary. studies in\,ol\ in? smohing cessation interventions include a randomized trial in which smohing cessation was the sole interventton and three intervention studies in M hich it was ;I component. The small six of the former and the mixing of a smohing intervention with other interventions in the latter mahe it impossible to reach con- clusions about the benefits of smohing cessation from these studies alone: however. nonintervention (i.e.. cohort) studies described in the previous Section clearI! indicate a benefit of smoking cessation on overall mortalit!,. SMOKING CESSATION AND MEDICAL CARE L'TILIZATIO\ Population Projections The relationship between smohinf cessation and medical care utilization is acomplcx issue. Data on differential disease and mortalit!, rates comparing smohers and abstainers are abundant. and man\ in\,ectigators have used these data to pro,ject the savings in dollars attributable to smohing cessation (Weinham. Roscnbaum. Sterling IYX7: Leu and Schaub 1'3x3; Lute and Schweit/el- 197X: O\ter. Coldit/. Kelly IYXIJ. Cenerall\~. these projections produce results that depend on the man> assumption\ ot the models that create them. For example. Lute and Schweitzer ( I Y~XJ projected that the total 1976 dollar cost of smohing in the United State\ was about 527.5 billion and that excess medical care costs accounted for about SX.2 billion of tho\r costs. Weinkam. Rosenbaum. and Sterling ( lYX7) and Leu and Schaub ( IYX3). both using population simulation approaches. concluded that mohin, (7 does not. o\er a lifetime. lead to increased medical care utilization. Thi\ is because the short-term higher levels of utilization of smokers are approximateI\, balanced b) shorter longevity and the resulting reduced need for medical care. Oster. Coldity. and Kelly ( 19X-I) used population prcjjcctions to estimate the medical care costs of smoking and the proportion of those costs that are potentialI> recoverable depending on the age at which smokin g is riven up and the level of smohing prior to c quitting. Male light smokers (I yr). and thtw htudiek are highlIghted. XX Data from the National Center for Health Statistics (US DHHS 1980) suggest that former smokers have fewer illness days than continuing smokers, particularly among younger women. Gallop (I 989) found that former smokers have absentee rates between those of current smokers and never smokers. Segovia, Bartlett, and Edwards (1989) conducted a telephone survey of 3.300 adults and found a strong relation between smoking status and the reporting of good health. Persons who had quit smoking for more than 1 year reported good health with about the same frequency as persons who smoked only I to 5 cigarettes per day, whereas those who had quit for less than 1 year reported good health at a frequency comparable with smokers of 16 to 20 cigarettes per day. Balarajan. Yuen, and Bewley ( 1985) examined the associations among various levels of smoking, recent and former cessation, and presence of acute and chronic illness, medical office visits, and doctor consultations. Current smokers had a higher prevalence of acute and chronic illness. and rates varied in relation to the amount smoked. Former smokers who had quit in the year prior to the survey had higher rates of illness compared with continuing smokers. and former smokers who quit more than 1 year prior to the survey had rates between those of never smokers and smokers of 20 cigarettes or more per day. Reed (1983) found no difference in general physical health status between current. former, and never smokers, not otherwise defined. Seidell and colleagues (1986) examined the number of reported health complaints, out of an inventory of 5 1 possible complaints, by smoking status and found that male, but not female, former smokers reported fewer health complaints than smokers. Astrand and Isacsson (1988) found that male employees of a pulp and paper plant who smoked retired at an earlier age than nonsmokers. Data from the 1979 National Health Interview Survey indicate that smokers have more restricted activity days, more bed disability days, more hospital days, more physician visits. and an increased probability of being unable to work or keep house, than nonsmokers (Rice, Hodgson. Sinsheimer 1986). Analyses of data for the 1976-80 Health Interview Surveys showed that smokers have a 55 to 75 percent excess in days with respiratory conditions associated with reduced activity (Ostro 1989). Smokers experience more school absences (Charlton and Blair 1989; Alexander and Klassen 1988) and work absenteeism (Andersson and Malmgren 1986; Coughlin 1987; Hendrix and Taylor 1987: Gallop 1989) than do never smokers. None of these studies reported information on former smokers. These studies are extremely heterogeneous, with some methodologic shortcomings (Chapter 2). Furthermore, smoking is associated with other behaviors that may affect health (Pearson et al. 1987; Stephens 1986). and the studies do not adjust for changes in other risk variables, such as increased exercise, that might be associated with smoking cessation. Taken together, however. the studies are consistent with the hypothesis that smoking cessation produces improvements in health status. This conclusion is evident particularly when considering that smoking-related morbidity is a powerful motivation to quit smoking and that recent quitters are likely to be sicker than continuing smokers. TABLE 6.-Relation of smoking cessation to various measures of general health status Sell-rcpofl ol ~llne\\ and (`hronic ilIne\\ ph!\lcian VI\I~\ Acure illW\\ Outpatient vl\n PhyGcian conwlliition I.0-r' 1.31" 1.76" I .03 I .OY I.29 I .46 I .46 I .43 I.12 I .0x I .OY Gig/day I yr ??I 51 yr >I yr -- Segovia, Bartlett. Edwards (IYXY) Telephone survey of representative sample us adults Self-report of "good health" 4. IX< 1.00" I .a' 3.42' 5.13" 6.13" Gallop (19X9) Workers in the pulp/paper industry Work absence\ I.3' I .OY' I .otf CONCLUSIONS 1. Former smokers live longer than continuing smokers, and the benefits of quitting extend to those who quit at older ages. For example, persons who quit smoking before age 50 have one-half the risk of dying in the next 15 years compared with continuing smokers. 2. Smoking cessation at all ages reduces the risk of premature death. 3. Among former smokers, the decline in risk of death compared with continuing smokers begins shortly after quitting and continues for at least IO to 15 years. After IO to I5 years of abstinence, risk of all-cause mortality returns nearly to that of persons who never smoked. 4. Former smokers have better health status than current smokers as measured in a variety of ways, including days of illness, number of health complaints. and self-reported health status. 92 CHAPTER 3 APPENDIX TABLE 7.-Age- and sex-specific mortality rates among never smokers, continuing smokers, and former smokers by amount smoked and duration of abstinence at time of enrollment for subjects in ACS CPS-II study who did not have a history of cancer, heart disease, or stroke and were not sick at enrollment 4s 1') so s4 55- SY hOM4 hS-hY 70-73 75-74 I Xh.0 42Y.2 25.5.6 702.7 44x.9 1.131.4 733.7 I .YX I. I I.1 IY.4 3,(H)3.0 2.070.5 3.6Yl.S 3.675.3 7.340.6 Current Former wwher\ (22 I cie/d;tv) TABLE 7.-Continued Females Age Never \mokrr\ I5 Current smoker\ Former woher\ IL.4 S-Y lOLl4 15-l') x!o Current waker\ Former smoker\ l-4 S-Y >I0 I .o (7) 15.X(123) lh.O(l5) S.Y(l') 5.3 (Y) 7.0 (7) 11.3(2.6OY) 1x.x (47) 7.7 (X6) 4.7 (I(H)) 4.x (I IS) 2.1 (123) 3.x 4.7 2.5 I .4 IY.Sl-71,Dyr followup: data on former smoker\ In wmmary form 195449, 16-yr followup TABLE 3.-Continued Reference Population Smoking status and yr since stopped wloking Hammond ( 1966) ACS CPS-I male% Never wwkerh Current v~x~k.er~ f%mer \moher\ I0 ACS (unpuhll\hcd tuhulatlww) ACS CPS-II malrb Never w~ohers Current smokers Former smoker\ Ih Mortality ratio5 (N)" Comments I-l') up/day IYSY-67. 7.5.yr followup. men aped SO-69 I .o (32) 1.0(37) 6.5 (X.01 13.7(351) 7.7 (`I) 2Y.I (73) 4.6 (5) 12.0(3X I .o ( I ) 7.2 (22) 0.4 ( I , I.1 ts, I-20 221 cig/dny clg/d;ly I.0 (XI) I .o (XI, 1x.x (60X) X.9(551) 26.7 (32) 50.7 (63) ??.4 (7 I ) 31.2(117) 16.5 (X2) 20.`) (Yh) x.7 (X01 IS.0 ( IOh) h.0 (6Y 1 I?.6 (Y5) 3.1 t I441 5.5 (I 121 TABLE .X-Continued Never \mohcr\ <`urrcnt wiokw I%rmcr \mohcr\ 20 +/day Cl@i) I .o ( IX l ) 7.2 ( 145) 7.Y (3 9.1 (13, 2.0 (7) I .o (4) I.5 (6) I .4 (23) I .o ( IX I ) 16.3 (334) 34.3 (3 I I IY.5 (42) 14.6 (42) Y.I (32) 5.Y (20, 2.6 (IX) TABLE 4.-Relative risks of lung cancer among former smokers, by number of years since stopped smoking, and current smokers, from selected case-control studies Reference Popuhtion Definition of former smoher Smoking status and yr \ince wpprd Graham and Levin (1971) New York At hospital admission Never smoker\ Current vnokers Former smoker5 0-03 >().%I >I-.? >3-IO >I0 Wigle, Mao, Grace (1980) Correa et al. (1984) Alberta. Canada, cancer patient5 At mtervww NR NWCI- \mohcln Current \moher\ Former amohers 3-s 6X >20 Rewlts Aci.juatment" Male\ Crude I .o X.X 42 2 z 3 3 IO.0 3.3 I.3 Mole\ l+males 0. I 0.1 I 0 I .o 3.4 0.9 0.7 0.s 0.7 0.5 0 2 0.4 M;lle\ d f?nlule\ I .o I2 h 77 7.0 3.9 TABLE 4.--Continued Deflnltlon of former maker Smoking status and yr since stopped Results Adjustment'l AItl~r\~~n. Lee. W;rnp (19X.5) (;;I0 c, al , I')XX) NK Never makers Current \mokrr\ Former smoker\ I-2 5-10 >I0 Never smoker\ Current \mokrr\ Former smokers IL4 s-9 2 IO Never smohw Former smokers 5 Mules 0. I I .o I .x 0.4 0.3 Female\ 0.2 I .o 2. I 0.7 0.3 Males Female\ ) .o I .o 3.9 2.9 6.9 7.2 3.1 3.9 LI 3.2 Male\ I .o I I .9 6.1 3.7 I .9 Males Femall3 I .o I .o I.? 2.0 0.6 0.9 Age Age and educatwn At lrab~ I yr at time of lntervleu NK Duration of \mokmg TABLE 4.--Continued Reference Population Defimtion of former \moher ~-.__~ Smoking %13tu\ and yr Gnce stopped -~~~ __. ~~ Lubin et al. (1984a) Pathak et al. (1986) European casexontrol study New Mexico At interview Current smoker\ Former hmokerk 1-4 s-9 l&l4 IS-19 2%?4 x.5 AI least I yr before interview Current smoker\ Former smoker\ S IO 20 Current smokers Former smokers I-S 6-10 >I0 Damber and Larson (19X6) Swedenh NR Males I .u I.1 0.7 0.6 0.4 0.4 0.3 Female\ I .o 0.9 0.7 0.4 0.5 0.5 0.3 Duration of smoking Male\ S6.5 >hS I .o I .o 0.5 0.7 0.2 0.5 0. I 0.3 Male\ 9.S 73 3.0 2.0 Number of q/day Age Graham and Levin I97 I; Pathak et al. 1986). Canada (Wigle. Mao. Grace 1980). Europe (Lubinetal. 1984a;DamberandLarsson 1986).Asia(USDHHS 1982:Gaoetal. 1988). and Latin America (Joly. Lubin. Caraballoso 1983). Although only a few studies had information on female former smokers, the pattern of risk reduction was similar to that observed for males. Decrease in risk after smoking cessation also has been reported for each of the major histologic types of lung cancer (Wynder and Stellman 1977; Lubin and Blot 1984: Benhamou et al. 1985: Higgins and Wynder 1988) (Table 5 and Figure I ). Higgins and Wynder ( 1988) found that the decline in risk after cessation was more consistent for Kreyberg I tumors (primarily squamous cell, small cell. and large cell cancers) than for Kreyberg II tumors (primarily adenocarcinomas and bronchiolo- alveolar carcinomas) (Figure I ). Smokers of filter and nonfilter cigarettes (Wynder and Stellman 1979: Lubin et al. 1984b) and of other tobacco products (Joly. Lubin. Caraballoso 1983: Lubin et al. 1984b; Damber and Larsson 1986; Higgins, Mahan, Wynder 1988) have reduced lung cancer risk following cessation (Table 6). Although the findings of the reviewed studies uniformly indicate lower risk among former smokers. the magnitude and rapidity of the risk reduction with smoking cessation varies among the studies. This variation has several potential explanations. First, years of abstinence among those who stopped smoking for the longest time interval varied from 5 to 25 years or more. Second, although former smokers have a risk of lung cancer between those of continuing smokers and never smokers. the pattern of declining risk as duration of abstinence lengthens has not been fully characterized. The small number of former smokers in some studies limits the precision with which the decline in risk can be described, particularly for the longer durations of abstinence. Third. aspects of the active smoking history. including cumulative smoking exposure up to the time of quitting. age at initiation. years of smoking. number of cigarettes smoked per day. inhalation practices. types of cigarettes and other tobacco products smoked, age at smoking cessation. and the reason for stopping, may modify the risk of lung cancer after cessation (Chapter 4. see section on Effect of Antecedent Smoking History). The varying extent to which these factors havJe been considered in analyzing the effect of cessation may partially explain the differences in risk observed in former smokers among the studies. As discussed below. failure to adjust for previous smoking history may exaggerate the benefit of smoking cessation. but adjustment for cumulative smoking history also may result in overadjustment of the risk estimate (Chapter 2). Fourth, the studies vary in the definition of former or es-smohers and in the analytic treatment of former smohers u ho have recently stopped smoking. In the case ,I? I II I .o I .o 31.3 IO 7 Ft!lll;llt2\ Kreyherg type I II I .o I .o 10.5 4.4 52.X I-t.? 13.6 6.7 74.0 5.0 6.2 3.6 17.1 6.6 5.1 4.1 13.7 5.-J x.x 5.6 5.0 I.7 O.`J Mnh Krc?tm$ t>t>c I II I 0 I .o .I-&.(> 6.1 I'.' 2.1 IO 9 0.J I .o 4.2 M;Itc\ I;CllldC\ ADEN sy ADENO I .o I .o I 0 t 0 0.x 0.6 0.0 0.5 I.1 0.7 0.0 I .o 0 4 0.4 0.4 I .7 0.3 0.3 TABLE &-Relative risks of lung cancer among never, former, and current smokers by types of tobacco products smoked Never smoker\ Former smokers Current smoker\ C`Igarettc~ only I .o 6.Y 16.0 CIg;ir\ only I .o 2.5 3.1 Pipes only I .o 0.7 I .9 Clfars and pipe\ t .(I 2.4 x.5 Mixed woher\ I .o S.1 10,s Y r Gnce stopped I4 2.5 0.6 0.7 4.4 0.0 2.0 0.Y t .2 0.8 I .o t .o I .o I .o C`lgarelte\ only" Plp13 only Y r since \topped t-10 >I0 S.0 1.2 5.0 4.5 9.5 x.0 KREYBERG I (N-330) MEN 30 25 20 15 10 5 0 E L i4 t KREYBERG II (N=204) Y 15 d n r-l r 35 30 25 20 15 10 5 0 15 10 9 10 F: 25 20 5 0 1 - 11 - 21 - 31 - 241 NUMBER OF CIGDAY Yr of abstinence WOMEN KREYBERG I (N-951 KREYBERG II (N=lOO) 01-4 05-9 810-19 sl20-29 * >30 FIGURE l.-Risk of lung cancer by number of cigarettes smoked per day before quitting, number of years of abstinence, sex, and histologic types SOC'RCE: Hlggn\ and W>ndrr (198X) Although this review has emphasized the results of cohort and casexontrol studies. descriptive data on lung cancer mortality in the United States are consistent with a beneficial effect of the declining prevalence of cigarette smoking. Devesa. Blot, and Fraumeni ( IYW) described declining mortality rates for lung cancer at ages belov, 15 years. The decreases were greatest among white men but also occurred among white women and blacks of both sexes. Effect of Antecedent Smoking History The preceding Section reviewed epidemiologic studies describing the pattern of lung cancer rish following smoking cessation. This Section considers factors related to smoking that plausibly could modify the effect of cessation on lung cancer risk: these factors include the duration of smoking. daily cigarette consumption. inhalation prac- tices, types of tobacco products smoked. and age at cessation. Duration of Smohing Duration of smoking prior to cessation is a potentially important modifier of the pattern of risk reduction in ex-smokers. Graham and Levin (1971) examined the rish of lung cancer associated with increasing durations of abstinence and with stratification by duration of smoking (130 or 23 I years and 5-I-10 or 231 years). The decline in risk associated with stopping v~as greater for those who had smoked for shorter periods than for those who had smoked for longer periods. Similar results were reported by Lubin and colleagues ( 19x41). who determined the rish of developing lung cancer by time since stopping hmohing (0. I--1. 5-Y. and 210 years) and total duration of smoking ( I-19. 20-N. 404Y. and 23) Jears). In each category of smoking duration. the rish of developing lung cancer decreased as the number of j'ears since stopping smohing increased. but the rate of decline LI as greater among those who had smohed for a shorter time. Among men who had smoked for I to IY years. the rish ofdeveloping lung cancer after IO ycurs of abstinence dropped to Ie\s than one-third of that among current smohers. On the other hand. t'or men 1% ho had smohed 50 ! ears or more and stopped for at least 10 \`ears. the rish M as still YO percent otthat t`or men LI ho continued to smohe. This analysis. which matched for age and controlled for both duration of smoking and length of abstinence. introduces too man! \anahlcs i'or the temporal dimensions 01` cifarette use (Chapter 7). B! simultaneously considering attained age. duration ot' smohing. and length of abstinence. the anal> tic model incorrect11 forces former smohers to ha\,e ;I ! oungcr age of starting to smohe than current smohers. Ill ;I case--Control stud!, in Sweden. Dambcr and Lars\on ( I YX6) also found higher rt'lati\.e risks among t'onncr smohcrs of pipes and cl,, `o,lrettes u ho had smohrd longer. Brown and Chu ( lYX7) ~ggestcd that t'ailure to ad.iu\t for pre\ ious duration ot smohing ma\ result in rish e\timatc\ i'or former smohers that are too ION and thus exaggerate the henei'ith of smohing cessation. Based on reanalysis of data from the large European cases _ . \ \ \ \ % `4 4 `\\ \ \ \ `A---- --&\ WITHOUT ADJUSTMENT FOR ' \ \ SMOKING DURATION \ \ \ - "' I 0 k lb 1; $0 2k io : YR SINCE QUIT SMOKING FIGURE 2.-Relative risk of lung cancer among ex-smokers compared with continuing smokers as a function of time since stopped smoking, estimated from logistic regression model, pattern adjusted for smoking duration compared with pattern unadjusted for duration SOCiRCE. Hroun and Chu (101171 time than men who had stopped for a shorter time. The relative risk of lung cancer continued to decrease sharply with increasing years of abstinence without adjusting for smoking duration. whereas the decreasing relative risk plateaued when adjusted for duration of smoking (Figure 2). The difference in this pattern was most noticeable for increasing years of smoking abstinence. For those who had stopped smoking for 27 years or more, the relative risk compared with continuing smokers was 0.30 when adjusted for duration, but 0.17 when no adjustment was made. However. control for previous duration of smoking (or cumulative previous smoking history) in determining the risk of lung cancer among former smokers may constitute overadjustment if age and duration of cessation also are included in the model (Chapter 2). In summary, only limited analyses address the effect of duration of previous smoking on the decline in risk following cessation. The data point to less decline of relative risk following cessation, comparing longer term with shorter term studiej. but additional investigation is needed. 123 Daily Cigarette Consumption Previous smohing intensity or number of cigarettes smoked per day also affects the pattern of risk reduction after smoking cessation. In the U.S. Veterans Study. the mortality ratios for lung cancer were 1.3 I, 3.37, 8.31. and IO.05 for ex-smokers who smoked I to 9. IO to 20.2 I to 39. and 40 cigarettes or more per day, respectively (Kahn 1966). The pattern of lung cancer rish reduction by years of smoking abstinence and number of cigarettes smoked has been reported for several studies. In ACS CPS-I and ACS CPS-II (Hammond 1966: Garfinkel and Stellman 1988). the decline in risk with stopping smoking showed a comparable proportional reduction in risk among those who had smoked less (Table 3). In the European case in the trend of ri\h reduction by years of hmohing abstinence (0. 14. 5-Y. and 210) and b>, type of cigarettes moked (filter. mixed. nonfilter) \\erc observed by Lubin and coworher\ ( 19XlhJ in the European case-i'ontrol stud>. Among men. the relative risk for former smokers after stopping smoking for IO lears or more has 0.4 for filter cigarette smokers. 0.3 for nonfiitercigarette smoher5. and 0.5 for mixed filter and nonfilter cigarette smokers. These data were collected in five western European countries from 1976 to IYXO: the tar yields of the products smohed were relatively high in comparison with cigarettes currently smoked in the Ilnited States (Lubin et al. IYX3b). In most studies, cigar and pipe smokers have louver lung cancer risks compared with cigarette smokers (US DHHS IYX2). Former smohers of only pipes or cigars also showed an intermediate risk of lung cancer compared v. ith current smokers and never smohers of these tobacco products (Table 6). In the U.S. Veterans Stud). the lung cancer mortality ratio. compared with never smohers. was I .67 among current smokers who used only pipes or cigars and 1 .SO among former smoker\ (Kahn lY66). In a case-control study ofsmoking-related cancers conducted in the United States. Higgins. Mahan. and Wynder (1988) reported that ex-smokers of cigars only showed a relative risk of 1.5 compared with 3.1 among current smokers of cigars only. The relative rish was 0.7 among ex-smoker\ of pipes only compared with I.Y among current pipe smokers only. Analysis of the pattern of risk among ex-smokers of cigars and pipes only by considering the amount and duration smoked prior to smohing cessation revealed similar patterns of risk reduction among light and heavy smokers. Lubin. Richter. and Blot ( 1984) also examined the pattern of risk reduction by years of smoking abstinence (0. I--1, 25 years) and types of tobacco smoked (cigars onI!,. mixed cigar and cigarette smokers, pipes only. and mixed pipe and cigarette smokers). No apparent differences were observed in the estimated rishs. ivhen analyred by tobacco products. among those who had stopped smoking for at least 5 years. but the numbers of cases who smoked cigars only and pipes only were quite small. On the otherhand. Damber and Larsson ( 1986) reported that the decrease in relative risk among ex-smokers was less pronounced in smokers of pipes compared with cigarette smoker\ only in a case-control study conducted in Sweden. However. in this population. the risk of lung cancer for pipe smokers (RR=6.9) was similar to that of cigarette smokers (RR=7.0). In summary, these analyses. limited by the sample sizes within strata of types of products smoked, do not characterize precisely the changing lung cancer risk following cessation for smokers of various tobacco products. Effect of Age at Cessation Several researchers have suggested that the reduction in rish after smoking cessation may differ by age at cessation. Wynder and Stellman ( 1979) reported that the reduction in risk after cessation was appreciably greater for people aged 50 to 6Y than for those 70 or older. However. only data for those aged SO to 69 were presented in this publication. Pathak and associates (1986) also reported a strong interaction between age and duration of cigarette smohing. Risk of lung cancer among ex-smokers was compared with that of current smokers with adjustment for the amount smohed. For ex-smokers less than 65 years of age. the estimated relative risks compared u ith current smokers declined to 0.39. 0.14, and 0.06 for 5. IO. and 20 years of smoking abstinence. respectively. For those aped 65 or older. the corresponding estimated relative risks were 0.73.0.54. and 0.29. respectively. These two studies suggest that the risk of lung cancer may decline less steeply with increasing abstinence for older ex-smokers. Multistage Modeling Multistage models provide a conceptual framework for facilitating understanding of the relationship of lung cancer incidence with amount smoked, duration of smoking. and time since cessation. These models. proposing theoretical constructs of fundamen- tal biologic mechanisms. have been useful for evaluating epidemiologic data in a biologic framework and thereby furthering the understanding of tobacco carcino- genesis. However, fitting these models to epidemiologic data cannot establish the veracity ofthe underlying biologic theory. Multistage modeling approaches have been used to describe respiratory carcinogenesis and to assess smoking cessation and lung cancer risk. Although a number of different mathematic models of carcinogenesis have been proposed (e.g.. two-stage. multicell, multistage). this discussion primarily ad- dresses the Armitage and Doll (1954. 1957) multistage model, which has been used most extensively in studies of lung cancer. Based on a series of studies examining age-specific mortality rates for various cancers. Armitage and Doll (1954. lYS7) proposed a multistage theory of carcino- genesis. Their model assumes that a single cell can generate a malignant tumor only after undergoing a certain number of genetic changes. Animal studies also support the multistage model. Multistage theories also predict the age pattern of occurrence of many tumors induced in experimental animals by continuous exposure to chemical carcinogens. Experimental regimens involving initiation and promotion provide direct evidence of the effect of early- and late-stage events in the carcinogenic process (Stenback. Peto. Shubik 198la.b.c). Using data from the British Physicians Study,. Doll (197 I ) showed that when the incidence of lung cancer in cigarette smokers was plotted against duration of smoking. incidence increased approximately in proportion to the fourth powerofduration. similar to the slope of the regression line when incidence in never smokers is plotted against age (Figure 3). Thu\. a first-stage effect uas implicated because the excess lung cancer risk among smokers increased with the same power of duration of smoking as the risk with ape among never smokers. Moreover. the lung cancer mortality rates among ex-smoker:, decreased someu hat initially and then increased ,Iowly in beeping with the increase in rish among never smohers vv ith age (Doll I97 I ). Armitage ( 197 I) noted that the stabilir.ation of excess lung cancer risk at the level when smoking stopped suggested that smoking also affected a late stage. namely. the penultimate stage in the carcinogenic process. Day and Brown (IYXO) conducted a detailed analysis of the pattern of change in cancer risk after cessation of an exposure. The results supported the Arnmitage-Doll model. In addition. Day and Brown proposed that the stage affected by the agent and the relative magnitude of the effect of the agent on early and late stages of the carcinogenic process are critical in the determination of risk subsequent to cessation of an exposure. To quantify the magnitude of smoking et'fectj on the two stages. Brown 1,000 100 10 1 X-X Cigarette smokers by duration of smoking x ---a# Cigaretie smokers by age .-. Never smokers by age I I I I I I I 20 30 40 50 60 70 80 YEARS FIGURE 3.4ncidence of bronchial carcinoma among continuing cigarette smokers in relation to age and duration of smoking and among never smokers in relation to age, double logarithmic scale SOCRCE Doll c I')7 I), xlth LO~XC~K~ (11 prIntin; ~`rrw m the w~yn,d figure and Chu ( 1987) reexamined data on ex-smokers from the European case+zontrol stud) of lung cancer (Lubin et al. lOX4a) and concluded that smoking had an almost double relative effect on late-stage events compared with first-stage events. Using data from a case within the framework ofthe two-mutation. recessive oncogenesis model. Ba\ed on this model. the second-mutation rate would be affected by \mohing. and a sudden decline in risk after cessation of smohing v.ould be predicted. HoNever. this model implies that smoking affect\ the last stage in a multi$tape process. contrary to current con\ider:t- tions. In summary. multistage models have been used to describe the interrelationships among number of cigarettes smoked dail>. duration. time \inctz e\posurr ended. and lung cancer incidence. Several In\,c\tigators hale interpreted the data on rish among former smokers in different ~a> \. The epidemiologic data clearI> indicate that the rish among former smohers i\ between that of continuin, (1 smoher\ and nekrr smohers. Various models can be fit to the different data ~1s. The expected pattern ofrith among former sniohers is sensitive lo the model \clectrd and dependent on the relati\ e magnitude of the effect of smohing on earl> \ er\u\ late stage\ of the proces\ ot carcinogenesis. Lsing multistage models. the data on t.ormer smohcr\ are insufficient to allow precise quantification of the relati\ c cffcct\ of \mohin, 0 on the earl\ and late stages of the carcinogenic proce\\. H hich smokin, (7 i4 assumed to affect. Ne~ertticle\\. data indicate that \mohing ha\ an dt'cct on the late \tagt'\ of the carcinogenic proce\c and that cessation reduce\ lung cancer occurrcncc. Cessation After Developing Disease Individuals who stopped smoking are not a randomly selected group in most studies (Chapter 2). Often. smohers quit as a result of developing symptoms of a life- threatening disease or immediately after diagnosis of cancer. This phenomenon is ev id,enced by the increase in risk of lung cancer in the immediate period after cessation. Sotne studies have grouped these former smokers with the continuing smohcrs or have excluded them from the analysis. A few epidemiologic studies have assessed the risk of lung cancer among those who quit for health reasons and for non-health-related reasons. In the U.S. Veterans Study. about 10 percent of the smokers quit because of a doctor's orders: these smokers here presumably ill. The lung cancer mortality ratio relative to never smohers for es- smokers who stopped because of non-health-related reasons MLIS 3.43 compared with 5.83 among ex-smohers who stopped on a doctor's orders and X.98 among continuing smohers (Kahn 1966). In the European case-control study. Brown and Chu ( I YX7) reported that the relative risk of lung cancer for those who stopped smoking because of health reasons compared with those who stopped for reasons other than health uas 1.3 (p?I erg/da\ q/da\ 7.4 i-l.3 Y I 19.5 7 Y 11.6 I .(I Y. I I .5 SY 1-l 26 extent. performance status. and type of protocol treatment. Similarly. statistical sig- nificance was maintained after simultaneous adjustment for both thbmosin and radia- tion therapy. The study b> Bergman and Sorenson ( IYXX) involved 153 small cell lung cancer patients who received combination chemotherap>. Thirty-two had stopped smohing at least 6 months before the initiation of treatment or had ne\`er smoked. 51 patients stopped smoking less than 6 months prior to the start of treatment. and 71 patients continued to smoke during the treatment period: the median survival was 39. 42. and 30 weeks. respectively. Reasons for differences in results betbeen the two studies are not clear. Overall. patients in the study hy Bergman and Sorenson ( 1988) had smoked fewer pack-years. but the median survi\,al and performance status of each of the three 130 smoking status groups were poorer than for the comparable smoking status groups in the study by Johnston-Early and associates ( 1980). LARYNGEALCANCER Pathophysiologic Framework Smoking has been firmly established as a cause of laryngeal cancer (US DHHS 1982. 1989) based on numerous epidemiologic studies. These studie, have employed diverse methodologies and have been performed in different countries and covered various time periods. Tobacco smoke exposure has been measured by number of cigarettes smoked per day. number of years of smoking, age when started to smoke, type of cigarettes smoked. and depth of inhalation (US DHHS 1982). In the larynx, as in the bronchus. a sequence of histologic changes occurs with continued smoking. These changes progress from cells with atypical nuclei. to car- cinoma in situ. to invasive carcinoma. Autopsy studies show that recovery of the laryngeal epithelium can follow smoking cessation. Auerbach, Hammond. and Gar- finkel (1970) studied postmortem specimens of laryngeal epithelium from 942 men (644 current cigarette smokers, 94 cigar and/or pipe smokers, I I6 ex-cigarette smokers. and 88 never smokers). Ex-smokers in this study had stopped smoking for at least 5 years. Compared with current smokers, ex-smokers showed fewer histologic changes: 75 percent of ex-smokers and never smokers showed no cells with atypical nuclei. whereas almost all current smokers showed some cells with atypical nuclei. Similar findings were reported by Muller and Krohn ( 1980). who obtained laryngeal epithelial specimens from autopsy. Of the 148 cases in the study. 24 were never smokers and 24 were ex-smokers who had stopped smoking for at least 5 years. Table 8 shows the relative distribution of selected histologic features by smoking status. Occurrence of all histologic changes was lowest among never smokers, intermediate among ex-smokers, and highest among current smokers. However. the histologic findings of ex-smokers in this study were more similar to those of light current smokers (I0 I IO 3.11 2.x I .o Y.5 7.2 I .o 7.x (1.3 Malt\ I~cnl;tle\ I .o I .o 17.x Y.5 (7.7 6.5 I .o 0.0 3.2 (`lg/d;l) II 70 `I 30 31 40 >40 3.0 J.(I 72 0.Y I.2 I .I) .3 I 3.5 TABLE 9.--Continued `l`U> II\ ct XI (IYXX) Former vnoher\ (yr \incc 4loppetl) I-3 44 7-10 II-15 >Ih Cutrent wider\ Never w~oher\ Relative risk\ Malea 17.9 8.5 3.0 3.4 1.5 I4 3 I .I) Female h.Y 2.6 - X.X I1.h I .o Entlolnry nx I .5 I CONCLUSIONS I. Smohing cessation reduces the risk of lung cancer compared M ith continued \moh- ins. For example. after 10 years of abstinence. the ri\h of lung cancer is about 30 to 50 percent of the rish for continuing smokers: with further abstinence. the ri\h continue\ to decline. 2. The reduced risk of lung cancer among former w~ohers i\ oh3erved in male\ and females. in smokers of filter and nonfilter cigarette>. and for all histologic types of luns cancer. 3. Smohing cessation lower\ the risk of larynyxl cancer compared with continued smoking. 1. Smohing ce\\ation reduce\ the severity and extent of premalignant histologic changes in the epithelium of the larynx and lung. References ALDERSON, M.R.. LEE. P.N.. WANG. R. Risks of lung cancer. chronic bronchitis. ischaemic heart disease. and stroke in relation to type of cigarette smoked. .lou/.rwl of E/?/d'nriolo,~~ trrrtl Con7/777//7i7~ Hcr~ltlr 3Y(4):2Xh-293. December 1 YXS. AMERICAN CANCER SOCIETY. Unpublished tabulations. ARMITAGE. P. Discussion on paper hy R. Doll. .lorrr-/rt/l of 7hc R(JJU/ S~c17i.s//c~c/I Soc.ret?. A134:155-156. 1971. ARMITAGE. P.. DOLL. R. The age distribution of cancer and a multi-stage theory of carcinogenesis. British ./07//77~1/ c$Cu/7wr 8: l-l I . 195-t. ARMITAGE. P.. DOLL. R. A two-stage theory of carcinogenew in relation to the age distribution of human cancer. B/-iris/7 .lor/r/7ct/ ofC~w7wr I I : I6 I-164,. 19.57. AUERBACH. 0.. GARFINKEL. L.. HAMMOND. E.C. Relation of smoking and age to findings in lung parenchyma: A microscopic study. Cl7cw 6% I t:2Y-35. January 1974. AUERBACH. 0.. GERE. J.B.. FORMAN. J.B.. PETRICK. T.G.. SMOLIN. H.J.. MLIEHSAM. G.E.. KASSOUNY. D.Y.. STOUT. A.P. Changes in the bronchial rptthelium in relation to smoking and cancer of the lung. .4 report of progress. i%`crc, h~ltrr7rl .lortr~7t/l of Merlic~i/rr' 256(3):97-104. January 17, 1957. AUERBACH. 0.. HAMMOND. E.C.. GARFINKEL. L. Histologtc changes m the larynx in relation to smoking habits. c`crww 2S( I ):92-10-l. January 1970. AUERBACH. 0.. HAMMOND. EC.. GARFINKEL. L.. BENANTE. C. Relation of smoking and age to emphysema. Whole-lung section stud!,. Nc,i\, E/7,g/tr/7cl .lor/r/7trl c!f Medic 717~ 2X6( 16):853-X57. April 70. 1972. AUERBACH. 0.. STOUT. A.P.. HAMMOND. EC.. GARFINKEL. L. Changes in bronchial epithelium in relation to sex. age. residence. smoking and pneumonia. R;rzic, E/7,~/o/7cl./o7//./7ol of`Mcdic~i/7r 267(j): I I l-l 25. July 19. I Yh'a. AUERBACH. 0.. STOUT. A.P.. HAMMOND. E.C.. GARFINKEL. L. Bronchial epithelium in former smokers. Nw E/7q/c//7d ./oI//~/~LI/ ~!f'MedicY/~e 267t3 ): I I Y- 125. July I Y. 1962h. AUERBACH. 0.. STOUT. A.P.. HAMMOND. E.C.. GARFINKEL. L. Smoking habits and age in relation to pulmonary changes. Rupture of alveolar septums. fibrosis and thickening of walls of small arteries and arterioles. hicu E/7,~/o/d Jorr7~/7c// of'M~dki/7c 269(X)): 103% 1054. November 14. 1963. AUERBACH. 0.. STOUT. A.P.. HAMMOND, E.C.. GARFINKEL. L. Interrelationships among various histologic changes in bronchial tubes and in lung parenchyma. An7er~ic~tu7 Ke\~ie~. r!fRes/)i~u/or.~ Discuw 90(6):867-X76. December 1964. BENHAMOU. S.. BENHAMOU, E., TIRMARCHE, M.. FLAMANT. R. Lung cancer and use of cigarettes: A French case-control study. Jorrr-/7u/ of the NuI~o/~u/ Cufrt CI lux7i717t~ 74(6):1169-l 17.5. June 19x5. BERGMAN. S.. SORENSON. S. Smoking andeffect ofchemotherapy in small cell lung cancer. 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The c;~u\es of lung cancer in Louisiana. In: Il~/ell. M.. Correa. P. (ed\.) Ll//+! ctnrc~c~r' C~/rc.\l~.\ ~111d Pi-c,1 l'/rfi/vr. P,-rlc~cc~/l~r~~.c ~lf`llrr~ Ilrrc~r~lrtrri~ltl~,/ LWI' C`rllrc-c,r L'/,clt/rc~ C~/tfi'w~~c.c, Ncu Orleans: Verlq Chcmic International. Inc.. 19X-l. p. 73. DAUBER. L.A.. LARSSON. L.G. Smohing and lung cancer utth special refxd to t!Je of smoking and type ofcancer. A c;tv--controI study in north Sv.eden. B,-iri\/,./or,r-,tcl/ofCo,rc (`I 535 ,:673-6X I. May 10X6. DAY. N.E. Epidemiological data and multistage carcinopenc\i\. In: Btirrsonyi. M.. Lapi\. K.. Day. N.E.. Yama\ahi. H. (edz.) Mc~t/c/.\. Mc,c~/rc/~~i.\/r/v t/lx/ Erio/o,p\. of' 7ltnlcw Proruo/io/r. Lyon: IARC. lYX5. pp. MY-357. DAY. N.E.. BROWN. C.C. Multt\tage model\ and primary pro cntton of cancer. ./ow~rtr/ ot t/w R;tr/io/rtr/ Ctrrtc w //t\/iro/c f&1):977-YXY. April I YXO. DEVESA. S.S.. BLOT. W.J., FRAUMENI. J.F. JR. Decltning lunp cancer totes among )outy men and \%omen tn the United State\: .4 cohort analysk ./c~rrrw/ off/w ,Vr///orw/ Cr/,rc.c,v /usrirt/fc~ X I : 156X- I 5 7 1 . I YXY. DOLL. R. The age distribution of cancer: Implication\ for model\ ofcarctnogenest~. ./rjr,r/~r// of'rtw Roy// .Srtr/r.\rrc~r// .Soc~icv,v A 131: 133-l 66. I97 I DOLL. R.. GRAk'. R., HAFNER. B.. PETO. R. Mortalit> in relatton to \mohtnf: 22 bear\` obwvation\ on kmale Britt\h doctor\. HI-I/;\/I .Wc,c//c c//./c~r//./rc// 2X0(62 lY):Y67-Y7l. April 5. IYXO. DOLL. R.. HILL. A.B. Mortality tn rclatwn to wtohing: Ten years' ohvrvation\ of British doctor\. Bvrrrsl~ Mcv//w/ .torowl I : I iYY-I-I IO. Ma) 30. I YhJ. DOLL, R.. PETO. R. blortality in relation to wiohin2: 20 yearh` oknations on male Britirh doctor\. &rri.sh Mrclic,ol .I~~rrm// 2: 1525% 1536. Dwemtw 25. I Y76. DOLL. R.. PETO. R. Cigarette \tnoking and bronchial carcinom;t: Do\e and time rrlattonhhlp\ atnonp regular wloher\ and lifelong non-moherz. ./owrttr/ c,f'E/,iclc,t,rr~j/,~~~, oml C~~w~~~~~~r\ Hctrlflr 31(1):303~3 13. December lY7X. ELWOOD. J.M.. PEARSON. J.C.G.. SKIPPEN. D.H.. JACKSON. S.M. Alcohol. smoking. wcial and occupational factor\ in the ac`tiology ot`cancerofthe oral ca\ It!. phar! nx and lar> nx. /,ttc~,.trt/tio/f[// .toromr/ ~~t'(`rr/lc~cv~ 31:6034 12. I YX1. FALK. R.T.. PICKLE. L.W.. BROWN. L.M.. !vlASON. T.J.. BUFFLER. P.A.. FRAUMENI. J.F. JR. Eftrct ofmohtn? and alcohol conwmption on lar). nseal cancer rt\h m co;t\tal Tc`u\. Ccr,rc,c>/. Rcsc,trr.c /I -!Y( I-l 1:-10211O'Y. Jtil! 15. I YXY. FARBER. E. The multtxtep nature of caner de\elopmwt. Cw( (`I' Kcccwj-c II 11:12 171223. October 19X-1. FLAbDERS. W.D.. ROTHMAN. K.J. Interaction of ;Ilcohol and tobacco in larl,n~~al c;Lnct'r. Anwit UII ./mmtr/ ,!l'E/~iclc,,trro/c,~?. I I& 3 ):37 I-i7Y. March I YX2. FREEDMAN. D.A.. NAVIDI. W.C. `vlulti\tuge model\ for carcinogencsi\. E/lr,f,-o,crlrc,rlro/ Hcwlrlr Prr-.\/w/i\ c\ XI : 169-l XX. May IYXY. GAFFNEY. M.. ALTSHULER. B. Exammatton of the role of cigarette mohc tn lung carcinogenesk u\tng multi\tage model\. .tltro-llc/t lff r/w rVr/rioll1/l COIli ('I' /ll.\rl/lrrc~ X0( 12):Y25-Y3 I, Augu\t 17. I YXX. GAO. Y.T.. BLOT. W.J.. ZHENG. W.. FRALMENI. J.F.. HSI'. C.W. Lung cancer and smohtnp tn Shanghai. //~rc~~~tftrr/o~rc//./or~~~~~o/ of E/Gc/c'r)lro/oq\. 17(21:277-2X0. June I YXX. 13X GARFINKEL. L.. STELLMAN. S.D. Smoking and lung cancer in women: Findings in a prospective study. Cuticer Rescc~rc~/t 48(23):695 I-6955. December I. 1988. GRAHAM, S.. LEVIN, M.L. Smoking withdrawal in the reduction of rish of lung cancer. Cancer 27(4):865-87 1. April I97 1. HAENSZEL. W.. LOVELAND. D.B.. SIRKEN. M.G. Lung-cancer mortality as related to residence and smoking historic\. I. White males. ./orrrxu/ of'rhc, Nutir~tinl Ca,rc~o- //rsrrf(((c~ 28:947-1001. April 1962. HAMMOND, E.C. Smoking in relation to the death rates of one million men and women. In: Haenszel. W. (ed.) El'idf,nlio/o~~;t,u/ Approtrc~tre.r I,J r/w Strtr!\ c!f'Cur~t~er (I/U/ Other Chrrvrrc~ Diseuws. NC1 Monograph 19. U.S. Department of Health. Education. and Welfare. Public Health Service. National Cancer Institute. January 1966. pp. 127-203. HIGGINS, 1.T.. WYNDER. E.L. Reduction in risk of lung cancer among ex-smokers with particular reference to histologic type. C'ar~c~rr 62( I I ):2397-2401. December I. 19x8. HIGGINS, I.T.T.. MAHAN. C.M.. WYNDER. E.L. Lung cancer among cigar and pipe smokers. P wI.eufi\,e Meclrr i/w 17( I ): 1 I61 28. January 198X. JOHNSTON-EARLY. A.. COHEN, M.H.. MINNA. J.D., PAXTON. L.M.. FOSSIECK. B.E. JR.. IHDE. D.C.. BUNN. P.A. JR.. MATTHEWS, M.J.. MAKUCH. R. Smoking abstinence and small cell lung cancer survival. ./or(/./rol c!t r/tc ilntc~r-rc~tr~~ M~~tl/c~u/ 4.\.xo( i&w 244( I9):2 175-2 179. November 14. 19X0. JOLY. O.G., LUBIN. J.H., CARABALLOSO. M. Dark tobacco and lung cancer in Cuba. ./arc/xc// c![rltc Nu/iomd Crrrrc,er Instit~r~e 70(6): 1033- IO.39. June 1983. KAHN. H.A. The Dom study of smoking and mortality among U.S. veterans: Report on etsht and one-half years of observation. In: Haenszel. W. (ed.) Et~iclet?~ir~/o,~ic~cr/At~t~,~ouc~hes 10 /kc Slur/~ of Cum er uful C)flw~- Chronir Di.wuse.c. NC1 Monograph 19. U.S. Department of Health, Education. and Welfare. Public Health Service. National Cancer Institute. January 1966. pp. I-12.5. LUBIN. J.H.. BLOT. W.J. Assessment of lung cancer risk factors by histologic category. ./ofrrrrc~/ r!j'fhe Nutinfiol Currt,t,,. //l.stitlctr 73(2):383-389, August I%-?. LUBIN. J.H., BLOT, W.J., BERRINO. F.. FLAMANT. R.. GILLIS. C.R.. KUNZE. M.. SCHMAHL. D., VISCO. G. Modifying risk of developing lung cancer by changing habits of cigarette smoking. Brifixh Medicd .lmrr7o/ 28816435 ): 1953-l Y.56. June 30. 1984a. LUBIN. J.H.. BLOT, W.J.. BERRINO. F.. FLAMANT. R.. GILLIS. C.R.. KUNZE. M.. SCHMAHL, D.. VISCO. G. Patterns of lung cancer rish according to type of cigarette smoked. Irtterrintiorrcrl ./oitrxal c!fCur~( (`I- 3:569-576. I984b. LUBIN. J.H.. RICHTER, B.S.. BLOT. W.J. Lung cancer risk with cigar and pipe use. Jor~mrrl ofthe Nurior~ul Corrcx~r. lnsrirrtre 73(2):377-38 I. August 19X-t. MCDOWELL. E.M.. HARRIS. C.C.. TRUMP, B.F. Histogenesis and morphogenesis of bronchial neoplasm. In: Shimosato, Y., Melamed. M., Nettesheim. P. (eds.) Mo,l7/1~?gc'"psi.(;.~ of'Lttrt,q Cartc,o.. Volume I. Boca Raton. Florida: CRC Press. 19X2. pp. I-36. MOOLGAVKAR. S.H.. DEWANJI. A.. LUEBECK. G. Cigarette smoking and lun,g cancer: Reanalysis of the British doctors' data. .Ioi(/xul r$(/tc, No/io,~c// Ctrjrc e/' //r.srinrrc 8 I (6):-l I5- 420. March IS, 198'). MULLER. K.M.. KROHN. B.R. Smoking habits and their relationship to precancerous lesions of the larynx. JOI(J-iitrl of Cuii(,ei. Rcvror.c,h trntl Cliiric UI Oiic~o/o,q~ 96(2):2 I l-217. IYXO. OLSEN. J.. SABROE. S.. FASTING, U. Interaction of alcohol and tobacco as risk factors in cancer of the laryngeal region. ./otoxc~l c!f`El'ic/c,nfir,/o,~~ tr& Conrnr(oiiry Hdtl~ 39(2 ): I65- 168. June 1985. PATHAK. D.R.. SAMET. J.M.. HUMBLE. C.G.. SKIPPER. B.J. Determmants of lung cancer risk in cigarette smokers in New: Mexico. .Ir~icrxc~/ of'tlu~ Ntrriorrnl C`trrrcx~r Iiistitrirc 76(3):5Y7- 604. April 19X6. PETO. J. Early- and late-stage carcmogene\is in mouse \kin and In man. In: BGrzs(inyi. M.. Lapis, K.. Day. N.E.. Yamasaki. H. (rds.) .Mr&/.\. Mc~c./l~/~~/\nl.c t/)1(/ &tirj/o,yx of' 7rrn,olr,. Pwnrorio~~. Lyon: IARC. 1 YXI. pp. 33%370. PHILLIPS. D.H.. HEWER, A., MARTIN. C.N.. GARNER. R.C.. KING. M..M. Correlation of DNA adduct levels in human lung with cigarette smoking. !%`c/ntr.e 336(6101 ):790-792. December 2?-2Y. IYXX. RANDERATH. E.. MILLER. R.H.. MITTAL. D.. AVITTS. T.A.. DUNSFORD. H.A.. RANDERATH. K. Covalent DNA damqe in tissues of cigarette smohers as determined hq "`P-postlabeling assay. ./o/r,-,ro/ c!f rhc, ,v"lc!tioflcl/ CUII(.LJI. //~.srj!ll/c 8 I (5):3-l I-337. March l 19X9. ROGOT. E., MURRAY. J.L. Smoking and causes of death among U.S. veterans: I6 years of observation. P~rhlic, Hculth /?q~~~/`~.s Y5(3):2 13-227. May-June 1980. SACCOMANNO. G.. ARCHER. V.E.. AUERBACH. 0.. SAUNDERS. R.P.. BRENNAN. L.M. Development of carcinoma of the lun, 17 as reflected tn exfoliated cells. Ctr,rcc/. 3 I ( I ):256-270. January 1971. STENBACK. F.. PETO. R.. SHUBIK. P. Initiation and promotion at different ages and doses in 7200 mice. I. Methods. and the apparent persistence of initiated cells. &.itr.slr Jolrj./lu/ of Co/1~~c/~44(1):1-13.July 198la. STENBACK. F.. PETO. R.. SHUBIK. P. Initiation and promotion at different ages and doses in 2100 mice. Il. Decrease in promotion bv TPA with age&g. B/.irich ./o~rr!,o/ (!/`Co!rc,~r. 44(l):]%`3.July IYXlb. STENBACK, F.. PETO. R.. SHUBIK. P. Initiation and promotion at different ages and doses in 2200 mice. III. Linear extrapolation from high doses may underestimate low-dose tumour risks. R/?risll Jorrr./itil of'Cojlc,cj,- W( I ):21-31. July I9X Ic. TUYNS, A.J.. ESTEVE. J.. RAYMOND. L.. BERRINO, F.. BENHAMOU. E.. BLANCHET. F.. BOFFETTA. P.. CROSIGNANI. P.. DEL MORAL. A.. LEHMAKK. W.. ET AL. Cancer of the larynx/hypopharynx. tobacco and alcohol: IARC International Case-Control Stud) in Turin and Varese (Italy). Zaragoza and Navarra (Spain). Geneva (Swnzerland) and Calvados (France). /,~rc'i.,~atio,lrr/ Jr)ro.,ltr/ of Ctr,,c,cl~- 4 I1J):4X3--20 I . April 15. 10x8. U.S. DEPARTMENT OF HEALTH AND HUM?rN SERVICES. Tllr Hcwlth Co,t.~eyrre/l(.r.s oj Snlokiq: CU~~C~O~. ,4 Kcy~,.t ,~t rlrc, .SII~C~O/~ &,~c/-~r/. L1.S. Department of Health and Human Services. Public Heath Service.Officeon Smohlng and Health. DHHS Publication No. (PHS, x2-50179. 19x2. U.S. DEPARTMENT OF HEALTH .4ND HCM.4N SERVICES. 7-/r<, Heulth C~,rr.\cc/ltolc,c,s of SnloXlrl,~.~ cIiwflic~ oh.\rrlct Ill`l' LlfU~ ni.\tYrw .A Rq""/ 1!/' /AC Sfrrywi Gcvlcv~tr/. U.S. Department of Health and Human Sen ice\. Public Health Serb ice. Office on Smokmg and Health. DHHS Publication No. (PHS) XJ-50205. IYXI. U.S. DEPARTMENT OF HEALTH r\ND HL'M.4N SERVICES. 7-11~~ Hctrlrl7 Co/l.\c,c/lrc,/lc,c,.\ of ImYdrorrrri~~ .stm~Aiu~. .4 Rt~/`fw/ cq r/w Sfri-,~l~~Jll GcrIc~rtrl. 1'3. Department of Health and Human Services. Public Health Sen ice. Centers for Disease Control. DHHS Publication No. ,CDC j X733YX. 19X6. U.S. DEPARTMENT OF HEALTH AND HC`XIAN SERVICES. Reclrrt ir,y //,c H~lrh Come- ~pm C.S 0f` .Snd~t~~ 2.5 ~~cw-.s of' PuJ:`I-CV. .4 Rrp/-t of //fly Sfrrqcwrl Grw,u/. U.S. Department of Health and Human Senlces. Public Health Senice. Centers for Disease Control, Center for Chronic Di\es\e Prevention and Health Promotion. Office on Smohins and Health. DHHS Publication No. (CD0 X9-X-II I. 19x9. U.S. DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE. Sn,oX~rq (11r~/ Hrc~lrh il Report c!frlrp S~lqco/l &,r~c?rz~/. U.S. Department of Health, Education. and Welfare. Public Health Service. Office of the Assistant Secretary for Health. Office on Smoking and Health. DHEW Publication No. (PHS) 79-50066. 1979. 140 U.S. PUBLIC HEALTH SERVICE. S,voX/,i,q tr/rt/ H~wlrh. Rc/~~wI of I/W AC/I isor:\. Cor~rnrirrc~c~ lo /Iw S~rr.qvcw <;c,wrx/ cd r/w P~rh//c, Hctrlrlr .Sc/-r~/c~c. U.S. Department of Health. Education. and Welfare. Public Health Scn~ce. Center for Disease Control. PHS Publication No. I 103. 196-I. WHITTEMORE. X.S. Effect of cigarette smohing in epidemiolofical \tudle\ of lung cancer. Sttrfrstic .< 111 Mcvlic~//rt~ 7( I-2 ):223-23X, January-February I OXX. WIGLE. D.T.. M.40. Y.. GRACE. M. Relative importance of \mohing ;I\ a ri\k factor for selected cancers. C`o,rtrmohing cehhation. and thu\ comparison\ olri\h berireen current and former smoker\ map' he conf'ounded b>, alcohol consumption (Chapter I I 1. In three investigation\. the effect of smoking ce\hation w;t\ examined and past alcohol coti- \umption was controlled by multiple logistic regression (Blot et al. IYXX: Kabat and Wjnder IYXY: Kabat. Hebert. Wynder IYXY ). In the three htudics. estimate\ ol`relatt\e ri\h\ t'or both current and t'onner hmoherh were similar to those observed in studies in which alcohol was not included ;I> an adjustment factor. The stability of the relative rich estimate\ for stnohing with adjustment for alcohol intahe suggests that alcohol doe\ not substantially confound the relationship befueen oral cancer ri\h and cigarette smohing status and that the lower risk of former smohet-\ cannot be explained b> lower levels ofalcohol consumption (Chapter I I ). One stud) was sufficiently large to permit detailed stratified analysis of the modification of the smohing effect by alcohol consumption (Blot et al. 198X). In thi:, study. former smoher\ were observed to have a lower risk than current smohers for both men and women at each of five levels ofalcohol consumption. The U.S. Veterans Study (Kahn lY66) demonstrated that at each of three levels of past cigarette smoking exposure. former smokers had lower rich of oral cancer than did current smokers. Kabat. Hebert. and Wynder (IYXY) controlled for past cigarette exposure by tnultiple logistic regression and found that relative rihk estimates. which were adjusted for past alcohol and cigarette consumption. did not difftr from the crude estimates for fortner smohers ( 1 .O vs. 1 .O relative to never smohers). Second primary cancers of the mouth and pharynx occur commonly in person\ v. ith an initial primary cancer in the mouth. pharynx. or larynx. Several studie\ ha\,e addressed the incidence ofhecond primaries ofthe mouth. pharynx. or larynx in relurion to smoking status after diagnosis and treatment of the first prima-\. The finding\ ot these studie\ are inconclusive. w)ith some indicating reduced rihk of a second primq af'ier cessation (Moore lY65; Moore 1971: Wynder et al. 196Y: SiI~erman. Gorshb. Greenspan 19X3) and others showins no clear benefit of cessation (Castigliano IYhX: Schottenfeld, Gantt. Wynder IY71: Chapter 5. 5ee section on blultiple Pi-imaE. Cancers). The result\ of t&o studies indicated that continued \mohinp after diagnosic of oral cancer may reduce survival. particularly in combination with alcohol consumption (Johnston aid B;tll;tntyne I Y77: Stevens et al. 1983 ). These analyses. however. did not aci.iu\t for the tnore advanced stage of cancer among u$cr\ of alcohol and tobacco at presentation (Johnston and Ballantynr 1977). The rehulth of studA of oral cancer and cigarette smoking cessation indicate that former smohers experience ;I lower ri\h of oral cancer than current hmohers and that this lower rish does not appear to be ;I result of confounding by alcohol or level of cigarette consumption prior to ces4on. The rish of oral cancer has been shoun to drop substantially within 3 to 5 years ofce\sation. Esophageal Cancer Smoking i4 a major cause of esophageal cancer (US DHHS 1981. 19X9). In the United States. the proportion of esophageal cancer deaths attributable to tobacco has been estimated to be 7X percent for men and 75 percent for women (US DHHS 19X9). .A5 for cancer of the oral cu\,ity. cigarette smoking is an independent risk factor for esophageal cancer but can also act in conjunction with alcohol to increase cancer risk. Table 7 summarixe~ the studie\ that have esatnined the relationship between smoking cexttion and esophageal cancer rish. In these studies. the risk of esophageal cancer for current stnoher\ range\ from I .7 to 6.4 titnes the risk among never makers (median of approximateI> 5). These tindinfs are Gmilur to those for oral cancer as shown in Table I. The risks for \mohinf and esophageal cancer uere similar among male\ and females. Three year\ after cessation. former smohers sho\sed lower ri\h\ than current smoher\ in each study summarized in Table 2. \sith the exception of the Swedish prospective \tud\; (Cederlofet al. 1 Y75) in M hich mohin, -associated risk\ were considerabl\ IOU er than in any other stud). tio\\ever. in follo~up of this cohort. more dramatic elevarionx in tnale mortalit> from s\ophageal cancer uere ohser\txi in current \moker5 relative 10 never mohcrx standardized mortalit! ratio\ were I I for I to 7 2 tobacco per ci;t~. 4.5 for X to I5 g tobacco per &I> . arid 5.4 for more than I5 g of tobacco per da (Car\ren\en. Pershqen. Ehlund 10X7). For fomxr moherh. the st;tndardi/ed mortality ratio ~34 I .i. Approximalel> 3 to 5 bear\ after ces\;ttion. rish ol'e~phngeal cancer ua\ reduced hq approximatcI> 50 percent in the t\\o \tudie\ ptxxtdin, (7 information b> duration of ahtincnce (Table 2 I. Data are \ er! \cmt about the effect\ of cesation on the ri\h ot esophafc~il cancer o\er long period\ of abstinence. The L'.S. Veteran\ Stud) shoued that the ri\h among former \mohrr\ \<;I\ lo\+c'r at each of four le\,els of pat number\ of cigarette\ 3mohcd per da>. A multivariate anal> \i\ in whtch Itfetime alcohol consumption M ;I\ irxluded ;I\ an adjustment factor (La Vecchia. Liati el al. IYX6) produced relati\ e ri\h\ for current and former \tnoher\ that \bcre similar IO those oh\er\ed in other \tudie\. In thi\ \tud!. the crude relative ri\h f'or ex-smohcrs LIH\ nexl! identical to one that ~34 xiju\ted for alcohol con\utnption (2.7 \\. 3.01. u,, \ ocTe\tiiig that ~rlcohol u:ih not 3 confounder in the estimates of the benefits of cc\\ation. X \tud\ that ~a'r limited to nondrinher~ (La Vecchia and Negri I YXY) ;tIw produced rish estimate\ for \mohiq that aerc \er! 152 TABLE 2.-Studies of esophageal ranter that have examined the effect of smoking cessation TABLE 2.--C'ontinued similar to those derived from other studies. supporting an earlier observation of elevated risk for esophageal cancer in nondrinking smokers (Tuyns 1983 ). This review of past research on esophageal cancer and cigarette smoking cessation indicates that former smokers experience a lower risk of esopha_peal cancer than do current smokers. and that this lower risk is not because ofconfounding by lower alcohol intake among former smokers. Pancreatic Cancer The association. noted for many years. between smoking and cancer of the pancreas is considerably weaker than that between smoking and oral or esophageal cancer (US DHHS 1982). Although the causal mechanisms underlying this association are unclear. smoking has nonetheless been regarded as a contributing factor in cancer ofthe pancreas (US DHHS 1982. 1989). In the United States in 19X5. the proportion of pancreatic cancer deaths attributable to smoking has been estimated to be 29 percent in men and 33 percent in women (US DHHS 1989). Table 3 summarizes studies of the relationship between pancreatic cancer and smoking cessation. In these studies, current smokers had risks ranging from I .O to 5.3 times (median of approximately 2) the risk among never smokers. Risks for pancreatic cancer associated with smoking were similar for males and females. Former smokers generally had lower risk than current smokers for pancreatic cancer. but the available data do not characterize adequately the change in risk with duration of abstinence. The large caseZ!O 70 NP risk of pancreatic cancer than current smokers. This diminution of risk with abstinence serves to strengthen the hypothesis that smoking is a contributing cause of pancreatic cancer. Although alcohol does not appear to be a confounder in the assessment of the benefits of smoking cessation. the possibility of confounding by other factors. \uch as diet or amount of prior cigarette consumption. has not been adequately studied. Bladder Cancer As with pancreatic cancer. the relationship between bladder cancer ri\h and smoking has been noted for many years. However. because relative rish\ have not been great]) elevated and because of uncertainty about the effects of unidentified confounding factors in this disease. the causality of this association haj been considered less certain compared with other diseases in earlier reports of the Surgeon General (US DHHS 19X2). Smoking has nonethelec\ been regarded a\ a contributing factor in bladder cancer: in 1985, it was estimated that in the United State\ 17 percent of bladder cancer deaths in males and 37 percent in females are attributable to smohinp (US DHHS lYX9). A particular problem with causal inference in smokin, CT and bladder cancer arise\ because of the inconsistent finding of clear exposure-response relationship\ in all studies. as has been observed between cigarette smoking and respiratory cancers. However. the usual measures of exposure to tobacco smoke may not accurately index the bladder's dose of tobacco-related carcinogens. The International Agency for Research on Cancer (IARC) concluded. based on evidence available through 19x5, that smoking of different forms of tobacco is causally related to cancers of the bladder and renal pelvis (IARC 1986). In addition to the studies reviewed in the 1982 Surgeon General'\ Report (US DHHS 19X2) and in the 19X6 report of IARC ( 19X6). more recent data document a consistent association between cigarette smoking and bladder cancer. In an extended followup of a cohort of 25,000 Swedish males, mortality rates for bladder cancer were increased fourfold among ever smokers compared with never smokers (Carstensen, Pershagen, Eklund 19X7). In current smokers, the risk of death from bladder cancer was approximately three times greater at all levels of consumption. The excess mortality from bladder cancer among current smokers was comparable in the American Cancer Society (ACS) Cancer Prevention Study II (CPS-II) (Table 4). An extension of a large hospital-based case-control study, originally reported in 1977 (Wynderand Goldsmith I977), showed similar increases in risk among male and female smokers (Augustine et al. 1988). The study included 1.3 16 male and 505 female cases and 3.940 male and I.504 female controls interviewed in 9 U.S. cities between I969 and 1984. For current smokers, odds ratios increased to approximately 3.5 for male and female smokers of 21 to 30 cigarettes per day. Odds ratios were lower among former smokers, although the risk did not decline as the duration of abstinence lengthened (Table 4). The findings of a recent population-based case-control study documented similar levels of bladder cancer risk associated with cigarette smoking (Slattery et al. 19XX). Slattery and coworkers (19XX) assessed cigarette smoking and bladder cancer in 3.72 white male cases and 6X6 controls in Utah. The overall crude odds ratio for current IL3 4-h 7.-IO II-15 216 IL.1 341 7-10 I I-I.5 zth TABLE 4.-Continued Reference Population (yr of DeGgn data collection) (number ofwhjecr\) (knder Rl\h ret;ltwc to nwer wwher\ Currcm Former smohcr\ rmohen Wynder and Gotdamith ( 1977) h US cities ( IYh%74) Cavz:control (574:56X) (ls5:154) Male 2.6 2.Y I .s I .h I .2 I.1 2.5 I 2 Vineih et at (IYX3) Cartwrlght et al. (IYX3) Mornwn et al (IYX4) Italy (lY7X-XI) Erlgld (lY7X-XI) Ca\e:controt (755:276) Case:control (Y.v:l.Jo') (3'757Y,, Bowm. MA (107677) Manchuter. UK (1976-7X) Nagoyii. Japan (lY7~7X~ Caw:controt t3'7:3', I ) (lfd:ll?l t3vX:4Yo) (lss:c!41) (`x:44?) (hh: 146) MLlltT 6.0 Male I .h (`awxontrol (5l?:s')h) (SOS: 13(W) Malt Female Mule Fwl;ltc 3.4 3.0 t .CJ I.2 7.v 2' t .h 1.7 I ..v 7.2 4.5 I.8 I .h I.1 2.2 .I 2.3' 22' ?.I' 0.Y' 1.7' I.? 1.2' NP NP TABLE 4.-Continued Slattery et al (IYXX) Claude. Frcn~el- Brymr. Kuwe ( IYXX) ACS CPS-II (unpuhl~~hed tshulathl\) Hurch et al. (IYXY) Utah (lY77-x.31 C;mxia (IY7Y-X2) Case:control (332:6x6) Caaexonrrol (531521) Prwpective (421.663) (h0.5.75X) Cohe:control (627flO2) (IYY:IYo) Male 3.7 3.7 2.7 I .Y 1.X MLlk 3.5 I .x M;k! 2.`) 2.0 Fl!malc 2.X 2.0 Mde 27 I .7 km;de 2.6 I.1 0.557 X-IS I6 29 ?70 NI' NP Y P smohing. compared M ith never smohing. was 3.69 (95-percent confidence interval (CI ). 2.5X-5.26). Ho&ever. an expoatre-response relationship u'a\ not evident with reported average number of cigarettes smoked daily. The odds ratios for former smokers declined only after X years or more of ab>,tinence. Table 3 summuri~e\ finding\ from studies that have examined the relationship between cigarette smoking cessation and risk of bladder cancer. Of all the non- respiratory cancer \iteh. the relationship betwteen bladder cancer risk and cigarette smoking cessation has been most extensively studied. In these studies. the risk among current smokers ranges from I .O to 7.2 times the risk among never smokers (median of approximately 3): rishs are similar among male5 and females. More recent studies conducted since the mid-1970s tend to show> higher ri$kh for current smokers than do the earlier studies. The higher ri5ks in more recent studies may reflect the earlier age of starting to smoke of more recent cohorts of smokers (US DHHS 1989) or the presence of a long latency period for the smoking effect to become fully manifest after initiation in susceptible personh. Beyond the first few years of abstinence. former smokers generally have lower risks than current smokers. The study conducted in six U.S. cities (Wynder and Stellman 1977; Wynder and Goldsmith 1977) indicated an approximate SO-percent reduction in risk after 6 years of abstinence. with risk returning to that of nonsmokers among men after IS years. A similar return to nonsmoker ribh was also observed after 6 year\ of abstinence in an English study (Cartwright et al. 19X3) and in an Argentine study after 20 years (Iscovich et al. 19X7). However. results from other studies (Howe et al. IYXO: Vineis. Esteve. Terracini 19X-t: Hartge et al. 19X7: Burch et al. 19X9) indicated that the reduction in rish in the first few years after ces;sation is followed by little subsequent additional reduction. even beyond IOor I5 years ofabhtinence. These observations are in contra\t to those for the other cancer site\ review,ed in this Chapter. In some studiej. the analyse\ controlled for the possible confounding effect3 of lower cigarette consumption among former smoker5 prior to cec\ation. The U.S. Veteran\ Study (Kahn 1966) showed no reduction in ri\h for former smokers. compared M ith current smoher\. at level\ of past cigarette consumption of I pack or less per dab. There wa\ an approximate SO-percent reduction in risk. however. for those former smokers who had previousI) \mohed more than I pack per dab. Mo\t studies that included past cigarette smoking exposure as a co\ ariatc in multiple logistic regression anal) se\ (Wigle, Mao. Grace IYXO: Howe et al. 19X0: Vinei\. Estete. Terracini 19X-l: Claude. Frent;rel-Beyme. Kun,v IYXX: Slatter; t'l ;I]. IYXX: Burch et al. IYX9) show,cd relative risks that were similar to those observed in studies in which no such adjustment M;I\ made. A large multicenter study conducted b!, NC1 (Hartfe et al. lYX7) contained sufficient numbers of subject\ for detailed subgroup analykrs. Table 5 displays the findings of thi\ study when both average cigarette do\e per da> and duration of smokiq are cross-classified for current and former \mohers. In each of these nine categories. bladder cancer ri\k was lob,er among former smokers than among current smokers. .A\ reviewed above. the amount of e\,idence supporting cigarette smohing as a cause of bladder cancer has become increasingly compelling \ince the 19X2 Report of the Surgeon General (US DHHS 19X3). which focused on cancer. Multiple studies of I63 TABLE 5.-Bladder cancer risk according to smoking dose, duration of smoking, and smoking status varying design conducted throughout the world have shown statistically significant increases in risk of bladder cancer among smokers. Cigarette smoking. determined to be a contributory factor in bladder cancer in past reports of the Surgeon General (L'S DHHS 1983. 1989). can now be identified as causally associated with bladder cancer. The evidence adequately meets the criteria for causality established in the 1964 Report (US PHS 1964). The decline in risk of bladder cancer with cessation further supports the conclusion that cigarette smoking causes bladder cancer. This diminution in risk cannot be explained by confounding from lower cumulative consumption among former smokers compared with continuing smokers. Cervical Cancer Recently, an association has been noted between cancer of the uterine cervix and cigarette smoking (Williams and Horm 1977; Stellman. Austin, Wynder 1980: Lyon et al. 1983; Hellberg. Valentin, Nilsson 1983: Berggren and Sjostedt 1983; Peters et al. 1986; Brock et al. 1988: Nischan. Ebeling. Schindler 1988). However, because of the possibility of confounding by unidentified factors (in particular, a sexually transmitted etiologic agent), this association has not been identified as causal (US DHHS 1981, 1989; IARC 1986). Components of tobacco smoke can be identified in the cervical mucus of smokers (Sasson et al. 1985; Schiffman et al. 1987). These compounds have been found not only to display mutagenic activity in this environment (Holly et al. 1986). but also to have the ability to impair local immunity by reducing the populations of Langerhans' cells within the cervical epithelium (Barton et al. 198X). The reduction in circulating levels of P-carotene caused by cigarette smoking is yet another mechanism whereby cigarettes may increase the risk of cervical cancer (Harris et al. 1986: Brock et al. 198X; Stryker et al. 1988). Thus. the association of cigarette smohing with cervical cancer is biologically plausible. Table 6 summarizes findings from studies that have examined the relationship between cervical cancer risk and cigarette smoking cessation. In these studies, the risk among current smokers ranges from 1.0 to 5.0 times the risk among never smokers (median of approximately 2). Smoking-associated risks for invasive cancer and for carcinoma in situ are generally similar. After the first year of abstinence, former smokers have lower cervical cancer risk than current smokers in most studies. Exceptions include the study conducted in Milan (La Vecchia, Franceschi et al. 1986). which showed risk reduction for invasive cancer but not for carcinoma in situ among former smokers. and the study conducted in Central America (Herrero et al. 19X9) in which no association with smoking was observed at all, even for current smokers. The effect of time since stopping has not yet been well studied for cervical cancer, but observations from a large multicenter study conducted by NC1 (Brinton. Schairer. Haenszel et al. 19X6) suggested that risk reduction may occur fairly rapidly after cessation. One study found that smokers tended to have a poorer prognosis for survival after radiation treatment for invasive cervical cancer, but no data were presented regarding smoking cessation (Kucera et al. 1987). A major concern in studies of smoking and cervical cancer has been the potential for confounding by factors that would predispose a woman to become infected with a sexually transmitted agent that might be causally related to the disease, such as human papilloma virus (Stellman. Austin. Wynder 1980; Winkelstein et al. 1984: IARC 1986). Therefore, it is important to note that those studies that controlled for risk factors for sexually transmitted disease (Trevathan et al. 1983: Greenberg et al. 1985: Herrero et al. 1989: Slattery et al. 1989) produced relative risk estimates for current and fomler smokers that were quite similar to those from studies that made no such adjustments. The association of smoking and cervical cancer has been considered by some to be a result of residual confounding by inadequately measured indicators of exposure to a sexually transmitted agent. Although factors such as the number of past sexual partners are only surrogates for a hypothetical etiolngic infectious agent, they are the very same social correlates of tobacco smoking that would suggest this type of confounding. Therefore. even though such factors as age at first intercourse and the number of sexual partners are imperfect indicators of infection by a possible etiologic agent. their inclusion as covariates in multivariate analyses may be sufficient to control confound- ing to some extent in the analysis of the effects of smoking on cervical cancer ri&. This review of the evidence on cervical cancer and cigarette smoking cessation indicates that there is a consistently observed association between cervical cancer rish and cigarette smoking and that former smokers experience a lower risk of cervical cancer than current smohers. even after adjusting for the social correlates of smoking and risk of sexually acquired infections. Thi, observed diminution of risk after cessation lends support to the hypothesis that smoking is a contributing cause of cervical cancer. Based on a recent c0mprehensiv.e review of epidemiologic studies providing data on smoking and cervical cancer. Winkelstein (1990) concluded that smoking is causally associated vvith cervical cancer. 166 TABLE &--Studies of cervical cancer and smoking cessation Reference Location (yr of Design data collection) (number of subjects) Risk relative to never smokers Current Former smokers smokers Yr since qwttmg Comment\ Cederlof et al. (lY7.5) Clarke. Morgan. Newman (1982) Marshall ct al. (1983) Trevathan et al. (IYX3) Greenberg et al (IYXS) Brinton. Schairer, Haenwel et al. ( IYXh) La Vecchin. Franccschi et al. I IYXh) Sweden ( 1963-72) Toronto, Ontario (1973-763 Buffalo. NY (1957-65) Atlanta, GA (19X0-81) England ( 1968-83) 5 US citieh (19X?-X4, Milan. Italy (IYXI-X4) Prospective (27,700) Case:control ( I785G.5) Case:control (5 13:4YO) Caw:control lYY:2KX) Prospective (17.032) Caae:control t4)30:7')73 Caaexontrol (1X3:1X3) (230:220) s.0 2.3 I.6 4.2 3.0" I.5 I.4h 1.7 3.0 I.7 0.x 2.1 0.7 2.2 I.1 I .o I.1 2.5 0.x NR NR NK NR NR 74 5-Y >I0 NK NR Cancer incidence Invawe cancer (`arcinomu in \itu Ad~uwxl for wxual partner\. birth control pill\. SE.5 Inva\iw anccr incidence Ad~uwd for age at marriage. birth control pItI\, SES Adjusted for sexual partner\. age at first mttxcourw. SES TABLE 6.--Continued Breast Cancer In general. prior research has shown little relation betvveen cigarette smoking and the risk of breast cancer (Baron 1984: Rosenberg et al. 1984: Baron et al. 1986): however. in recent years, several reports have raised the possibility that there might be a weak positive association (Table 7). Because there has been considerable discussion about the possible role of smoking in breast cancer in recent literature. the relationships among cigarette smoking, smoking cessation. and breast cancer risk are reviewed. Cigarette smoking creates a set of physiologic conditions that result in various antiestrogenic effects (Baron 1984: Jensen, Christiansen. Rodbro 1985: Michnovicz et al. 1986). as well as affecting body mass (Camey and Goldberg 1984: Hofstetter et al. 1986: Chapters 9. IO, I I ). The relationship betvveen cigarette smoking and body mass is a particularly important consideration in studies of breast cancer, because body mass has a complex age-dependent association with breast cancer risk. with obesity being protective in premenopausal ages but slightly risk-enhancing later in life (Willett et al. 1985). Table 7 summarizes findings from studies that have examined the relationship between breast cancer risk and the cessation of cigarette smoking. The risk of breast cancer among current smokers ranges from less than I .O to 4.6 times greater than among never smokers (median approximately I ). The relative risks of smoking do not consistently differ in premenopausal and postmenopausal age groups. In addition, there is little consistency regarding the change in risk observed after smoking cessation. Former smokers have lower risks in some studies, but higher risks in others. Adjustment for other breast cancer risk factors does not appear to completely remove the weak association observed in some studies (Schechter. Miller, Howe 1985; Rohan and Baron 1989). In one study it was found that smokers tended to have a greater prevalence of tumor-positive axillary lymph nodes at the time of diagnosis than did never smokers and former smokers, a finding that could not be explained by patient delay (Daniel1 1988). This association was not confirmed, however, in a recent report based on I O-year followup of the Nurses Health Study cohort that included 1,373 cases with information on extent of disease at diagnosis (London et al. 1989). This review of breast cancer and cigarette smoking suggests that cigarette smoking is not associated with breast cancer. Consistent changes in risk are not observed with smoking cessation. Endometrial Cancer The relationship between cigarette smoking and cancer of the endometrium is unique among the associations of smoking with cancers at various sites; of the sites for which smoking has been associated with a change in risk, endometrial cancer is the only cancer for which there is fairly consistent evidence of an inverse (protective) relationship (Baron 1984; Lesko et al. 1985; Stockwell and Lyman 1987), an effect that may be limited to postmenopausal women (Smith, Sowers, Bums 1984: Koumantaki et al. 1989). The reasons for the lower risk among women who smoke are not well under-. 169 TABLE 7.-Studies of breast cancer and smoking cessation LocatIon (yr ot DestJy data collection) tnumber of suhjcct\) Menopau\al XtatUS Kisk relative to never smokers Current Former smoker\ smoker\ Yr since ywtting Commenrs Cederlof et 31. (lV75) Schcchter, Mtllrr. Howe (IYX.5) Hiatt and Fireman ( I YXh) Brinton. Schurer, Stanford et al. (10x6) stochw~ll and Lyman ( I YH7) Brownson et 01. (IYXX) Adami et al. (IWX) Rohan and Baron (19X')) Sweden (lYh3-72) Canada (IYXO~X2) Northern Calil'omta (IY6`~XO) Untted State\ t 1973-75) Flortda (IYXI) Missourt ( IY7Yw%) Sweden and Norway ( Iox4-~x5 ) Awtralia (IYK~X4) Prospective (27.700) C~w:control (4`): 134) (7 I:?IY) Proqxtnw (X4.172) Caae:wntrol (447503) thl4:XIX) Caw:control (4.01 1:2.`)52) Ca~rxontrol (1 14:20X) (206:x72) Cnbexontrol (427,517) Ca\e:control (146: 132) (2X0:2xX) Pre and pot Pre po\t Prr po\t Pre Po\t Pre Pwt Pre Pwt Pre and pwt Pre Pwt 0.6 4.6 I.1 I.2 I.1 I.1 I.1 1.3" 1.2" 2.3 1.2 I .o I.3 I.5 0.4 1.x 0.x I.2 I.3 I .4 NR I .o NR 0.9 NR 0.`) NR I.2 0.7 0.x 2.4 0.9 NR Cancer incidence >I >_I NR NR Adjusted for xveral breast cancer risk factory Cancer incidence NK NR Relative risk calculated from crude data >I tl Adjusted fbr szveral breast cancer ri& fnaor5 TABLE 7.--Continued Reference Location (yr of Design data collection) (number ofsuh,jects) Menopausal \tatus Kid relative lo never mohers ~`urrent Former smokers smoherh Yr since quitting Comment\ London et al. (19x0) United State\ ( IY7h-X0) Prohpective ( I 17.557) Pre Post I .O" I.1 NR 1.1" I.1 NR stood. but may be due to smoking effects on estrogen production and metabolism. including increased 2-hydroxylation ofestradiol in smokers (Michnovicz et al. 1986). an earlier age at menopause in smokers (Baron 1981). and indirect effects of the body weight differences between smokers and nonsmokers. such as the production ot estrogens from precursors within adipose tissue (MacDonald et al. 197X: Chapters 8 and IO). Table 8 includes a summary of findings from studies ofendometrial cancer that have examined cigarette smoking cessation. Although the risk ofendometrial cancer among current smokers in these studies is approximately 30 percent lower than that among never xmohers. the risk among ex-smokers is similar to. or slightly greater than. that among current smohers. This review of past research on endometrial cancer risk and cigarette smoking cessation sugests that current smokers are at lower risk of endometrial cancer than never smokers. but it is not clear whether this protective effect of smoking on endo- metrial cancer risk might be reversed soon after cessation of cigarette smoking. Although further investigation of the mechanisms for the protective effect of smoking on endometrial cancer is of scientific interest to better understand the effects of smoking on hormones and of hormones on endometrial cancer risk, this inverse association with smoking has no public health relevance, as the well-substantiated risks to other organ systems from continued smoking far outweigh any potential benefits to the endo- metrium. Other Cancer Sites The metabolic products of tobacco smohe can be found in ovarian follicular fluid (Hellberg and Nilsson 198X). However. there i\ little evidence that smohing ih as- sociated with cancer of the ovary (Byers et al. 1983: Baron 1983: Baron et al. 1986: Stockwell and Lyman 1987; Whittemore et al. 198X: Mori et al. 1988). The rish of ovarian cancer differs little for either current or former mohers. a\ indicated in the only two studies that have examined the effect of cigarette smoking cessation on ovarian cancer rish (Table 8). Tobacco has been regarded as a contributing f;ictor for cancer of the kidne? (US DHHS 1982. 1989). The U.S. Veterans Study (Kahn 1966: Repot and Murray 19X0) and ACS CPS-II (ACS. unpublished tabulation\) qgest onI1 \msll difference\ in mortality from renal cancer between current and former amohers (Table XI. A study of renal pelvis and ureteral cancers in Copenhagen (Jensen et al. 198X). hob,ever. showed a pattern of risk diminution with abstinence Gmilar to that observed in bladder cancer. a site with the same histologic type of transitional-cell tumors. Cancers of the anu1r and peni\ are considered possibly to result from infection by a sexually transmitted agent in a v.aj analogous to cancer of the uterine cervix (Daniel1 1985; Daling et al. 1987: Hellberg et al. 1987). Smokers hake been found to be at increased risk both for cancerofthe penis (Hellberg et al. 19X7) and anus (Daling et al. 1987: Holmes et al. 198X) in recent ctudie\. Only one study has examined the effect of cessation on the risk of these cancers (Hellberg et al. 1987). This study found that 172 TABLE I.--Studies of cancer at selected sites that have examined the effect of smoking cessation Cederlof et al. (197% Lrsko et al. (1985) Stockwell and Lyman ( 19X7) Cederlof et al. (lY75) Stockwell and Lyman (19X7) Franks et al. (IYX7) Kahn ( 1966) Roget and Murray I IYXOJ Jensen et al. (IYXX) Sweden ( 1963-72) X North American citte\ (1976-X3) Florida (IYXI) Sweden (1963-72) Florida (IYXI) United Stab (IWO-X2) US veterans (19.54&62) [IS veteran\ (1954-6Y) Copenhagen ( 1979~X2) Proqxctive (27.700) Casexontrol (50X:706) Ca5e:control (9Yo:?.Ys2) Prospective (27.700) Case:control (hwx2,YS2) Cawxontrol Prospective (24X.lY.5) Prospective (293.YSXJ (`nxexontrol (Y6:`XX) Endomctrtum Endomctrnm Ovary Ovary Kidney Kldncy 0.5 l).x'l 0.x" 0.5 1.1" I.1 I .4 I .`I 3.7 I .h O,kJ 0.0 I .6 II.0 0.`) I.5 I.2 I .4 N P NI' NI' NI' >I NF' NI' NI' TABLE X.--Continued Kisk relative 1o never Keterencc Population (yr o! data collectwn 1 Design (number of\uhject~ Cancer site smoker\ Current Former smokers \mokcr\ Yr since quitting Comment\ Hcllhcrg et al. SWd~ll (I`JX7) (NPI Cederlof'ct 31. (1')7S) S\*cdcn (lY63-77) Rogol and Murray ( I YXO) IIS veternn\ (lYS4dY) Yu e1 al. (14X3) Lo\ Angclr\. CA ( l'J7Sm 70) Kahn ( IYtx) (`rdcrlof et a. (l'J7.5) Roger and Murray (IYXO) Nomura er aI. (IYYO) Kahn ( IYhh) US veteran\ ( l'JSJ~h2) Prwpectivr t17.300) <`ahe:comrol (76:76) Prospeclive (23X.195) Prwpect ivc (?7.3001 Pro\pective (2YJ.YSX) Prwpectwe l7.YYO) Plnqeclive (74X.l'JS) Pt!Ill\ Liver Liver Liver Stomach Stomach Stomach I .h 2.4 2.3 1.X" I .4 I.3 I.5 2.7 I .J I .7 I .o I .X I.1 I.1 0.7 I.1 I .o I .s NP NP NP NP NP NP NP NP N P Cancer incidence in males Cancer mortality Abtnincr\ for 210 yr were considered never hmokers Excludes "doctor`s order\" quilter\ Cancer mortality Cancer mcldence in males Extension of US Verrran\ Stud) Cohort identified 1065-6X and followed through October 19x6 Exclude\ "dnctor`x order\" qulttw Cancer mortality TABLE &--Continued Reference Population (yr of data collection) Design (number of wbjects) Cancer Gte Rihk relative to never \molLer\ Current Former wloherh smokers Yl \ince quitting Comments Cederlof et al. (1975) Roger and Murray ( I980) Trichopoulos et al. (1987) ACS CPS-II (unpublished tabulations) Sweden (I 963-72) US veterans ( 195449) Greece ( 1976-84) United States ( 1982-86) Prospective (27.300) (27.700) Proqxctive (24X.ooO) Case:control ( 104:454) (X9:454) Prospective (42 I .623) (605.758) Leukemia (Males) (Females) I.1 0.4 0.X I .o NP NP Cancer incidence Leukemia I .h I.5 NP Extcmion of US Veterans Study Liver HB,Ag HR,Ag+ 3.3" I .6'( 2.x I.3 NP NP Kidney (Mules) (Females) NP NP Cancer mortality current smokers had a penile cancer risk I .6 times that of never smokers. but the risk among former smokers was similar to that among current smokers (Table 8). Primary hepatocellular cancer has been associated with smoking in a number of recent studies (Trichopoulous et al. 1980: Lam et al. 1981: Yu et al. 1983: Oshima et al. 1984: Trichopoulos et al. 1987; Hirayama 1989). This association is of potentially great public health importance because of the high incidence of primary liver cancer and the epidemic of cigarette smoking worldwide, which is increasingly involving countries in which liver cancer is the leading cause of cancer mortality. The mechanism whereby smoking might affect liver cancer risk is unknown. Although potential confounding by alcohol consumption is of concern in interpreting this association. the association of smoking with hepatocellular cancer has remained significant in several studies after controlling for alcohol intake (Trichopoulos et al. 1980: Yu et al. 1983; Oshimaet al. 1984; Trichopoulos et al. 1987). One case. /r,lc,,.rfrrtiorfu/ .lor,,.,kr/ <$Crrrrc.rr. 3 I (3):557-S6 I. April 15. 19xX. JENSEN, O.M.. WAHRENDORF. J.. BLEITNER. M.. KNUDSEN. J.B.. SORENSEN, B.L. The Copenhagen case,nw~/c Ilt>.c lo r/w Slrtrl~ of CU/iW/~ 1111d Orlrar CIlI~olllr~ Di\cw\c~.\. NC1 Monograph 19. U.S. Department ot Health. Education. and Welfare. L1.S. Public Health Service. National Cancer Institute. January 1966. pp. I-125. KINLEN. L.J.. ROGOT. E. Leukemia and \mohmp habIt\ among Cnited States wtcran\. B~.rti.cll M&rr (I/ ./orcwtrl 207(66-l9):657-65Y. Scptcmber IO. I YXX. KOUMANTAKI. Y.. TZONOL. A., KOUMANTAKIS, E.. KAKLAMANI, E.. ARXV,4N- TINOS. D.. TRICHOPOULOS. D. A ca\e irradl:rtmn in the treatment ofcarcmoma of the cervix. Ctrr~c,r,. hO( I ): 11, July I. 10x7. LAVECCH1A.C.. FRANCESCHI. S.. DECARLI. A.. F.4SOLI. M..GENTILE. A..TOGNONI. G. Cigarette smoklnf and the risk of cervical neoplu\ia. .-\rwrlc.o,~ ./orf,.~rtr/ of E/)/k,~rc~>/~~,q> 113 I ):27-2Y. January IYXh. LA VECCHIA. C.. LIATI. P.. DECARLI. A.. NEGRELLO. I.. FR.4NCESCHI. S. Tar ) leld\ ofcigarette\ and the ri\h ofwqhagral cancer. /~~rc,~.,rtr/io,rr//.I,~rc/.,r~~/ofC~r,~~ c~r'iX:.3X I -3X5. 1086. LA VECCHIA. C.. LIATI. P.. DEC.4RLI. A.. NEGRI. E.. FRANCESCHI. S. Coffee conwmp- tion and rish of pancrcatlc cancer. /r,lr,.,ftrt,~jrrt,l ./r~l/,-,w/ o/`Ctl/lc (`I' 10:3OY%.3 13. September IS. 19x7. LA VECCHIA. C.. NEGRI. E. The role of alcohol in ocwphafca1 cancer in non-mohcrr. and the role of tobacco in non-drinhcr\. //lrc~,-,/~///rj/r~// .I<),,, w/ /$Ct///c (`I' 1315 ):7X-&7X.5. Md! IS. IYXY. LAM. K.C.. YC. M.C.. LEUNG. J.W.C.. HENDERSON. B.E. Hepatltij B virus and cigarcttc wiokmg: Ri\h factor\ for hcp~ttocellular c;Lrcinomil in Hong Ken:. C`tr/rwf. Ro.wtr/-c Ir -13 12):5116-52-1X. Deccmhrr IYX2. IX? LESKO. SM.. ROSENBERG. L.. KAUFMAN. D.W.. HELMRICH. S.P.. MILLER. D.R.. STROM. B.. SCHOTTENFELD. D.. ROSEh3HElY. N.B.. KNAPP. R.C.. LEWIS. J.. SHAPIRO. S. C&arette smoking and the rixh of endometrial cancer. !Vtr\t. E,!q/c/,I 77~~ o/r~,g> 130:43x355. 197x. MACK. T.M.. YU. M.C.. HANISCH. R.. HENDERSON. B.E. Pancrea\ cancer and amolin?. beverage consumption. and pa\t medical history. .I~~r~/~rl~// of thc~ Norio/~cl/ (`0/1(.cr /nstif,r/c 76( I ):49%60. January I YX6. MACMAHON. B.. YEN. S., TRICHOPOULOS. D.. WARREN. K.. NARDI. G. Coffee and cancer of the pancreas. N~M, E77,~/~77~l./orr7-71~7/ c$MrdicY7rc 303i 1 I ):630-633. March I?. 1 YX I MARSHALL, J.R.. GRAHAM. S.. BYERS. T.. SW.4NSON. M.. BRASURE. J. Diet and smokmp in the epidemiology of cancer of the cen!ix. .Icwurrrl off/w Ntrfio77rrl Ctr77c cr /n.srrt~c~r 70(5):X37-851. May 1983. MICHNOVICZ. J.J.. HERSHCOPF. R.J.. NAGANLMA. H.. BRADLOW. H.L.. FISHMAK. J. Increased 7-hydroxylation of estradiol as a possible mechanism for the anti-estrocpenic effect of cigarette smoking. N~TM. O7gla77rl.lor77.77r~l cfMeclrc~i77c 3 I S(2 I ): INS- 1309. Novem- ber 19X6. MILLS. P.K.. BEESON. W.L.. ABBEY. D.E.. FRASER. G.E.. PHILLIPS. R.L. Dietap habit\ and past medical history as related to fatal pancreas cancer risk among Adventists. Co77w7- 61(12):257X-2585. June IS. 19Xx. MOORE. C. Smoking and cancer of the mouth. pharynx. and larynx. ./o~r~~rcd of`tlrc Anwr% m Medicul Assoc~ic~tior7 19 l(4): I07- I 10. January 25. I Y6S. MOORE. C. Cigarette smoking and cancer of the mouth. pharynx. and larynx. A continuing study. Jo1tr77ul of t/w Ar77rrko77 Mcdic~ul Assoc~irrtiot7 2 I X(3):553-558, October 2.5. lY7 I. MORI, M.. HARABUCHI. 1.. MIYAKE. H., CASAGRANDE. J.T.. HENDERSON. B.E.. ROSS. R.K. Reproductive. genetic. and dietary risk factors for ovarian cancer. An7c7~ic~trrr .lort777u/ ofEpidemio/o,qy 12X(4):77 l-777. October IYXX. MORRISON, A.S.. BURING. J.E.. VERHOEK, W.G.. AOKI. K.. LECK. I.. OHNO. Y.. OBATA. K. An international study of smoking and bladder cancer. Jo7tr~7trl c!f` b'~-o/o,p~~ 13 I (4):6SC-654. April 19X4. NISCHAN. P., EBELING, K.. SCHINDLER, C. Smoking and invasive cervical cancer rish. Results from a case-control study. An7rr.ir,cu7 .Jo~rmu/ of Epidcn7io/o,q~ 12X( I ):74-77. July 198X. NOMURA, A., GROVE. J.S.. STEMMERMANN. G.N.. SEVERSON. R.K. A prospective study of stomach cancer and its relation to diet, cigarettes, and alcohol consumption. Cru7wr- Re.seu7~l7 SO:67743 I. February 1. 1990. NORELL. S.E.. AHLBOM. A.. ERWALD. R.. JACOBSON. G.. LINDBERG-KAVIER. 1.. OLIN, R., TORNBERG. B., WIECHEL. K.L. Diet and pancreatic cancer: A case-control study. Am~ricu~7 ./07rr77c1/ of Epidcn7iology 124(6):X94-901. December I9 X6. OLSEN. G.W.. MANDEL. J.S.. GIBSON. R.W.. WATTENBERG. L.W.. SCHLMAN. L.M. A casexontrol study of pancreatic cancer and cigarettes. alcohol. coffee. and diet. ,A777c1-ic U/I .lo7rr77ul ofPuhk Hculrh 79(X ): IO1 6-l 019. 19X'). IX3 OSHIMA. A.. TSLIKUMA. H.. HIYAMA. T.. FI~JJMOTO. 1.. YAMANO. H.. TANAKA. M. Follovv-up study of HBs AX-postttve blood donors u ith special reference toeffect ofdrinhing and amohing on development of Itver cancer. //rrcwtrr~~wtrI ./w/./w/ of Ctwwr. 31:775-779. IYX4. PETERS. R.K..THOMAS. D.. HACAN. D.G.. MACK. T.M.. HENDERSON. B.E. Risk factors for invasive cetvical cancer among Latinas and nonLatinus in Los Angeles County. ./~~f~17t(1/ o/'t/re Norior7/// C///r/ ('I' I/rv//r//!t* 7715): 1063-1077. November 19X6. ROGOT. E.. MURRAY. J.L. Smoking and causes of death among U.S. veterans: I6 years' of obsewation. P///dir Hcolrh Rqxj/~\ 9.5( 3 ):2 13-2-92. May/June 19X0. ROHAN. T.E.. BARON. J.A. Ctgarette smohtng and breast cancer. AnM~r~/t~url Jolo-IlUl of Epitkt77io/r~,q~ l29( I ):3632. January IYXY. ROSENBERG. L..SCHWIKGL. P.J.. KAUFMAN. D.W.. MILLER. D.R.. HELMRICH. S.P.. STOLLEY. P.D.. SCHOTTENFELD. D.. SHAPIRO. S. Breastcsncerandciparette smoktng. .NcM. &/7,~/t~r7t/./orr/~/7c// of'Mct/ic~//rc 3 lOt2):92-93. January 12. 19X-t. SASSON. I.M.. HALEY. N.J.. HOFFMANN. D.. WYNDER. E.L.. HELLBERG. D.. NJLSSON. S. Cigarette stnohing and neoplasra of the uterine cervix: Smohe constituents in cervical mucus. Nc\t~ E/rglr//rcl ./o~rrxcr/ /fMctlit i/7c 3 I2tS ):3 15-3 16. January 3 I. 19x5. SCHECHTER. M.T.. MILLER. A.B.. HOWE. G.R. Cigarette smohing and breast cancer: A case-control study of screening participants. Anro-ic.trrr .lo~r~xcr/ of`E/,ir/c~n7iolr,,y~ I Z I t4):379- 4X7, April I YXS. SCHIFFMAN. M.H.. HALEY. N.J.. FELTON. J.S.. ANDREWS. A.W.. KASLOW. R..4.. LANCASTER. W.D.. KURMAN. R.J.. BRINTON. L.A.. LANNOM. L.B.. HOFFMANN. D. Biochemtcal epidemiology ofcetvical neoplasia: Measuring cigarette smoke constttuents in the cervix. C'r/ww Rc\co7-c.h J7( 14):3Xx6-3X88. July IS. lYX7. SCHOTTENFELD. D. Multiple primary cancers. In: Schottenfeld. D.. Fraumeni. J.F. Jr. (eda.! Ctr/7w/. Epit/cr77/o/o,~~ /1/7/l Pre~~c~/rr/o/r. Philadelphia: W.B. Saunders. Co.. I YX?. p. 1025. SCHOTTENFELD. D.. GANTT. R.C.. WYNDER. E.L. The role of alcohol and tobacco tn multiple prima? cancers ofthe upperdigestive sy stem. larynx and lung: A prospectiw stud!. P/~c~~c/~c~I`~ Mctlic i77c' 3(1):277-2Y3. June 1971. SEVERSON. R.K. Cigarette smohtnp and leukemta. Cur7r c~-60(2t:111-111. July IS. 19X7. SILVERM,4N. S. JR.. GORSKY. M.. GREENSPAN. D. Tobacco uwpe in patients ~tth head and nech carcinomas: A followup study on habit changes and second prnt~ary oral/oropharyngeal cancers. ./,w/Y7cl/ of //7/Z Ar77c~/-/c~~l/7 ne/rrtr/ .A.\srJc~/~rrro~7 lO6( I t:33-35. January 19x3. SLATTERY. M.L.. ROBISON. L.M.. SCHCMAN. K.L.. FRENCH. T.K.. ABBOTT. T.M.. OVERALL, J.C. JR.. GARDNER. J.W. CtXarctte smokmg and exposure to passive smohe are risk factors for cervical cancer. Jofr~~~rul of r/7/3 r\r71~/-1c~trt7 Mctlic trl AMOC rtrf7017 26l( I I ):lSu)-ISYX, March 17. IYXY. SLATTERY. M.L.. SCHUMACHER. h1.C.. U'EST. D.W.. ROBISON. L.M. Smokmp and bladder cancer. The modifytng effect ofcifarettes on other factors. CC//~< (`I. 61(_7):402-t(lX. January IS. 19xX. SMITH. E.M.. SOWERS. M.F.. BURNS. T.L. Effects ofsmohing on the development of female reproducttve cancers. ./or(/.rrc// wl ................................ 211 Studies of Smohing Cessation and Rish of Aortic Aneurysm ............... 211 Smohing Cessation and Peripheral Arterial Occlusive Di\ea\e ............... 211 Smohing Cessation and Development of Peripheral c\rtery Di\ea\e Z-l.3 Smohinf Cessation and Prognosi\ of Peripheral Artery Disease Z-l.1 Surnmar~ ........................................................ 11-J Smohing Cehation and Cerebrovascular Disease .............. ........... 215 Studies of Smohing Cessation and Ri+ of Cerebrovawular Disease ......... 2-W Cro\s-Sectional Studic\ .......................................... 7-K Case-Control Studieh ........... ................................ 7-K Prospective Cohort Studies ....................................... 2IY Summary of Observational Studies ........ ........................ 75 I Intervention Studie\ ............................................. 251 Influence of Prior Levels of` Smohing ............................... 25 I Effect of Duration of Abstinence ................................... 32 Oral Contraceptives and Stnohing Cessation ......................... 25X Effect of Smoking Cessation After Strohe .... ...................... 260 Summary ........................................................ 2hO Conclusions ..................................................... ..~60 References ...................................................... ..26 I IIVTRODLCTION Cigarette smoking is firmly established as an important cause of coronary heart disease (CHD). arteriosclerotic peripheral vascular disease. and stroke (US DHHS 1983. 1989). Eliminating smohing presents an opportunit) for bringing about a major reduction in the occurrence of CHD. the leading cause of death in the United States. Before examining the epidemiologic evidence relating zmohin, ~7 cessation and rish of CHD and other forms of cardiovascular disease (CVD). the mechanisms by uhich smohing leads to these diseases are briefly reviewed. The objectives in considering these mechanisms are to address the plausibility that smoking cessation reduces rish of CVD. to estimate the expected magnitude in rish reduction. and to assess the rapidit) with which any risk reduction might occur. Whether these mechanisms are immedi- ately reversible. irreversible. or slowly reversible i\ of particular rele\,ance to the rapidity with which smoking cessation will reduce rich. The role of smohins in the pathogenesis of CHD is discussed at length. Th e etiologies of peripheral \ ascular disease and stroke share several common features M ith CHD: thus. discussion focuses on distinguishing features. PATHOPHYSIOLOGIC FRAMEWORK Smoking and Development of CHD Pathogenesis of CHD. which includes the clinical manifestations of myocardial infarction (MI). angina pectoris. and sudden death. is extremely complex and mediated by multiple mechanisms and etiologic factors (Munro and Cotran 198X). At least five interrelated processes are likely to contribute to the clinical manifestations of MI- atherosclerosis. thrombosis, coronary artery spasm. cardiac arrhythmia, and reduced capacity of the blood to deliver oxygen. Smoking appears to influence many steps in the development of CHD. Although not all of these effects are proven fully. the evidence for an influence on several mechanisms is convincing. The exact components of cigarette smoke that are responsible are not known in each instance. but experimental data have implicated nicotine and carbon monoxide (CO) in several processes. Other products of cigarette smoking, such as cadmium. nitric oxide. hydrogen cyanide. and carbon disulfide. have been hypothesized to play a rote. but their quantitative contribu- tions remain unknown (US DHHS 1983). Atherosclerosis Atherosclerosis is the mechanical narrowing of medium-sized arteries by the proliferation of smooth muscle cells. lipid accumulation. and ultimately. plaque forma- tion and calcification (Munro and Cotran 1988). These lesions develop over decades and are not immediately reversible; whether they are substantially reversible at all in humans is a matter of current interest. Reversibility has been demonstrated in non- human primates (Clarkson et al. 1984: Malinow and Blaton 1983) and huggested in studies of humans using repeated arteriography (Blanhenhorn et al. 1987). Smohing is I91 clear]) associated with the presence of atherosclerosis of the coronary arterie>, small arteries of the myocardium. the aorta. and other vessels ;I\ demonrtrated in man! autops) and angiographic studies (US DHHS lYX3). The development of athero- sclerosis is complex. and several processes are likely to be important. Endothelial damage is thought to play ;I primary role in the development of atherosclerosis by exposing the arterial intima to blood lipids and white cells and bj stimulating platelet adhesion. The endothelial damage can be an actual physical denudation. but toxic functional damage may have similar consequences. In animal studies. serum nicotine at levels similar to those of human smokers caused endothelial damage (Krupshi et al. 19X7: Zimmerman and McGeachie 19X7). Evidence that smoking has a direct toxic effect on human endothelium is provided by the observation that smoking 9 tobacco cigarettes approximately doubled the number of nuclear- damaged endothelial cells in circulating blood (Davis et al. 198.5. 1986): smoking non-tobacco cigarettes had little effect. In addition. Asmussen and Kjeldsen (1975) found pronounced degenerative changes of the umbilical artery endothelium at the time of delivery among mothers who smoked: these changes were not present in the arteries of nonsmoking mothers. Smooth muscle cell proliferation is a primary feature of atherosclerotic lesions and may result from several stimuli: the mo5t clearly demonstrated is platelet-derived growth factor from adherent platelets. Smoking appears to increase the adherence of platelets to arterial endothelium: blood draun from persons after smoking 3 cigarettes results in a more-than-hundredfold adhesion of platelets to rabbit endothelium than does blood drawn from persons before smoking or from ne\`er smohers (Pittilo et al. 19X1). Platelets from chronic smohers have a greater tendenc) to aggregate on an artificial surface than do those from nonsmokers (Rival. Riddle. Stein lY87). In minipig>. both cigarette smoke and CO increase the adhesion of platelets to arterial endothelium (Marshall I YX6). The intluence of smohing on platelet activity is discussed further in the following section. Lipid infiltration of the arterial intima. largely cholesterol, is another primaq feature of atherosclerosis and is directly related to higher blood levels of low-densit! lipoprotein cholesterol (LDL-C) and reduced blood levels of high-density lipoprotein cholesterol (HDLC'). Smoking reduces the level of HDL-C. A strong inverse associa- tion betv,eren daily cigarette consumption and HDL-C has been observed in man) cross-sectional studies in the United States (Freedman et al. 19X7; Gordon and Doyle 19X6: Reichle!, Mueller. Hanis et al. lYX7: Willett et al. IYX3) and in other countries (Assmann. Schultc. Schrleuer IYXI; Goldhourt et al. I9Xh: Gomo lY86; Jacobsen and Thelle IYX7: Pellctier and Baher IYX7: Robinson et al. 19X7: Tuomilehto et al. 19X6). In a longitudinal. community-based study. HDL-C decreased among persons starting to smoke and increased among those &ho stopped smoking (Fortmann. Haskell. Williams 19X6). In other prospectike studies. smoking abstinence ha\ been associated M,ith substantial increases in HDL-C levels in both men and women (Hulley. Cohen. Widdouson IY77: Hubert et al. 19X7: Rabhin 19X-t). In a stud) among young adults in Louisiana. those \vho began smohing experienced substantial reductions in HDL-C compared with those u ho did not start (Freedman et al. I%%). HDL-C increased among I3 adult women who \uccessfully stopped smohing for 18 days. but decreased to its previous levels among those vvho returned to smohing (Stamford et al. IYXh). Thus. data indicate that smoking reduces the level of HDL-C. a potent protective factor against CHD. In a number of studies. smokers ha\,e been found to hav,e higher levels of triglycerides (Freedman et al. 19X6: Jacobsen and Thelle 19X7; Gomo 19X6: Willett et al. lYX3): however. the independent relation of triglyceride level with rish of CHD is not clear. Smoking appears to have little. if any. relation with LDL-C level. Howsever. smokers have approximately twice the level of serum malondialdehydt of nonsmohers (Nadiger. Mathew. Sadasivudu lYX7): malondialdehyde can alter LDL-C and may promote its incorporation into arterial wall macrophages (Steinberg et al. IYXY). In a metabolic study among young men. smokers had a decreased cholesterol net transport from cell membranes into plasma. which could partially explain the accumulation of cholesterol in arterial walls (de Parscau and Fielding 19X6). Thrombosis Coronary artery thrombosis, resulting from platelet-fibrin thrombi, is a key element in most cases of MI. Thrombi are visualized in a high percentage of coronary arteries studied angiographically within hours of the onset of infarction (DeWood et al. I YXO). and agents that lyse thrombi are effective treatments for MI (Stampfer et al. 19x7; Loscalzo and Braunwald IYXX). The efficacy of aspirin. an antiplatelet agent. in preventing MI further supports the role of thrombus formation (Steering Committee of the Physicians' Health Study Research Group lYX9). The finding that smoking is associated with history of MI even after controlling for atherosclerosis (Hartz et al. 19X I ) emphasizes the importance of mechanisms in addition to those that promote atherosclerosis. Platelets play a central role in thrombus formation in addition to releasing growth factors that stimulate the proliferation of smooth muscle cells in arterial intima (Pack- ham and Mustard 19X6). Platelets can form microthrombi that become incorporated into the arterial wall, thus contributing to plaque formation and participating in generation of larger platelet-fibrin thrombi that may acutely occlude a coronary artery. Smoking cigarettes acutely increases spontaneous platelet aggregation in humans (Davis et al. 1985) and in dogs with coronary artery stenosis (Folts and Bonebrake 19X2). Madsen and Dyerberg ( 19X4) observed that smoking 2 high-nicotine cigarettes substantially reduced bleeding time among healthy young men, although ex vivo tests of platelet aggregability vvere only minimally inhibited. In this study. smoking low nicotine cigarettes and inhalation of CO had little effect on bleeding time. Shortened platelet survival, an indirect indicator of activation. was observed in smokers and reverted to normal after 4 weeks of smoking abstinence (Fuster et al. 19X I ). Studies of smoking and platelet aggregation ex vivo in response to the typical stimuli used in the laboratory. such as adenosine diphosphate (ADP) or thrombin. are incon- sistent. Increased aggregation has been seen with platelets from chronic smokers (Belch et al. 1984) and in blood drawn IO minutes after smoking I cigarette (Renaud et al. 19x5; Renaud et al. 1984); in the latter study. aggregation was associated with blood nicotine levels but not with carboxyhemoglobin (COHb) levels. However. in other studie\. ex viva platelet aggregation was not related to cigarette smoking (Pittilo et al. 19x3; Dotevall et al. 19X7: de Loyeril et al. IYXS: Madsen and Dyerberg 19X3). In one large study. aggregation in response to ADP stimulation was actually somewhat greater in nonsmoker\ (Meade et al. 19X5). Studies of the effect of smoking on platelet production of thromboxane. which mediates the aggregatorv effect. have also been inconsistent. In some studie\. smohing was found to acutely increase thromboxane blood levels. which reflect the capacity to produce thromboxane in response to stimula- tion. and urinary metabolitea. which reflect the normal steady-state production (Toivanen. Ylikorhala. Viinihka 19X6: Marasini et al. 19X6: Fischer et al. 1986). However. serum thromboxane B? level\ were found to be similar among chronic smokers compared with nonsmokers in another study (DotevaIl et al. 19X7). The serious limitation\ of cx vivo aggregability measurements in the evaluation of in vivo platelet activity have been noted (Fitqerald. Oates. Nowak 19Xx). These researchers meawred urinary excretion of a thromboxane metabolite and found elevated levels in chronic smohers that were reduced to the level ofnon~mokers after aspirin administra- tion. suggesting ;I platelet origin of the excess excretion (Nowak et al. 1987). The luch of a consistent relation between making and ex viva te\ts of platelet aggregability despite the demowtration that platelets of smoker\ adhere more readily to endothelium has led to the suggestion that wioking inhibits the production in arterial walls ofprostacyclin. an inhibitor of platelet aggregation (Mad\en and Dyerberp 1984). Reinders and coworkers ( 19X6) demnnwated that the production of prostacyclin b) cultured human endothelial cells is impaired by incubation with cigarette \mokc condensate. Pittilo and colleague3 ( 1982) also found that smoking reduce\ endothelial cell synthesis of pro\tacyclin in rats. Thu\. in \.i\o making-related effects on platelet function may be mediated in part b>, an interaction with endothelium. Fibrinogen levels have been found to be elevated among smoker\ in numerow cross-sectional studies (Meade et al. 19X6: Kennel. D'Agostino. Belanger 19X7: Wil- helm\en et at. 19x3: DotevaIl et al. 19X7: Belch et al. IYX3: Ballei\en et al. IYX5). Fibrinogen levels. in turn. are \trongl!. related to ri\h ofCHD and stroke (Meade et at. lYX6: Kannel. D'Ago\tino. Bel;inycr 19X7: Wilhelmwn et al. t9X4). Smohing ce\w tion rewlted in ;I decrease in fibrinogen levels after 1 w,eeh\ among Y female moher\ (Harenberg et aI. t YX5) and after X LI eeh\ among I1 mule maker\ (Ernst and Matrai 1987). In the latter stud\. the level\ after X v,eeh\ \+eere similar to those among nc\`er maker\. When fibrinogen M;I\ remeasured after 5 bears. \ alues had decreased to the level\ofnever smoker\ among men u ho had stopped wiohin, L ~7 ,tnd had incren\ed amonp thaw M,ho started or rrsumcd wiohing (Made. Imcson. Stirling 19X7). In multivariate analk\e\ ofdata from the Fram~ngham Stud! (Kanncl. D'.Qo\tino. Belrmger 19X7) and Northu ich Parh Stud! (Me& et al. 19X6) that both included cigarette smoking as uell ;I\ fibrinogen le\ttl\, fibrinogen retained a clear independent a\socistion \\ ith ri\h ot CHD. whereas the effect of smohing \~a\ sub~tantiatt! reduced after the inclusion of fibrinogen in the model. Thi\ anatysi\ wggest\ that elevated fibrinogen le\,els ma> mediate a quantitativeI! important part of the effect ot` smoking on CHD rish. Other clotting abnormrrlitie\. such as increuwd plasma viscosity and reduced red cclt deformabilit>. that tend to promote thrombw formation ha\,e alw been obwrwd in smohers (Belch et al. IYX-!). In addition. Iewls of plawiinogen. which promote\ I\\i\ of thrombi. are lower in smokers (Wilhelmsen et a). 1983: Belch et al. 1984). but the levels increase after smoking cessation (Harenberg et al. 1985). Spasm Coronary artery spasm can cause acute ischemia manifested as angina pectoris and may promote thrombus formation at the site of repeated arterial constriction (Felts and Bonebrake 19X2). Both chronic and acute cigarette smoking have a demonstrable vasoconstrictor effect on the coronary vasculature (Klein 1 YX3). Compared V. ith never smokers. current smokers have an approximately twentyfold risk ofvasospastic angina pectoris (Scholl et al. 1986). Coronary artery spasm has also been identified bl angiography after smoking a single cigarette (Maouad et al. 1983). Smohing-induced vasoconstriction has been demonstrated in patients with atherosclerotic coronary artq disease (Martin et al. 19X3) that is mediated by an cx-adrenergic increase in coronary artery tone (Winniford et al. 19X6). In addition. smokin, L 0 3cutely increases platelet and plasma vasopressin (Nussey et al. 19X6) as well as the carrier protein of vasopressin and oxytocin (de Lorgeril et al. 1985). In addition to causing acute arterial spasm. cigarette smoking appears to be associated with a reduction in long-term coronary arter) diameter independent of atherosclerotic plaque (Fried. Moore. Pearson 19X6). although the mechanism for this relationship is unclear. Arrhythmias In some instances, arrhythmias can precipitate Ml by reducing cardiac output or increasing myocardial demand. More importantly. arrhythmias are a major complica- tion of infarction. Thus. reducing the threshold for serious arrhythmias tends to increase the case-fatality rate of MI. Cigarette smoking was found to lower the threshold for ventricular fibrillation in a study of animals (Downey et al. 1977) and was found to be associated with a 2 I -percent increased prevalence of ventricular premature beats on two-minute electrocardiographic rhythm strips obtained from IO. I I9 men (Hennekens et al. 19X0). Smoking-related ventriculararrhythmias may contribute to the occurrence of cudden death and to increased case-fatality ratios during the courre of MI. Reduced Blood Oxygen Delivery Cigarette smoking acutely increases myocardial oxygen demand b\, raising peripheral resistance, blood pressure, and heart rate (Martin et al. 1983: Klein 1984). Concurrently, the capacity of the blood to deliver oxygen is reduced by increased COHb, greater viscosity (Galea and Davidson 19X.S). and higher coronaq vascular resistance. Imbalance between oxygen requirement and delivery as a result of these factors is not likely to be a cause of MI but may contribute to infarction in the presence of significant atherosclerotic narrowing of vessels. Consistent with these mechanisms. low levels of COHb exacerbate myocardial ischemia during graded exercise (Allred et al. 19X9). and smoking is associated with more frequent and longer ischemic episodes detected by ambulatory electrocardiographic monitoring among patients M ith chronic stable CHD (Barr\ et al. 19X9). Blood and plasma 1 iscwities among former smokers are lower than thaw among current smoker\ and Gmilar to thaw amon never smoker\ (Ernst and Matrai 19X7 ). In the wit stud>,. both blood and pluma viscosity decreased after wioking ce\\ation and were similar to levels of never makers after X weeks. Reduced oxygen delivery to the myocardium ma) play a role in lowering the threshold for ventricular arrhythmias. In addition to influencing the development ofCHD. smoking ha\ been hypotheGzed to have direct toxic effect\ on the myocardium. Hartz and coworkers ( I9X-I) found ;i nearly threefold increavzd prevalence of diffuse ventricular hypoLine\is among heavy smoker5 compared with never makers within 3 population of patients undergoing diagnostic coronary ungiography and ventriculogrsphy. Smoking and Development of Peripheral Arterial Disease The extremely strong aswcistion between smoking and peripheral artery disease is likely to be mediated largely through the mechanisms that promote atherosclerosis (Criqui et al. 1989). The peripheral \awcon\trictive effect\ of smoking. mediated bj nicotine-stimulated release of catecholamines (US DHHS 19X3). are likely to play a further important role (Lusty et al. 19X I ). Smoking and Development of Cerebrovascular Disease Cerebrovawulur diwae reprewnt\ a heterogeneous group of pathologic processes that include infarction due to jteno\is and thrombo\i\ (referred to here a\ ischemic stroke). embolism from the heart. and hemorrhage from medium-hized vessels in the wbarachnoid space (wbarachnoid hemorrhage) and from microaneutyms of smaII penetrating vessel\ (intracerebral hemorrhage). The association of \mokinp with ischemic strobe i\ likely to be mediated largely through the mechanisms that promote atherosclerwis and thrombus formation. Associations between smoking and extent of cerebral artery athcrowlero\i\ ha\ e been obher\ ed at Irutop\) among persons u ho haw died of cauw\ unrelated to CVD (Reed et al. I9XX) and among volunteer\ in 3 crowaectlonal stud> evaluated b! ;I nonin\as~\.t` method (Rogers et al. 19X.3). Smoking was a1w ;I strong predictor of the extent and w~erity of cerebral ve\\el atherowlcro\i\ in an Italian multicenter \tud> of rever\ible cerebral ischemic attack> fPas\ero et A. 19X7) and in an in\c\tiyation of 2X pair\ of Finnish tn in\ (Haapanen et al. 19x9). The mechanistic ba\i\ i\ unhnoun for the strong relation hettieen smoking and \ubarachnoid hemorrhage (US DHHS 19X9: Shinton and Beever\ 19X9). which is thought to result mo\t commonl! from the rupture of a baccuI;Lr aneurysm. .Although hypertension i\ a\sociatcd uith thij occurrence. chronic \mohing is unrelated to w\tained elwation in blood prehwre. A ueah and clinically unimportant inverse relation with hypertension ha\ been \een in several studie\ ISchoenenbeqer 19X2; US DHHS 1983). although the association betw,ecn cigarette smoking and risk of hyper- tension was obser\,ed in 3 large pro\pecti\e ime5tigation (Witteman et al. 1990). .Anticipated Effects of Smoking Cessation on Risk of Cardiovascular Diseases Based on Know ledge of Mechanisms The possible effects ofsmohing cessation on the rish of CHD are illustrated in Figure 1. The incidence of CHD increases sharpI!, with age mm~, `7 both smohers and net CI smokers: similar patterns are seen V. ith other smohing-related cardio\,ascular diseases. At each age. the rates are higher for smohers. and the increase with age is more rapid among smokers (US DHHS 19X3: ACS. unpublished tabulations). probabl\ because ot the ongoing. cumulati\,e damage caused bj smoking. Thus. the absolute excess incidence or mortalit>. (attributable rish) of CHD due to smohing. represented b> the vertical difference bet&eeen the lines for- smokers and never smokers in Figure I. increases u ith age. However. the relative rish. represented b!, the ratio of incidence or mortality rates, tends to decrease with age. Theoretically possible outcomes ofsmokinfcessation are depicted by lines A. B. and C (Figure I ). Line A represents an immediate and complete reversal of the effect ot smoking. so that the quitter ahnost instantly assumes the rate of the never smoher. Line B represents the worst-case scenario: although the stimulus for progressive damage is removed. no reversibility exists so that the former smoker assumes a constant absolute excess risk above that of the never smoker. In this case. it is apparent that quitting would still provide a substantial benefit compared with not quitting and that the relatiic risk for a former smoker compared with a never smoker w,ould decline over time. An intermediate effect of smoking cessation is depicted by line C: the effects of smohinp are slow~ly reversed. and the rate for the quitter gradually approaches that of the never smoker. The effects of smoking on CHD are probably mediated by multiple mechanisms. several of which are well established. Some of the effects of smoking appear to be reversible within days or weeks, including the increase in platelet activation. clotting factors. COHb, coronary artery spasm. and increased susceptibility to ventricular arrhythmias. Other effects may be irreversible or only slowly reversible. such as the development of atherosclerosis as a result of smooth muscle proliferation and lipid deposition in the arterial intima resulting from lower HDL-C levels. Thus. persons who stop smoking are likely to experience a component of rapid decline in risk compared with those who continue to cmoke and another component that more slowly approaches the risk of never smokers. Because the effects of smoking are multiple and complex. the rapidity and magnitude of risk reduction achieved by smoking cessation can best be estimated by empirical data based on epidemiologic studies in humans. Available data are examined in detail in the remaining sections of this Chapter. SMOKING CESSATION AND CHD Epidemiologic evidence on smoking and CHD has been reviewed in detail in previous reportsofthe U.S. Surgeon General (US PHS 1964: US DHEW 1971. 1979; US DHHS 1983, 1989). After an exhaustive review of the data, the 1983 Report of the Surgeon General concluded that "cigarette smoking is a major cause of CHD in the United States for both men and women" and "should be considered the most important of the knon n CHD Mortality (par 100,000 porron - yrrrd 700 800 600 400 300 200 100 0 1 I 40 46 I I 60 66 Age L L 60 06 FIGURE I.-Hypothetical effects of smoking cessation on risk of CHD if mechanisms are predominantly rapidly reversible (A), irreversible (I!), or slowly re\ ersible (C ). (CHD mortalit! rates shown in solid lines are for men in ACS CPS-II, 198246.3 modifiable riA t`actors t'or CHD" I C'S DHHS 1983. p.6). O\erull. the Report noted that smoher\ ha\e about a 70-percent e\c`c`\\ death rate t`rom CHD. and hea\ ier vwLer\ have an even greater eaces\ risk. IYX Since IYX3. additional e\,idence has accumulated to further support these con- clusions. Some of these data were presented or summarized in the I YXY Report of the Surgeon General (US DHHS IYXY). For IYX5. cigarette smoking was estimated to be responsible for 71 percent of all CHD deaths in the United States among men aged 65 years or older and for 15 percent of CHD deaths among younger men. Tv.elve percent of the CHD deaths among women aged 65 or older and -1 I percent of those in bounger &omen were attributed to cigarette smoking. In 19X5. I I5.0()0 deaths from CHD were attributed to cigarette smoking. A large amount of data supports the vie\+ that active cigarette smohing substantialI! increase5 risk of CHD. Data also indicate that former smokers have a lower risk ot CHD than do current smokers. Despite methodolofic and geographic differences. the studies are remarkably consistent in demonstrating a reduced risk of CHD among former smokers. Much of this literature has been reviewed in earlier reports of the Surgeon General (US DHEW lY7Y: US DHHS lYX.3) as dell as h> Kuller and colleagues ( 1987). This Section reviews the epidemiologic e\,idence of the effects of cigarette smohing cessation on CHD rish. specifically MI and CHD death. The relevant studies ma\' be divided into those that examine the effect among apparently healthy individuals (primary prevention) and the effect among individuals already diagnosed uith CHD for risk of recurrence or CHD death (secondary prevention). Cross-sectional studies of the extent of coronary atherosclerosis also provide relevant information. Cross-Sectional Studies In a detailed study of coronary atherosclerosis. Auerbach and couorhers (lY76) examined I .O% autopsied hearts from patients at the East Orange Veterans Administra- tion Hospital and found that smokers had more severe disease than never smohers. with past smokers having intermediate levels. Those who died from CHD or diabetes or those who had hearts weighing more than 500 g were excluded. After aci,iustment for age. current cigarette smokers had a prevalence of advanced CHD that ranged from 11.7 to 33.4 percent. depending on the number of cigarettes smohed per day. The prevalence among never smokers was 5.3 percent compared with I I .O percent among former smokers. The prevalence odds ratio of advanced versus no disease or minimal disease was 2.4. when former smokers were compared with never smokers. In contrast. among current smokers of I to 2 packs per day. the ratio was 6.7. A similar pattern was observed for different pathologic manifestations of CHD. The effect of duration ot abstinence among former smokers was not analyzed. Ramsdale and coworkers ( 1985) used arteriography to assess the extent of coronar) atherosclerosis before surgery for valve replacement among 3X7 patients. All patients provided a smoking history, including age at initiation of smoking and cessation of smoking and average number of cigarettes cmoked per weeh. Among never smohers. X7 percent had no stenosis greater than SO percent: only 60 percent of past smohers and 60 percent of current smokers were without this degree of stenosis. Of never smohers. only 2.6 percent had three or more arteries affected compared with 10.6 percent of former smokers and 13.2 percent of current smohers. Both current and past smoher-\ had more were coronary artery diseaw. The median xx~re among ne\er smokers and current smokers was 0.2 and 7.X. respectively. For pa\t smokers. the data were prehented by duration since quitting. There was no evidence for a trend of decreased effect by increasing time since cesation. The median score for those quitting within the previou\ 5 year\ wa\ 5.0; for 5 to 10 year\. 5.0: and for IO year\ or more. 7.5. Coronary atherosclerosi\ was positi\,ely correlated with lifetime number of cigarette\ smoked among both current or past smokers. In this study. past smokers had a slightly worse coronary ri~ not repre~entati\e of the general popula- tion. Nonethelchs. the\e studies wpport the view that hmohing cause\ an increase in atherosclerosi\ and that very recent quitting has little impact on coronar!~ \teno\i\. Fried. Moore. and Pearson ( IYXh) studied the effects of \mohing h> a\he\Gng the coronary diameter in 3 I men \\ho had normal coronar\' arteringrams. Men M ith an! detectable \tenoGs in the main coronary arterie\ or more than 75 percent in an! coronq branch were excluded to assess the effect\ of mohing on the caliber of coronary arterie\ in the absence of atherosclerosi\. These researcher\ found that after udjuhtment for alcohol intahe (which i\ ;l\\ociated M ith u ider arteries ). current and former \moher\ had 10 to SO percent nxro~~er urterie\ than did neker smoher\. The pa$t \moher\ had someuhat narrower arterie\ than current smokers although thi\ uas not stati\ticall!. Ggniticant. Of the I I cx+mohcr\. 6 had quit in the previous year. This \tudg sugge\th the po\\ihility of another per\i\ting effect of mohing. apart from promoting atheroxlero\i\. not rapidI! raerwd b) cc\\stlon. Studies of Smoking Cessation and Risk of MI Among Healthy Persons Case-Control Studies Table I wmmarizes data from ca\e+wntrol \tudie\ (Wlllett et al. 198 I : Rosenberg. Kaufman. Helmrich. Miller et al. 1985: LaVecchia et al. IYX7: Rosenberg. Palmer. Shapiro 1990). of men and Momen from the LInited State\ and abroad. Prospective \tudie\ of CHD are generally considered lea prone to bias than ca\exontrol htudie\. although casexontrol \tudie\ are probuhly 1~54 susceptible to mi\cla~sificntion rewlt- in? from resumption of smohing mnong former smoker\. For example. an individual diagnosed u ith a recent MI can probably recall his or her \mohing \tatu\ .just before the infarction with cowiderable accuracy (Chapter 7). Thu\. c:l\exontroI \tudiek ma> TABLE I.-Case-control studies of CHD risk among former smokers Reference Population Number of CBIC\ Willett et al. (19X1) Nurses Health Study: women aged JO-55 263 5.260 Nested m cohort 2Y Overall I .o 10.7-1.h) 2.0 (7.34.0) Quit I-4 yr I .s (0.7-3. I ) Rosenberg. Eastern US men aged 45 1.x73 2.775 Hwpitnl-bawd Kaufman. Helmrich. Shaptro (19x5) Rosenberg. &tern US women aped 40 5.55 1364 Ho\pitnl-bawd Kaufman. Helmrtch, Miller et al. ( 1985) LaVecchia et al. (10x7) Italian women aged 45 IhX 2.51 34x 3s @It S-4 yr I.3 to.x-3.0) Quit 210 yr O.h(O.l-1.3) I.1 (O.`J-1.4) I 0(0.7-1.0) I .A-7.0 depending 011 cig/da, TABLE I.--Continued @IIt oungcr age group. and the excess risk declined with increasing duration of abstinence. In men aged 31 to 53 year\. the relative rish among former smohers of I to 4 \ ears' duration M ;I\ I .Y compared u ith ne\ er smohers: relative ri$k further declined to 1 .4 to 1 .3 with a maximum of 20 years' duration ot abstinence. In contrast. persistent smohers had a relative rish of3.S. In this study. those who quit had smoked about IO percent fewer cigarettes per day before quitting than did persistent smokers. The British Physicians Study also included 6. IY4 women. for whom the data \h'ere reported sepsrately (Doll et al. 19X0). These women completedquestionnaires in IYS I. I Y61. and 1973. In contrast to most studies among adults. a substantial minority of nonsmoking women in this cohort initiated cigarette smohing between 195 I and 1961. Thus. the rates of smoking-related diseases among thoe classified as never smokers are likely to be overestimated because never smokers. defined according to the 195 I data. included a proportion of subsequent current smokers. Overall. the relative risk of CHD mortality among former smokers was 0.Y compared with I .O to 2.2 among current smokers. depending on the amount smoked. Because there were only 26 cases among former smokers. a detailed analysis was not performed. The first large-scale American Cancer Society (ACS) cohort was assembled in 1952 when 1X7.783 men aged SO to 6Y. living in 9 States, completed a questionnaire related primarily to smoking (Hammond and Horn 19SXa.b). The men were enrolled by over 22.000 ACS volunteers each of whom was asked to enroll IO individuals, excluding those who were seriously ill. There was no further update of cigarette uce. These men were studied for fatal outcomes for an average of 44 months. for a total of 667.753 person-years. Cause of death for 1 1,870 individuals was determined by death certifi- cate. Compared with never smokers. the relative risk of death due to CHD among current smokers of less than I pack per day was 1.75. Among former smokers of less than I pack per day, those quitting within the previous year had a relative risk of 2.09. those quitting 1 to 10 years earlier had a risk of 1 .S4, and those quitting for more than 10 years had a relative risk of I .09. A similar pattern was observed among smohers of 1 pack or more per day: among current smokers, the relative risk was 2.3: among quitters within the past year. 3.00: among quitters of I to 10 years. 2.06; and among quitters of more than IO years, I .60 (Figure 3). The authors speculated that the elevated 20s TABLE 2.--Cohort studies of CHD risk among former smokers Aged 55~64 Quit I 3 yr I .9 5 0 yr I.4 lO~bl4yr 1.7 ?I5 yr I.3 I.7 Awl 26.5 < Quit I ~4 yr I .O 5 Vyr I.3 IO l4yr 1.2 >lSyr I.1 I .3 TABLE 2.--Continued Reference Populallon Followup Numtwr of caes cinlollg former smohers Rcl:n~vc rd.\ compn~wtt \* irh nwcr w~,her\" Ftrrmer Currrm \mohrrs winher\ (`ommenl\ L)oll cl al. (10X0) Brni\h phyxicinns: 6. IYl women Hammond and Horn (1YSt-h.h) I X7.7X3 men aged SW50 44 mu for CUD denth\ 2.3 x0 40 IX fl4 40 Hammond and ACS CPS-I: 35X.533 men free of (iarflnhrl ( 1069) diagnosed CHD 6 yr for CIID mortatlty 7') 57 SS S2 70 0.01 Quit< I )r 2.OY I 10>1- I.54 >I0 y,- I.OY Prevlou\ly >I ppd Quit i I yr 3 (H) I-IOyr 7.06 >I0 yr I .hO Prevwu\ly I-t') clg/d:q Qull cl yr I.hl I--l\r I.21 5 Yir I.26 IO 141, ().%I >20 \r I .IlX TABLE 2.--Continued Reldive ri\ks compnred with never smoker\" Kelerrncc tlalnmond ;md (Llrllnhcl I IYW) ~C(IIltIIlUcd) anlonp former wlokerr 62 IS4 13s I33 x0 Former Current wlnher\ wwkrrs Comment\ 2.5s Prevlou\ly 220 clg/dsy Quit lhjr 1.17 I 76 Women 220 L?r/d;l) QW Nyr 1.10 0.Y I. I (W-2.7) 0.7 Aged 3Y40 I .Y Aged SOL5Y I. I 2.3 Only baseline kmohing data wed 2.0 3.0 depending on amount mokrd No data on duratwn I.3 Smohing intirrm;ttion upduted biennially 2.5 TABLE 2.-Continued Number of case\ Rclativr ri\h\ compared wuh never vnohcr\" Reference Population Followup among former \moher\ Former smoher\ Current 5moher~ Comments Cederlofet al. (lY75) Sample ofSl. 91 I Swedish IOyr 07 Quit I-Y yr I .s lOLlI 1.7 men aged I X49 Only hawlme Smoked . SOURCE. Hammond and Horn ( lY5Xhl. risk among recent quitters reflected the inclusion of men who stopped smoking because of early symptoms of heart disease. A second cohort study. the ACS Cancer Prevention Study 1 (CPS-I) (formerly called the ACS Z-State Study). was undertaken between 19% and 1972. Recruitment was by family, and eligible families had at least one person aged 35 or older. All family members aged 3.5 or older wtere asked to participate in the study: more than I million persons were enrolled. In a 6-year followup of 358.513 men free of diagnosed serious illness. clear reductions in risk ofCHD mortality were observed among former smokers compared with current smokers (Hammond and Garfinkel 1969). Among those smok- ing less than I pack per day. the relative risk among current smokers was I .90. Among those who stopped in the previous year. the relative risk v.as 1.61. and amon_e those with 10 years or more of abstinence. the risk was nearly the same a\ that for never smoher5. A similar pattern was observed among those smoking 1 pack or more per day. Current smokers at that level had a relative risk of 2.55. Quitters of less than 1 year had a relative risk of I .6 1. and those with between IO and 20 years of abstinence had only a slightly elevated relative risk of I .2S. Because of the very large number of deaths and the careful followup. the estimates of effect are relatively precise. In this period. cigarette smoking declined substantially. especially in the predominantly white, mid- dle- to upperclass groups represented by the study population. Hence. some misclas- sification of the current smoking group may have occurred. but the relative risks among former smokers. apart from the most recent quitters (some of whom inevitably resumed smoking). are likely to be accurate. In 19X2. a third ACS cohort. CPS-II. was initiated in SO States. The methods for recruitment and the population enrolled were similar to CPS-I. but the cohort was larger, vvith more than I .2 million participants (Chapter 3). Preliminary data based on 4 years of followup were published in the 19X9 Surgeon General`s Report (US DHHS 1989). Among men. former smokers aged 35 or younger had relative risks of CHD of 1.31. those aged 36 to 63 had I .7S. and those 65 or older had 1.29; the relative rijhs among current smokers were 1.94 . 3.X I. and I .62. respectively. A generally similar pattern wa\ jeen among women. When the data are examined by amount of previous smoking and time since quitting. the pattern of changing risk is influenced by the presence of disease at enrollment. When those who reported themselves a\ sick or as having previously diagnosed cancer. heart disease. or stroke at baseline were not excluded from the analysis, men who previou4y smoked fewer than 2 I cigarettes per day and who had quit smoking within the previous 3 years experienced a CHD mortality rate that was about 6 percent higher than that among current smokers. However, vvith increasing duration of abstinence, the risk among former smokers came very close to that of never smokers: after I6 years or more. the relative risk was 1.01 (US DHHS 1989). It is likely that the early peak in mortality among recent quitters partly reflects the effect of having included those vvho quit because of smoking-related illness. After excluding those with cancer. heart disease, and stroke at baseline, this early excess mortality is less apparent (Table 2). In all categories. those who quit 1 to 2 years earlier had relative risks substantially lower than those of current smokers. Findings are less consistent for those who quit within the past year. presumably because of a high incidence of smoking resumption in that group and the possible inclusion of persons who stopped smoking as a result of symptoms due to undiagnosed illness. A very similar pattern was observed among men who smoked 21 cigarettes or more per day, except that the relative risks were higher for all but those with the shorter period of abstinence. The absolute rates were lower for women, as expected, and the relative risks are thus statistically unstable. Neverthe- less, the overall patterns among female smokers were generally similar to those among male smokers. To examine the effects of smoking cessation at different ages. CPS-II data on cumulative mortality rates due to CHD were tabulated for 5-year categories of age at cessation. (See Table 3 and Chapter 3 for a description of the methods used to calculate these rates.) The mortality rates used for these calculations were based on subjects not TABLE 3.- Estimated probability of dying from ischemic heart disease in the next l&5-year interval (95% CI) for quitting at various ages compared with never smoking and continuing to smoke, by amount smoked and sex Age at quitting or at start of mterval Never smoker\ Continuing \moken Former smoker\ ,sician's orders were excluded from the analysis. Mortalit!, in this cohort uas monitored. and death certificates were obtained to assess cause of death. Smohing status after the baseline questionnaire was not ascertained. After 16 years offollo~up. quitters at enrollment when compared with never smohcrs had relative risks of I. IS for all cardio\,ascular mortality and I. 16 for CHD death specifically (Roget and Murray IYXO). In contrast. men who uere current smokers at baseline had relative risks of 1.5X for these two categories. Among past smokers. risk of death due to CVD increased with higher pre\,ious usual daily cigarette consumption. The relative risks among past smohers. compared Gth never smohers. ranged from I .02 for less than IO cigarettes per day to I .33 for 40 ciparettes or more per day. This gradient M as more pronounced among current smokers I Figure 1). A gradient was also apparent for decreasing rish with increasing duration of cmohing abstinence. For both cardiovascular and coronary mortality. there was a moderate decrease in risk with short duration of abstinence and a smaller. but consistent decline in rish uith longer periods of abstinence (Figure 5). After 20 years or more of abstinence. the relative risk of CVD was I .04. and for coronary death. the risk M as I .05. The major strength of the U.S. Veterans Study is the large numbers. M ith 2 I.1 Ii deaths from CVD among smohers and 9.077 among former smokers. The long followup period without reclassification of smokin, (7 status is a limitation. \\ hich M ill tend to lead to an underestimate of the effect of sustained smohing and an underestimate of the benefit5 of quitting (Chapter 2). This source of potential bias ma! not ha\e marhcdl~ distorted the estimates in this stud!: in the follo~up of this cohort (Roget and Murray 19X0). the relative risk for cardiovascular mortalit\ associated M ith current smoking at enrollment \\a\ I .h? at X.5 years and I .5X at I6 !ears: for coronar\ disease. the relative rish U;I\ I .6l at X.5 years and 1.5X at I6 vex\. Thus. the impact of misclassification of current smohers M ho quit (and therefore lowered their rish) as persistent smohcrs appears to be slight. A similar comparison of the relati\.e rishs among former smohers is less int'ormati\e in assessing the impact ofmisclassificati~,n. hfost quitters u ho resume smohins do 40 ~~ithin 2 years after cessation. Thcret'tore. IniscI~Issit`ication of e\-smoher5 betuecn X.5 and I6 fears of cessation is likeI> to he small. For both cardio\us~ular mortalit! and coronar! mortalit>. the relati\ e ri&\ among ex-smohers declined slightI> from I .2 I at X.5 hears of follo\vup to I. I5 and I. I6 at I6 yxrs of` follow up. This is consistent u ith the in\ crst` relation bet~reen duration of smohing cessation ;und mortalit\' ratio. Among current mohers In the l:.S. Veterans Stud!. the relati\.e rishs of coronar> disease \\ere slightI> hisher after X.5 years of follow up (relati\ e rish (RR )= I .Y5 for >20 cig/da\ ) than after 2.5 \cai-s of follo~up (RR=1 .75 I tDom 10.54). As expected. tho\e M ho stopped smohing on ;I ph\ slcian's orders v,ere at higher rish of death regardless of their smohinf statu\. An earl!, report of combined data from the Framinyham and Albany Heart Studies (Do! Ie et al. I Yh2) included 4. I20 men free from coronq di\easc at entr) into the stud!.. The Framingham Stud) data were bard on 6 lrars oft`ollouup and the Albany &art Stud! data on X bears of follo\~up. .4mong the 4 I I former smohers in the combined cohort. the rcIati\t' rish of Ml (age-adiusted) U;I~ 0.Y compared u ith nt'\`cr 71X . Gordon, Kennel. and McGee (1471) assessed the effects of \mol\ing cessation. In thi\ analysis. anyone who smoked for I lear or more during the mo\t recent ?-year interval between examinations was considered ~1 current moher. Ap- proximately 20 percent of men who reported that they had quit smoking a~ entr! into the studs resumed \mohing: about halfofthose smoked very little oronly intermittentI> after resumption. Compared with current smoker>. former smokers had B 30.percent reduction in fatal and nonfatal CHD (escluding angina): the relati\,e ri\h ;imong current smokers compared w>ith that among never \moken was 1.3. Other coronary ri4 factor\ were examined in detail: there uere no \ipnificant difference\ between per\i\tent smohers and those who quit. but those who quit Mere more likely to be ill. Hence. it would be expected that acl.justment for confoundin, ~7 would have revealed even greater benefit from cea\ation. The benefit of quitting seemed more marked in younger men. However. there w'ere only 73 cases ofCHD amon? the quitter\ \o that a detailed analysi\ could not be performed. The Western Collaborative Group Study monitored a cohort of 3.514 men for an average of X.5 years for CHD incidence (Rosenman et al. lY75). Information collected at baseline among men aged 3Y to 39 indicated that former maker\ had a relative rirh of 1.9 compared with that of never smokers . 30 percent lower than among current makers. For men aged SO to SY. former smokers had a relative ri\k of I. I compared with never smokers. 40 percent less than among current makers. Thih effect of cessation wa\ slightly greater than that observed after 4.5 years of followup (Jenkin\. Ro\enman. ZyLanski 196X). The difference between the age groups could be a true effect or may reflect different levels of misclassification: it is possible that a greater proportion of the quitters in the younger group than in the older group resumed smoking. In 1963. a prospective . Ury lY7Y ). The Seven Countrie\ Study (Keys IYXO) provided a valuable resource for analysis of rish factors for CHD. A total of I6 cohorts of men. aged 40 to 59. living in 7 countrie\. were examined and monitored for IO vear\ for CHD incidence. The cohorts were assembled between lY5X and 1064. and consisted of I ?.OY6 men free from CVD. In each rrouping of cohorts. former smohers had a lovver ri\h of CHD than did current c mohers. Houever. only about 7X case\ of CHD death among former smokers were reported: therefore. no detailed analysis w'as possible. Data on the health effects of smoking cessation are also available from the Health Insurance Plan of Greater Nevv York. The incidence of MI uas ascertained over a 17-J --- 3-year interval among I lO.OOO individuals (Shapiro et al. 196Y ). A total of 613 cake\ of MI were reported among men aged 35 to 6-l in this group. Compared u ith current smokers. those who quit in the preceding 5 years had a %-percent lower risk: compared with never smokers. the relative risk was 1.0. As in other studies. the percent reduction in ri\k associated with smoking cessation tended to be lower in the older age group>. but a decreased risk associated with quittin g wa\ apparent among all ages. Many studies of smoking cessation have focused on middle-aged men and women. Even as recently as the late 1970s. current smoking was considered to be a minor ri\h factor for CHD beyond age 65 (US DHEW 1979 ). and the benefits ofce\sation among older persons have been questioned (Seltzer 1971. 1975 ). Jajich. Ostfeld. and Freeman (1984) assessed the effect of quitting among 7 2.674 recipients of public as\i\tance aged 63 to 75 in Cook County. IL. Of the 2.674 individual\ studied. 770 were paht \moher\. 873 were current smokers. and 1.248 were never smokers. Participant> were screened at baseline and monitored for 4 years for CHD mortality. Overall. former smoher\ had a relative risk of CHD mortality of I. 1 I (based on 20 exposed cases). whereas current smokers had a relative risk of I .94. The number of cases was inadequate for a detailed analysis of the effect of duration of abstinence. Perjon\ with heart problem\ \vere not excluded at baseline. Approximately one-third of the CHD deaths were among those with such a history: therefore, it is likely that the apparent benefits of quitting may be understated because of the tendency of such individuals at high risk to quit because of illness. These data provide some evidence that the benefit\ of cessation extend to older adults. The British Regional Heart Study (Cook et al. 1986) monitored 7.735 men aged 10 to 59 who were randomly selected from general practice lists in the United Kingdom. The men were screened at baseline and studied for 5 to 7.5 years for incidence of fatal and nonfatal CHD; in this interval, there were 336 CHD outcomes. Those with CHD at baseline were not excluded. Compared with never smokers. quitters had a relative risk of approximately 2.5: compared with current smokers. the relative risk u'a\ approximately 30 percent lower. Men who quit smoking within the previou\ 5 years had a relative risk of approximately 3.3, compared with 3.6 among persistent smokers. Those who had quit more than 5 years earlier had a relative risk of approximate11 2.3. but there was no evidence for a trend of decreasing risk with increasing duration since cessation. Even those who had quit 20 or more years earlier had an elevated rish. After adjustment for other risk factors, the relative risk in this group was I .6 (p=O. I I 1. As expected, the prevalence of CHD at baseline among quitters was significantI> higher than for either current or never smokers. Presumably. the diagnosis of dihea\c provided a motivation to quit. When these men waere excluded. the relative risks were attenuated. Nonetheless. for those who had quit in the previous 5 years. the relative risk was still elevated at 3.2. The total years of smokin, (7 w'as suggested ah the mo\t important variable. It was also suggested that cessation lowered ri\k primarily b\, preventing the accumulation of further years of smoking. It i\ noteworthy that although results of this study are adequate to show an elevated risk among past \mhers. the number of cases among former smokers is too small to provide precise estimates of rish at the various durations since quitting. For example. there are only I I ca\es in the proup that quit 20 or more year\ earlier. Many studies of large cohorts examined the effects of smoking primarily among men. However, the Nurses Health Study investigators reported on smoking and CHD in a cohort of 12 I.700 women monitored through biennial questionnaires from I976 to 1989 (Willett et al. 1987). Women with previously diagnosed CHD were excluded from the analysis. Compared with never smokers. former smokers had a relative risk of I.5 (9S-percent Cl. I .&2. I ). In contrast. current smokers had a substantially elevated relative risk. ranging from 2. I for smokers of 5 to I4 cigarettes per day to 10.8 for those who smoked 45 cigarettes or more per day. There w'as no further analysis for the effect of duration of abstinence. The authors suggested that the slight elevation in risk of ex-smokers was due. in part. to resumption of smoking by some fraction of the former smokers. Adjustment for age: obesity; menopausal status; estrogen use: family history of MI: and personal history of diabetes. hypertension. and high cholesterol in a multivariate analysis led to an identical relative risk of 1 .S. demonstrating the absence of confounding by these coronary risk factors in this population. In another cohort study. Floderus. Cederlof. and Friberg ( 198X) monitored 10.945 twins born in Sweden between IX86 and 1925. Smoking behavior was ascertained at baseline in I96 1, and the cohort was studied for mortality for 3 I years using matched- pair analysis. Among the males. former smokers compared with never smokers had a risk of coronary mortality of 1 .O (95-percent CI. 0.X-I. 1). In contrast. current smokers had relative risks ranging from I .4 to I .8 depending on amount smoked. There were no data on duration of abstinence at baseline. and there may have been changes in smoking prevalence during the long followup that would tend to attenuate the relative risk. In a unique cohort design. Raichlen and coworkers ( 1986) examined progression of atherosclerosis among 33 men who underwent coronary angriographies at least 7 years apart. Among current smokers. progression of disease waj statistically significant and was correlated with pack-years smoked during the interval. Among pa\t smoker\. the degree of progression of atherosclerosi\ was far Ies\ than among current smokers: it w'as not statistically different from lack of progression. Several other cohort studies have reported on the relation of smoking cessation M ith risk of CHD: however. the number of sub.jects was generally too small to contribute substantially to knowledge in [hi\ area (Table 7). Intervention Trials In >everal clinical trials. an attempt has been made to ev aluatc the effect of altering ri\h factors for CHD. including smohing (Chapter 3). !Uost of the trials including smoking cessation have also incorporated interventions for other CHD rish factors mahing it difficult to assess the independent effect of quitting. Nonetheless. the\e data have extended the understanding of the effects of mohing ce\\ation on CHD rish. AssesGng \elf-report of smoking cessation or decrease in cigarette consumption is another potential difficulty. There may' be a tendency for sub.jects in a trial to seeh approv.al and avoid ne gative feedbach by, reportin, 17 le\s cigarette use than i$ actually the case (Chapter 2). Such a tendency would have the effect of miscI:t\\ification and would yield an underestimate of the benefits of cessation (Table 1). 72-l TABLE 4.--Intervention trials of smoking cessation and CHD risk Rcferencc Population Intervention oulcome caw\ among fwnmer moher\ Effect of wlohing ce\sttton (nonrandom~~ed) Hughe\ et al. ( I')81 ); MRFIT: I?,Xhh healthy US Diet, reduction in weight. CHD death\ I5 7% declme iI1 4J1k reduction MRFIT Research tnen aged 35-57 at high CHD hypertenswn, and smoktng interventwn group compared with Group ( 1982. I YX6): r&k peralwnt smokers Grimm (19X6): Ockene et al. MRFIT: 7,663 participant (IYYOI smokers at entry Diet. reduction in weight. hypertension. and smohmg (`HD dcnth\ 33 Quitter\ had 42% reduction t Ih~hO'% 1 MRFIT: h.Y43 participant smoker\ at entry Diet. reduction in weight, CHD death5 I2 hypertrn~ion. and amohlng Iljrrmann et al. (IYXI) Oslo study: I.232 healthy Diet and wioking Oslo men aged 4(WY 31 high C`HD risk Kornttxr et al. (IYX.31 I Y.409 male Helgian tlctory workers. aged 40-51) Anti\moking. hypcrtcn\ion control The Multiple Risk Factor Intervention Trial (MRFIT) was designed to test whether reduction of diastolic blood pressure. serum cholesterol. and cigarette smoking decreases the incidence of CHD (Hughes et al. IYX I: MRFIT Research Group IYX6: Grimm 19X6). Men aged 35 to 57 were screened: of those in the upper IS percent ot CHD ri\k (based on coefficients from the Framingham Study ). but without overt CHD. 6.428 were randomized to special intervention. and 6.438 were a\\iyned to usual care. Men in the special intervention group were given intensive instructions concerning diet and hmokinp cessation and were treated for hypt'rtenxion. Thox in the usual care group were referred to their regular source of medical care. The difference in total cholesterol between the two groups was only half that expected: because of better than anticipated hypertension treatment in the usual care goup. the difference in blood pressure w;ts also substantially less than expected. At the outset. 5Y percent of the participants were current cigarette smokers. After 12 months. 3 I percent of the smokers in the interven- tion group had quit (verified by thiocyanate (SCN-) levels) compared with 12 percent of the smokers in the control group. At the end of the h-year trial. 16 percent of smohers in the intervention group had quit compared with 2Y percent in the control group. Mortality resulting from CHD was only 7 percent lower in the special care group. a difference that did not approach statistical significance. The authors suggested that the small decrease in risk was due in part to the smaller than anticipated differences in risk factor levels between the twogroups and that aomeofthe benefit in rich factor reduction might possibly have been counterbalanced by an unfavorable response to antihyperten- sive therapy in some of the hypertensive patients (MRFIT Research Group 1982). Within the intervention group. those who quit in the first year had a multivariate- adjusted relative risk SO percent lower than that of persistent smokers: in the control group. adjusted relative risk 30 percent lower than that of persistent smokers. In thi4 trial, risk of sudden CHD death was reduced 65 percent among quitters compared with persistent smokers. Because all participants were seen at least annually. the possible misclassification of smoking status vvas minimized. The lO.S-year followup data from MRFIT have recently been published (MRFIT Research Group 1990). Deaths due to CHD were 10.6 percent lower in the special intervention group (95percent Cl.-23.7 to 4.9) compared with the usual care group (two-sided p value=0.24). This reduction in risk was largely attributable to a 24.3. percent lower risk of death due to acute Ml (2-sided p value=O.o4). Total cardiovaxular mortality was 7.1 percent lower after 10.5 years in the special intetvention group compared with the usual care group (p>O.OS). In one analysis not based on randomized groups. CHD mortality rates of smokers who had quit within the first I2 months of the trial and of those who were still smoking at that time vvere compared (Ockene et al. 1990). Quitters had a 37-percent reduction in mortality. After adjustment for other CHD risk factors. the reduction was 42 percent (95-percent Cl. 16-60). The slightly greater benefit observed after adjustment for risk factors indicates that there w.as little confounding and that it w'as in the direction that would tend to underestimate the benefit of cessation. This analysis ignored any changes in smoking status after the first annual examination. To the extent that either some of the quitters resumed smohing or some of the current smokers quit. that analysis would yield an underestimate of the benefits of cessation. A second analysis compared quitters who remained abstinent at the first "7 -- three annual examinations u ith persistent smohers. In this analysis. which uould be aft'ected to a lesser extent by misclassification. former smohers had a 65-percent reduction in risk compared with persistent smokers (YS-percent Cl. 37-80). A trial using a somewhat similar design was conducted in Oslo. Norway (Hjermann et al. 1981: Hjermann. Holme. Leren 1086). Males aged 40 to 19 were screened for coronary risk. and normotensive men at high risk of CHD due to elevated serum cholesterol, smoking, and other risk factors were identified. The participants had no clinical CHD at the time of randomization to the intervention or control group (N=603 and N=h?X. respectively). The intervention consisted of advice and instruction on altering diet and reducing smoking. Participants Mere examined at least annually during the 5 years of followup. After 5 years. fatal and nonfatal CHD was reduced in the interventioryroup by 37 percent. There uas greater success in reducing cholesterol in this trial than in inducing smohiny cessation. The mean serum cholesterol was ap- proximately 13 percent lower in the intervention group than among the controls. However. only 3 percent of the smohers in the intervention group and I7 percent in the control group quit entirely. although many reduced the amount moked. There was an inverse relation between CHD incidence and percentage change in tobacco con- sumption. but this did not attain statistical significance. The authors calculated that approximately 3 percent of the difference in CHD incidence betbeen the two youp\ was attributable to differences in smoking. A second report (Hjermann. Holme. Leren et al. lY86) included fo`ollowup through 101 months. Statistically significant reduction\ among the intervention group com- pared with the control group were seen for fatal coronary events (reduced 59 percent ). total coronary events (reduced J-1 percent). and total cardiovascular events (reduced 61 percent). The World Health Organiration European Collaborative Trial in the multifactorial prevention of CHD M;IS conducted at several sites in Europe. Pooled results \rere reported from center\ in the United Kingdom, Belgium, Itall. and Poland (WHO European Collaboratik e Group I YXi ): separate reports have also been published from centers in the United Kingdom (Row. TunstalI-Pedoe. Heller IYXi) and Belgium (Komitler et al. 19X3 ). A total of 66 l`actories invoh ing 19.78 I men u ere randomi& to a multitactorial risk t`actor reduction program or to the control group. The reduction ot Ieve]\ of risk t`actor\ \ arictl considerahl\ among the center\. O\wal I. the reduction in risk factor Ie~els \+:I\ modest. and there \+ ;I\ no significant decline in CHD endpoints in the intervention group. The et`t'cct on CHD \$a\ broadI\ correlated u ith changes in rish factors. There M as no qecitic anal! sic on the impact of smoking cessation. The Belgian center M ;I) the Iaryst in the European Collaborati\ e Trial. Fifteen pair\ of factories uere rundoml! allocated IO the inttwention or control group\. u hich included IY.-lOY men aged 10 to 5Y vearc. The intervention included ad\ ice about smoking cessation and reduction of h!,pertension and clc\ ated cholesterol. Subjects were screened as part of the trial. but referred to their ou n phb sicians for therap!,. After 6year\. there ~a\ a 24.5percent reduction in fatal and nonfatal CHD in the intrr\ention group compared M ith the control 5 woup (p=O.O3) (Kornit/er et al. 19213). The rates in the intervention and control groups continued to diverge throughout the follow up period. No specific analysis wasconducted to assess the independent effect ofsmohing cessation on risk of CHD. The multifactor primary prevention trial in Gotebor,. 0 Sweden focused on reduction of hypertension, elevated serum cholesterol. and smoking (Wilhelmsen et al. 19X6). A random sample of 10.003 men aFed -IS to 5.5 years was included in the inter\.ention group. and 2 other random samples of the same size were identified as controls. Ot those invited to participate in the intetvention group. 7.3YS attended the first screening examination. At the outset. w'ithin the interv/ention and control groups combmed. 70.6 percent were former smohers. After 1 years. the proportion of former smohers in creased to 17.7 percent. and after IO years to 3Y.4 percent in the intervention group. In the control group. the percentage of former smokers also increased-to 22.3 percent at 4 years and to 36. I percent at IO years. The differences achieved for other risk factors between the intervention and control groups were also quite small. After IO y'ears. there w'ere virtually no differences in fatal and nonfutal outcomes between the groups. The center in the United Kingdom was also large (Rose. Tunstall-Pedoe. Heller 19x3 ). with I2 pairs of factories and I X.7 IO men aged 40 to SY years. There were only very modest changes in risk factors other than cigarette smoking. The reported number of cigarettes smoked per day in the intervention _rroup decreased by I6 percent. but the proportion of current cigarette smokers decreased by only 4 percent. Rose and Hamil- ton ( 197X) stated that whereas self-report ofcessation is likely to be reasonably accurate. reported decreases in smoking are probably exaggerated. With such small net changes in risk factors, it is not surprising that there was virtually no difference in the rate of CHD between the two groups. Only one trial has attempted to assess the effect of advice for smoking cessation without intervening for other risk factors simultaneously. In theory. trials of this design can provide the clearest indication of the effect of such advice in the absence of other effects. Participants were selected from a cohort of 16.016 from the Whitehall Civil Servants Study (Fuller et al. 1983). From this group. I .44S high-risk male smokers aged 40 to 59 were randomized to a normal care group or the intervention group that received antismoking advice. At year one, 5 I percent of the intervention group reported that they were not smoking. and at year three. 36 percent reported the same. In the normal care group. the corresponding percentages were IO and I3 percent. A third of the quitters reported smoking cigars or a pipe. It is important to note that the question- naire response rate at 3 years w/as 64 percent in the intervention group and 70 percent in the normal care group (Rose and Hamilton 197X). The 9-year response rate was X3 percent. At that point. 55 percent of responders in the intervention group reported quitting. as did 41 percent in the normal care group. Despite the similarity of smoking prevalence of the two groups, at IO years CHD mortality decreased by IX percent in the intervention group. This difference did not attain statistical significance (YS-percent CL 43 to +I8 percent) (Rose et al. 1982). Smoking Cessation and CHD Risk Among Persons With Diagnosed CHD Studies examining smoking cessation and CHD risk among persons with diagnosed CHD may be less prone to some of the methodologic pitfalls discussed in Chapter 2. In many instances. studies are primarily of individuals who were smokers up to the time of the infarction. Such a major health event can be a powerful motivation to quit smoking permanently. Moreover. the timing of quitting often coincides with the infarction and is therefore ascertained quite accurately. Because those with a prior diagnosis of CHD are at such high risk for another event. the estimates of effect can be relatively precise, even with a modest number of individuals under study. One difficulty in interpreting these studies is in the comparison of quitters with never smokers. Never smokers who suffer MI tend to have a worse CHD risk factor profile (apart from smoking) than smokers (Mulcahy 1983). However. most of the other risk factors are less amenable to change than smoking. After smoking is removed as a risk factor among former smokers. the effect is often a better prognosis than that for never smokers. Several of these issues and a review of the literature prior to 1983 are discussed by Mulcahy ( 1983). This researcher found that studies were quite consistent in showing that quitters had about half the risk of recurrent MI or CHD death compared with persistent smokers (Mulcahy 1983). Nearly all studies of this issue have indicated a benefit of cessation (Table 5). A cohort of 113 patients who survived for 28 days a first attack of coronary insufficiency or Ml was studied for 5 years (Mulcahy et al. 1977). Of these, I90 were smokers at the time of the event. Of the 89 who stopped. the cumulative 5-year death rate was 14.6 percent. Of the 32 who reduced cigarette use. the rate was 13.1 percent. However, among the 59 persistent smokers. _ 78.8 percent died within 5 years. Nearly all of the deaths were associated with CHD. This study was extended by further accrual of patients and followup of 55 I men less than 60 years of age (Daly et al. 1987). Of the 406 current smokers at the time of the event. I40 had stopped by year two. Those quitters had a IO-percent reduction in risk of sudden death and a lo-percent reduction in risk of total mortality compared uith those who continued to smoke. A 197X report from the Framingham Study (Sparrou. Dawber. Colton 197X) com- pared the survival of 56 individuals who quit smoking after a first MI with I39 who continued to smoke after the diagnosis. Within 2 to 3 years after diagnosis. former smokers had a significantly better survival rate than persistent smokers. The 6-year mortality rate (estimated by life table methods) wa\ IX.8 percent among quitters compared with 30.4 percent among persistent smokers. When the risk of recurrent Ml ~`as a\se\sed. the authors found that former smoker\ had a lower risk than persistent smokers. with a h-year reint`arction rate of IS.5 percent in quitters versu\ 2 I.5 percent among smoker\. Howe\cr. with only eight reinfarctions among the quitter\. the differences were not statisticull~ Ggnificant. The rate of decline in risk could not be assessed because of the small \ampie\. Framingham Study investigators (Hubert. Holford. Ktinnel 1982) conducted a long- term followup study of I30 sub.jects uith angina pectoris. They found that smoking statu\ at the examination ascertaining unyina ~a\ modestly associated with jubsequcnt risk of a later. more \etious CHD outcome. Apparently. the change in smoking behavior explained this findin:. Of the angina patients who smoked. 1-l percent quit between the onset of disease and the biennial examination v, hen the diagnosis uas confirmed. Another 29 percent quit during the follow up period. In this cohort. the heavier makers TABLE S.-Studies of the effect of smoking cessation on persons with diagnosed C:HD Rctlucl~on in r14 Population Mulcahy et al. (lY77) I90 Dublin men aged 40 who smoked at time of first coronary inwfficlency or MI Daly CI al. (1987) 373 men aged <60 who smohed at mnr of first MI or unstable angina and wrvwed ? yr Sparrow. Dawher. and Colton ( 107X) Framingham Heart Study: lY.5 cohort member\ who \mohed at time of first MI Hubert, Holford. Framingham Hzxi Study: a~h~ject~ Karmrll ( IYX2) with anpin;i Average Y.4 yr: NR <16yr 6 yr IO dcxh\ Qh yr NR Salonu1 ( IYXO) North Karrlla. Finland: 523 men aged 4.5 who smokc`d 31 first MI 3 yr 76 tlc;uh\: 71 (`HI) tlc;nh\ `I'AHLE S.--Continued Followup Keductmn ,n rl?k compared with persistent smoker\" Comments Aherg et al t 10x3) YX3 (iotchorg n~lc wwher\ < 10.5 yr ;,I time ot MI 44 recurrent nonfatal MI NK IO4 recurrent nont`a~al MI: X0 CHD death\ 33% reduction: X% in qumer\. 12% in per\iwnt \mokers X0% (tormer and never Former and never wwhw \moher\ ~5. perhlhtent consdrred together. not hmoher5) \epararcly 30%; dltterence klwren groups increawd with tune 30% quitters had wow predlcted prognwls at hawline. no further a\w~wvznt of smoking kyond 3 mo after Initial MI 60% ovemll: 40% firct h yr: X0% 7-l 3 yr Followup kgan 2 yr after MI. when smobmg status was as\ewzd TABLE S.--Continued Reductmn in rlsh Reference Population Followup Cahes among former smokers compared with per&trnt Amoker? Johansson et al. (198.5) I56 Giitehorg women aged 565. smokers at time of first MI S yr I? deaths 60% (X0-20) Quitter\ had wow baseline progno\i\: dlfferencea hrtwren group\ were apparent early and incrrawd with time Perkins and Dick (10X5) I IY UK patient\ who smoked at first MI S yr Y death\ Vlietctra ct al. (19X6) I I.605 patients in CASS who woked S yr By risk quartile: at time CHD was diagnwed hy angiography the\11 I: 13 2: ?I 3: 44 (wow) 4: 1.56 ovel.illl: 234 Hcrmanson et al. (IYXX) 3.045 CASS patients with CHD aged x-54 5.3 yr for Ml or death 35 54 y,: NR I .X93 CASS patients with CllD aged 2.55 SS-SO yr: YY 6lMv-l yr: Y2 6%6Y yr: 4X >70 yr: 1Y Total mrwtality: 30% 40% 50% 20% 10% (X-20) 4O'X tso-20) 30% (SO `0) 30% (SO IO) 10% (60 0) 70(/r (X0-30) Quitter\ had worw hawl~ne prognw~\: e\cluwn of thow H ith mixed amohinp hchnvior and clwc' follouup reduced lihelihood 01 nli\cla\\ificalion 01 cxpowrc: iilw. ho\l~~t;~ll/atio~i for MI -a\ wh\lantially Ircduccd in former \mohcr\ Rcanaly\,l\ of :I \uhwt ot p;ltlent\ an;~ly/cd hy VIIC`thtra ( IYXh) TABLE S.--Continued 1 yr 5 yr IO yr YY% YX'k Y7% X-l% YS% 5 I % v.ere more likely to quit than the lighter smokers. Former smokers had a lower rate of subsequent CHD. There was a suggestion that older persons benefited less: however. this finding could not he confirmed because only a small fraction ofthe 25 older smokers actually quit. Salonen ( 1980) monitored a Finnish cohort of men less than 6.5 yeaJ3 of age ~4 hose smoking behavior \Y;IS assessed 6 months after MI. Of these. 352 were never smokers. 302 were persistent smokers. and 231 quit smoking u,ithin 6 months after Ml. Three years after MI. quitters had a -K-percent reduction in risk of total mortality (95percent CI. IO-60 percent) and ofCHD death (95percent Cl. IO-60 percent) compared uith persistent smokers. The reduction in risk was more pronounced in earlier periods: between 6 months and 1 year. mortality was reduced by 60 percent (95percent Cl. IO-80 percent). It is possible that the apparent decline in benefit may represent misclassification because current smokers continued to quit but were still analyxd as current smokers. The benefits of quitting were strongest among those with the best prognosis after infarction. Of post-MI deaths. 2X percent were estimated to be at- tributable to continued smoking. As part of the Norwegian trial of timolol use after Ml. mortality of the I.881 participants was ascertained over an average of 17 months according to smoking status. Virtually no differences were observed (Von der Lippe and Lund-Johansen 1982). Across both the timolol and placebo groups. 8 percent of the nonsmokers died. compared with 8 percent of those who stopped smoking before entry into the trial. 7 percent among those who quit in the first month of the trial. and 8 percent amon? persistent smokers. However, there was a reduction in reinfarctions, 8 percent among those whoquit in the first month of the trial compared with 12 percent among persistent smokers (Ronnevik. Gundersen. Abrahamsen 1985). Shapiro, Howat. and Singh (1982) monitored 142 patients who survived a first MI that occurred when the patient was younger than age 45. Of these patients, 50 who continued to smoke more than 20 cigarettes per day had substantially higher mortality rates (5%percent IO-year mortality by life table methods) than did the 61 never and former smokers (12-percent mortality). The survival curves began to diverge I year after MI. Unfortunately. data were not presented separately for former smokers. and apparently there were only a small number of never smokers. Aberg and colleagues ( 1983) studied 983 men aged 67 years or less who were listed in the MI Register of Giiteborg between 1968 and 1977. The men were smokers within 3 months of their initial MI. who survived hospitalization. Not all men listed in the Register were included in the study. but the selection process did not introduce bias. Quitting was defined as not smoking 3 months after the infarction. Followup began at that point and continued for IO.5 years. The 542 males who had stopped smoking by 3 months after infarction had a significantly worse prognosis. based on predischarge characteristics. than did the 441 persistent smokers. Those who quit had substantially more left ventricular failure and higher peak enzyme levels during hospitalization. Based on these and other preinfarction and hospitalization variables. those vvho quit had a predicted 2-year mortality that was 8 to 9 percent higher than that of persistent smokers. However. despite this slightly worse baseline prognosis. quitters had a significantly lower mortality than did persistent smokers. Overall. the j-year mortality was significantly reduced among quitters. with a cumulative mortality rate 30 percent lower. The effect was somewhat stronger among those aged SO or older than among younger men. but wa\ significant in both age groups. The cumulative S-year reduction in recurrence of Ml was 30 percent. These estimates almost certainly underrepresent te true effect of cessation for two reasons: quitters at baseline had a distinctly worse prognosis. and smoking cessation was defined only at the point 3 months after infarction. It is likely that some of the smokers quit at a later point: this would tend to dilute the smoking group with ex-smokers who enjoy a lower risk. Thus. the rates of mortality and reinfarction among truly persistent smokers would be underestimated in this study. The two groups began to diverge for both endpoints after as little as I year postinfarction. and the differences increased with time. This report confirmed and extended initial findings from that study (Wilhelmsson et al. lY75). Several studies have monitored patients with angiographically diagnosed coronary disease. Kramer and coworkers (19X3) studied 37X men with sequential coronary angiograms. These researchers found that neither cigarette smoking at the initial or followup examination nor smoking cessation was predictive of progression of atherosclerosis. Daly and colleagues (I 9X3) studied 2 I7 men who stopped smoking after a first diagnosis of unstable angina or MI and IS7 persistent smokers. Smoking status was defined 2 years after the first diagnosis. As in the Aberp study ( 1983). those who quit tended to have a more serious diagnosis than the persistent smokers. However, quitters enjoyed substantial protection compared with persistent smokers. For total mortality. risk was reduced by 60 percent among those who quit smoking compared with continuing smokers: for fatal reinfarction. risk was also reduced by 60 percent. During the first 6 years of follow up. the reduction in risk was 40 percent (95percent CI. IO-60 percent). but in the follouup period of 7 to I3 years. the benefits of quitting were more marked. with a reduction in risk of 80 percent (C)S-percent CI. SO-90 percent). The benefits of quitting were more marked among those with less severe initial disease. In this study, quitters had a lower cumulative mortality than did never smokers with these diagnoses. Those never smohers may havse had more coronary risk factors other than smoking which may be less amenable to change than smoking. In a later study with some of the same patients. Daly and covvorkers (1985) found that I year after the initial event. 24 I quitters had a IO-percent lower prevalence of angina compared with I33 persistent smokers. However. by 6 years of followup. the prevalence of angina waj the \ame in both group\ and remained similar throughout the followup pertod of I7 y'ears. Green ( 1985) noted that the prevalence of angina 6 months after infarction among X5 I ex-smokers was equivalent to that among smokers. How- ever. it is unclear whether the ex-smohrrs were smohing at the time of the event. Mo\t studies of the effect of post-411 cessation have been conducted among men. Johansson and colleagues ( lY85) examined I56 women in Goteberf. younger than 6.5. who were \moher\ at the time of their first MI. The definitions and criteria were the same as those in the study by Aberg and coworhers (1983). Three months after infarction. 75 women continued to smoke and 8 I had stopped. As in the Goteberg Study of men (Aberg et al. IYX3). women who quit had more severe infarctions. Despite the worse prognosis normally associated with the higher enryme elevations and other 236 indication\ of severity. the quitters had a significant11 better \urvi\aI. The reduction in rich compared with \mohers remained at 60 percent (95percent Cl. 20-80 percent 1. and after adjustment for prognostic feature\ before and during the Infarction. the reduction remained at 60 percent. When compared u ith never moher\. the relative risk among quitters w'as I. I, The reinfarction rate ~`a\ \lightl>. though not \ignit`icantl>. higher among persistent smokers. Similar finding\ for a rapid benefit Mere observed in the small \tud> of Pcrhins and Dick ( 1985). For S year\. these re\earchera monitored 53 paticnt~ (including I I women) \h.ho stopped \mohing at the time of the infarction and 67 prrsi\tcnt \moher\ (of whom IX were women L Men u ho quit had ;I SO-percent reduced ri\h of death: for women it was 60 percent loner. As part of the Coronary .Artery Surgery Stud!. the effect of \mohing cr\\ation on rish of clinical CHD outcome\ ua\ as\e\\ed in men with documented coronar! atherosclerosis by angiography (Vtictstra et at. iYX6). The death rate\ among t .490 quitters were compared with those of 2.675 persistent makers and 2.Yl2 never smokers. Men who were quitters at baseline but who \ub\equcntll resumed mohing and those who were smokers initially but later stopped were excluded from the analysis. Hence. this study was largely free of mi\clu\Gficstion. As in most of the other studie\. the quitters had slightly worse prognoses than did the persistent smohers. At e\`ery level of risk. however. quitters had a significantI>, better S-year survival. Overall. the reduction in risk (from Cox regression) was 10 percent (YS-percent Cl. N-SO percent). The benefit was slightly more pronounced amon, 0 those uith the worst baseline prognosis. Overall. the S-year survival rate among quitters uaz similar to that of never smokers (85 vs. 87 percent. respectively). Nearly all the benefit was attributable to a decreased rate of CHD death. After adjustment for prognostic score. the rate of hospitalization for MI was substantially higher among persistent smokers than among quitters (I I .3 vs. 7. I percent, respectively). For both fatal and nonfatal endpoint\. the rates began to diverge substantially after about I year (Figure 6). Because of the careful study design and the unusually large number of cases, the results of this study must be accorded considerable weight. In an extension of the analysis of survival data from the Coronary Artery Surgery Study, the effects of smoking cessation were examined in a population of individuals aged 55 and older with angiographically documented coronary disease (Hermanson et al. 1988). As in the previous report, persistent smokers were defined as those I .086 smokers who did not quit throughout the 6-year followup period, and quitters were those 807 who stopped smoking I year before the baseline angiogram and who did not resume smoking during followup. The experience of 3,045 younger subjects aged 35 to 53 years was also examined. At every age. quitters had better survival rates than did persistent smokers, and there was no evidence that the benefit was attenuated with increasing age. Employing a different approach, Hallstrom, Cobb, and Ray (1986) studied a cohort of 310 men who smoked and were discharged from the hospital after an episode of out-of-hospital cardiac arrest. After the arrest. i 7 I9 men continued to smoke and Y 1 men quit. During the average 47.5 months of followup. 67 persistent smokers and IX former smokers died of a recurrent cardiac arrest. After adjustment across baseline rish 3 I 1 2 3 4 5 TIME (YR) 0 Quitters A Continuers FIGURE 6.-Effect of smoking cessation on survival among men with documented coronary atherosclerosis: pooled survival among quitters ~3) (X=1,490) and continuers (A.) (N=2,675) SOI'RCE: Vltrlstrn et `11. ( IYX6). strata. this difference was of borderline significance in a life table analysis (p=O.O76). After exclusion of crossovers ( 14 smokers quit 26 months after the arrest. and 2 quitters resumed smoking). the benefit of cessation was slightly more pronounced (p=O.O48). Analysis of data from a trial of practolol also provided information on the effects of smoking cessation after MI (Green 1987). There were X55 never smokers. 1.344 persistent smokers. and X5 I individuals who quit smoking after the entry MI. Those who stopped smoking had a worse outcome initially than persistent smokers. and the benefit from cessation did not appear until 2 years after the event. When events in the first 6 weeks after the index MI were excluded. the benefits of cessation appeared at about 18 months. By 14 months, those who stopped had a 30-percent CHD risk reduction. As in other studies, former smokers when compared with continuing smokers tended to have more severe Ml. with significantly more pulmonary congestion noted when x-rayed and significantly greater occurrence of faster dysrhythmia. Thi\ supports the view that those with a worse MI are more likely to quit. and it explains why quitters in the study had a worse initial outcome. In a trial of rehabilitation after MI. l-17 patients in a Sw,edich hospital were routine11 invited to participate in a rehabilitation program: IS8 patients in a comparable hospital were not (Hedback and Perk 1987). The cardiovascular experience in the intervention 238 group was favorable, and when the specific effect of smoking cessation was examined among the X7 patients from both groups who quit after MI. approximately IS.9 percent died in the subsequent 5 years compared with 30.6 percent among the persistent smokers and I I .X percent among the never smokers. The influence of smoking cessation on frequency of restenosis after coronary angio- plasty was assessed by comparing X4 persistent smokers with 76 individuals who stopped at the time of angioplasty (Galan et al. 19Xx). Patients were reexamined angiographically after an average of 7 months. Restenosis was significantly higher in persistent smokers (55 vs. 3X percent. p=O.O3). Several other studies (Fleck et al. IYXX: Vandormael et al. 19X7) failed to find an association between smoking at angioplasty and subsequent restenosis. but those studies did not consider the impact of cessation at the time of angioplasty. Although the mechanisms of restenosis are not clear. the findings of Galan and coworkers (IYXX) are consistent with a fairly rapidly acting process for decreased risk after cessation. As part of the British Regional Heart Study described above. investigators also monitored I ,S 15 men with evidence of CHD but without Ml and 42X men with evidence of prior Ml at entry (Phillips et al. IYXX). Smoking behavior was assessed at baseline. and the men, aged 40 to 59, were studied for an average of 7.5 years. There was no update of the smoking information. After ad,justment for age and other risk factors. for those with non-MI CHD at baseline. the relative risk comparing former with never smokers was I .4: for current smokers, it was 2.1. For those with a history of MI. the relative risk for former smokers was I .7: and forcurrent smokers. it was 1 .Y. The degree of misclassification that may have occurred during the followup period is difficult to assess. No information is available on the duration of abstinence or the degree of severity of CHD as distributed by smoking status. In acommunity-basedfollowupof 325 post-MI patients in Baltimore. MD. Goldberg. Szklo, and Chandra (1981) found that after control for several clinical and sociodemographic factors. survival among those who quit at the time of MI was substantially improved. The I-. S-. and IO-year survival rates among those who quit were 99. 97. and 95 percent, respectively; in contrast. the rates among persistent smokers were 9X. X4, and 51 percent, respectively. Despite the lack of updates on smoking behavior. there was a trend for diverging survival between the two groups. Summary of Smoking Cessation and CHD Risk Within the past 40 years. large amounts of data regarding the effect of smoking cessation on CHD risk have been accumulated from numerous studies. However diverse in design and location, these studies consistently find that the risk of CHD is reduced among former smokers compared with those who continued to smoke. The data are compatible with a rapid, partial decline in risk, followed by a more gradual decline reaching levels of never smokers after a prolonged period. The initial decline appears to occur within I year of cessation or perhaps even less and constitutes a reduction of about one-half or more of the excess risk associated with current smoking. The remaining decline in excess risk is more gradual. with the risks reaching those of never smokers only after a number of years of smoking abstinence. This pattern of decline in excess rish is compatible with multiple effects of smoking on the process of developing CHD. including both short-term influences on platelets and other factors relating to thrombosis which may be more rapidly reversible and long-term increases in atherosclerosis which are only slowly reversible. Persistent smokers may differ from those who quit in other ways that could affect the risk of developing CHD. A number of investigators have examined whether such differences would account for some or all of the decline in risk among those who stop smoking. The risk profiles of quitters and persistent smokers vary among studies: In some studies. there are no material differences; however. in other studies. quitters have a healthier profile: the opposite is true for still other studies. In the studies of primary prevention. none of these differences could explain even a minor portion of the decreased risk among quitters. Most studies of cessation after an MI have found that quitters had a higher baseline risk; however. their risk decreased compared with persistent smokers. Thus. both in primary and secondary prevention studies. confound- ing effects of other risk factors do not explain the apparent benefits of cessation. To the contrary. in many studies. the decrease in risk is even more pronounced after adjustment for baseline characteristics. Only a few studies have examined the impact of smoking cessation in relation to v'arious other CHD risk factors. No data are available to suggest that the relative risks differ substantially in the presence or absence of other CHD risk factors: that is. the percentage reduction in risk most likely occurs across risk factor categories. However. because individuals at high risk for other reasons such as family history. hypertension. or elevated cholesterol have higher rates of CHD. a given percentage decrease in risb among these indivtiduals is a greater absolute decrease than among those with a lower risk profile. Hence. it is ofespecially great importance to achieve high rates ofcessation among individuals who are otherwise at high rish for CHD. Most data on the effects of smohing cessation are derived from white males. but sufficient information is available about women to indicate that the findings are similar for both sexes. Less is hnown about the effects of cessation among minority groups: however. there is no reirson to believe that the benefits of cessation would be any different for these groups. Several studies have examined the effect of smohinz cessation after age 60 on subsequent CHD rish. Data are novv available that demonstrate that the benefits of cessation extend to older adults ;ts well as to young and middle-aged adults for both primary (Table 3) and secondary prevention (Hermanson et al. 19x8). Although the relative rishs of CHD among current smohers tend to be loner among older persons than among younger persons. smohing cessation among older persons can hav,e a greater absolute effect because their rates of CHD are so much higher. Considerable data address the effects of smoking cessation among individuals LI ith diagnosed CHD. A reduction in risk of further CHD-related morbidity and mortality that accompanies smohing cessation has been conclusi\,ely demonstrated. Cigarette smoking is considered the leading modifiable CHD rish factor: over\\ helminp evidence demonstrates that cessation reduces that rish substantially. 240 SMOKING CESSATION AND AORTIC ANEURYSM Abdominal aortic aneurysm refers to the dilatation or expansion of the aorta because of degenerative or inflammatory destruction of the components of the arterial wall. Most abdominal aortic aneurysms are a result of atherosclerosis. although other conditions cause abdominal aortic aneurysm\. The preponderance of evidence from autopsy studies reviewed in the 1983 Report of the Surgeon General sugfects that cigarette smoking aggravates or accelerates aortic atherosclerosis (US DHHS 1983 ). In addition. epidemiologic studies published up to that time indicated that mohers had elevated death rates from ruptured abdominal aneurysm compared with nonsmokers (Hammond and Garfinkel 1969: Hammond and Horn 195Xa.b: Kahn 1966: Weir and Dunn 1970). Mechanisms whereby smoking causes atherosclerosis are reviewed in this Chapter. Studies of Smoking Cessation and Risk of Aortic Aneqsm Several of the larger prospective cohort studies reviewed above have reported results for mortality by cause of death. The data on mortality among~ former smokers from abdominal aortic aneurysms reported in five prospective cohort studies are summarized in Table 6. A consistent pattern is seen among men in these studies, with an excess risk of mortality approximately 50 percent lower among former smokers than among current smokers. However, excess risk among former smokers has remained about two to three times higher than that among never smokers. A similar pattern was also present for women in ACS CPS-II. Although data for women are limited. Doll and associates (1980) reported 11 deaths due to aortic aneurysm occurring during 32 years of followup among 6,194 women. Overall. these data indicate that former smokers have a reduced risk of death from aortic aneurysm compared with current smokers. More detailed analyses by duration of smoking abstinence have not been presented. SMOKING CESSATION AND PERIPHERAL ARTERIAL OCCLUSIVE DISEASE The peripheral arteries include those branches of the aorta that supply the upper and lower extremities and the abdominal viscera. Most peripheral arterial occlusive disease results from atherosclerosis. although other conditions may cause obstruction of these arteries. Symptomatic atherosclerosis of peripheral arteries occurs most often in the vessels of the lower extremities. The I983 Report of the Surgeon General reviewed risk factors and epidemiologic data relating to the etiology of peripheral artery disease (US DHHS 19X3). In that Report. an extremely strong association between cigarette smoking and diagnosis of peripheral artery disease was observed (US DHHS 1983). Cigarette smoking was the strongest risk factor for peripheral artery disease in the Framingham Study (Kannel, McGee. Gordon 1976). In this Section. the impact of smoking cessation on risk of developing peripheral artery disease is reviewed. In addition, the influence of cessation on treadmill time, rest pain, progression to amputa- tion. and survival among patients with diagnosed peripheral artery disease is discussed. 231 TABLE 6.-Studies of smoking cessation and risk of death due to aortic aneurysm I)011 Cl had undergone amputation compared L\ ith 1 1 percent of the patients ~4 ho were nonsmokers or jmohed I5 cisarettt'\ or less per da>. The eft'ect of mohlng on the patenq. of fcmoropoplitcal \ rin b> pass grafts u\ed for treating periphcrul arterial occlusion u a\ studied among 7 157 patients monitored for I year (Wiseman et al. 19X9). Patients \4 ho continued to mohc. identified b> elevated serum SCV. had a graft patent! of 63 percent after I bear compared u ith X-I percent among nonmoher\ (pcus\ed in Chapter 2. miscla\Gfication of former smoker\ because of recidivism during the followup period ih a general concern in prospective studies. However. ca\e+control studies of stroke are limited by the relatively high fatality rate for incident cerebrovascular events. particularly for sub- arachnoid hemorrhage. This often exclude5 man) incident cases or force5 the use of proxy information from next of bin or other relatives. In all epidemiologic studies of past smohing and ri\h of strobe. careful classification of stroke by pathophyiologic type is important. Details of the relation between past smoking and risk of .strohe are presented in Table\ 7 and 8 for each type of stroke reported bj investigator\. Cross-Sectional Studies In a cros\-sectinal analysis of 1.691 black 2nd u hite men and women admitted for diagnostic evaluation ot' the carotid arterie\. Tell and couorkers ( 1989) reported ;I Ggnificant relation between cigarette smohin g an the thichne\\ ofcarotid artery plsque assessed using B-mode ultraonography. Ba\ed on self-report. patient\ were charac- teri/ed as either nonsmoker5 (never smohed or quit more than IO bears earlier). former hmoher\ (quit between IO !`ear\ and 1 month earlier). or current \moher\. After ad.justing for a patient'\ age. race. WX. and hi\torq ofdiabete\ mrllitu\ and hypertension. the mean plaque score\ diftred Ggniticantl>, amon g the thrrc smoking group\. The mean difference in plaque thichnc\\ compared M ith that M hich could be expected M ;I> -0.3 I mm for non\moher\. 0.04 mm i'or former \moher\. and 0.31 mm for current >moher\. The ah\olutc difi'erencc in mean plaque score\ between nonsmoher4 and current mohers ~+a\ 0.63 mm (95percent Cl. 0.-154).X I mm). betueen non\moher\ and former \moker~. 0.35 mm (95percent Cl. 0. I7-0.51 mm ). and hetheen t'ormer and current smohrr\. 0.27 mm (95.percent Cl. 0.0X-0.47 mm). The\r data jugge\t 11 4o\\er rate ofproge\\ion ~lfutiic'rcl\clcrcl\i\ among person\ ~4 ho ha\ e quit \moking compared with those who continue to \mohe. In ;I cro\\-sectional \tud! of cerebral blood tloL4 IcLels in 26% neurologicalI! normal volunteer\. Roger\ and co~orhcr\ ( I OX5 J obs?r\ ed that \ublects M ho quit smoking had \ignificantl\ higher cerebral pt'rt'u\ion Ic'\el~ than subject\ i+ho continued to smoke. Case-Control Studies Case-control studies addreaing the relation bct\\een \mohing and ri& of \trohe are \ummuri& in Table 7. In man! other publi4ed ca\e--ControI ctudies. t`ormer \moher\ have not been \pecificall> identified ac ;I distinct e\po\ure group. In those stud& that identify former smoher\. the numberot`ca\e\ has been ver! mall or unspecified except for the \tud\, by Donnan and collrague~ I 19X9). In \e\,eral \tudie\ (Bell and Ambro\c TABLE 7.--Case-control studies of smoking cessation and risk of stroke Krldi\c rid. :b c01~~tx11cd n1111 ncvcr vrrcAc~\" Qwt I0 yr I .`)3 3.X') 2.52 3.72 I.11 I.IX I.76 3.27 2.0(1.3 3.1) 3.7 3.2 3.1 2.1 1.7 I YX7: Taha. Ball. Illingvvorth I YX2: Bell and Symon 1974, ). population smoking rates rather than a true concurrent control group were used for comparison purposes. Despite these limitations, the risk of stroke among former smokers haj been consistently lower than that among current smohers. Data for subarachnoid hemorrhage (Bell and Symon 1979; Taha. Ball. Illingworth 19X2) show a persistent elevation in risk among former smokers compared with never smokers: however. this rish is lower than among current smokers. Prospective Cohort Studies To date. a total of I4 prospective cohort studies have reported sufficient detail to categorize former smokers as a specific subgroup monitored for incidence of strobe. These studies have obtained information on smoking status at baseline through inter- view or self-administered questionnaire and have observ(ed populations for 2 years (Nomura et al. 1974) to 26 years (Wolfet al. IYXX). Other cohort studies have reported the relation between cigarette smoking and stroke but have not included sufficient details to categorize ex-smokers as a unique exposure group. In each of the studies included in Table 7. the risks among former smokers and among current smokers are reported compared with the risk among never smokers. The earlier prospectivje studies tended not to show a positive relation between smoking and stroke. and in several studies. the risk among past smokers was higher than that among current smokers. In a multivariate analysis of data from the Whitehall Civil Servants Study ( IX.403 male British civil servants). the relative risk of stroke was 2.2 among current smokers of IS cigarettes per day compared with never smokers. whereas the relative risk among former smokers w/as I .S (Fulleret al. 1983). Among British women. current smokers experienced a 3.0 relative risk of subarachnoid hemorrhage. and former smokers experienced a 2.3 relative risk (Vessey. Lawless, Yeates 1983). Lower elevations in risk were found among individuals experiencing ischemic strokes. No excess risk of stroke was observed among 2.748 current or former smokers. residents of Cook County. IL (Ostfeld et al. 1974) or in 47.423 residents of Washington County, MD (Nomura et al. 1974). Doll and Peto (1976) studied 34,440 male British physicians for 20 years and updated information on cigarette smoking after 6 and IS years. These researchers used similar methods for studying female British physicians among whom smoking status was updated after 10 years (Doll et al. 1980). Only slight elevations in risks of stroke were seen among male current or former smokers, and no excess risk was found among female current smokers. Similarly, Okada and colleagues ( 1976) found no significant elevation in risk of stroke among current or former smokers in a Japanese population. In I4 cohort studies published after 1980. the relative risks among former smokers were lowerthan those reported for current smokers (Table 7). Rogot and Murray (19X0) observed U.S. veterans and defined the population of former smokers as those who had stopped smoking for reasons other than a doctor's orders. These former smokers had a relative risk of I .02; current smokers had a relative risk of 1.32. In a study of 7.895 Hawaiian men of Japanese ancestry (Abbott et al. 1986). 65X smokers who quit in the first 6 years of followup were monitored for another 6 years: their age-adjuwd relative rish for total strobe uas I .5 compared 1% ith never smokers (Y5-percent Cl. l.(L2.3). Ri\h\ were similar for ischemic and hemorrhagic stroke$. Concurrently. current smohers had ;I relative rish ot'3.5 compared with never \mo!-.er<. Former >moLer\ had 3 cignificant reduction in ri\h oftotal \trohe compared with current \moher\ (p4.05). Thi\ analysi\ wggests that after adjusting for other rkh factorh. former wloher\ may be at increawd ri\h of \trohe. This residual rik may be due to the irreversibility or slov, rcverGhilit> of the underlying mechanisms of' \mokins- attributable \trohe. or the resumption of making among former smokers. Welin and colleagues ( 19X7) followed 7XY men born in IYl3 for 18.5 years. Smoking information H;IS updated during ;I follouup examination after 6 years. Investigators then identified ;I wbgroup of former smokers who were monitored for I2 years. Among these former\mnhers. the relative rish of stroke W;I\ 1. IX compared with I .67 forcurrent smohers. Wolfandcouorkerk ( IYXX) studied 1.255 men and women in the Framingham Stud!, and updated cigarette smoking information at Z-year intervals. Among current smokers. the relative rishs of overall stroke were 1.33 for men and I.61 for women. During the 26 year\ offollowup. SO percent of the normotensive smokers quit smohing compared with 33 percent of the hypertensive smoker5 (p4J.05). Former \moher\ had a Ggnificantly lower ri4h compared with current makers. This relation wa\ olxer\ed among men and women in each of the blood pwsure categoric\. Benefit\ of mokinp cessation were oh\erved in the hypertewiw and nonnotensive subjects. In the Nurse, Health Stud!,. current smohing \\;I\ \trongl> awxiatrd \h ith rish ofhoth wbarachnoid hemorrhage and thrcllnboemholic \trohe (RR=lO.3 and 3. I. re\pectivel!. for 3 cigarette\ or more per da ) (Coldit/ et al. IYXX). The relative rish\ for former smoker5 were sutxtantially Io~er. A4 described in the IYXY Report of the Surgeon General. the relative ri\h\ of \trohe for smokers \houed an increase when CPS-II data f`rom I YXZ to IYX6 Mere compurcd uith CPS-I data from lY5Y to lY6S I US DHHS IYXY 1. The\e studies. using the same design and method\. \houed an increaw in the relati\r rish ofdeath from strobe among current \moher\ for men aged 33 to (11 \car\ from 1 .7Y in I Y5Y-65 to 3.67 in I YXLX6. For women of the ~me age. the rel:rti\t' ri\L Incrcrcrwi l`rom I .Y2 to 1.X0. The number of former wohers among ~~omcn in CPS-I M;I\ too small to report the\e data separateI!. HoNever. t'or male\. the rcl;lti\e ri\h ot`\trohe among t'ormer smoher\ has \ho\\ n little increase and remanned onI!, \lightl! higher than among nt'\`cr mohers. The reawn\ are uncle;tr f`or the stronger a\soci;uion\ hetnce11 cigarette mohing and ri\h of strobe noted in more recent \tudie\. tfoL\t'\t`r. this tendew! for higher relative ri\h\ in the more recent \tudic`\ ha\ been documented t`or ;I u ide varier> of smohing- related d\\ea~e\ (CS DHl1S IYXY). One lihcl~ e\pl;m;lticw i\ that the effect of\moking i\ related to duration ot`\mohing. and the cohwt\ ot` pcrxon\ (e\pcciall> women) u ho stxted smohing before ase 20 irr'e onI\ IIOU reachin, (7 middle and late xiulthood (Garfinhel and Stellmxn I YXX). Control of h!yertenslon has lmpro\ ed in the L.nitetl State\ during the Ia\t decade. and the incidence of 4trohe ha declined. Thu\. wiohing ma\ iio~ pta!, ;I rrlativcl! cc wxtc'r role in the eti(~lw\ or thi\ d~waw than it did In t`xlier 2 . period\ u hen uncontrolled h\ perten\ion M ;I\ more con~~~mn. 250 Summary of Observational Studies In a meta-analysis of cohort and case-control studies of cigarette smoking and stroke (Shinton and Beevers 1989). the overall relative risk of stroke among former smokers was I. 17 compared with never smokers (9Spercent CI. 1.05-l 30). This estimate is based on a summary of I8 relative risks from 13 studies that separately identified former smokers (Kahn 1966: Doll and Peto 1976: Abbott et al. 1986: Colditz et al. 1988: Ostfeld et al. 1974; Kono et al. 1985: Khaw et al. 1984: Vessey. Lawless, Yeates 1984; Bell and Symon 1979: Bell and Ambrose 1982; Bonitaet al. 1986; Bonita 1986; Taha. Ball. Illingworth 1982). As observed for the relation between current smoking and stroke. the risk among former smokers was greater when the analysis was repeated using only those studies with stroke occurring before age 75 (RR= I .47.95-percent Cl. I. I S-l .X8 compared with never smokers). By comparison. the relative risks for current smokers were 2.9 for those younger than SS years and I .8 for persons aged 55 to 74 years. Thus, although a modest elevation in risk persisted among younger former smokers, this relative risk was substantially less than that which was observed among current smokers. Intervention Studies Intervention trials described above provide little direct evidence relating to change in risk of stroke after smoking cessation. Only the trial of smoking cessation conducted among I.445 British men used a single intervention (Rose et al. 1982). During IO years of followup, five men in the normal care group died because of stroke, and seven men in the intervention group died because of stroke. The small numbers in each group and the small difference in smoking cessation rates between the intervention and control groups limit any conclusion regarding the impact of smoking cessation in this popula- tion. Other intervention studies have included management of hypertension and cholesterol as well as smoking cessation programs. As discussed under randomized trials of smoking cessation and CHD. these multiple interventions make drawing conclusions difficult regarding the relation between smoking cessation and risk of stroke (Steinbach et al. 1984: Wilhelmsen et al. 1986: MRFIT Research Group 1982. 1986; Salonen, Puska, Mustaniemi 1979; Hjermann 1980; Holme 1982). In a nonrandomized intervention, Rogers and colleagues (1985) measured changes in cerebral artery blood flow among volunteers who were encouraged to abstain from cigarettes. Cerebral perfusion was improved after smoking abstinence. Influence of Prior Levels of Smoking Using data from the followup of 248,046 U.S. veterans monitored for I5 years, Rogot and Murray (1980) reported the mortality ratio for stroke among former cigarette smokers who stopped smoking for reasons other than a physician's orders according to the level of prior cigarette smoking. Based on 1,279 strokes among past smokers, the mortality ratio for stroke among former smokers relative to never smokers increased 75 I with higher previous daily cigarette consumption from 0.94 for those smohing less than IO cigarettes per day to I .33 for those smohing 30 cigarettes or more per day compared with never smokers (Figure 7). Data from ACS CPS-II also address this relationship (Table X). Within each level of previous smoking. the risk of stroke was clearly lower for former smokers than for continuing smokers, except among men who smoked 2 I cigarettes or more per day. Other studies have had too few former smokers to classify them according to previous number of cigarettes smoked. ~10 cig/day 1 O-20 cig/day 2 l-39 ciglday ~40 cig/day O ?????????? m Current Smokers FIGURE 7.-Mortality ratios for stroke for current smokers and ex-smokers compared with never smokers, b> daily cigarette consumption, US Veterans Study, 1954-69 Effect of Duration of Abstinence The relation between duration of abstinence and rish of strohe has been addressed in only a few studies. In a case, ratios for those who had abstained. Assuming that an individual classified as a former smoher at the beginning of the study would remain a former smoher throughout the IS Iears of TABLE S.-Prospective cohort studies of smoking cessation and risk of stroke Population OIlreId et al. (lY74) NomLlra et al. ( 1074) 2.738 Cook Coun1y. Il. rek.lcnt~ receiving old age ;I\\l\txlce aged 65-74 47.423 Washington Count). MD rc\itlent~ O.Vlh I 4 cl)!/`la): I .7v IO IV clp/day: 0.x5 20 cIg/tl:ly. 0.x I I .03" 0.7') 0.7') 0.X6 I .ot) I ..I0 O.Y7 I).`)0 Doll and Pet0 (1976) Brirlxh phykians: 3J.440 men Ohada et al. ( lY7h) 4. I X6 Jnpanew 20 yr h)l NK NK TABLE S.--Continued Relative risk compared with never smoker\" Reference Outcome Former smokers Current smohers Doll e1 ill. ( IYXO) British phy\Icl;ms: 6.lY4 vso"lell Kogot and M way (IYXO) FullcreI al. (IYX7) Whwhall CIVII wrvant\: I X.403 men aged 40-64 Vea\ey. Lawleh5. I7.000 l.lK women aged Yelltea t IYX4) 2% 3Y Abbott et al. ( I YXh) Honolulu Heart Study: 7,XYS men of Japanese orIgIn: hSX \mokcr\ who quit In first 6 yr Welin cI al. t IYX7) 7X0 men living In Gothrnhurg. 67X examined Car\Iensen. Pwhagen. Eklund (IYR7) ?S.lSY Swede\ 22 yr IS yr IO yr It&l6 yr l2yr: 6 Yr IX.5 yr: I I yr Ihyr NK I.279 34 2 4 I I 3 NK I24 DeaIh due to cerebral thromboG% Stroke ICD 336343 (7th revision) Strobe mortality Subarachnoid NonhemorrhagIc Thromboembolic Hemorrhage Total Excluded subarachnoid hemorrhage Cerehrovascular mortality ICD 43%43X I.IX I .02 I-14q/day: 0.03 14-24 cIg/day: 0.45 225 cig/day: 0. I Y I.32 I.52 I-Y rig/day: I .O' I%lYcig/day: 2.0 220 cig/day: 2.3 2..Jh 3.0 I.3 I.4 I .6 (0.7-3.X) 3.00 1.X (0.4-9.0) 6.10 I.5 ( I &2.3) 3.50 I.IXh 1.67 1.10 I-7 g/day: 0.9 X-I 5 g/day: 0.9 >IS g/d/day: I.1 I'S I)tltis (I'JXY) AC'S (`PS-I (2%St:lle Stud) ) h yr ( I OS--h.! 1 NR TAHIX X.--Continued Qwt Ihyr l.Y)2 Qutt ratios clo\e to I .O for all durations except for 5 to 9 years after quitting. Based on 26 ye;irs of\tud!,ing 4.35 men and u'omttn in the Framingham Study (Wolf et al. 19X8). the ri& of\troLe among person\ u ho stopped was significantly lower than that among persons who continued to smohe cigarettes. Furthermore. persons u ho quit smohing developed strobe at the mte of never smoker\ soon after discontinuing cigarette smohing (Figure 8). Wolf and coworhers ( 198X) estimated that the risk of stroke among smokers had decreased significantly ? yean after quitting and reverted to the level of never smokers within 5 years. The\e results persisted after controlling for age. blood pressure. serum cholestrol level. relative weight. left ventricular hyper- trophy on electrocardiogram. and blood glucose level. Thu\. the reduction in risk after smoking cessation is not attributable to differences in other rish factor\ for stroke between those who quit and those who continue to smohe. In the Nurses Health Study (Colditr et al. 198X). B lower ri\h of stroke was ohserved with increasing time from cesation. Compared with the ri\h among never smokers. the relative risk was 3.6 among women who had stopped for les\ than 2 j'ears (95percent Cl. 1.11.7). However. among women who had stopped tbr 2 lears or more, the relative rish was reduced to I .3 (9S-percent CI. I .O-2.0). Women currentI). smoking IS to 14 cigarettes per day had ;I relative risk of 2.9 compared with never smoker\. Again. the elevation of the relative risk during the first 3 year\ after cehation is consistent with high recidivism among the\e women. Prospective data from ACS CPS-II \ho\ved that among men who quit smoking. the risk of \trokc returned to that of never smohers after I I year\ or more of smohing abstinence for those originally smohing fewer than 2 I cigarette\ per dab. However. for men who pre\,iousl\ smohed 21 cigarette\ or more per da\. the rish among former smokers did not return to the level of ne\`er smoker\. even after I6 bears or more of cessation. Among women who quit. the rate of decrease &;I\ much more rapid: h! 3 to 5 years after cessation. the ri\h of a-ohe wa\ 4milar to that of never smoher\ (Table 8). Oral Contraceptives and Smoking Cessation In two studies the risk of subarachnoid hemorrhage was augmented m~ong cigarette smokers who also take oral contraceptive\ tPetitti and Wingerd IY7X: Collahorati\e Group for the Study of Strohe in Youn, 17 Women 1975). In the Collaborative Group Study of stroke among youn, ~7 women ( 1975 1. the cutegot-\ of former smoher\ was not cleat-l), defined: rather. ;I group of"once regular \moher\" XI\ compared with "never regular smoker\." In this stud\ there u :I\ no ;t\\oci;ltion between current smoking or former smoking and risk ofthromhotic strobe. O\,erall. the relutiie rish for hemorrhqic strobe was I .X among once regular moher\ and 3.3 anon2 current smoker\. Within the group of once regular hmoher\. uomen currently usins oral contracepti\,e\ had approximately twice the risk compared u ith women not u\in, ~7 oral contraceptives. The Royal College of General Practitoner\ \tud! of oral contracepti\,e\ did not separate former smokers from never smoher\ (Luyde. Beral. Kay I98 I ). Hence, data to address the relationshipamongoral contraceptive\. smoking cessation. and risk of \ubarachnoid 258 --\ o ? o ? o ? 1 . I 5 10 15 20 5 10 15 20 Years of Follow-up FI(;URE &-survival free of stroke in cigarette smokers (dotted line), never smokers (solid line), and former smokers (dashed line), aged 60, using 00x proportional hazard regression model. among men and women SOtJK~`E. Wolt'rt al. I IYXX). hemorrhage are not available from that study. Because oral contraceptive preparations used today provide substantially lower doses. the risk of cardiovascular disease as- sociated with their use and their interaction with cigarette smoking may be different than observed for the early high-dose preparations. Effect of Smoking Cessation After Stroke In contrast with CHD. in which the focus after MI is prevention of recurrent disease. the center of attention after a major cerebrovascular event is rehabilitation. For CHD. substantial evidence shows the benefits of abstaining from smoking after onset of CHD. Comparable data are not available on the benefits of abstinence after stroke. Summary Risk of stroke resulting from occlusion of the cerebral arteries and from subarachnoid hemorrhage is increased approximately twofold to fourfold among current smokers compared with never smokers. After cessation. the excess risk decreases steadily. In some studies, the rish of stroke among former smokers becomes indistinguishable from that of never smokers within 5 years: in other studies. this decrease did not occur until after IO years or more of smoking abstinence. The reduced risk of stroke among persons who stop smoking is independent of the amount prel iousl) smohed and other knoun risk factors for stroke. Similar reductions in risk of stroke after cessation are seen among men and women. but fev. data are available for minority populations. I Compared with continued smohing. smoking cessation substantially reduces rish ot coronary heart disease (CHD) among men and women of all ages. 2. The excess risk of CHD caused by smoking is reduced by about half after I qear ot smoking abstinence and then declines t ~~raduall>. .After I5 years of abstinence. the risk of CHD is similar to that of persons u ho ha\e never smohed. 3. Among persons u ith diagnosed CHD. smohinf cessation murkedl! reduces the risk of recurrent infarction and cardiovascular death. In many studies. this reduction in risk of recurrence or premature death has Hun SO percent or more. 3. Smohing cessation substantialI!, reduces the rish of peripheral artery occluG\e disease compared M ith continued smoking. 5. Among patients N ith peripheral arter? disease. smohing cessation impro\ es exercise tolerance. reduces the risk of amputation after peripheral arter! turgq. and increases overall survival. 6. Smoking cessation reduces the risk of both ischemic strobe and subarachnoid hemorrhage compared M ith continued smoking. After smoking cessation. the rish of strohe returns to the Iehel of never smohers: in some studies this has occurred within 5 years. but in others as long as IS bears of abstinence were required. References ABBOTT. R.D.. YIN. Y.. REED. D.M.. YANO. K. Rixk of \trohe in male cigarette smoker\. 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For the purposes of this Chapter. emphysema refers to pathologic abnormal permanent enlargement of the airspace\ distal to the terminal bronchiole. accompanied by destruction of airspace walls and uithout obvious fibrosis (American Thoracic Society 1987). Chronic bronchitis refers to chronic cough and/or sputum production for at least 3 months per year for 2 consecutive years. Asthma ha\ t-wn defined as "a disease characterized by increased responsiveness of the airua!s to various stimuli and manifested by slowing down of forced expiration. which changes in severity either spontaneously or as a result of therapy" (American College of Chest Physicians. American Thoracic Society Joint Statement I Y75). The term COPD is used to describe persistent obstructive ventilatory impairment as determined b> ;I teht ot pulmonary ventilatory function (O'Connor. Sparrow. Weiss 19X9). Overlap of these conditions is extremely common. although discrete cases of each can be identified (Figure I ). It is estimated that 60 to IO0 percent of COPD patients also have airways hyperresponsiveness (Klein and Salvaggio 1966: Parker, Bilbo. Reed 1965: Ramsdell. Nachtwey. Moser 19X3: Ramsdale et al. IYX4: Bahous et al. 1YX-I). Almost one-half of all asthmatics suffer from chronic bronchitis (Burrows et al. I YX7). and asthma may be a risk factor for the development of chronic airtloh obstruction (Fletcher et al. 1976: Schachter. Doyle. Beth lYX4: Buist and Vollmer 19X7: Peat. Woolcock. Cullen 19X7). Although the extent of emphysema. as documented b! postmortem examination of the lungs. correlates significantI>, with the degree of fixed airflow obstruction. the correlation is modest. suggesting that emph! sema alone does not full) explain the functional impairment in most persons u ith COPD tCosio et al. 1977). CHRONIC BRONCHITIS EMPHYSEMA ASTHMA AIRWAYS OBSTRUCTION FIGURE I.--Nonproportional Venn Diagram of the interrelationship among chronic bronchitis, emphysema, asthma, and airways obstruction. SOL RCE: Snider I IUXX). Researchers in the United States and the United Kingdom tend to separate asthma from the other obstructive airways diseases and to deemphasiLe the importance of cigarette smoking in this particular clinical entity. However. the data suggest that cigarette smoking may influence asthma and that allergy and airway hyperresponsive- ness. strongly associated with asthma. may play a role in the development of fixed airflow obstruction (O'Connor. Sparrou. Weiss lYX9). The generally accepted model of the pathogenesis of COPD is based on the result\ of longitudinal investigations of lung function (Fletcher and Peto 1977: Becklahe and Permutt 1979: Burrows I9X I: Speizer and Tager I97Y) (Figure 2). The model suggests that disease development is preceded b\ a long latent period during which lung function declines at an accelerated rate. FEVl as% ofvaiueal aga M25 & I L I I L a L I 5 10 15 20 30 40 50 60 70 00 AGE-yWt3 FIGURE 2.Theoretical curves depicting varying rates of decline of FEV 1 NOTE: Curves A and B represent never smokers and smokers. respectively. declining at normal rates. Curve C shows increased decline without development of COPD. Rates of decline for former smoker\ are represented hy curves D and E for those without and with clinical COPD. respectively. Curve\ F and G show rates of decline with continued smoking after development of COPD. SOURCE: Spewer and Tager (1979). Several features of this conceptual model merit emphasis in relation to smoking. First, disease development may occur as a result of factors that accelerate decline in adult life. lead to less than maximal growth, or both. Second, because of the extremely long latent period from the onset of smoking to disease development, factors important in childhood and young adulthood cannot be addressed in longitudinal studies that begin in adulthood. Third, longitudinal studies of children and adults have shown that pulmonary function levels are very stable over time with tracking correlations ranging from 0.70 to 0.90. This high degree of longitudinal correlation, consistent with both environmental and genetic determinants of disease, demonstrates the importance of previous level of function as a major determinant of future disease risk. Research on risk factors for COPD was reviewed extensively in the 1984 Report of the Surgeon General (US DHHS 1984). The review leads to several general findings with regard to smoking. Cigarette smohing is associated with low levels of 1 -set forced expiratory volume (FEVI) in cross-sectional investigations (Knudson. BUITOWS. LebowitL 1976; Burrows et al. lY77; Beck. Doyle. Schachter 198 1; Dockery et al. 1988: US DHHS lYX3). with accelerated decline of FEVI in longitudinal studies (Burrows et al. lYX7: Beck. Doyle. Schachter 1982: Boss? et al. 1981: US DHHS 1984), and with increased mortality from COPD (Best 1966; Doll and Peto lY76; Hammond 196.5: Hammond and Horn 1958: US DHHS IYX4). The effect% of cigarette smoking on lung function level or rate ofdecline and on mortality increase with the duration and amount of smoking (US DHHS 1Y83). Because the development of COPD in adults is associated with a long latent period. the age at which cigarette smohin g might have a critical effect has not readily been addressed. Passive smoking impairs lung growth in children and thus, may limit maximal lung growth (Tager et al. 1983: US DHHS lYX6). Smoking in adults may shorten the phase when lung function tends to plateau between the ages of 20 and 10 and/or may accelerate the decline in lung function (Tuger et al. 1988). Cigarette smoking is the predominant cause of lung function decline at a rate greater than the annual volume loss of 20 to 30 mL associated with aging. Although cigarette smoking has been clearly established as the major risk factor for COPD. the interactions of the intensity of smoking with factors determining suscep- tibility have not been fully characterized. For example. Burrows and coworkers ( 19X7) suggested that two subsets of COPD patients can be differentiated by the presence or absence of accompanying asthmatic features. According to thi:, hypothesis. subjects with chronic asthmatic bronchitis have a better long-term prognosis. smaller cumulati\ e exposure to tobacco smohe. and greater prevalence of allerg> and airway responsive- ness. The second group of patients ha\ emphysema. poorer long-term prognosi\. greater cumulative tobacco make exposure. and reduced prevalence of allerg!, and airway hyperresponsiveness (Burrows el al. 1087). Available data do not discriminate the relative contribution\ of cigarette smoking in these clinical subtypes of patients. Studies of the mechanisms b\ which cigarette smoking cause> lung injur! \\ere reviewed extensively in the 19X-l Report of the Surgeon General (US DHHS 1081). That Report and other rtf\ itfb s (Thurlbeck 1976: Snider lYX9: Wright IYXY) also co\ t`r the relationship between the structural changes associated with smoking and the severity of airtlow obstruction. Cigarette smoking causes inflammation of both the airways and parenchyma of the lun,. $7' the resulting structural damage has functional consequences that can lead to the development of clinically diqnored COPD if there is sustained making. Franh parench\,mal damage is preceded by an increase in intlammator> cells in lung parenchyma at the level of the hronchioli (Nieuoehner. Kleinerman. Rice 197-I). Both neutrophil\ and alveolar macrophages are important in the development of this inflammatory bronchiolitis. Although neutrophils store and release greater quantities ofelastuse than alveolar macrophages (Janoffet al. 1979). the macrophage may be an important cell in attracting neutrophils to the lung (Hunninphahe and Cr) stal 1 YX3). Cigarette mohing-induced bronchiolitis is associated h ith func- tional abnormalities detectable in the early stages onI!. with sensitive tests of small airway function (Bui\t et al. I Y7Y: Casio et al. 1977: McCarthy. Craig. Chemiach 1976: Ingram and Schilder 1967: Ingram and O'Cain 197 I ). E\en before Ggnificant t'n- physema is present. destruction of peribronchiolar alveoli can be found in the lungs of smokers (Saetta et al. 1985; Wright 1989); the loss of alveolar attachments may result in loss of elastic recoil (Wright 1989). The protease-antiprotease hypothesis proposes that the destruction of lung tissue resulting in emphysema occurs as a consequence of genetic or acquired imbalance of proteolytic and antiproteolytic enzymes in the lung. As noted in the 1984 Surgeon General's Report (US DHHS 1984). this theory derives from two principal observa- tions: ( 1) (Y- I -antitrypsin. a major anti-elastolytic enzyme of the lower respiratory tract. is absent in persons genetically deficient in a- 1 -antitrypsin: these persons often develop emphysema at an early age (Laurel] and Eriksson 1963), and (2) administration of proteolytic enzymes in animal models produces emphysema (Gross et al. 1965). Cigarette smoking is associated with increased numbers of neutrophils and activated macrophages in the lungs of smokers, and neutrophil elastase can cause emphysema in animal models (Harris et al. 1975: Galdston et al. 1983). In addition. the a-l-anti- protease of cigarette smokers has reduced functional activity (Gadek. Fells. Crystal 1979: Gadek et al. 1981). However, although damage to the airways and parenchyma of the lung by cigarette smoke underlies excess lung function loss and COPD in smokers. the factor\ determin- ing the development of disease in individual smokers have been only partially charac- terized. A minority of cigarette smokers develop COPD. and cigarette smoking only partially explains the variability in FEV t decline (Burrows et al. 1977: US DHHS 1984). Data suggest that cigarette smoking may influence airway as well as parenchymal inflammation. Thus. host factors determining the response of the airways and parenchyma to cigarette smoking. as well as the intensity of smoking. are likely to determine the development of disease. Cigarette smoking has a variety of effects on the immune system: those effects may be important in determining the risks of COPD and other respiratory diseases. Cigarette smoking is associated with elevated total serum IgE. This total IgE does not exhibit seasonal variability, as seen in atopic individuals. and the antigens responsible for this increase have not been identitied. Cigarette smoking may influence the development of an atopic diathesis via effects on T-cell helper and suppressor activity (Ginns et al. 1982: Milleret al. 1982). epithelial permeability (Joneset al. 1980; Simani, Inoue. Hogg 1974). or functional alterations of antigen-presenting cells (Warr and Martin 1977). Cigarette smoking is associated with skin test positivity among children exposed to maternal cigarette smoking (Weiss et al. 1985: Martinez et al. 1988); however. this association is not seen in studies of active adult smokers (Burrows, Lebowitz. Barbee 1976). Jn adult subjects, skin test positivity is most prevalent among former smokers (Taylor, Gross et al. 1985). These data are consistent with the hypothesis that atopic individuals may not become or remain regular smokers because of airway inflammation secondary to inflammatory effects of cigarette smoking. Thus, cigarette smoking may interact with atopy in a complex manner, inducing atopy in less susceptible or initially nonatopic subjects and discouraging highly atopic subjects from taking up smoking. Eosinophils are primary effector cells for allergic inflammation (DeMonchy et al. 1985). Increases in eosinophils are associated with the severity and exacerbations of asthma (Horn et al. 1975). Increased eosinophils are also associated with the occurrence of respiratory symptoms and the level of pulmonary function (Burrows et al. 1980: Kauffman et al. 1986). Cigarette smokers exhibit elevations of the peripheral blood eosinophil count (Taylor. Gross et al. 1985). although it is unknown if allergen-induced and cigarette smoking-induced eosinophilia occur by similar or different mechanisms. Eosinophils in peripheral blood are also related to clinical correlates of emphysema (Nagai. West, Thurlbeck 1985). Cigarette smoking has also been associated with increased levels of airway respon- siveness (Woolcock et al. 1987: Sparrow et al. 1987; Burney et al. 1987). Several mechanisms could explain the relationship between cigarette smoking and increased airway responsiveness. including smoking-associated reduction in prechallenge level of lung function, chronic airway inflammation due to smoking. and smoking-induced impairment of epithelial function. The potential central role of cigarette smoking in parenchymal and aitways inflammation is depicted in Figure 3. BRONCHIOLAR AIRWAY --- ~~-- NARROWING INFLAMMATION ,_ -. * -.. `\ . `\. * CX%Fl~;&E /' AIRWAY HYPERRESPONSIVENESS `\ \\ o ?? ALVEOLAR INFLAMMATION -. -w EMPHYSEMA FIGURE A-Hypothesized mechanisms by which airway hyperresponsiveness may be associated with developing or established COPD without necessarily being a preexisting risk factor 4OTE: COPD=chron~c oh\trucfi\ e pulmon~r) dieax.. When considered in this pathophysiologic framework. the potential consequences of smohing cessation on the degree of impairment and future rish of COPD var) with the extent of irreversible change\ at cessation and with host characteristics of the quitting smoher. In adults. cigarette smoking cessation i, associated with a blowing of FEVt decline to the rate of never smokers (Figure 2). To the extent that airway and alveolar inflammation have cau\ed reversible epithclial and parenchymal inflammation. pul- monary function could improve after cessation. particularly if heightened airway responsiveness and bronchiolitis can resolve. To the extent that cigarette smoking has caused permanent damage to lun g \tructure (e.g.. emphv\emu). those changes are 2X-1 unlikely to be reversible. Thus. the amount and duration of smoking. the relative extents of parenchymal and airway inflammation. and the degree of permanent structural damage are probably the key determinant\ of the ic\;el of function after smoking cessation. Even in the settinp ofcytabli\hedCOPD. smohing cessation ma\ potentialI> reduce the rate of functional los\. Former smokers may differ from continuing smohers with regard to ho\t charac- teristic> that potentially determine suxeptibility to ci garette smohe. Because presmoh- ing levels of atopy and airs ay responsiveness modif) the short-term re\pon\e to smoke. individual\ with atopy or heightened airway re\ponsivene\\ ma)' be les\ likely to tahe up smoking. to reduce \mohing. or to quit smoking if respirator! symptom\ occur. Thi\ potential bias. termed the "healthy smoker effect" by O'Connor. Spurrou. and Wei ( lYX9). cannot be evaluated in cro\;+\ectional studies. PART I. SMOKING CESSATION AND RESPIRATORl' MORHIDITY Respiratory Symptoms Since the 1950s. strong evidence has accumulated documenting increased respirator! symptoms in smohers of all ages compared with nonsmokers (US PHS 1963: US DHEW 197 I. 1979; US DHHS 1984). Further. the number of cigarette{ smoked per day is the strongest risk factor for the principal chronic respiratory symptoms including chronic cough. phlegm production. wheeze, and dyspnea (Lebowitzand Burroh s 1977: Dean et al. 1978: Higgins. Keller. %tzner 1977: Huhti and Ikhala 19X0: Higenbottam et al. 1980: Schenker. Samet. Speizer 19X?). The widespread effects of chronic smoking on the lung, including decreased tracheal mucous velocity (Lourenqo. Klimeh. Borowski 197 I : Goodman et al. 197X: Thomson and Pavia 1973). increased secretion of mucus on the basis of mucous gland hypertrophy and hyperplaaia (Thurlbeck 1976). chronic airway inflammation (Niewoehner. Kleinerman. Rice 197-I). increased epithelial permeability (Jones et al. 1980; Minty. Jordon. Jones 1981: Mason et al. 1983). and emphysema (US DHHS 19X4), underlie the development of these symptoms. Smoking cessation has been associated with a reduction in respiratory morbidity, presumably through reversal of some of these pathophysiologic abnor- malities. Relevant evidence can be found in clinical studies, which involve follow,up of the symptoms of persons participating in smoking cessation clinics. and epidemiologic studies. Clinical Studies Buist and coworkers (lY76) found that smohing cessation w'as associated with a dramatic reduction in respiratory symptoms w)ithin I month of cessation. These researcher7 assessed spirometry and respiratory symptoms for over I3 months in 75 cigarette smokers enrolled in a smoking cessation program. Subject\ were divided into quitters (those who did not smoke during the entire I?-month period). modifier\ (individuals who reduced their cigarette consumption by 25 percent ). and nonmodifiers (subjects who continued to smoke at the same level). The three groups were of comparable ages (35 to 39 years) and had a cumulative cigarette consumption of 20 to 26 pack-years. A symptoms ratio was calculated at I. 3, 6. and I2 months by taking the number of symptoms (e.g., cough, expectoration, shortness of breath, and wheezing) observed and dividing by the total number of possible symptoms for that group. All groups started with ratio values of approximately 0.55. The ratios for quitters declined within I month of cessation and continued to decline over the course of the study from 0.52 to 0.08. In contrast, the ratios for modifiers decreased less than quitters, and nonmodifiers had no change in their ratios over I2 months (Figure 4). Data on individual symptoms were not presented, and smoking abstinence was not verified by biologic markers. In a followup study of more than 30 months. Buist . Nagy. and Sexton and colleagues (1979) again showed that among IS quitters, respiratory symptoms disappeared by the third or fourth month of followup and did not return during the remainder of the study. However. after a small initial decrease in symptoms among 45 continuing smokers. further decreases were not recorded. The small sample sizes and a 4 1 -percent loss to followup must be considered in interpreting the latter findings. Three studies reported different results for the effect of smoking cessation on respiratory symptoms in asthmatics. Higenbottam. Feyeraband. and Clark ( 1980) conducted a cross-sectional study of I06 consecutive asthmatic clinic patients and concluded that symptoms decreased after stopping smoking. Age-standardized prevalence rates for chronic cough. chronic cough and phlegm. and wheezing among asthmatics were lower for the 27 former smokers than for the 27 current smokers and the 52 never smokers. Only breathlessness was found more often in former smokers than in the other smoking groups. possibly reflecting irreversible smoking-induced changes. Quantification of smoking history and time since cessation among former smokers was not reported. In contrast. Fennerty and colleagues (1987) as well as Hillerdahl and Rylander ( 1984) reported increased respiratory symptoms in asthmatics who stopped smoking. Fennerty and coworkers (1987) found that 7 of I4 asthmatics ( 13.3 percent) who stopped smoking for 23 hours complained that asthmatic symptoms were worsening. Neither of the\e two subjects showsed a decrease in specific airway conductance or peak flow. but one had an increase in airway responsiveness to methacholine. However. four of seven asthmatics who abstained from smoking for 7 days recorded a reduction in symptoms. Hillerdahl and Rylander (1984) studied SC) asthmatics who were recruited from an office practice and who had stopped smoking "permanently or for short periods of time." Using questionnaires. these reseachers found that symptoms worsened in IX asthmatics (30.5 percent) who had stopped smoking. Three subjects claimed onset of neu asthmatic symptoms uithin months of cessation. Asthmatics younger than 30 years of age were more likely to complain of worsening of their asthma than those subjects older than -IO year\ of age. Hillerdahl and Rylsnder (1984) concluded that among asthmatics v.ho smoke. psychological reasons. improved secretion clearance. or both could explain the findings. The uncon- trolled nature of these studies. the small numbers of subjects. the potential for selection and information bias. and the noncomparability of treatment regimens among study participants limit the usefulness of the\e findings. 0.8 0.7 0.6 0.5 0.4 0.3, 0.2 0 5 ; 0.1. !z 2 0 19 NONMODIFIERS 3 3 il.... --..*.- .._,_. ., ,3 Q",rrERS _ _.. . - . . . . . . . ._ .* _._,..__... -.... TIME FROM 3 6 9 12 INITIAL (MO) FIGURE k--Symptom ratio (number of observed symptoms to number of possible symptoms) in nonmodifiers, modifiers, and quitters at each test period; symptoms are cough. sputum production, wheezing, and shortness of breath SOl'KCE: Bui\t e( al I 1976). In summary. studies of participants of smoking cessation clinic\ have shown that respiratory symptoms have disappeared rapidly on quitting, even after 20 path-\ear> of exposure. Limited studies of asthmatics have provided conflicting rewlts. Cross-Sectional Studies of Populations The results of community-based studies have shown lower prevalence of respiratory symptoms among former smokers compared with current smokers (Table I ). Twoearly investigations evaluated symptoms ofchronic nonspecific lung disease among smoking groups. Ferris and Anderson ( 1962) studied a random sample of subjects. aged 25 to 74. from an industrial town in New Hampshire. Using spirometry and interviewer-ad- ministered questionnaires. these researchers recorded lung function and symptom\ associated with chronic nonspecific respiratory disease in 1.167 individuals. Chronic nonspecific respiratory disease was considered present if ( 1) phlegm production was reported six or more times per day for 3 day\ per week for 3 months per year for the past 3 years (chronic bronchitis): (2) if a diagnosis of asthma had been made and was still present: (3) if wheezing or whi\tling in the chest occurred most days or nights; (4) if shortness of breath occurred while walking at subject's normal pace on level ground: or (5) if an FEVI less than 60 percent of forced vital capacity (FVC) w'as noted (chronic obstructive lung disease). Age-standardized prevalence rates per 100 for chronic nonspecific respiratory disease showed that both male and female ex-smokers had rates of abnormality similar to those of never smokers and lower than those of current smokers (for males. 18. I vs. X.4 vs. 50.3. and for females. 17.2 vs. 19.3 vs. 3 I.0 for never smokers. ex-smokers. and current smokers. respectively). In 1967. a resurvey of the population using a slightly different random sample was performed (Ferris et al. 1971). Again. the age-standardized rate\ were less for both male and female ex- smokers than for current smokers. Mueller and colleagues ( I97 I ) studied a random sample of one-fifth of the population of Glenwood Springs. CO. S!,mptoms ofchronic nonspecific lung disease.comparable with those defined by Ferris and colleagues ( I97 I ). wpere reported by 30 percent of 55 male former smokers and by Y percent of 22 female ex-smokers. These percentage5 were between those ofcurrent and never smokers. Age trend\ were not apparent amonp males: the small sample Gre precluded analysi\ for females. In the mid-1960s. two surveys assessed the effects of smohing on respirator) symptoms in older men (Table I ). Wilhelmsen and Tibblin ( I Yhh) analyzed data from 334, men aged 50 jears. born in IYli and living in Giiteborf. an industrial town in Sweden. Of 73 former mohers. the percentqes with morning cough for 3 month\ per year. sputum for 3 month\ per >ear. and wheeling other than from colds were lower than those for I X2 current mohers of le\s than or greater than I5 g of tobacco per da! and similar to those of84 never smoher\. Dy\pnea n hen n,alhing fast or up a small hill wa\ reported mo\t frequentI> b! current smohrr\ of more than I5 g of tobacco per da\,: all other group\ \ho\\ed comparable percentage\ of \uhjects reporting this symptom. Weis\ and coworkers ( IY63) \tudicd 350 consecutive men. aged 50 )car\ or older. undergoing routine examination in the Philadelphia Pulmonary Neoplasm Re\carch Pro.ject (N=h. 1.37). Fifty-three percent of former ciFaretts moher\ (N=6X) reported one or more symptom\ of` cough. w bee/e. or dyspnea compared with 57 percent ot current \rnoker\ tN=lX3) and 42 percent of never mohers (N=361. Furthermore. former smoher\ complained of cough a\ frequentI! :I\ ne\er \moher\ (Y \ \. I I percent) and complained of d) spnea ;I\ ot'tm :I\ current \mohcr\ (16 \`L 14 percent). Onl! 70 3XX TABLE I.-Percentages of subjects in cross-sectional studies with respiratory symptoms, by cigarette smoking status and gender S>mptom\" ReferLWX Cough 3 mo/yr Wtlhelm\en sot33Yl and Tlbhltn I IYhh) Wei5\ et al. I lY63, XMY (7X7) Fletcher and 4(bSY (i63) TmhertIYhl) Mueller et al. 20-69 (Xc)3 (lY71Jh Manfreda. Nelwn. Chemiach (lY78) 25-54 (256)' 25-94 (246)" Schenker. 17-74 (5.670, &met. Speiler (19X')* Phlegm 3 mo/yr Wilhelmwn and Tihblm (lY661 Fletcher and Tinker(l96l) Mueller et al. (1971,h Manfreda. Nelson, Chemiack ( 1978) 2S-S4 (256)' 25-94 (246)" Hawthorne and Fry (1978) 4sJ54 Miller et al. ( lY88jh Male (mean): 42.0(1.169) Female (mean) 42.9(1.1691 36.2 x.2 4 I .o Y.0 lY.Y 13 (I I3.0 7ll.O s.0 25.4 31,s 70.3 31.7 0.1' 17s1' 3 1.x' x.1 2.0 I I.5 I .4 17.6 16.9 I X.0 10.0 12.0 16.9 10.2 10.x 24.7 25.3 5.7 36.2 23.0 16.1 40.8 28.4 14.7 IO.0 IO.0 73 5.0 5.0 IO.9 6.9 4.x I I .o 0.0 Y.0 x.3 4.0 I.2 7.5 4.0 0.0 4.0 IO. I 12.1 5.0 4.0 5.6 I .(I 0.0 4.0 6.7 0.4 2X9 Schenher. Samet. Sprurrt lYX2jh Lrbowlt, ll-Y6t2.X57) and Burrov. \ (1977, Dvs~nea undy' Wtlhelm\en and Tihblin ( IYhhr Fletcher et al. (IMY) Grde\ 2 or more 4-54 Fletcher and TmhrrtlY61) Gmde 3 or more Mueller et rll. (lY71th Grade 2. Grrrdr 3. or more Manfreda. Nrl\on. Chemiach (197X? Grade 2 or more Hav.thome ;md Fr? t lY7X? Vlller et 31. (IYXX)" Grade 7 GrJdr 3 Schrnhcr. Samet. Speller t I YX2 1" Grade 3 I I.2 71.7 44.0 73.5 Xl 1Y.O 7.0 5.6 II.2 Ii.2 7.2' 16.7' `1.X' I I.0 3.Y 2 I .Y - 4h .o 72. I 5.1 17.5 5.X I X.6 Y.Y 6.7 12.6 `3.1 -I I .o I I .o 6. I 5.0 Xl.5 47 15.h 7.1 12.7 3 0 XY 3.3 II 5 5.6' h.I' 17.6' X.7 45.5 20.2 36.0 IO.0 2.5 L'S) h.0 x.7 1.0 7.0 4.5 35.X 3 I .A 32.0 7.0 7.0 12.0 13.2 3.0 Y.5 0.4 2.h 5.Y TABLE I.-Continued Current smoker\ Fomw \moher\ Symptom\" Reference Age (number of wbiect\) Wheeze Wilhelmsen and Tibhlm (lYh6# 17.6 - t-J.9 1.x Wei\\ et al. ( lY6iT x.0 - 6.0 3.0 Fletcher et al I l9SY $ Mueller et al. I IO7 I lh ' Manfrrda. Nelwn. Chemiach t IY7X)" 25-N (2Sh) 16.3 12.Y I x.0 10.0 `6.X 23.4 II 25 `1 2.1) s 0 -I.0 I .(I 0.x 11.1 4.2 3.5 2%.51(246 )`I 31.5 30.7 11.1 70.0 x.0 x.0 Hawthorne and `I x 19.2 4.x I0.h hl 6.0 Fry ( 1978)' Milleret al. ( 19XXjh ' 30.X 2x.1 11.7 6.Y 12.2 1.4 Schenker. Samet. Speizer ( 19X21h ' men reported wheeze. precluding meaningful analysis for this variable. The high symptom rates seen in this study may reflect the older ages of the participants and the selection factors contributing to enrollment in the Philadelphia Pulmonary Neoplasm Research Project. Three other early investigations confirmed a lower prevalence of specific respiratory symptoms among former smokers (Table I ). Fletcher and coworkers (1959) reported the respiratory symptoms of 244 British post office workers, aged 40 to 59. as part of the study of the relationship between symptoms and tests of lung function. Former smokers of both sexes reported wheezing on most days or nights less often than current smokers, but former smokers also complained of grade 2 dyspnea (i.e.. stopping for breath when walking at one's own pace on level ground) as often as current smokers. Fletcher and Tinker ( I96 1) studied respiratory symptoms in 363 London male transport workers. Former smokers had lower prevalence rates for cough. phlegm production. and grade 3 dyspnea (i.e., stopping for breath after walking about 100 yards on level ground) than current smokers of IS cigarettes or more per day. In a large community- based study in Tecum\eh. MI. Payne and Kjelcberg (1963) reported age- and sex- specific prevalence rates for cough and phlegm production that were comparable for former and never smokers (Figure 5). In contrast. sex-specitic rates of dyspnea were highest among former smokers and increased with age (Figure 6). More recent studies have also found lower prevalence of respiratory symptoms among former smokers and documented sex-specific differences among smoking categories (Table I ). Mueller and colleagues ( I97 I ) showed that male former smokers had fewer symptoms than current smokers. including cough for 3 months per year. grade 2 dyspnea. and wheezing. Only sputum production for 3 months per year was higher among male former smokers than among never smokers. Female former smokers had lower prevalence rates for cough and phlegm production but higher rates for dyspnea and wheezing than current smokers. Rates for female former smokers were generally higher than those for male former smokers. Manfreda. Nelson. and Cherniack ( 1978) studied subjects from urban and rural communities in Canada. and found very similar overall and sex-specific prevalence rates for these respiratory symptoms among former smokers. In this study. however. female former smokers had prevalence rates between those of current and never smokers for all symptoms. In three separate surveys, Hawthorne and Fry ( 1978) evaluated the association among smoking, respiratory symptoms, and cardiopulmonary mortality in I I.295 men and 7.491 women from southwest Scotland. Former smoher\ had prevalence rates for phlegm production and wheezing intermediate to those of current and never smokers. Male former smokers reported \hortnr\s of breath as often a\ male never smokers. whereas female former smokers had an increased prevalence ofdyspnea compared u ith current smoker\ of either \ex. Miller and colleagues ( 1988) determined sex-specific prevalence rates for a wide range of respiratory symptom\ in a stratified random sample from the general popula- tion of Michigan. Mean age for the three smohing groups ma\ comparable. Male current and former smohers had similar lifetime cigarette pack consumption (9.09 x IO' vs. Y.93 x IO"). whereas female current smokers had almost twice the cigarette consumption of former smokers (X.32 x IO' ~4. 1.50 x IO'). The prevalence rates of persistent sputum and wheezing were Iovver among male former smokers compared with current smoLer\. In contrast. the prevalence of dy\pnea uas similar for male former and current amohers. and findings Mere Gmilar among females. Furthermore, female former smoherj had higher rate\ for dyqtea than males but lower rate\ for all other respiratory variables a\\es\ed. Schenker. Samet. and Speirer (lYX7) ev,aluated the effect of smoking status on respiratory symptoms of 5.686 women. Age-aci.ju\trd prcv,alence rates for chronic cough. chronic phlegm. and wheeze most day \ or night\ among fommcr mohers were between those for current and never \mohers. Grade 3 dyspnea M as reported more often by former smokers than current maker\ of I to 2-l cigarette\ per day or by never smokers. Several reports have addressed the occurrence of >ymptoms in an epidemiologic study in Tucson. AZ (Lebouitz and Burrows lY77: Paoletti et al. 1985). Cro\s- sectional analyses, ha\ed on the first survey of the population. indicated that former smokers had a higher prevalence of chronic phlegm production than did never smoker\ 292 MEN 50-T 50 - 7 40- I I `.. . . `. I I 30- . . `. . . . : .-.. ..y,.`. `.t .-- /' . ..' / \ j..,/ . -- / \ ._. A.7. .I` .... 20 - / `. / / ,.-`>f< / \ / \ \ 1' 10 - v 01 I 1 I 0 10 20 30 40 5b 60 70 AGE Cigarette Smokers . - Ex-Smokers .s....... Pipe & Cigar Smokers --- -- Never Smokers FIGURE S.-Prevalence of cough and phlegm by smoking group NOTE: Person with grade 2 cough and phlegm had both symptoms and at lea\! one symptom for 23 mdyr. SOURCE: Payne and Kjelsberst 1964). WOMEN 10 20 30 40 50 50 AGE 70 50 40- 30- 10 20 30 40 50 60 70 AGE Cigarette Smokers -. Ex-Smokers Pipe & Cigar Smokers - - - -- Never Smokers FIGURE 5. (Continued)-Prevalence of cough and phlegm by smoking group NOTE: Prrwn\ u ah grade 7 cough and phlegm had horh \gmptorn\ dnd ;II Iea\~ one \!mptom for 23 mo/~ r. SOURCE: Payne and Kjcl\hty( 19641. MEN 100 - 90 - 80 - 70 - 60 - ,: 10 ---~~ . ..-. ____-- --___a. /-- ___I- I I 1 I , I I 10 20 30 40 50 60 70 AGE WOMEN 10 20 30 40 50 60 70 AGE - Cigarette Smokers -.-.-.--- Ex-Sm&e~ ......... Pipe 8 Cigar Smokers ------------ Never Smokers FIGURE 6.-Prevalence of dyspnea by smoking group SOLIRCE: Payne and Kplhcrg (lY641. but a lower prevalence compared with current smokers (Table 1). When examined within age groups. the prevalence of chronic phlegm tended to be higher among older male former smokers with substantial past consumption of cigarettes. suggesting that symptoms may not revert quickly to those of never smokers. To evaluate the effect of cumulative tar consumption on respiratory symptoms and lung function in the Tucson population, Paoletti and coworkers (1985) studied the predictive value of estimated tar exposure and pack-years on respiratory symptoms of 582 current smokers and 62 I former smokers. Tar exposure was calculated from the Federal Trade Commission data on tar yield of each type of cigarette smoked and was used to classify retrospectively the smokers' exposures into categories of low and high tar pack-years as well as total tar (kilograms). Only current and former smokers with consistent consumption behavior were analyzed. Ex-smokers had lower prevalence rates of cough. chronic cough. phlegm. and chronic phlegm than did current smokers. Multiple logistic regression analysis was used to determine risk factors for any cough. any wheeze. and dyspnea. Statistical models for former smokers could not be derived using total pack-years, total tar estimates. age. or deep inhalation that significantly predicted respiratory symptoms among former smokers of either sex. The low prevalence rates of symptoms among former smokers may have limited the modeling. Ballal (1984) analyzed the effect of depth of inhalation on respiratory symptoms in 75 former smokers as part of a larger study of the smoking behavior of 753 Sudanese medical practitioners. The proportion of former smokers complaining of any wheeze increased with degree of inhalation (slightly. moderately, or deeply). but the trend was not statistically significant. Small numbersand subject selection restrict the importance of this finding. In summary. cross-sectional population-based studies have generally shown that former smokers have reduced prevalence rates for cough. phlegm production. and vvheezing compared with current smokers. Dyspnea may not completely reverse after cessation as shown by the compamble prevalence rate\ for current and ex-smokers in several studies. However. dy\pnea may prompt cessation when sustained smoking has caused significant physiologic impairment. Differences in symptom rates by gender have been documented in former smokers: potential explanations include sex-specific differences in reporting. differences in xmohing practices. or distinct underlying physiologic responses to cessation by gender. Although the relevant data are limited. rev,ersal of most symptoms reflecting mucous gland hypertrophy and hyperplasia and airways inflammation appears to be rapid and not dependent on cumulative smoking at the time of cessation. Measures of past cigarette consumption have not been associated with current respiratory, symptoms among former smokers. Occupational Groups Studies of grain elevator uorhers. dairy farmers. cedar mill workers. and persons exposed to dust. gas. fumes. and ashesto have addressed the influence of occupation and smoking on respiratory symptoms (Table 2). Broder and coworkers ( 1979) and Dopico and colleagues ( 1983) compared respiratory symptoms in grain handlers with those of civic outside workers and of city worhers. respecti\ ely. In both studies. former TABLE 2.-Percentages of subjects in cross-sectional occupational surveys with respiratory symptoms by smoking and occupational exposure status S! mptomr" Reference Cmxnt \molLer\ Former smokers Never smokers Mean age Occupationally Occupationall) Occupationall> (TowI) eXpO\ed Control eXpO\d Control expwed Control Coush 3 mo/\ r Broder et al (lY7YIh Ghan-Yeun; et al. I IYXI) Kllbum. Warshnw. Thornton t 1986) Phlegm 3 mo/yr Broder et al ( I979$ Dopico et al Gram handlers 42.0 ( 1984jd 41.0?1?.0(310) Gram elevator 67.0 worLer\ (A) 39+13(18Y) Gram elevator SO.0 worker\ (B) -II?13 (752, Cwic out\ide - H orkers I B I 41?lJ t IX01 Whne cedar 30.7 mill worhcr\ 44.3+11.1 (51 I I Nonuhne cedar 30.7 mill uorher\ 39.hk9.I 1141) White office worker\ 43.31 I.5 I3931 Nonwhite office worker5 39.os.9 (46) Shipyard worker\ S8 (288, 55.0 Michigan men 5 1 .O 42 1.595) 45.0 City Norkerb - 41.M12.0 (239) 38.0 23.0 56.0 17.3 12.3 `I.8 `1.X 33.0 48.0 30.0 17.0 15.0 - 32.0 - 37.0 26.0 4.0 8.0 `3.0 15.0 IS.0 s.0 X.5 x.s 3.0 - 7.5 3.0 3.5 33.0 13.0 IS.0 3.0 297 TABLE 2.--Continued S>mptornr" Keferencr Babbott et al. (19X0)' ' Dar? farmer\ 7') 0 I IYX, Indu\tr! norker\ ~ ISlh) ChowYetme et al. t IYXJ) Ktlbum. War\han, Thornton t I YXh) Dy\pnea > grade 2 Brodrr et al. t lY7Y lh Doptco et 31. t 19X-I) Babbott et ill. I IYXO# Ghan-Yeung et al. t IYXJ) Ktlbum. War\haH, Thornton t lc)Xh~ Wheerr Broder et al. t lY7Y )" Dop~co et al. ( 19X-1)' Babhnt et al I IYXOI' ' Ghan-Yeuns et al. t IYX~I"' Kllbum. Wur\hau, Thornton ( IYXh)' 26. I ss.0 27.0 IS.0 77.0 IS.0 31.1) 65.0 5.0 70 2' 0 -17.0 2.7 1 6X.0 31) 0 21 x 3.0 2 I .n 2.0 36.0 21.1 7.0 4.0 50.0 10 24.x 13.0 IY 0" 11.1 39.0 12.0 16.0 sx.0 s I A)' 26.1 54.0 x.0 7.0 I7 0 -ll.(? 12.3 43.0 Y.OF 8.2 15.0 I I .o 6.0 34.0~ IO.4 6.0 6.0 1 I.0 7Y.W 7.5 x.0 16.0 IO.0 3x.0 15.0 5.0 57.0 27.0 IX.1 s4.n 4 0 70 17.0 3 I .(I 0.2 32.0 IO.0 7.5 7.0 5 0 2.0 IY.O 6.4 2.0 x.0 30.0 77.0 7.5 I .o smokers had intermediate prevalence rates for cough, sputum production. wheeze. and shortness of breath compared with current and never smokers. Additionally. former smokers who were grain handlers had more acute and chronic symptoms than ex- smokers who were outside civil or city workers. For grain workers, length of employ- ment had no effect on the prevalence of respiratory symptoms within each smoking group. The results of these two studies differ in that the occupational effect u as minimal and less than the smoking effect in the former investigation but significant and greater in the latter. The choice of control subjects may explain this discrepancy. Babbott and colleagues (1980) assessed the respiratory symptoms of I98 Vermont dairy farmers and 5 I6 nonmineral industrial workers. Former smokers were matched on age (mean 43 years) and years since cessation (mean 8 years). Chronic sputum production, wheezing, and dyspnea were more common among current smokers than among formeror never smokers. and more frequent among dairy farmers than industrial workers. Similar results were found by Chan-Yeung and coworkers (19X-I) in a study of 652 cedar mill workers and 440 control office vvorken. Korn and associates ( I YX7). in a population sample of 8.515 white adults. showed that smoking and exposure to dust. gases, or fumes were independently associated with an increased prevalence of chronic cough, chronic phlegm. persistent wheeze. and breathlessness. Former smokers with gas or fume exposure were more likely to have respiratory symptoms. particularly breathlessness. than exposed current or never smokers. A multiplicative relationship between smoking and occupational exposure was found for breathlessness but not for other symptoms. Kilbum. Warshaw. and Thornton (1986) conducted an investigation of respiratory symptoms. cardiopulmonary diseases. and asbestosis among 338 male and 8 I female shipyard workers and their families. In general, the study group had more symptoms than reported from a similarly stratified random sample of the Michigan population (Miller et al. 1988). The authors suggested that environmental influences in the Los Angeles area may explain the higher rates. Male shipyard workers who were former smokers had more cough, sputum production. and wheezing than shipyard workers who were current smokers, whereas the pattern was reversed for female shipyard workers. In summary, results from selected occupational groups support the findings from the community-based studies, although work exposures may interact with smoking in determining the occurrence of symptoms among former smokers (US DHHS 1985). The results of these investigations may be affected by misclassification of exposures and by selection or recall bias. As in the community-based studies. limited descriptive information is provided on former smokers. Longitudinal Studies Numerous longitudinal population-based studies have found rapid resolution of most respiratory symptoms after smoking cessation (Table 3). A study by Woolf and Zamel ( 1980) indicated that 302 female former smokers with a mean cigarette consumption of I5 pack-years had dramatic resolution of respiratory symptoms within 5 years. These investigators defined former smokers as women who had not smoked for at least I year before entry into the study. Persistent former and never smokers were comparable in TABLE 3.--Change (%) in presence of respiratory symptoms, longitudinal studies, by cigarette smoking status Continuing smoker\ Former \moka-\ Never smokers Symptom\ Ape Ketcrencc ( mem ) LOX1 No change" (klld LU\I No change" Gained Lwt No change" Guned IX.0 hh.0 16.0 2.0 xs.0 13.0 5.0 X6.0 Y.0 h&!h1: 43.2+ I .7` Mcrtcrclte: 2'). Ii I. I t lea\) : 3X.h ti0.Y Ptltelm 3 mo/yr `T`a\hh~n et ill. ( I `JX4) 43 -5x X.3 77.6 1.l.I Id.? x7.7 2.0 NCI change: I .O Net change: -2 I .O 10.7 7x 0 7.6 x5.5 7.3 x5.2 53 x0.2 5.0 x0.7 x.x 77.4 II 3 lh.7 7x.5 h.Y 7.4 5.3 5.3 IO. I XY.3 5.0 Y?.S I.3 97 1 2.0 96.6 I3..? 7.7 X6.3 4.X 0.6 2.5 I.3 I.5 6.0 Nel change: 3.0 J.S Y0.X 1.7 - TABLE 3.--Continued Cornstock et al. ( I Y70) Net change: 4.0 Ner ch;qc: IS.0 Net ch;qc: 0.0 Sharp et al. (1073) IS.4 X6.2 6.4 IO.2 77.0 I1.X x.0 x5.0 7.0 pJLq'"Llnea > rru Woolf and Zamel ( IYXO) `Ta\hkm et nl (IYX3r' C`om\tock t't 01. (IY70) Sharp et al. t lY73) Fwdm:cn et al. ( lY7.3) White male >I ppd Whate female >I ppd Wh,a/. Woollantl %amrl (IYXO)' Ta\hhin et al c IYX4)' 17.0 4.h II 0 IX.0 I I.2 x9.9 Ner change: 2.0 72.x Net ct1arrp!: -X.Y Net change: -I I .X 7 I .o 77.x 13.0 5.5 16.2 I I.0 I I .o IX.0 75.0 x.0 7.0 Yl .I) 3.2 x0.x 0.0 Net chance: I I .O Net chance: 1.0 14.4 72.x 12.x IO.1 70.x 0.0 %.I) s.0 5.0 YI .o 13.7 x2.1 4.2 7.0 - to.0 4.0 E TABLE 3.-Continued Continuing smokers Former smokers Never smokers Symptoms Age Reference (mean) Lost No change" Gained Lost No change' Gained Lost No change" Gamed Comstock et al. (1970)`" Net change: 5.0 Net change: -5.0 Net change: -2.0 Sharp et al. 13.4 77.0 9.6 II.1 7x.7 10.2 7.3 xx.4 4.3 (1973jrn "No change mdlcate\ that rqxratory symptom\ were ather conristently absent or conslstentty present. hOnly females. cough and/or phlegm. S-yr wdy period. `Llght=<70c1g./wk; moderate=?I-14Ocl~wk: hravy=more than 14Ocig/wk. `Former rmokers defined ab those who atoppd between haselms and followup. x4ales only. S-Cyr f~lltowup. `Males only. former htudws defined as thox who stoppd between baseline and followup. 7.yr t~llowup "Former studa defined as those who stopped between baaehne and followup. I.5yr followup. hppd=packs/day. `Grade 2 or 3 dyspnca. `Dyspnea not defined. `Dyspnea at ordinary pax. `Wheeze not defined. mEver wheeze. age: former smohers had a shorter duration of smoking in years than current arnoher5 of I /? to I pack per day. but similar cumulative pack-years ( 1 1.5 vs. 15.0). More former and never smokers reported consistent absence of cough or sputum. dyspnea. or u heerr compared with current smokers. Thirteen percent of former smokers developed cough or phlegm during the study period compared with 9 percent of never smoker\ and I6 percent of smokers. At enrollment. smokers had more respiratory symptoms and were more likely to develop symptoms over the 5 years of the study. Similarly, in a large population study in the Los Angeles area. respiratory symptom\ diminishedamongformersmokersafteronlySyearsofabstinence(Tashkinetal. 19X-l). In this study, the following 4 smoking groups were defined: 27X persistent \moher\: 3 I4 never smokers; IO6 quitters. subjects who smoked regularly at baseline but were nonsmokers at the conclusion of the study: and 294 former smokers. individual\ who were regular smokers but had quit at least 2 years prior to baseline. The mean age for female quitters (45.6 years) was comparable among the smoking categories: the mean age for male quitters (43.4 years) was similar to the mean ages for current and never smokers: however. it was 6.2 years less than that for former smokers. Quitters and former smokers had smoked similar numbers of cigarettes per day (26.3 vs. 23.6 for males: 19. I vs. 19.0 for females). but quitters had higher pack-years (3X.6 vs. 76.X for males; 27.4 vs. 16.2 for females). In addition. quitters had pack-years comparable with current smokers (38.6 vs. 40.5 for males: 27.4 vs. 30.9 for females). Over the 5 years of the study. quitters recovered from the symptoms of cough. sputum. and wheeze more frequently than continuing smokers. No difference in shortness of breath was found between the two groups in the 5-year study period. Quitters and former smokers were not compared to determine the relative importance of cumulative exposure versus time since exposure on the observed reduction of symptoms among ex-smokers. Comstock and coworkers (1970) reported comparable findings in a study of respiratory symptoms in 670 male telephone company employees studied for 5 to 6 years. Symptoms of chronic cough, phlegm production, and wheeze decreased sig- nificantly in quitters whose baseline prevalence for these symptoms was similar to persistent smokers but whose followup values were comparable to never smokers. Baseline and followup prevalence rates for breathlessness in quitters were equivalent to those of persistent smokers. Sharp and colleagues ( 1973) found similar trends in respiratory symptoms in 1,263 middle-aged males from an industrial population surveyed in 1961 and again in 196X. Former smokers were defined as individuals who stopped smoking after entry into the study; previous smoking histories were not provided. Over the 7 years of the study. 72.3 percent of former smokers with persistent cough and 64.4 percent with persistent phlegm recovered from the symptoms. These rates of recovery were higher than for the other smoking groups with similar symptoms. Additionally, former smokers who originally complained of dyspnea and wheeze tended to lose these symptoms over the study period, but less dramatically (49-percent and 45.5percent recovery, respective- ly). New reports of cough and phlegm were made by less than IO percent of never and former smokers and I6 percent of continuing smokers, whereas new wheeze was found in 13.5 percent of former and 14. I percent of continuing smokers. In contrast. dyspnea developed in 18. I percent of former smokers and 22.4 percent of continuing smokers. In a study of shorter duration. Friedman and Siegelaub ( 1980) confirmed the findings of Tashkin and coworkers (1983). Cornstock and associates ( 1970). and Sharp and colleagues ( 1973). Over approximately I.5 years of observation, 3.815 recent quitters more often reported decreased chronic cough but noexertional dyspnea when compared with 9.391 persistent smokers. Findings from two Finnish studies and one British study support the results of these North American investigations (Huhti and Ikkala 1980; Poukkula. Huhti. MPknrBinen I982 Leeder et al. 1977). In the I O-year study of Huhti and lkkala ( 1980). respiratory symptoms increased in all groups of smoherr except male quitters. who had lower prevalence of phlegm production and wheezing (Table 4). Similarly. in a IO-year followupof male pulp mill workers. Poukkula. Huhti. and Makarainen ( 19X2) observed a decrease in respiratory symptoms only for quitters and only for cough and phlegm production. No explanation for the increase in symptoms over time for never smokers was provided in either study. During a 6-year period. Leeder and colleagues ( 1977) evaluated chronic cough and phlegm annually in 3.9 I6 young married adults. Men who pave up smoking had a progressive decline in the reporting of cough and phlegm. Only, a small number of female ex-smokers were included. In summary. the findings from these longitudinal studies agree with those from the cross-sectional surveys and suggest that cough. phlegm production. and vvheering reverse after cessation. regardless of duration or quantity prev#iously smoked. Dyspnea. however. may he less likely to resolve in subjects with longer smoking histories. possibly indicating irreversible damage induced by smoking up to time of cessation. Clinical Studies of Possible Mechanisms Few studies have investigated the mechanisms by vv hich respiratory symptoms improve after smohing cessation. Reversal of mucous gland hyperplasia and reduction in airway inflammation have been considered likely mechanisms but have not been documented. Recovery of epithelial integrity has been shown in two small clinical studies of epithelial permeability (Minty. Jordan. Jones 1981: Mason et al. 19X.3). Improvement in tracheal mucous v,elocity. another possible mechanism by, which respiratory symptoms may' decrease after smokin, cr cessation. has also been examined. Goodman and coworkers ( 197X) reported that five of nine y'oung former smohers had tracheal mucous velocities that were comparable uith age-matched never smohers. One subject had a minimally~ depressed velocity,. and three had markedly depressed values. Only one subject was restudied 2 months after baseline and 9 months after cessation. and at that time. tracheal mucous velocity was found still to be reduced. Because subjects were not studied while smohin,. 0 the change after cessation could not be determined. Camner. Philipson. and Arvidsson ( 1973) studied tracheal v,elocity in subjects before and after smohinp cessation. They found that in I I of I7 male former smokers. tracheal mucous v,elocity improved 3 months after cessation and that in the remaining 6 former smohers. velocity was slower or similar when compared with baseline values. Improved tracheal mucous velocity may lead to less mucus in the airways and thereby reduce symptoms of cough and u heere among fomrer smohers. 303 TABLE A.-Percentage of subjects with respiratory symptoms b> smoking status, 1961 and 1971, in a cohort of middle-aged, rural Finns 1 \e\er \moher\ IY61 se\er \nlohrn 197 I Mule\ S! mptom\ (X0) Phleem all da\-* inter I')61 -I I')71 6 b'heetms! most daw 1961 1071 2 Weather affect\ chru 1961 6 1071 1') Breaihle\we\\ grade< 34 IY6l 1 lY7l IO Chrome bronchitk IY61 Y IY7l II Mean ape (y) so in IYhl Femab 1573) II Evwwhw lY6l I Y7 I Female\ 1261 1 III IV Smohrr\ IYhl Smr)her\ I Y6 I Ex-vnoher\ I Y7 I Smohw I Y7 I Female\ Mdf\ , I41 I?111 Female\ 117, I I IX 27 -I Ii 3 -l I IO 3 IO I? IS I6 II Y I7 I7 I6 `I 21 6 I4 I5 so I5 23 IS I? 10 13 24 2') Y so 4 Y I I I3 I6 39 I6 36 5 11 47 4Y 2 II 6 IY 71 71 46 Respiratory Infections Numerous clinical studies have shown alterations in immune and inflammatory function among cigarette smokers compared with never smokers. Studies of peripheral blood have shown that current smokers have as much as 30 percent higher leukocyte counts than never smokers (Corre. Lellouch. Schwaart/ 1971: Friedman et al. 1973). Increases have been reported in polymorphonuclear leukocytes (Bridges. Wy,att. Rehm 1985). which appear to have nonnal chemotactic. microbicidal. and secretory functions (Nobel and Penny 1975: Abhoud et al. IY83). and monocytes (Nielsen IYXS). which may partially lack the ability to kill intracellular C`rr~rtlitltr (Nielsen IYXS). Total 305 numbers of T lymphocytes are increased among \mohers (Kas7uhowki. Wysocki. Machatski IYXI: Robertson et al. 1983: Burton et al. IYX?: Smart et al. 15%). Light and moderate smokers have increa\ei in OKT3+ (total T cell\) and OKT3+ (T-helper cells) (Hughes et at. 1985: Ginns et al. 1982). and heavy smoker\ have decreases in OKT4+ and increases in OKTX+ (T-suppressor cells) (Ginns et al. IY81: Miller et at. 1982). Additionally. functional changes in T lymphocyte\ from smokers have been observed (Whitehead et ai. 1974: Suciu-Foca et at. 1974: Onxi et al. I YXO). but these findings remain controversial. Changes in serum components have also been reported. Smokers have higher levels of CS. CY. Cl inhibitor (Wyatt. Bridges. Halatek I%1 ). C-reactive protein. and autoantibodies (antinuclear and rheumatoid factors) (Heiskett et al. 1962). but lower levels of specific immunogtobutins (IgG. IgM. and IgA) (Ferson et al. 1979: Vos-Brat and Rumke 1969: Kosmider. Fetus, Wycocki tY73: Dale\ et al. 107-l: Wingerd and Sponzitti 1977: Guts\,ik and Fugerhot tY7Y: Gerrard. Heineret al. 1980: Leitch, Lumb. Kay IYXI: Andersen et al. 19X1: Bartetik. Zioto. Bartetik 19X-l: McSharry. Banham. Boyd 1985). As previously dewribed. IsE is elevated in smoker{ (Burrows et al. 198 I: Zetterstriim et at. 19X1: Hittgren et al. 1982: Warren et al. 1987: Bonini IYX?: Stein et at. 19X3). and this increase may result from suppression of regulatory T-lymphocyte function (Hott 19X7). Bronchoatveotar lavage has provided evidence on the noncellular and cellular com- ponents of the peripheral airways and alveoli amon, 0 smokers and nonsmokers. Data have indicated that smokers appear to have normal or \lightt!, elevated level? of IgA and IgG (Reynotd\ and New ball 1973: Warr and Martin I Y77: Bell et al. I YX 1: Vetluti et at. 19X3: Pre. Btudier. Batte\ti 19X0: Gotoh et at. 19X3). Similarly. value\ for lysoqme (Harris et al. 1975). complement component\ (Rohertwn et al. 1976). and fibronectin (Villiger et al. IYXI ) are elevated in tavage fluid from \mohers. The total number of cells retrieved from tavage of smoher\ i\ increawd with marked elevation in the percentage\ of activated mucrophages and neutrophils (Hunninghahe et al. IY79: Harris. Swenson. Johnwn 1970). Ahwlute typhncyte number\ remain unchanged. although T-cell function ma!' be altered (Danielc et at. IY77: DeShaLo et al. 19x3). Recovered mucrophage\ have increaed chemotactic funcrwn (Warr and Martin 197-t: Labed/ki et at. I%.?: Rwhartts et HI. 19X4) and increaed release of damaging product\ huch a\ wperoside anion\ (Hoidat ct at. 1970: Hoidat et at. 19X0: Jowph et al. 19X0: Hoidat and NieHoehncr 19X2: Grecnin, cr and Loarie 19X3: Rwma et at. IYXI). hut diminished microbicidal acti\ it? (iLlartin and Wxr tY77: Fisher et al. 14X2: Ando et al. 19X1). Smoker\ hake twn \houn to have reduced \peciiic immune reywnws to inhaled antigen\ 111 4ever;lt occupation;lt \tudieh. Fxmer\ u ho Mere newr w-ioher\ had higher levels ofwrum precipitin\ to .~~rc,/,o/lr~/\.\/~r~/.c~,f;/[,/r/ than furmer~ u ho ~rnohed (.\lorgan et at. tY71: Morgan et at. I Y75: Gruchw ct al. 19X I: Cormier and B2tunser I YXY: Kuuh et 111. I YXY). M herca\ pigeon breeder\ \j ho had ne\ er wohed had higher precipitating antibodic\ to pigeon 7 globulin compared u ith their mohin? counterpurts (McShurr> ct at. IYXI: Andcrsen and Chri\tcnwl IYX3: Bo>d et 4. 1977). Similar result\ h3i.e been t'ound in pouttr) N orhcrs ( Anderwn and Schonheyder I YXI) and proceaing uorher\ (McSharr! XICI Withinwn 19X6, in relation to I@.2 rr\ponses to hen serum antigen and prawn antigen, respectively. Whether smokers have a lower in- cidence of hypersensitivity pneumonitis has not been adequately studied. Finally. smokers manifest a blunted immune response to influenza vaccination. Although smokers and nonsmokers have similar postvaccination titers at 3 months (Knowles. Taylor. Turner-Warwick I98 1). current smokers have reduced titers at 1 year when compared with nonsmokers (Finklea et al. 197 1; Mackenzie. Mackenzie. Holt 1976). In a large clinical trial comparing responses to killed and live attenuated vaccine. smokers had a decreased primary immune response to the killed vaccine (Mackenzie. Mackenzie. Halt 1976). Although effects of smoking on the immune system have been demonstrated. feM studies have investigated the association between smoking and acute respirator) illnesses of presumed infectious etiology. Aronson and coworkers ( 1982) found that smoking was associated with an increased risk of acute respiratory tract illness. In addition. these investigators found that smoking increased the likelihood of having a lower respiratory tract illness and increased the duration of the symptom of cough. These findingscorroborated the resultsofother investigations (Haynes. Krstulovic. Bell 1966: Peters and Ferris 1967: Parnell. Anderson. Kinnis 1966) that showed the came trend for increased respiratory infections among smokers compared with nonsmokers. In contrast, Pollard and associates (197.5) found no difference in the incidence of respiratory illness observed among smokers compared with nonsmokers. Short fol- low-up of 9 weeks and selection of Naval recruits who had a high prevalence of acute respiratory disease as patients may explain the discrepancy in results. Kark. Lebiush. and Rannon (1982) studied an outbreak of influenza among 3.76 men serving in a military unit in Israel. They found that 68.5 percent of 168 current and occasional smokers had clinically apparent influenza as compared with 47.2 percent of never and former smokers. Smokers and nonsmokers with influenza had comparable serologic response rates. Among smokers, the attributable risk percentage for severe influenza, defined as illness resulting in bedrest or loss of workdays. was 40.6 percent (95-percent confidence interval (CI), 2 1.6-54.8 percent). Similar results have also been reported by several other researchers (Finklea, Sandifer. Smith 1969: MacKenzie. Mackenzie, Halt 1976; Kark and Lebiush 198 I ). Smoking Cessation and Respiratory Infection The relationship between altered immune and inflammatory functions and the occur- rence of respiratory infections among ex-smokers has not been extensively investigated. This Section reviews available relevant studies. Studies of animals have shown a return to normal immune and inflammatory function after cessation of cigarette smoke exposure (Holt and Keast 1977). Investigations of humans have yielded similar findings. Specifically. among former smokers, serum concentrations of IgG, IgA, and IgM (Hersey, Prendergast. Edwards 1983) and bronchoalveolar lavage cell numbers and percentages return to those of never smokers (Holt 1987). Additionally, Miller and coworkers (1982) found that within 6 weeks of smoking cessation. the number and function of T lymphocytes reverted to normal. Finally, Raman. Swinburne. and Fedulla (19X3) found that 3 year\ after smoking 307 ce\hation. former \mokra had pneumococcal orophar> ngeal adherence value\ com- parable uith those of nwer smoker\. The \ignific;mcc of thehe change< in specific component\ of ho\t defense\ to the ri4. of \uhsequent respiratory infection\ amon? f'ormer smokers ha\ not been chxrcterixed. Mortality from int1uenc.a and pneumonia M ith wpect to ciyxette \mokin_c ha\ been as\e\sed in several cohort \tudie\ (Table 5). Mortality from influenza and pneumonia was increaed in ever smoher\ reluti\ e to never smohera in the American Cancer So&t) Cancer Prevention Study I (ACS CPS-I) t'ollouup from I959 through I963 (Hammond 1965). In the British Phyhicilrns Study. current and former smokers had small excesses of mortality from pneumonia. but annual mortalit) rate\ from pneumonia increaed with the amount smoked (571 IOO.000 for I - I4 g tobacco/day. 61/iOO.O00 for 15-21 g tobacco/day. 9l/lOO.tMK~ for 29.5 p/day) (Doll and Peto 1976). A similar exposure- response relationship v. 3s found in the U.S. Veterans Stud! (Roget and Murray 1980). Finding\ from ACS CPS-II WI afe-ad.justed mortality from influenza and pneumonia have been examined for the effect\ of active smoking and smoking cessation (Table 5). Male former smokers of t'eber than 21 cigarette\ per day have mortlrlit~ ratio\ after IO years of abstinence that are approachin, ~7 unit\ Male former smohers of' more than 1 I _ cigarettes per day have mortalit! ratio\ approaching unity after I5 years of abstinence. hut much higher for shorter period\ ot` abstinence. Female former smohers of an) amount have mortalit> ratios that approach those of never smokers within 3 to 5 years ofab\tincnce. The a\\ociation het\+een cigarette \mohing status and mortality from intlurwa and pneumonict ma)' partlall!, retlect the rft`ects of smohing on respirator> defense mechanism\ including immune rwponws. The ~ulnerahilit\ of perxon~ M ith clgarztte- related cardiopulmonar! di\c:r\e\ to resprratorl infection\ ma\ alo cwntribute to the association. For ewiiple. Glexn. Decher. 2nd Perrotta ( 1987) studied underl!,ing diagnow\ in patient\ hwpitalixd u lth xutr reyrator> disease during intluewu epidemics in Houwn. TX. Chronic pulmonar! condition\ were the mwt co1~m~o11 underI> in? condition. and cardiac condition\ \\ere the ne\t most frequent. PART II: PI~L1IONARY FI'NCTIOV AI\IO\v(; FORILlER S1ZOKERS Cross-Sectional Population Studies of FEYI `OX TABLE K-Age-standardized mortality ratios for influenza and pneumonia for current and former smokers compared with never smokers Doll and Pete 34.440 male (1876) Briri\h doctor\ 20 vr TABLE K-Continued ..J I.4 2.1 I .x t.x I.1 I.1 7 0 .3 2.4 2.2 2 I 7.1 0.`) I 2 .2 h - - 2.7 .I) -- I.4 0.6 0.3 I.2 3-t `I'AHLE 6.-Association between cigarette smoking status and C'KVI levels in selected cross-sectional studies of'adult populations `TABLE k--Continued I `)0X Finding\ AliJU\td "XX, kVeh FEVl FEV I/FVC ratlo Nwrr \moher\ 2.7 X6.7 Former \moher\ 1.6 xs.0 Current \moher\ 1.5 X4.6 Mean value ol the FEVl/FVC ratio Never \mohcr\ 76.0 Former \moher\ 74.3 Current \moher\ 73.6 Adfuwf FEV, (L) Never vnoher\ 3.3 Former \moher\ 3.2 Current maker\ 3.0 Mean normnlwxl FEV 1 wow MtX Women Never \moher\ 10.2 IO. f Former wwher\ Y.0 IO.0 Current smoker\ 9.6 Y.X `TABLE 6.--Continued Krtrrrlce Anderwn ( I Y7Y) Year of sludy Location Lufa. Papua New Gutnea Popui;~lion 733 men and women aged 25 and older H~penbottm et al. ( IYXO) Huhti and Ikkalu (IYXO) IY6l BO\\t! et ill. ( IYXO) I Y6.1 London. Englmd I X.403 male civil wrvant5. aged 40-W Bwton. MA 703 healthy male veteran\ lolloued for IO yr `I'AHLK h.--C'ontinued TABLE 6.--Continued Reference Year of study Location Carnilli et al. (10X7) Tucson. A% Dockcry et al. (19Xx) 1974-77 6 US communities h54 men nnd XY3 women agctl ?I) and older, who had FEV, at hnwline and fbllowup exams Initial FEVl a percentage of predicted Men Women Nonsmoher\ 0Y.X 97.x Former \moher\ Y3.7 9.5.6 Current vnohw" s1.x YI .h Deficit ot FEVl (L) compared with expected K. IO I men and women aged 15-74 Nonvnoherh Former \mohcr\ Current \moher\ Mf3l Women 0.03 -o.oL? -O.`h -0.05 A).51 -0.23 reported that the level of FEVl had a highly significant quantitative relationship with pack-years in a general population sample of 1.369 subjects in Tucson. AZ. and that smokers and former smokers had comparable levels accounting for pack-years. Higenbottam and coworkers ( 1980) assessed lung function in the I X.WO males in the Whitehall Civil Servants Study. Mean FEVl values among former smokers. adjusted for age and height. were lower than those for never smokers. but greater than those for current smokers. FEVl among former smokers decreased with increasing total con- sumption of cigarettes. but length of abstinence had little effect on FEV I among former smokers, although the minimum period considered was less than 6 years. The authors suggested that the depression of lung function associated with cigarette smoking has two components-an irreversible component related to total consumption and a com- ponent rapidly reversible on cessation. Beck. Doyle. and Schachter ( I98 I ) analyzed FEVI data from 4.690 subjects. aged 7 years and older. in 3 separate U.S. communities. These investigators also found that the deficit in FEVl compared with that expected for never smokers increased with cumulative smoking as measured by pack-years and duration of smoking. After adjusting for cumulative smoking. FEVl was I47 mL lower among male smokers and 78 mL lower among female smokers compared M ith former smokers. Dockery and coworkers ( 198X) studied X.191 randomly selected adults in 6 U.S. communities. These researchers found that the deficit of observed FEVl compared u ith expected age-. height-. and sex-specific values increased linearly Lvith cumulative pack-year\ among former smoher\ and current smoher\ (Figure 7) (Dockery et al. 198X). For the same pack-year\. FEV 1 M as I3 mL higher among male former makers and I07 mL higher among female former smoher\ compared with current smoker\. In a follow up study of 227 men. Tal lor. Joyx. and cob orher\ ( 1985) reported that percent-predicted FEVl for former \mohers ( 107.X percent predicted, uas between that of smokers ( 100.5) and neier smoker\ ( I 19. I ). Within each smoking catego?. men with increased bronchial reactiliry to inhaled histamine had lower level\ of percent- predicted FEVl than did nonreactor\. Thehe differences Mere srati\tically \ignificunt among smoher\ (K-l.6 ~`4. 10X.5 percent predIcted for reactors and nonreacrorz. respec- tivel! ) and former \moher\ (96.1 1'4. I I! I .S percent predicted for reactors and nonreac- tor4. re\pccti\cl! 1. Pulmonary Function Studies After Smoking Cessation .Studie\ in v. hich the lung function ofmoherc M;L\ measured hefore and after smoking ce\\ation are re\ ie\rctl in thi4 Src~iori: tt'4t\ ofpulnionar! function included \pirornetr) nitrogen u;r\hout. and other technique\ potentialI! wn\iti\e to the effect\ ofce\\a1ion. Inflammatory le\ionh of the small air\+ ;t! \ hai e been demonstrated to occur in 1 oung adult wwher\ before the :lppcarance ot` clinicall! significant Artlo% ob\truction MEN 8 -1000 300 200 b 5 100 8 0 300 200 c-r 5 100 8 0 PACK-YEARS 0 10 20 30 40 50 60 70 60 90 295 A m c5 10 20 30 PACK-YEARS fJ;;F?tT SMOKERS L- 40 50 60 70 60 90 295 FIGCRE 7.-Sex-specific mean height-adjusted FEV 1 residuals versus pack-years for current and ex-smokers, and distributions of number of subjects by pack-Jears NOTE: FE\`l=I -WC forced c\p~raror> \ ol~m~. SO1 RCE: Do&r~ c`t al. I IYXX, 317 WOMEN PACK-YEARS 0102030405060r65 I 2l t; 2 -250 I5 8 -500 s Ei $ -750 5 ii -1000 300 200 g 100 8 0 EX-SMOKERS CURRENT SMOKERS 8 <5 10 20 30 40 50 60 ~65 PACK-YEARS FIGURE 7. (Continued)--Sex-specific mean height-adjusted FEVl residuals versus pack-years for current and ex-smokers, and distributions of number of subjects by pack-years NOTE: FEV I =I -vx forced erpirxor~ 1 olume. SOURCE: Docker> et al. (I%#). (Niewoehner. Kleinerman. Rice lY73). Te5ts sensitive to abnormulitie\ of the small airways (e.g.. helium-oxygen flop volume curves. the single breath nitrogen test or other tests of closing volume, and frequency dependence of compliance) uould be expected to be particularly sensitive for detecting changes in function after cessation. In most of the studies reviewed in thi$ Section. participants were enrolled through smoking cessation clinics and subsequentI), monitored for pulmonary function and smoking status. The data from these studies can assess reversible effects of smoking throqh documentation of functional change coincident with ceh\ation; irreversible effects can be estimated by comparison of lung function le\,el M ith predicted value\ for normal function. Changes in Spirometric Parameters After Cessation Studies ofspirometric measurements of pulmonq function before and after smoking cessation are cummariLed in Table 7. Many of these studies suggested an improvement in pulmonary function following cessation. although the magnitude of the improvement was \mull in some of the studies. Dirksen. Janzon. and Lindell ( lY73) studied a randomly selected sample of men born in 19 14 in MalmB. Sweden. Fifty-eight heavy smoker\ were solicited to participate in a smoking cessation program. with 31 abstaining for 2 months. Vital capacity (VC) and FEV l/FVC improved 8 to 10 days after cessation. Bode and coworkers ( 1975) studied IO healthy subjects who participated in a smoking cessation program and remained abstinent for 6 to I4 weeks. Small and nonsignificant improvements were found for VC (0.3 percent change) and FEVt (0.9 percent change). Maximum expiratory flow rates with helium at SO and 25 percent of VC sifnificantlq increased. Martin and colleagues (1975) observed 1 2 successful subjects from a smoking . . cessation clinic for 1 to 3 months. Changes of V~XX) and Vrnak2c after smohins cessation were variable and not statistically significant. Residual volume and total pulmonary resistance w/ere also unchanged. McCarthy, Craig. and Chemiack (1976) studied a group of smokers who volunteered to participate in a smoking cessation program. At 25 to 4X weeks after cessation. only IS participants were still not smoking. Among these subjects, FVC increased from 3.92 L to 4.04 L (3.1 percent change). but FEVI (Go.3 percent change) and mid-maximum expiratory flow (MMEF) (-9.6 percent change) decreased. Fifty-nine subjects were evaluated between 6 and 23 weeks following cessation. Significant improvements were noted for FVC (2.3 percent of initial value) and the peak expiratory flow rate (6.7 percent of initial value). The FEVl. Vmax~. and \jmax25 did not change significant]}. Bake and colleagues ( 1977) observed I7 subjects who were abstinent from cigarette\ for at least 5 months. During this int$rval. VC a;d FEVt improved by 4.3 and 4.X percent predicted. respectively, while Vrnax~n and Vmax2 were reduced by 2.5 percent predicted and 7.3 percent predicted, respectively. At 3-vear followup. only nine , subjects were still smoking. No significant differences from baseline function were found in this group. 3 I 0 TABLE 7.-Spirometric studies of participants in smoking cessation programs l-1.(` WC or vc I IO mL 20 ml. 0.3'X 4.x I.h -40 ml. -70 ml. +30 ml. +hO IllL I.5 I.6 3.3 -V.h'/r -2.5 -7 3 0.7 -I I.1 ho rnL/wc t IO IllL/wc +10 IllL/W IMI lllL/W TABLE 7.--Continued Buikt and coworherh ( 1976) observed a group of \ix men and seven women who stopped \mohing for at Ieat I year after a smoking cessation program. Small changes were noted in \pirometric parameters. The author\ reported that MMEF distinguished between smokers and quitters in that over a 1 -year period MMEF declined significantly among smohers but not among quitters. Buist. Nagy. and Sexton (1979) supplemented this sample with participants from another smoking cessation program and extended followup to 30 months for both groups. Significant improvement> were observed in VC. FEVl. and MMEF among the quitters during the first 6 to 8 months (Figure 8). No further improvement was observed up to 30 months. FVC FE'/1 7 4 -2 * 0 .-mm"" --- * 10 20 30 MO AFTER CLINIC Quitters - - - - - - Smokers FIGURE &--Mean values for FVC and FEL'l, expressed as a percentage of predicted values, in 15 quitters and 42 smokers during 30 months after 2 smoking cessation clinics SOTE- .A\tt`rIAx t I know ;I \tfntttc.mt d~ltrrct~cc from thr IIIIILII \.IIw .II p41.05 F\`C=f~wrd t it,il cnpacit!: FE\`, = I -a. ttvccd c`\plral,rr> i OILIIW Zamel. Leroux. and Ramcharan ( 1979) studied X healthy hmoher\ for 2 month\ after cessation. They reported Ggnificant increase\ in VC and FEVl of 3.0 and 3.0 percent change. reqecti\,ely. In contra\t. Pride and coworkers ( 1980) in a -t-year study of eight male smokers "who thought they would find it easy to give up smoking." reported no improvement in apirometric tehts of MMEF. Taken together, these studies suggest that smoking cessation quickly results in small improvements in lung function. as assessed by spirometry. Although the changes were not uniformly statistically significant in the investigations reviewed in this Section. the number of subjects was small in most of the studies. Compared with baseline before cessation, FVC or VC and FEVt may improve by about 4 or 5 percent at 3 to X months after cessation. In absolute value, this improvement is COtnpmbk with the ap- proximately IOO-mL improvement reported by Beck, Doyle. and Schachter ( 19X I ) and Dockery and coworkers ( 198X) based on cross-sectional comparison of former smoherc to current smokers. Tests of Small Airways Function Several investigators have studied the effects of smoking cessation using measures of small airways function as determined by the single breath nitrogen test (Table X) and other tests. In the single breath nitrogen test, the subject breathe\ one breath of l(K) percent oxygen from residual volume to total lung capacity (TLC). A concentration gradient of nitrogen is thus established with the highest concentrations at the apex. Subsequently, the subject exhales, and the nitrogen concentration of the exhaled air is monitored. The indices of small airways function provided by this test include the closing volume (CV) expressed as a percentage of the vita1 capacity (CV/VC percent). the closing capacity (CC) expressed as a percentage of TLC (CC/rLC percent). and the slope of the nitrogen concentration during the alveolar plateau (slope of phase III). Both CV and CC are increased by abnormalities of the small airways, whereas the slope of the nitrogen concentration reflects the evenness of the ventilation distribution. Buist and colleagues (1976) studied a group of 25 cigarette smokers who attended a smoking cessation clinic. Cessation resulted in significant improvements in CV. CC. and the slope of alveolar plateau at 6 and I2 months after cessation. Participants in a second smoking cessation clinic were added, and the followup continued to 30 month\ (Buist. Nagy, Sexton 1979). At the 6- to g-month followup, CV had improved by 33 percent predicted among those who quit. CC by 20 percent predicted, and the slope of the alveolar plateau by 52 percent. No further improvements were evident at the 30-month fo1lowup (Figure 9). Similar improvements have been reported by several other investigators. Bode and coworkers (I 975) found that CV improved by 20 percent 6 to I4 weeks after cessation compared with initial values among 10 subjects. These investigators reported that the slope of phase III was unchanged by cessation. McCarthy. Craig, and Cherniack ( 1976) observed 131 smokers aged 17 to 66 years who volunteered to attend a smoking cessation clinic. For I5 persons abstinent from 2.5 to 48 weeks, cessation resulted in a significant 13-percent reduction in CC and a 27-percent reduction in the slope of phase 111. Bake and coworkers (1977) showed a 33-percent reduction in the percent-predicted slope of phase III among I7 subjects at 5 months after cessation. On the other hand. only small changes in CV and CC were observed. Zamel. Leroux. and Ramcharan ( 1979) investigated 26 smokers for an average of 62 days after cessation. Similarly. 323 TABLE: K-Studies of closing volume (CV/VC% ), closing capacity (CC/TLC% 1, and slope of alveolar plateau (SBNrlL) among participants in smoking cessation programs HAC Cl ;d. I 1977) Hui\t. Nag>. SL~\ll)ll I IO70) (I.O'A -o.X'k + I .h% -5.7% 2.6% t .x 0.3 -I .h - 19.5 --15.4 TABLE 8.--Continued cwvc CCi-rLC 140 - z c LYi a 60 - MO AFTER CLINIC 200 A N2/L f501p#e---------: al00 5 I 1 6 I i 2 0 10 20 30 s 2 50- z La 2 o ??? ? ?? MO AFTER CLINIC - Quitter\ * - - -0 StlloLer5 FIGURE 9.--Mean \.alues for the ratio of CI'IVC. of CC/TLC, and slope for phase III of the single breath 32 test (XVI/L), expressed as a percentage of predicted values in 15 quitters and 42 smokers during 30 months after 2 smoking cessation clinics NOTE: .A\trn\L\ I `I ¬e ;I ~~~n~l~~.mt dlttzrmcc tram the Initial \duz .H p of COPD has been described in longitudinal studie\ of up to tL\ o decades. Although a population ha\ not been studied from childhood to the develop- ment of COPD during adulthood. the available data from existing separate investiga- tions encompass the entire course of the disease and support the conceptual model presented earlier (Figure 2). Measure\ of pulmonar). function begin to decline after 25 to 30 year\ of aFe. For FEVl. the annual rate of decline. as estimated from cro\s-sectional studies. i4 about 20 to 30 mL annually (US DHHS lY83). Fa\ter lash of function over a sufficient period of time can lead to the development ofclinicall> significant airflow obstruction (Figure 1). The available longitudinal data indicate that cigarette mokinf i\ the primary ri\h 90 80 70 60 , cl0 lo-24 PACK-YEARS SMOKING * ??????? O Ex-Smokers FIGURE IO.-Percent-predicted diffusing capacity (%pDL) by pack-years of smoking, current smokers and former smokers, in a study of adults in Tucson, AZ NOTE. humben above bar\ rrprrwnt ample \ite\. SOL'RCE: Knudwn. Kaltenbom. Burrow ( IYXY ). factor for excessive loss of FEV) (US DHHS 1984). and smokers have much faster rates of loss of FEVt than never smokers (Table 9). Table 9 describes rates of change in lung function in selected major longitudinal studies. In each. former smokers or quitters have less decline than current smokers during the followup period. In many investigations. dose-response relationships have been found between the amount smoked during the followup interval and the rate of the FEVt decline (US DHHS 1984). For example, Fletcher and colleagues (1976) conducted a study of 792 employed men and performed pulmonary function measurements semiannually for 8 years. They reported that the annual loss of FEVl was 36 mL per year for never smokers. The rate of decline among cigarette smokers increased with amount smoked per day (44 ml/year for 54 cigarettes/day: 46 ml/year for 5 to IS cigarettes/day: 5-l ml/year for I5 to 25 cigarettes/day; and 54 ml/year for >25 cigarettes/day). The rate TABLE Y.-Population-based longitudinal studies of annual decline in pulmonary function i:r:v, l'iiyl, t.t:Vl/FV(' (%/yr) 3.3 27 0.3 I.3 52 6') 45 27 0.' I .1 57 72 -0.1 0 T 30 3') 0.1 10 3x 50 JO 0.7 1.7 (72 73 TABLE 9.--Continued Followup Y-l3yr 4 exam\ 7.5 )I 2 CX3"1\ Male and FEVI (ml./yrb' 16.6 13.4 24.5 Female VC (mL/yr)' 13.7 13.2 I5 7 M;1k FEV I (mL/yr," Sh FVC (mL/yrf' 60 57 h( ) h' 70 6X 64 :2 I-2 TABLE 9.--Continued of loss among former smokers (i.e.. smokers u ho stopped before the first examination) was 3 I mL per year. not significantly different from that of never smokers. In addition, smohers M ho stopped in the first 2 _ vears of the follow up had an annusl decline of 3X mL per icar. The authors concluded that smokers M ho stopped before or early, in the study had FEVt declines similar to nev'er smohers. In spite of FEVt lev,els having been reduced by previous smohin_. (7 further damage to FEV t due to smohing ceases within a few years of cessation. Hovvever. recovery of function vvas not documented in the study, of Fletcher and colleagues ( I Y76). These results have been confirmed in multiple population-based longitudinal studies of FEV) and other pulmonary function parameters (Table Y ). Camilli and associates ( lYX7) examined longitudinal decline of FEV) in a population sample of I.705 adults in Tucson. AZ. Mean follow up uas Y.-t years uith an averqe of 5.2 examinations. Fomler smohers were defined as having stopped before enroll- ment and continuing to abstain at their last two follo\*up examinations. Quitters smoked on entry into the program but stopped before their last tuo follo\~ up c`\amina- tions. Rates of loss for former smokers and quitters were comparable M ith those for never smokers and less than those for smokers (Table Y ). The age-specific rates of loss (Figure I I ) suggest that the benefits of cessation may be greatest among the youngest smokers. that is those with the shortest smoking historv,. FEVt increased in the youngest group. a finding that the authors interpreted as indicating that the earliest effects of smoking are relatively reversible and could represent. in part. a bronchoconstrictive effect. Among the males in the SO- to 69.year-old age proup (Figure I?). I Oof the 2-l subjects who quit did so before their second followup examination. For these IO subjects. the revised annual loss of FEV) from the time of cessation returned to that of never smokers. and was much less than that among smokers. In several years, reduced lung function due to previous smoking was not recovered. except possibly among former smokers who had only been smoking a short time. Taylor, Joyce. and coworkers ( 1985) examined the annual decline of height-corrected FEV) (FEVt divided by height') over 7.5 years in 227 men who were free of a clinical diagnosis of asthma and had not received bronchodilator treatment. Former smokers had an annual decline of FEV) divided by height3 (X.0 i 0.8 ml/year/m') that Was not statistically different from that of never smokers (6.6 31 0.6 ml/year/m') but was significantly less than that of continuing smokers (10.9 + 0.7 mL/year/mj). The 7 I former smokers included 50 smokers who had stopped during the followup period. Smokers with bronchial reactivity to inhaled histamine had significantly accelerated annual decline of FEVt. but an effect of bronchial reactivity was not found among former smokers or never smokers. The reactive former smokers had a lower level percent-predicted FEV) at the end of the followup (96.3 vs. I I I .3 percent predicted). Because their annual rate of loss was not accelerated. the low level of former smokers must be attributed toeither steeper decline while they were smoking. low level of FEVt before they starred smoking. or both. Townsend and colleagues (in press) have recently reported on FEV) decline in participants in the Multiple Risk Factor Intervention Trial. The analysis was limited to 4.926 subjects who had not used P-blocking agents or smoked cigars. cigarillos. or pipes 30 20 10 0 -10 -20 c 3-30 .G 5- I2 c -40 I- - MALES L <35 (75) (53) (39) (28) (15) (47) (47) (82 hxx so xx ss NN NNL xx 35c50 5oc70 `1 6 !4) (72) AGE GROUPS (YR) FIGURE 1 I.--Mean AFEV 1 values in neber smokers (NN). consistent ex-smokers (XX), subjects who quit smoking during followup (SC)), and consistent smokers (SS) in several age groups \Ol-E: .\utnher\ cd \uhlrct\ 11, each ci~t~~rg .trr hu I, 111 parcnthc\e\ EL',= I -WC Iorccxi r\plrmr~ \olumr. during the trial and M ho uere ohser\ ed over 2 to 1 year\ during the latter half of the study. Subjects who quit smoking during the first I? months of the study lo\t FEV 1 at a significantly lower rate than those reporting \moLing throughout the trial. Crowsec- tional analysis of data from the midpoint of the trial indicated the highest level ofFEV1 for never smokers and the loueht level\ for continuing \moher\ at all age\: FEVI level\ for former smokers at ttnrollment and [how quitting during the first year Mere inter- 333 3c 2c 1C 0 -1c -2c 2 s-30 s i c -40 (`6 d (91 NN X> 14 FEMALES (64) (33) (9) (50) (154) (72) (29) (96) (156) (3d iQ ss ss - NN- xx -X: 5% NN <35 35<50 50<70 ?70 AGE GROUPS (YR) FIGURE 11. (Continued)-Mean AFEV] values in never smokers (NK), consistent ex-smokers (XX), subjects who quit smoking during followup CSQ), and consistent smokers (SS) in several age groups KOTE: Number\ of wbject\ in each catepory are shown in parenthrw\. volume. FEV t= I -wc forcrd exptrutor) SOURCE: Camilli et al. t 1987) mediate. The findings in the group quitting smoking during the first 12 months may underestimate the benefits of cessation because of subsequent relapse within this group: 16 percent of the quitters had an elevated serum thiocyanate level (>I00 pm/dL) indicative of smoking at the first examination compared with 6 percent of never smokers and 7 percent of former smokers. C -l( -2( -3( c P $ - -4( E c -5t )- I- I- l- 24 (72) I- 3- *Computing :_ starting from last smoking value FI(iCHE: Il.-Effects of quitting smoking during follow up among men aged 50-69 In the Copenhqen Cit! Heart Study. spiromrtr~ 44 AS pcrtormed on 2 occ;t\ion\ separated by !i years for I7.hYX adult resident\ of the tit! selected at rundom t Lange et aI. I YXY). In fentzral. perwn\ v. ho stopped smohin, (7 during this Inter\ ;\I e\pcrienced less decline of FEVl thnn those \i ho continued to srnohc tT;tble IO): the effect ot cessation varied 1% ith whjtxt age and ;uwunt smohetl Bt the time of quitting. In IYM. the Nxtional tIeart. Luns. xxi Blood ln\titute (NHLBI) initiated ;I multi- center in\e\tifation, the Lung Health Stud!. to determine v hcther smohinf ce\\atwn and bronchodilutor themp!, can influence the course of subjects u ithout clinical ilIne\\ M ho are at high rich i'or the de\.clopmcnt of COPD ( Anthoniwn I YXY I. Six thourand smoker\. aFed 3.5 to 5Y year\. with evidence of airua\\ oh\trwtion v.ert' recruited. They uerr randomi> a\\igned to one of three youp\: a group that received no intervention or usual care group: :I group that receivd 311 inten\i\e state-ot`-the-art 336 TABLE IO.- Decline of FEVI (mL/yr) in subjects in the Copenhagen City Heart Stud? making cessation program and regular therapy with an inhaled hronchodilator (ipratropium bromide): and a third group that received the smohinp cessation program and a placebo bronchodilator. Placebo/bronchodilator therapy was administered in double-blind fashion. All group\ were studied at yearly intervals for 5 years. with rate of change of FEVl as the primary end point and respiratory morbidity as a secondary end-point. In this investigation. a large number of smoker\ with early airways obstruction were characterized and will be studied clocely for 5 years. An extenGve data base will be created to test numerous hypotheses regarding smoking cessation. The question of airways reactivity as a risk factor for rapid lung function loss will be tested definitively in that methacholine sensitivity will have been measured both at the beginning and at the followup period. The findings of the longitudinal studies on smoking cessation and decline of FEVI have important implications. Persons losing FEVt at a greater rate are at risk of developing COPD. After cessation. the return of the rate of decline of FEVt to that of never smokers implies that the process leading to COPD can be arrested by cessation. PART III. AIRWAY RESPONSIVENESS, CIGARETTE SMOKING. AND SMOKING CESSATION Population-based studies support a role for smoking as a cause of heightened airway responsiveness (Woolcock et al. 1987; Sparrow et al. 19X7: Burney et al. 1987). Most cross-sectional studies that have evaluated this relationship have not adjusted for baseline airway caliber. which may be reduced among smohers (Woolcoch et al. 19X7: Bumey et al. 19X7: Welty et al. I983: Van der Lende et al. 1981: Pham et al. 1983: Buczko et al. 1983). so that it is difficult to determine how much of the Increase in airway responsiveness is accounted for by a direct smoking effect or by a reduction in 337 prechallenge pulmonar! function (I.,I~LI md Ingram I YX I ). Atop) ma) modif!, the inlluence of wwhinp b! further increa\in, 0 nowpeci tic air\< a\, responG\ enes\. ,A\ noted h> O'Connor. Spxrou. L ,uxi Wei\\ ( IYXC)). thi\ modification may be undercs- timated in mo\t \tudic\ hecau~e thaw I+ ith an allergic prcdi\po\ition and heightened nonspecific rrspon\i\ene\s ma> not begin smoLing+x ifthc>,tlo begin. they may won quit. The importance of \mokin, `T-induced heightened ;tiruav responsiveness in the puthogencsi\ ofa\thma i\ unhnwn. and airNay hyperre\ponsi\enes\ i\ ;I suspected rish factor for COPD. Mechanisms of Heightened Airway Responsil eness Among Smokers and Former Smokers In both clinical and population-bawd htudie\. smohing ha been ;I\\ociated uith increased airway epithelial permeability (Jones et al. IYXO: Mint),. Jordan. Jones IYXI: Mason et al. lYX3). elevated levels of IgE t Burrow\ et ~11. IYX I: Warren et al. IYX? Zetter\trcim et aI. IYXI: H%llpren et al. IYX2: Bonini et al. IYX2: Stetn et 4. lYX3). and greater nutnbers of peripheral ro\inophil\ (Burro@\ et al. IYXO: Taylor. Gro\s et al. IYXS: Tollerud et al. IYXY: Kaut't'mann et al. 19X6). Thtx physiologic and im- munologic alterations may partI! explain the obwr\,ed relationship between cigarette consumption and heightened uir\say respon\iveness and/or a\thma (Brown. McFadden. Ingram lY77: Mulo. Filiatrnult. klxtin IYX2: Cochcroft Ed al. 197'): BucLhoet iti. IYXI: Casale et al. I YX7: Van der Lende et al. I OX I : Gerrard. Cochcroft et al. I YXO: Kabir:!i et al. lYX2: Phatn et al. IYXI: Enarwn ct al. IYX5: Talor. Jobcr et al. IYX5: Woolcoch ct al. lYX7: Sparrw et al. IYX7: Rijchcn ct al. IYX7: Burnq et al. IYX7). Allerg to environmental antigen\ i\ known to modit'! thi\ relution\hip (Burrw~~. L&on it/. Barbee 1976: Welt) et al. 1YX-l: But/ho et al. 1YX-l: Schxhtzr. Dole. Beth 19X-l: Kiviloog. Irnell. Ehiund lY7-1: Dodge and Burrow\ IYXO). The complexity of these interrelationship\ i\ onI> partially explained h! published tindin+ and additional clarif!,ing \tudie\ are needed. Thi\ Section rwieu\ \tudie\ that ha\e ;tddre\\ed the above awciation\ hith rwpect to c\-wiohcr\ uhich III;I~ e\pluin uhy airua) wpon- sivenas return\ to normal M ith ab\tincnce. Smoking increase\ pultnonar> cpithelial permeabilit>. u hich rapidI> return\ to normal among young wloher\ attcr ce\\ation. \lint>. Jordan. xd Jonr\ ( I YX I ) uwd ;I radiolabeled aerosol technique to \tud\ IO boun g ;i\\ mptomatic male smoher\ M ho had _ stopped mohing tot- I. 3. 7. 11. and 2 I da! h. The! t`~wnd that rrcwer! ot`the epitheli:ll integrity began M ithin 21 hour\ and reached m;1\imum at 7 da> \. blawn and c`ollt`a~ut`~ ( IYXi) later confirmed these t`indiny\ in IO !oun, ~7 wiohcr\. The\c \tudirs included wi;dl number\ of \ub.jcct\ ;md had +ort t'ollo~ up pcriodh after cc\\ation. rnahing interpretation and genrrali/lttion of the finding\ dift`icult. Cross-Sectional Studies Cros\-wctwnul poptil~itiorl-b3\td data hu\,c \ho\r 11 that former wioherc ha\e It`\\ airMa> re\pon\ivene\\ than current wiohers. Burnr! and colleague\ t 19x7) \tudit'tl 5 I I r~indoml\ selected subject\ aged I X to 64 bear\ u\in, (7 inhaled histamine chalkngc. 33X Ofthe population. 14 percent were histamine-responsive as defined by PD20 (the dose of histamine resulting in a 20-percent decline in FEV]). Responsiveness was related to atopy in younger subjects (aged ~40 years) and smoking in older participants (aged >40 years). Former smokers (N= I 16) had bronchial reactivity similar to never smokers but lower than current smokers across all age strata (I2 vs. IO vs. 24 percent. respectively). The increase in threshold dose of histamine with age for former smokers was 0.053 per year compared with 0.0X6 per year among current smokers and 0.027 per year among never smokers. However, for those aged 35 to 44 years. former smokers were more responsive than the other smoking groups ( I4 vs. 13 and 7 percent for current and never smokers. respectively). The criteria for classification of former smokers were not provided. Cerveri and colleagues ( 1989) found similar results in their study of 295 normal never smokers. 70 normal current smokers, and SO former smokers randomly selected from the general population of a small town in Lombardy. Italy. The daily amount smoked was a stronger predictor of airway responsiveness than the duration of cigarette use. Further. among ex-smokers. duration of abstinence did not significantly influence airway responsiveness; however. former smokers with longer abstinence tended to have less bronchial reactivity. Longitudinal Studies Longitudinal population-based studies have not been conducted specifically to evaluate temporal changes in airway responsiveness among former smokers. Several cohort studies designed to measure declines in spirometric function have included single measurements of airway reactivity. These studies generally confirmed lower responsiveness among former smokers than current smokers and suggested an associa- tion between bronchial reactivity and a more rapid decline in ventilatory function. Vollmer. Johnson. and Buist (1985) examined bronchodilator responsiveness among subjects from 2 cohorts. 35 I members of the Portland Cohort. which included a random sample of SO7 Multnomah County employees, and 444 adults from the Screening Center Cohort, consisting of 1,024 subjects screened for emphysema. Individuals were classified as responsive if they showed a 7.72-percent increase in FEV I after two puffs of an isoproterenol metered-dose inhaler. Although no data were presented. former smokers were reported to have a distribution of responsiveness similar to that of current smokers and skewed toward higher values. In caseniptonik. and initial lung function \kere not predictive of decline in lung function. Finall. Taq lor. Joyce, and couorher\ ( 19X.5) conducted an imestipation over a 7.5year period of bronchial reacti\ it) and FEV I annual rate of decline among 137 London men, aged 3 to 6 I years. Theke investigators confirmed the result\ for current smoker\ of Vollmer. Johnwn. and Bui\t (1985) and Tabona and coworkers ( 19X-l). Similarly. former smoker\ had intermediate level\ of methacholine responsi\ene\s compared with the other groups. and those former smokers u ho were responsive had lower rate\, of baseline ventilatoy function. In contrast. how,ever. former smokers had comparable rate\ of ventilatory decline. regardless ofmethacholine re\ponsivcne\s. In all of thew longitudinal \tudie\. hronchodilator or methacholine responhivene\\ was measured near the end of the study period. Furthermore. precise definitions of former smoherh u ith regard to amount smoked. duration of abstinence. and reasons for quitting were not provided. A\ diwu\>ed previously. the prevalence of' airway wpon- \ivenes\ may alw lead to ;1 decision to 5top smohing. Thehe limitations in \tud) design muht be considered in interpretin, o the associations among \mohing cessation. non- specific ;tirw;L> re\ponsivene\s. C xxi annual decline in FEVl. Clinical Studies In contrast. Bolin. Dahms. and Slavin (19X0) and Fennertl and co\+orhcrs ( 1YX7 J found increases in airway responsiveness after cessation. Bolin. Dahms. and Slavin ( 1980) evaluated the effect of discontinuing smohing on methacholine sensiti\ it!, in seven asthmatic sub,jects. PC20 was measured before and I da> after stopping smohing and was found to be 5.63 mg/mL and 1.56 m&L. respectivelv. This increase in air\+ a~ responsi\,eness ~iis 4een amon g four of the se\en subjects. Finall\. Fennerth and colleques ( IYX7) recorded PD70 to histamine in l-1 asthmatic\ before and 11 hour\ after smoking cessation. PD20 did not increase significantI\. In se\en subjects ~4 ho abstained for 7 da),\. honever. PD20 dose increased significantI> (0.67 + 0.43 mg/mL vs. 7.X F 2.03 mg/,mL). These studies are limited by short follow up. small numbers of sub.jects. and ;I lack of ad.justment for baseline airway caliber or pulmonary function. Additionally. the analyses did not control for seasonal variation in te\tlng. and the latter three studies did not include 3 control group. In summq. former smohers appear to ha1.e bronchial reactivity comparable LI ith that of never smokers. The comparabilit>, of bronchial rexctivitb among formel smokers and never smokers implies that smohing-induced changes in airway respon- siveness may resolve with abstinence. Available data. hov.ever. are limited and not definitive. More research is needed to determine the interaction of jmohing cessation with nonspecific airway responsiveness in altering rates of decline in \,entilatq function. PART IV. EFFECTS OF SMOKING CESSATIOIV ON COPD MORTALITY The Centers for Disease Control reported that 7 I .OYY persons in the United States died in IYE-33 with COPD (ICD-9-CM 4Y I-2.496) as the under11 ing cause. and 161.04Y prrsonsdiedwithCOPDas theunderllingcauseorasacontributingcause(CDC 1989). It was estimated that 8 I .S percent ofCOPD mortality was attributable to mohing (Table I I ). Data from both prospective and retrospective studies have consistently indicated an increased mortality from COPD in cigarette smokers compared ivith never smohers. In addition. the degree of tobacco exposure. as measured by the number of cigarette\ smoked daily or duration of smoking. strongly. affects the risk of death from COPD. This literature was reviewed in the 1983 Report of the Surgeon General (US DHHS 1984). in which cigarette smoking was identified as the major cause ofCOPD mortality for men and women in the United States. The proceedings of a recent worhshop sponsored by NHLBI address the rise in mortality from COPD (SpeiLer et al. IYXY ). Several prospective studies have shown that cessation of smoking leads toadecreased risk of mortality compared with that of continuing smokers (Table 13). In the British Physicians Study, Doll and Peto ( 1976) reported on a X-year followup of 33.440 male British doctors who completed a questionnaire about their smoking behavior in I95 I. Compared with never smoker\. age-adjusted death rates for chronic bronchitis or emphysema were elevated for current smokers and for former smohers (mortalit! ratio= 16.7 and 13.7. respectively). TABLE I I.--Mortality attributable to COPD, United States, 1986 Smohlng \tatu\ Current 5mohen Male Female Former vnoker\ Male Female TOTAL Kekmve rirh Y.6 10.5 x.7 7.0 A study of mortality among female British physicians has also been reported (Doll et al. 1980). A cohort of 6.194 female doctors who had responded to the I95 I questionnaire was studied for ?I? years. The ape-adjusted mortality ratio for chronic bronchitis and emphysema among continuing smokers increased with reported cipa- rettes smoked per day (Table 12). Former smokers had a mortality ratioofS.tlcompared with never smokers. which represented a reduction in mortality ratios of 52 percent t I to I3 cigarettes/day) when compared with light smokers and of 84 percent when compared with heavy smokers (215 cigarettes/day). Peto and coworkers (1983) reported COPD mortality based on a 20. to Z-year followup of 2.7 IX British men N ho had been enrolled in 5 different respiratory studies in the lY50s. There were no deaths attributed to COPD among never smokers. The ratio of observed to expected COPD deaths M;LS I .20 and 0.65 for current and former smokers. respectively. with expected deaths based on the entire cohort including smokers and nonsmokers. Thus. the mortality ratio for former smokers was 46 percent lower than that of continuing smokers (Pete et al. 1983). Ebi-Kryston (19x9) recently reported on chronic bronchitis mortality in a l5-year followup of 17.717 male British civil servants. Compared with nev{er smokers. former smokers had a mortality ratio of 5.57 and continuing smokers had a ratio of X.2 I. Thus. former smokers had a mortality ratio reduced by 32 percent compared with continuing smokers. Although the data were not presented for COPD. the author reported that the results were similar (Ebi-Kryston IYXY ). In the United States. Roget and Murray ( 1980) reported data on emphysema and bronchitis mortality. among 1Y3.YSX U.S. veterans studied for I6 years. Former smokers were restricted to those v. ho stopped smohing cigarettes for reasons other than a physician's orders. Current smokers had a mortality ratio of 17.07 compared with 342 t .I) i h TAHIX 12.~Continued I3 yr (`OPD t 0634X I.(H) I .h 1.1 lObY- I.ZI I .o 7.5 20 yr (`OPD t Yf&6Y I .tn1 7.0 \.Y t Y7fL74 I.4 4.3 I .x I Y7S-70 2.0 I .Y 2.7 I `)X%X4 1.7 I.1 5.7 never smokers. Former smokers had a mortality ratio of 5.20 compared with never smokers. The proceedings of the workshop sponsored by NHLBI on rising COPD mortality included several reports from population-based cohort studies (Speizer et al. 1989). Tockman and Comstock ( 1989) described mortality in more than 3S.000 white residents of Washington County, MD, who were enrolled in 1963 and followed through 1975. Based on the 1963 smoking information. former smokers generally had lower mortality rates for COPD than did current smokers. Marcus and colleagues ( 19X9) reported similar analyses for subjects in the Honolulu Heart Program cohort. Coding of death certificates for COPD differed substantially between the Honolulu Heart Program and the State Health Department. Mortality rates based on the Honolulu Heart Program coding showed a temporal pattern of declining mortality from COPD among former smokers with increasing mortality among the current smokers during the followup period 1965-l 983. Recent data from ACS CPS-II provide new evidence on mortality from COPD (ACS. unpublished tabulations). The age-adjusted death rates for COPD for men and women were approximately tenfold higher among current smokers compared with never smokers. The mortality ratios for male and female former smokers compared with never smokers were 8.5 and 7.0. lower than for current smokers (ACS. unpublished tabulations). Several studies have reported on variation in COPD mortality by duration of abstinence (Table 13). In these studies. COPD mortality for former smokers initially increases after cessation above the rates for continuing smokers. The maximum mortality ratio for former smokers was found within the first 5 years of abstinence for ACS CPS-II and between 5 and 9 years after cessation for the British Physicians Study (Doll and Peto 1976). As discussed in Chapter 2. this initial increase in mortality probably reflects cessation by persons with smoking-related illnesses or symptoms. However, even in the U.S. Veterans Study (Roget and Murray 1980). in which only former smokers who stopped for reasons other than a physician's orders were con- sidered, death rates for emphysema and bronchitis among former smokers were higher than for those of current smokers after 5 to 9 years of abstinence. Following this initial rise in COPD mortality after cessation, the mortality ratios drop with increasing duration of abstinence (Table 13). However, even after 20 years or more of abstinence, the risk of COPD mortality among former smokers remains elevated in comparison with never smokers. PART V. FORMER SMOKERS WITH ESTABLISHED CHRONIC OBSTRUCTIVE PULMONARY DISEASE Effect of Smoking Cessation on FEV I Decline Among COPD Patients The beneficial effects of smoking cessation on reducing the annual loss of pulmonary function are clearly shown in population studies and followup of smoking cessation participants. These populations have been relatively young and largely free of TABLE 13.~-Standardized mortality ratios for COPD among current and former smokers broken down by years of abstinence 11.1 Former w~ohcr\ by yr of ahqinrnce S-9 Il.4 IO-13 IS~20 21.5 IO.' 5.7 7.6 Former vnohrr~ hy yr of ab>tmence respiratory disease. The question arises whether the course of the disease can be influenced by smoking cessation once clinically overt COPD becomes apparent. Hughes and coworkers ( 1982) examined the annual change in lung function among 56 male patients with radiologic evidence of emphysema. Patients who had stopped smoking prior to entry into the study and who did not smoke subsequently had a lower initial level of FEVJ compared with patients who were smoking (45 vs. 55 percent predicted). but the annual rate of loss of FEV I for the former smokers was less (I 6.4k8.8 ml/year vs. 53.5f5.4 ml/year). Similar results were reported for annual decline of VC ( 14.9+18.6mL/year vs. 53. If I I .3 ml/year). Diffusing capacity was lower at the initial assessment among smokers. 57 percent predicted. compared with former smokers. 75 percent, but diffusing capacity did not change significantly during followup. Postma and coworkers ( 1986) examined the change in lung function in a 2- to 2 I -year followup of 81 patients with chronic airflow obstruction. Fifty-nine of the patients smoked throughout the study, and 22 stopped at the start or some time during followup. Initial level of FEVt was lower among former smokers. but the annual loss of FEVt was smaller (49*7 mL/year) than for smokers (X5*5 ml/year). In the National Institutes of Health Intermittent Positive Pressure Breathing Trial. 985 patients with COPD but without chronic hypoxemia were enrolled and studied for almost 3 years (Anthonisen et al. 1986). Spirometry was performed at entry and repeated every 3 months. The mean annual decline of FEVl was 44 mL per year: the investigators reported that neither past nor present smoking behavior affected the decline of FEVl although the data were not provided. In summary, two of the three studies suggested that cessation of smoking is followed by a reduction of the annual loss of pulmonary function, even among patients with advanced COPD or emphysema. However, a beneficial effect of smoking cessation was not found in the large Intermittent Positive Pressure Breathing Trial. Additional investigation of the effect of continuing to smoke on lung function decline in patients with COPD is warranted. Effect of Smoking Cessation on Mortality Among COPD Patients The evidence for an effect of smoking cessation on survival of patients with COPD is limited. Traver, Cline. and Burrows (1979) found no association between the smoking status and the survival of 2 patient groups, 200 COPD patients in Chicago. IL, who were studied for 15 years and 100 patients in Tucson, AZ, evaluated for up to 7 years. In a followup of up to I3 years, Kanner and coworkers ( 1983) examined the survival of 100 patients with chronic airflow limitation, aged 32 to 55 at enrollment. Twelve- year survival probabilities were 86. 79, and 64 percent for never, former, and current smokers, respectively. Postma and colleagues (1985) studied survival of 129 patients with severe chronic aifflow obstruction (FEVt II ,000 mL) for up to I8 years. All nonrespiratory deaths were censored. Patients were classified by the degree of reversibility of airflow obstruction. For both smokers and former smokers. relative survival was highest among those with the greatest reversibility of airflow obstruction. Smokers who quit smoking 347 before the start of followup had a higher survival rate than did continuing smokers (Figure 13). Within each stratum of reversibility, former smokers had lower mortality than current smokers. In contrast. mortality in the 3-year followup period of the Intermittent Positive Pressure Breathing Trial was not significantly related to smoking status. The followup period was relatively brief. however. Patient age and the level of FEVt at enrollment were the strongest predictors of mortality. In those prospective studies, smoking was evaluated on entry into the study. Sub- sequent changes in smoking status (i.e.. smokers ceasing to smoke or former smokers reverting back to smoking) would reduce the estimated effects of smoking cessation compared with continued smoking. Overall, the extent of the evidence is limited. and a conclusion cannot yet be reached on the effect of smoking on mortality following diagnosis of COPD. 348 CONCLUSIONS I. Smoking cessation reduces rates of respiratory symptoms such a\ cough, sputum production. and wheezing. and respiratory infections such as bronchitis and pneumonia, compared with continued smoking. 2. For persons without overt chronic obstructive pulmonary disease (COPD). smoking cessation improves pulmonary function about 5 percent within a few months after cessation. 3. Cigarette smoking accelerates the age-related decline in lung function that occurs among never smokers. With sustained abstinence from smoking, the rate of decline in pulmonary function among former smokers returns to that of never smokers. 4. 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Education. and Welfare. Public Health Service. Office of the Assistant Secretary for Health. Office on Smoking and Health. DHEW Publication No. (PHS) 79-50066, lY79. US. PUBLIC HEALTH SERVICE. S n7o rtr,q und Her/Irk. Repwr of/he Ad\,i.so~~ Conmitree X' lo rhe S/rrqeon Ger7eral of tlte P~thlic, Heulth .Ser~\,icr. U.S. Department of Health. Education. and Welfare. Public Health Service. Center for Disease Control. PHS Publication No. 1103. 1964. VAN DER LENDE. R.. KOK, T.J.. REIG. R.P., QUANJER. P.H.. SCHOUTEN. J.P.. ORIE. N.G.M. Diminutions de cv et de vems avec Ie temps: Index des effets du tabagisme et de la pollution de l-air. [Decreases in VC and FEVt with time: Indicators for effects of smoking and air pollution. ] B/r/let;// Eur-&en de Ph?siorutl7oloaie Rrspir-utoiw 171775-792. 198 I VAN GANSE. W.F.. FERRIS, B.G. JR., COTES. J.E. Cigarette smoking and pulmonary diffusing capacity (transfer factor). An7e/~`c~u/7 Re,,ieu, ofRespi/zrlo/;v Diseuse lOS( I ):3031. January 1972. 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November 1963. WELTY. C.. WEISS. S.T.. TAGER. J.B.. MUNOZ. A.. BECKER. C.. SPEJZER. F.E.. JN- GRAM. R.H. JR. The relationship of airways responsiveness to cold air, cigarette smoking. and atopy to respiratory symptoms and pulmonary function in adults. A~JJ~J~UJI Re~k-t~ of Rcspiruror~\ D;.w~.w 130: 198-203. 19X4. WHITEHEAD. R.H.. HOOPER. B.E.. GRJMSHAW, D.A.. HUGHES, L.E. Cellular immune responsiveness in cigarette smokers. Lm~cvr 1(786X): 1232-1233. June IS. 1974. WJLHELMSEN. L.. ORHA. I.. TJBBLJN. G. Decrease in ventilatory capacity between ages of SO and 54 in representative sample of Swedish men. B,?rish Medicvl JOIIUJNJ 3:SS3-556. September 1969. WJLHELMSEN. L.. TJBBLJN. G. Tobacco smoking in fifty-year-old men. I. Respiratory symptoms and ventilatory function tests. Smndimn~iutJ JOUJYJOI I++` Respiruto,:v DiseuseJ 47:121-130. 1966. WJNGERD. J.. SPONZJLLJ. E.E. Concentrations of serum protein fractions in white women: Effects of age. weight. smoking. tonsillectomy. and other factors. C'/jttic,ul Chenrist~;v 37): 1310-1317. 1977. WOOLCOCK. A.J.. PEAT, J.K., SALOME. C.M.. YAN, K.. ANDERSON. S.D.. SCHOEF- FEL. R.E.. MCCOWAGE, G.. KJLLALEA, T. Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population. Thortr.( 42:361-36X. 1987. WOOLF, C.R., SUERO. J.T. The respiratory effects of regular cigarette smoking in women. Anrf~~-ic~~~~r Rm.im. ~~fRr.~p~~~u~o~~~ Diseuse 103 1 ):26-37. January 197 I WOOLF. C.R.. ZAMEL. N. The respiratory effects of regular cigarette smoking in women. A five-year prospective study. Chesr 7X(5):707-7 13. November 1980. WRIGHT. J.L. Small airway disease: Structure and function. In: Hensley, M.J.. Saunders. N.A. (eds.) C/i!ticc// Epitkn~ido,y~ of`~l~rwric ~hsrr~~rc~tir~c~ f'dmt~J~u~~ Di.sea.sr. New York: Marcel Dekker. Inc.. 19X9. p. 55. WYATT. R.J.. BRIDGES. R.B.. HALATEK. D.G. Complement levels in cigarette smokers: Elev,ations of serum concentrations of CS. C9 and C I -inhibitor. JOUJYJ~~ c$ Clinic,tr/ tJ/~d LuhoJ~rtr~J~v /JJJ~JJJJJo/cJ,~~ 6: I 3 I-l 35. 19X I ZAMEL. N.. LEROUX. M.. RAMCHARAN. V. Decrease in lun~g recoil pressure aftercessation of smoking. AJJJCJ.~CYIJJ R~rerc, CJ~RC.S~~J-UJCJJ~~ Drscuse I I9(2):2OS-2 I I. February I Y7Y. ZAMEL. N.. WEBSTER. P.M. Amelioration de la dynamique du debit expiratoire apres at-ret du tabac. [Improved expiratory airflow dynamics with smoking cessation.] Bllllt~/l,l ~~rrq~crJr t/c PlrcsrrJ/,u/lJo/ogic Rc.\piruroir-c> 20: 19-23. 19X4. ZETTERSTRGM. 0.. OSTERMAN. K.. MACHADO. L.. JOHANSSON. S.G.O. Another smokinp hazard: Raised serum JgE concentration and increased rish ofoccupatronal allergy. Brirrsh Mcdrcd ./ouJ~JJo/ 783: I7 I S- I2 17. November 7. 19X I 366 CHAPTER 8 SMOKING CESSATION AND REPRODUCTION 367 CONTENTS PartI. Female ................................................... ..37 I PregnancyandPregnancyOutcome ................................ ..37 I Introduction ................................................. ..37 1 Pathophysiologic Framework ..................................... 37 I Nonexperimental Studies ......................................... 374 Fertility and Infertility ......................................... 374 Ectopic Pregnancy and Spontaneous Abortion ...................... 375 Fetal, Neonatal, and Perinatal Mortality ........................... 376 Birthweight and Gestational Duration ............................ 379 Introduction ................................................ 379 Continued Smoking .............. .`. .......................... 381 Cessation Before Conception .................................. 381 Cessation After Conception ................................... 383 Birthweight ............................................. 3X3 Preterm Delivery ........................................ 386 Complications of Pregnancy ................................... 387 Randomized Trials of Smoking Cessation During Pregnancy ............ 387 Prevalence of Smoking and Smoking Cessation During Pregnancy and Time Trends in Prevalence and Cessation ............................... 390 Introduction ............................................... ..39 0 Prevalence of Smoking and Smoking Cessation ..................... 390 Time Trends in Smoking and Smoking Cessation ................... 393 Estimates of Attributable Risk Percent .............................. 393 AgeatNaturalMenopause..........................................39 6 Introduction ................................................... 396 Pathophysiologic Framework ..................................... 396 Studies of Former Smokers ....................................... 39X PartII. Male ___..~ ~ ~. ................................... Introduction ................................. Pathophysiologic Framework .................... Sexual Activity and Performance ................ Sperm Density and Quality ..................... Conclusions ............... ..j ................. Referencer .................................... . . . . . . . . . PART I. FEMALE Pregnancy and Pregnancy Outcome Introduction Since the late 1940s. cigarette smoking during pregnancy has been linked with poor pregnancy outcome (Bernhard 1949; Athayde 1948). Adverse effects of smoking on pregnancy began to receive considerable attention after publication of the results of a study of 7,499 pregnant women in San Bernardino County, CA. in which the rate of prematurity, defined as birthwjeight less than 2.500 g. was found to be about twice as high among smokers as among nonsmokers during pregnancy (Simpson 1957). Early reports of the Surgeon General (US DHEW I97 I. 1973. 1978) concluded that maternal smoking during pregnancy retards fetal growth and is a probable cause of late fetal and infant mortality (US DHEW 1973). The 1977 Report of the Surgeon General (US DHEW 1978) concluded that smoking during pregnancy has dose-response relationships with abruptio placentae. placenta previa. bleeding during pregnancy. premature and prolonged rupture of the membranes. and preterm delivery. The 1979 and 1980 Reports of the Surgeon General (US DHEW 1979; US DHHS 1980) comprehensively reviewed information on the association of maternal smoking with pregnancy outcome and further concluded that the risk of spontaneous abortion in- creases with the amount of smoking and that the risk of sudden infant death syndrome (SIDS) is increased by maternal smoking during pregnancy. The 1980 Report (US DHHS 1980) also indicated the possibility of a link between cigarette smoking and impaired fertility. Two earlier reports of the Surgeon General (US DHEW 1979; US DHHS 1980) concluded that mean gestational duration is not affected by maternal smoking and that data are not sufficient to support a conclusion that maternal smoking increases, decreases, or has no association with risk of congenital malformations. This Section reviews observational studies of smoking cessation and the following reproductive outcomes: fertility and infertility; ectopic pregnancy and spontaneous abortion; fetal, neonatal, and perinatal mortality; birthweight and gestational duration: and complications of pregnancy. Three randomized trials of smoking cessation and pregnancy outcome are described and discussed in detail. Information on the prevalence of smoking during pregnancy and time trends in prevalence is presented, along with estimates of the attributable risk of several pregnancy outcomes. SIDS and congenital malformations are not considered because of the limited information on smoking cessation. Pathophysiologic Framework The effects of smoking that might mediate adverse effects on the developing fetus and on fertility, fetal loss, and pregnancy complications have been reviewed in other publications (Long0 1982; Mattison 1982: US DHHS 1980). These reviews are summarized with attention to the temporal course of the relation between exposure to 371 cigarette smoking and pregnancy outcome as well as the distinction between reversible and irreversible effects of smoking. Reversible effects would be espected to result in similar risks for never smokers and former smokers. whereas irreversible effects would be expected to lead to different risks in both current and former smokers compared with never smokers. Several pathways have been postulated by which tobacco smoke might adversely affect fertility (Mattison 1982) (Table I ). These include disturbance of hypothalamic- pituitary function, interference with motility in the female reproductive tract (Chow et al. 1988). and impairment of implantation, all of which are thought to be reversible consequences of exposure to absorbed chemicals in tobacco smoke (principally nicotine). It has also been suggested that smoking results in oocyte depletion through direct toxicity (Mattison 1980), which would have irreversible consequences for fertility. Chow and colleagues (1988) postulated that altered immune function (Hersey. Prendergast, Edwards 1983) may predispose smokers to pelvic inflammatory disease. which in turn can result in permanent scarring and occlusion of the fallopian tubes. Alterations in the neuroendocrine control of ovulation have been suggested to account for increased amenorrhea reported among smokers (Pettersson. Fries, Nillius 1973): this mechanism, as an effect of smoking on fertility. would be reversible. TABLE I.-Possible mechanisms for the effect of smoking on pregnancy and pregnancy outcome OUtCWlle Po\ublr mechant\m Hormonal effwth Impaired tubal motilir) lmpalrrd implantatton Ooq te drpkrion Altered lmmunit> Ieadmg to peI\ ic intlammator) di\ea\e spwltaneou\ ahntlon Reduced birth\rsight Mechanisms for an effect of cigarette smoking on apontaneou\ abortion have not been clearly defined. partly because so little i5 known about the pathophysiologic basis for spontaneou\ abortion. The cause\ of spontaneous abortion are broadly divided into genetic and nongenetic causes (Kline 19X-1). Because smoking seems to have its primary impact on chromo\omally normal spontaneous abortions (Kline 1984: Alber- man et al. 1976). nongenetic pathways are implicated for hmokinp (Table I ). 372 Most attention has been focused on the mechanisms mediating a reduction of fetal growth among smokers (Table 1). An indirect, nutritionally based mechanism in which smokers are postulated to eat less and gain less weight during pregnancy. thus delivering smaller infants, has been prominent in discussions of fetal growth retardation in smokers (Papoz et al. 1982: Rush 1974; Meyer 1978; Davies and Abernethy 1976). This subject has been reviewed in depth in previous reports of the Surgeon General (US DHEW 1979; US DHHS 1980) and more recently by other researchers (Werler. Pober. Holmes 198.5). Differences in weight gain do not entirely explain fetal growth retardation in smokers because differences in weight gain during pregnancy between smokers and nonsmokers are very small and have not been observed consistently and because a relationship between growth retardation and smoking persists after adjusting for mater- nal weight gain. In this context. however, the studies of weight gain in women who quit smoking during pregnancy are of interest. Pulkkinen (1985) found that women who quit smoking during the first trimester gained more weight than nonsmokers or continuing smokers (I .O vs. 1.3 kg average difference. respectively). Kuzma and Kissinger ( I98 I ) also found that women who quit smoking during pregnancy gained more weight compared with women who did not smoke during pregnancy (average difference of 4.7 kg) and women who smoked throughout pregnancy (average difference of 5.6 kg). Also, women who quit smoking before the onset of pregnancy were reported to gain more weight during pregnancy than nonsmokers or smokers ( I .3 kg and 0.9 kg average difference, respectively) (Anderson et al. 1984). Rush (1974) reported a reduction in weight gain of 0.12 pounds per week among continuing smokers compared with those who quit. This pattern may reflect the well-established tendency to gain weight following smoking cessation (Manley and Boland 1983: Rabkin 1984). as discussed further in Chapter 1 I. There are several hypotheses that attempt to explain the mechanism by which fetal growth is affected by cigarette smoking (Table I), but cigarette smoking is believed to impact on fetal growth through intrauterine hypoxia (Long0 1977). Carbon monoxide. a component of cigarette smoke, has the ability to cross the placenta and bind with the hemoglobin in both the mother and the fetus producing carboxyhemoglobin. Car- boxyhemoglobin reduces the ability of the blood to carry adequate levels of oxygen to the fetus. Smoking is also believed to cause vasoconstriction of the umbilical arteries. and therefore. impact on placental blood flow (Lehtovirta and Forss 1978; Naeye and Tafari 1983; Longo 1982). Cigarette smoking during pregnancy decreases the availability of oxygen to the fetus by both mechanisms. These mechanisms imply a reversible effect of cigarette smoking for fetal growth because normal function would resume shortly after nicotine or CO is cleared from the system. Support for the suggestion that these effects are reversible is derived from several sources. Davies and coworkers ( 1979) found that 48 hours of smoking cessation late in pregnancy increased oxygen availability to the fetus. ViSnjevac and Mikov (1986) found similarly low levels of carboxyhemoglobin (COHb) in mothers and newborns when the mother was a former smoker or never smoker; mothers who smoked during pregnancy and their newborns had high levels of COHb. 373 Mechanisms for the effects of smoking on neonatal. perinatal. and infant mortality are poorly understood. although the reduction in birthweight is often considered to be the mediating process. However. smoking appears to cause a shift in the distribution of birthweight without having much effect on mean gestational age (US DHEW 1979; US DHHS 1980), and shifts in birthweight distribution across different populations do not always produce corresponding shifts in mortality (Wilcox 1983: Wilcox and Russell 1983a.b). That gestational age is little affected by smoking, whereas birthweight is reduced at every gestational age. explains why small infants of smokers have a better prognosis than small infants of nonsmokers (Yerushalmy I97 I; MacMahon. Alpert. Salber 1966). Increases in perinatal mortality among smokers may result not from the reduction in birthweight, but rather from the modest increases in preterm delivery, very low birthweight, and specific pathologic conditions such as placenta previa and abruptio placentae. However, this has not been addressed explicitly in any study. Because the smaller smoking-related increases in less frequent, more severe outcomes parallel the pronounced smoking-related reduction in birthweight. birthweight serves as a useful empirical marker of smoking's harmful consequences. even if it is not the direct mediator of those effects. Nonexperimental Studies Fertility and Infertility Consistent evidence indicates that smokers have lower fertility than nonsmokers (Dal@ et al. 1987: Howe et al. 1985: Baird and Wilcox 1985; Hartz et al. 1987). as noted in the 1989 Report of the Surgeon General (US DHHS 1989). The studies that have assessed indicators of fertility in former smokers are summarized in Table 2. Pettersson. Fries. and Nillius ( 1973) studied secondary amenorrhea. one mechanism for reduced fertility, and found an increased prevalence among smokers. However. prevalence among former smokers was even higher than among continuing smokers. Hammond ( 196 I ) found that irregular menstrual cycles were more common among smokers than never smokers and that former smokers were at slightly lower risk than never smokers. Howe and colleagues (19X5) analyzed data on more than 4.000 women in a British cohort study. which assessed the safety of oral contraceptives. Compared with never smokers, women who smoked 20 cigarettes or more at entry into the study were twice as likely to be undelivered 5 years after ceasing contraceptive use with the intention of becoming pregnant. whereas former smokers had the same likelihood of being un- delivered as never smokers. Baird and Wilcox ( 1985) reported that the time period until pregnancy was the same for 3 I women who quit smoking in the year prior to attempting to conceive as it was for never smokers. Daling and coworkers (1987) conducted a large case-control study in Washington State and found that. compared with never smokers. the relative risk of primary tubal infertility was 1.7 among current smokers and 1. I among former smokers. Information 374 TABLE 2.-Summary of studies of fertility among smokers and former smokers Relatme mh of meawrr of fertlllt!" Reference Location Meaure ol fertilit! SlllddX\ Prttrrwm. Frm. NllliU\ t IY73) Sweden Secondary amenorrhea I.3 I .6 Hov.e et al. (10X5) Bad and Wilco\ (19X.5) England Minnewto 2.11h I (I 3.4 I .(I Ihlltlf er 31. t 19x71 Seartle Prtmq tuhd infertilit> `7 -. I .o Dalq! er 31. (lYX.5) Se;rttlr Secondary tubal infertilit) I .6 I.3 on secondary tubal infertility from the same study (Daling et al. 1985) revealed a smaller difference between current and former smokers. Although the study focused on prior induced abortion, data are presented that allow computation of crude odds ratios for current and former cigarette smokers. Current smokers had a I .6-fold increase in the risk of secondary tubal infertility. and former smokers had a I .3-fold increase in risk. It is difficult to assess the causal effect of smoking on tubal infertility independent of the effects of sexually transmitted diseases (STDs) known to co-v'ary with smoking in many populations. In summary, the data suggest that impairment of fertility measured as delay in time to conception is related to smoking near the time of attempting to conceive and that smoking cessation prior to conception returns fertility to that of never smokers. Conclusions about smoking and the risk of tubal infertility cannot be drawn because of concern about uncontrolled confounding. Ectopic Pregnancy and Spontaneous Abortion Tubal (ectopic) pregnancy occurs at about the same time in the reproductive process as fetal loss. However, the mechanisms are thought to be similar to those operating in tuba1 infertility and largely concern tubal motility and patency. Several reports indicate an increased risk of ectopic pregnancy in smokers (Campbell and Gray 1987: Mat- sunaga and Shiota 1980), but only Chow and associates ( 198X) examined the associa- tion with prior smoking in detail. In a case elevated for the infants of women who smoked in all categories of low birthweight. even after adjustment for marital status. education. age. and parity (Table 1). This data set is unique in its sile. consisting of more than 3SO.OfW) births. The data indicate that even in the nomtal birthweight infants of smokers-those that wjeiahed 7.500 g or more-mortalitv was significantly elev#ated for infants of c mothers who smoked. Information on fetal. neonatal. and perinatal mortality in former smokers is sparse (Table 5). Butler. Goldstein. and Ross (1973) analy,red data from the British Perinatal Mortality Survey and estimated that perinatal mortality was the same for women who 376 TABLE 3.-Summary of studies of perinatal and neonatal mortality in smokers and nonsmokers during pregnancy Reference Number of birth\ Perinatal mortality" Uronalal morlalIl~" Carepq Smnher\ Non\mohrr\ Smoher\ Non\mohsr\ Com\toch and 12.37 Lundin t 1967, Meyer and 5 I .lYO Tona\cia llY77, Rantahalllo 12.06X (lY7XI Ru\h and ca\\ano lI9X.3) Butler. 2 I .7X8 Goldstein. Rev 1972) Whltr\ Blach\ Amount mohrd I ppd 33.3 Social cl9s. ~.. .______~. I+11 III+IV Farmer\ Lnhnown XI" 22.4" 25.1 14.6 753 I5 cigda) IS.0 IX.7 26. I 2x.3 Andrews and McGarry t 1972) IS.63 I Nihwander 37,912 and Gordon (1972) I4 cig/day S-9 c&/day IObl9cigiday t70 ctg/day Race and Amount smoked White I-IOciddq 2 I I cig/da) Black IplOcigjdq 21 I c&iq 11.1 32.0 2s 20 32 36 25 31.1 31.5 3x.2 3x.5 41.5 57.1 17.6 13.7 377 TABLE X-Continued TABLE L-Estimated relative risk of fetal plus infant mortality for maternal smoking in several birthweight groups, adjusting for maternal marital status, education, age. and parity Y.i'i Cl Perinatal mortality among those who smoked before pregnancy but quit during preg- nancy (lS.O/l,OOO) was lower than for either nonsmokers during pregnancy ( I8.7/ I .OOO) or smokers of 5 cigarettes or more per day throughout pregnancy (26.9/1.0(K)). TABLE 5. --Summary of studies of perinatal mortalit? in smokers throughout pregnancy, smokers who quit in the early months of pregnancy, and nonsmokers during pregnancy Reference Fetal, neonatal, and perinatal mortality are rare events. This limits the study of their association with smoking cessation. Lack of data makes it impossible to draw a firm conclusion about the association of smoking cessation with the risk of fetal, neonatal. or perinatal mortality. However, the limited available data are consistent with the conclusion that perinatal and neonatal mortality are lower among infants of women who quit smoking than among those women who smoke throughout pregnancy. The possibility must be considered that differences between women who quit smoking and those who continue to smoke account for the lower rate of perinatal and neonatal mortality in the studies in which this has been observed. Birthweight and Gestational Duration Fetal. neonatal. and perinatal mortality are the most direct measures of pregnancy outcome. Mortality is relatively uncommon, and very large samples are needed for study. This has led to the widespread study of birthweight and the percentage of births that are low birthweight (<2.500 p) as surrogates for the study of mortality. This strategy has been justified by the extremely strong association between birthweight and the percent of low birthweipht and each of the measures ofmortality (Figure I 1. Equally important is weight at birth as a determinant of infant health (McCormick 1985 J. W Perinatal mortality = fetal deaths and neonatal deaths/total births x-.. .. .,x Neonatal mortality = death through 28 days in liveborn infants/live births 0 - -0 Fetal mortality = stillbirths/total births 500- lOOO- 1500- 2000- 2500- 3000- 3500- 4000- 749 1249 1749 2249 2749 3249 3749 4249 BIRTHWEIGHT (g) FIGURE I.-Perinatal, neonatal, and fetal mortality rates by birthweight in singleton white males, 1980 SOURCE: Williams and Chen (1982). Birthueight is. ho&ever. :I result ofgestational age at birth and the rate of fetal yrou th. Recognition ot the complex relationship5 amon, 0 ft3tationul duration. rate of fetal growth. birth\\teight. and mortalitv has led to attempt\ to classif\ infant\ according to cre\tational duration or joint distribution of hirthueight and ~~c\tatioii;il duration. Eenerallj. births are catefori/ed ;I!, preterm (~37 ueehs gr\tatiotyl and/or 34 \mal I for gestational age (SGA) (oci;ltcd V, ith incrc;Lht`\ in the risk of fetal. neonatal. and perinatal mortalit\ and \j ith significant childhood morbidit!. Both preterm delivery and SGA increase the rish of cerebral pal\!. although the ri4 i\ much greater for prcterm delivery (Ellenberg and Nelson Ic)7Y). SC;+. I\ as\ociatcd M ith increased ri\k of neonatal and perinatal mortalit) at e\`er! c catation;d qe (Koop\. hlorgan. Battaglia 19X2: Lubchenco. Searl$. Bralie 1071): Lsith SIDS tBuch et al. IWSJ: and with neurocognitive deficits. 4ort \taturc. :md small head circumference in childhood (Fitzhardinge and Steven IY72: Hill et al. IYX4: We\thood et al. lYX3; Ounted and Taylor 197 I; Harvey et al. 19X7: Ounsted. Moar. Scott IYXI. I YXX: Fancourt et al. 1076). A\ reviewed in previous Surgeon General'\ report\ (US DHEW lY7Y: US DHHS IYXO) and in other literature (Landesman-Dv. yer and Emanuel 1979: Longo 19X2: Werler. Pober. Holme\ 19X5: Kramer 1987). cmokin2 during pregnancy decreases mean birthweight and increase\ the proportion of IOU' birthweight births. Ei;timates vary among studies. but birthweight is reduced by an average of approximately 100 g. and the proportion of 1ow birthweight is approximately doubled by cigarette smoking (Meyer. Jonas. Tonascia 1976: US DHHS 19X0: L'S DHEW 1979: Mclnto\h 19X-I: Committee to Study the Prevention of Low Birthweight IYXS: Kramer 19X7). Mean birthweight decrea5e.s and the percent low birthbeight increases with increasing num- ber of cigarettes smoked daily. The relationship between cigarette smoking and decreased birthweight is considered to be causal (US DHEW 1979: US DHHS 1980. I9XY). Smoking affects birthweight and the percentage of babies who are born of ION birthweight by retarding fetal growth. A measure of fetal growth retardation is the probability ofdeliverinp an infant who is in the lee than 10th percentile for gestational age. The relative risk of SGA is about 3.5. to l.O-fold higher among the infants ot \mokerc than for the infant4 of nonsmokers (Ounsted. Mnar. Scott IYX5 1. Preterm birth is also associated with maternal smoking. although not as strongly. Estimates of the relative risk of delivering before 37 weeks of yestation are typically about I.5 for smoking during pregnancy (Committee to Study the Pre\zntion of Low Birthueight 19X5: Kramer 19X7: Shiono. Klebanoff. Rhoads 19X6). Mean Fe\tntional duration among makers i\ not significantly shorter than it i\ among nonsmoher\ (C`S DHEW 1979: US DHHS 19x0). This finding is consistent with the observation that the ri\h ot delivering early ik greater amon? smokers than nonsmoher\. but the percentay of preterm deliveries is so small that the mean would not be affected unless the shift were very large (US DHEW 1979; US DHHS 1980). Most studies of cigarette smoking and birthweight have failed to separate never smokers from women who quit smoking prior to conception. MacMahon. Alpert, and Salber (1966) first examined the association of pre-pregnancy smoking with birthweipht and found no significant difference in the mean birthweight of infants whose mothers smoked before but not during pregnancy compared with never smokers. Subsequent research has confirmed the absence of an association between smoking prior to conception and reduced birthweight (Table 6). In all of these studies. smokers who quit before conception had mean birthweight values that were equivalent or higher than those of never smokers. Other studies in which information on mean birthweight could not be derived (Kline, Stein. Hutzler 1987: Anderson et al. 1983: Wainright 1983). with the exception of Zabriskie (1963). have also consistently shown no association between birthweight and smoking that ceased prior to conception. Zabris- kie (1963) failed, however. to adjust for smoking during pregnancy. and these results are not directly pertinent in a comparison of birthweight in never smokers and smokers who quit before conception. TABLE 6.-Summary of studies of mean birthweight, by smoking status In interpreting these data. misclaa\itication of exposure needs to be considered. MacArthur and Knox ( 198X) reported that women who quit smoking during pregnancy. and possibly those who quit before pregnancy. were more often living with a partner who smoked. Passive smoke exposure may adversely affect the fetus (Martin and Bracken 1986). Furthermore. for whatever reason, some women ma) misrepresent their smoking status, denying that they have continued amohing. thus leading to an underestimation of the benefit of smoking cessation prior to conception. More important. women who quit smoking prior to conception differ in other respects from women who continue to smohe. Women who quit may have smohcd feuer cigarettes per day prior to quitting. Studies of smoking cessation prior to conception have not accounted fully for other difference\ between women who quit and those who continue to smoke. Birthweight Table 7 summarires nonexperimental studies in u hich information on mean birthweight in nonsmokers. smohers throughout pregnancy. and smoker\ u ho quit after conception could be derived. The data from each of these studies are con\i\tcnt in t\j o important ways. First. women who smohed throughout pregnancy delivered infant\ who weighed less than the infants of nonsmokers. Second. women who quit smoking delivered infants who weighed more than the infants of smokers throughout pregnancy. In most of these studies. mean birthweight values among infants whose mother\ \toppcd smoking were the same or higher than those of infant\ of nonsmokers. Table 8 summarizes nonexperimental studie< estimating the relative rish of IOM birthweight for continuing smokers and quitters some time during pregnancy compared with nonsmokers during pregnancy. These studies are consistent with those examining mean birthweight. Compared with nonsmokers. the risk of low birthweight is elevated among smokers throughout pregnancy. and the risk is about I .O for women M ho quit. In addition. Kleinman and Madans (1985) reported no association between the rish ot low birthweight for women who quit smoking during pregnancy compared with those who had not smoked in the I2 months prior to conception among participants in the 1980 National Natality Survey (NNS ). An important aspect of smoking cessation and pregnancy outcome is the timing of cessation during pregnancy and its relation to birthweight. How early in pregancl cessation must occur to avoid the adverse effects of smoking on birthweight is a ke\ issue with important implications for counseling pregnant smokers. In most of the studies examining this question, only information on cessation in the early months of pregnancy is presented. However. Rush and Cassano ( 1983) found that mean birthweight among women who quit as late as the seventh to eighth month of pregnancy was higher than for women who smoked throughout pregnant)`. but lower than for nonsmokers and for women who quit earlier in gestation. MacArthur and Knox (1988) concluded that quitting any time before the 30th week of gestation increase\ birthweight when compared with continuing to smoke. Cooper (19X9) assessed patterns of cigarette smoking by trimester of pregnancy. Women who reponed smoking during the "first trimester of pregnancy only" had a X)-percent increased ri\h of having a low birthweight baby. while women who reported smohinp during the "first and second trimester of pregnancy only" had a 7%percent higher rt\h ot. ;I lo\{ TABLE 7.-Summary of nonexperimental studies of smoking cessation after conception, mean increase (+I or decrease (-) in birthweight (g) according to timing of cessation Month of ce\\ation Smohed Reference I 2 3 4 5 6 7 x Y L'tlktlOWl throughout Lowe (IYSY) Underwood et al. t 1967) Butler. Gold\tein. Ro\\ (1972) Andrew and McGarry t I472 1 Pap07 et 31. (19X?) +9X Rush and Cnssano ( 19x3 1 Pulhkinen (IYXS) Councilman and MacKay t 19x5) Kline. Stein. Hutrler (19X7) MacArthur +`17 and Knox (IYXXI +I3 -IX' -IOX -152 -730 +Jh -160 -x0 -170 + IO -70 +-I.? c.76 -90 -155 41 -22s 10 -3s +I? -202 -sx -2-t: birthweight baby. Women M ho reported mokin, 17 throughout their pregnancy had a 90.percent increased risk. of having a low birthweifht babl in contrat to nonjmohers. Most fetal gwwth occurs late in pregnancy. and the primary smoke comtituents considered as candidate\ in mediating the effect of wloking on fetal grow. th (i.e.. CO and nicotine leading to intrauterine hypoxia) have short-term reversible effects. The data in Table\ 6 and 7 wpport the conclusion that the adverse effect of making on birthweight occur5 in the latter part of Fe\tation. primarily during the third trimester. and that cessation at any time during gestation i4 lihely to mltlzL `vte the adverse effect of smoking on fetal growth. Because it is difficult to perwade ull pregnant \moher\ to quit vnohing entirely. the benefit of reducing the number of cigarette\ smoked per day becomes a public health issue. The obhervstion that cigarette mohing retard\ fetal gro\hth in ;I do\e-rehpon\e 3x3 TABLE 8.-Summary of nonexperimental studies of relative risk of low birthweight for smoking cessation after conception Fruier et al. ( IYhl I Van den Berg (lY771~ Petltti and Coleman on prr\\I Vv'hlte\ I0 cigarettes per day ). Using data from a longitudinal study of pregnant women. Van den Berg and Oechsli ( 1984) reported rates of preterm delivery (137 weeks) among never smokers. smokers who stopped at the beginning of pregnancy. and continuing smokers for 10,937 white women whose singleton pregnancies progressed beyond 22 weehs. The rate of preterm delivery was 5.3 percent in nev'er smokers. 6.X percent in quitters. and 7.6 percent in continuing smokers. The difference in the rate of pretemr delivery between never smokers and quitters was not statistically significant (pN.05): however. the difference between never smokers and continuinp smokers was significant. In a population-based casek of bleeding during pregnancy and of placenta previa and abruptio placentae (US DHEW 1979: US DHHS 1980: Naeye 1978: Naeye 1980). These women are probably at decreased risk of preeclampsia (US DHEW 1979: US DHHS 1980: Marcoux, Bribson. Fabia 1989). Few data on these pregnancy complications among former smokers are available. In Naeye's ( 1980) analysis of data from the Collaborative Perinatal Project, smoking for more than 6 years (but not short-term smoking) was found to be associated with a relative risk of I.6 to 1.9 for abruptio placentae and a relative risk of 2.4 to 2.8 for placenta previa. Women who had stopped smoking by their first prenatal visit were not at increased risk of abruptio placentae, but were still at twofold increased risk of placenta previa if they were long-term smokers. However, the latter result was based on only 18 exposed cases. Marcoux, Brisson, and Fabia (1989) found that. compared with women who had never smoked, those who smoked at the time of conception were protected from preeclampsia (estimated relative risk (RR)=OS 1). whereas women who smoked but quit prior to conception had the same risk of preeclampsia as never smokers (RR=O.97). Women who smoked at conception but quit prior to 20 weeks' gestation were not as protected from development of preeclampsia as were continuing smokers. Because of the otherwise serious adverse effects of smoking on the fetus, this minor "benefit" of smoking during pregnancy probably has no public health consequence. Randomized Trials of Smoking Cessation During Pregnancy Three randomized trials have been conducted on pregnancy outcome in relation to advice to stop smoking (Donovan 1977; Sexton and Hebel 1984: MacArthur, Newton, Knox 1987). Table 9 summarizes the studies and birthweight results. Two other randomized trials have also been conducted on the effect of various programs on smoking cessation rates among pregnant women (Ershoff, Mullen, Quinn 1989: Windsor et al. 1985). and other trials are in progress. Information on pregnancy outcome is not available, and these studies are not reviewed. Donovan (1977) studied smokers in three maternity units in England. Women aged 35 years or younger at the start of pregnancy. who smoked more than 5 cigarettes per day, who had less than 30 weeks of gestation at the first prenatal visit. and who had no prior perinatal deaths, were randomly assigned to a control group that received usual prenatal care or to a test group that was given intense individual antismoking advice by a physician at each prenatal care unit. There were 263 women in the test group and 289 in the control group. Mean daily cigarette consumption decreased from 17.1 cigarettes per day early in pregnancy to 9.2 cigarettes per day late in pregnancy in the intervention for women who quit between the 6th and 16th weeks of pregnancy, and 0.3 days longer for women who quit after the 16th week of pregnancy. Because of the limited data on the risk of preterm delivery among women who quit smoking after conception. a firm conclusion about benefit. or lack of benefit. at- tributable to smoking cessation for this pregnancy outcome cannot be drawn. Women who smoke during pregnancy are at increased risk of bleeding during pregnancy and of placenta previa and abruptio placentae (US DHEW 1979; US DHHS 1980: Naeye 1978: Naeye 1980). These women are probably at decreased ri\k of preeclampsia (US DHEW 1979: US DHHS 1980: Marcoux. Brisson. Fabia 1989). Few data on these pregnancy complications among former smokers are available. In Naeye's (1980) analysis of data from the Coltabordtive Perinatal Project. smoking for more than 6 years (but not short-term smoking) was found to be associated with a relative risk of I .6 to I .9 for abruptio placentae and a relativ*e risk of 2.4 to 2.8 for placenta previa. Women who had stopped smoking by their first prenatal visit were not at increased risk of abruptio placentae, but were still at twofold increased risk of placenta previa if they were long-term smokers. However, the latter result wa$ ba$ed on only I8 exposed cases. Marcoux, Brisson. and Fabia (1989) found that, compared with women who had never smoked, those who smoked at the time of conception were protected from preeclampsia (estimated relative risk (RR)=O.Sl). whereas women who smoked but quit prior toconception had the same risk of preeclampsia as never smokers (RR=O.97 ). Women who smoked at conception but quit prior to 20 weeks' gestation were not as protected from development of preeclampsia as were continuing smokers. Because of the otherwise serious adverse effects of smoking on the fetus, this minor "benefit" of smoking during pregnancy probably has no public health consequence. Randomized Trials of Smoking Cessation During Pregnancy Three randomized trials have been conducted on pregnancy outcome in relation to advice to stop smoking (Donovan 1977: Sexton and Hebel 1984; MacArthur. Newton. Knox 1987). Table 9 summarizes the studies and birthweight results. Two other randomized trials have also been conducted on the effect of various programs on smoking cessation rates among pregnant women (Ershoff. Mullen, Quinn 1989: Windsor et al. 1985). and other trials are in progress. Information on pregnancy outcome is not available, and these studies are not reviewed. Donovan (1977) studied smokers in three maternity units in England. Women aged 3.5 years or younger at the start of pregnancy, who smoked more than 5 cigarettes per day, who had less than 30 weeks of gestation at the first prenatal visit. and who had no prior perinatal deaths. were randomly assigned to a control group that received usual prenatal care or to a test group that was given intense individual antismoking advice by a physician at each prenatal care unit. There were 263 women in the test group and 289 in the control group. Mean daily cigarette consumption decreased from 17. I cigarettes per day early in pregnancy to 9.2 cigarettes per day late in pregnancy in the intervention ix7 TABLE 9.-Summary of birthweight outcome in randomized trials of smoking cessation in pregnancy Reference Number of Smohmg aI end \uhjecr\ of prq"""c) I c I c Binhueiyht rp) 1 c Difference (g I' Donovan I lY77) x? Sexton and Hebel 463 liYX4 MacArthur. Newton. 4Yi Knox (IYX7) group. but increased slightly from 13.7 to 16.4 in the control group. Mean birthweight was 3. I72 g in the test group and 3. I83 g in the control group. In the test group IO percent of the infants had low birthweight (4.500 g) compared with 9 percent in the control group. There were four perinatal deaths in the test group and one in the control group. None of the differences in birth outcome betueen the test and control groups were statistically 4gnificant. Although this trial might be regarded as evidence against a benefit of smoking cessation during pregnancy. a number of limitations of the study must be considered. First. no data are presented concerning the percentage of pregnant smohers who quit smoking entirely. Reducing cigarette consumption almost certainly has a smaller c benefit for pregnancy outcome than complete cessation. Second. the time at uhich smoking behavior changed during pregnancy is unclear: data on cigarette consumption for three periods during pregnancy uere obtained postnatally. and may have been affected by recall bias. Data from ohser\ational studies discu\\ed in the pre\ ious section strongly suggest that mohing during the last trimester of pregnancy i\ a critical mediator of reduction in fttal growth among smokers. Information from another British randomized trial (MacArthur. Neti ton. Knox 19x7) alsoquestions the benefit ofmohing ce\\ation during pregnancy. In this \tud!. ~\omen who \mohed at the time thei were scheduled for ;I prenatal 1 isit ;II a large hospital v.crc assigned randomI> to a control group that received routine care or to an intervention group that received supplementary health education about mohing during pregnant! The planned intervention consisted of ad\ ice to 4top \mohin= 11 and information about the effects of smoking on the fetus. pre\cnted I isuall> h! a bnohlet or \erball! by the obstetrician. There were 4X9 \tomen in the control group and 193 in the inter\rntion group. Mean birthweight for infant\ in the control group v.34 3. I30 g compared with 3.163 g for the intervention group. The pcrccntage\ of 1~ birthueight and perinatal mortality in the tv.o groups \\erc not reported. The difference in mean hirth\\eight was not statistically significant as determined by the conventional 0.05 probability value and a two-sided test. In this trial, only Y percent of the women in the intervention group quit smoking entirely. compared with 6 percent of the women in the control group. The failure of the intervention to cause smoking cessation makes this trial essentially uninformative concerning the benefit. or lack of benefit. of smohing cessation during pregnancy. In the intervention group. 28 percent of the women reduced the number of cigarettes smoked per day, compared with IY percent of the women in the control group. The greater reduction in cigarette consumption in the inter\,ention group. in the absence of a difference in mean birthweight between the intervention and control groups. suggests that reducing smoking does not entirely prevent the adverse effects of smohing on birthweight. The third randomized trial (Sexton and Hebel IY8-t) recruited women in a large metropolitan area from various sources. Smokers of at least locigarettes per day at the beginning of pregnancy, who had not passed the 18th week of gestation. were randomly assigned to a control group that received routine advice or to a treatment group that received intensive. ongoing advice throughout pregnancy from specially trained profes- sional staff. There were 472 women in the control group and 363 women in the treatment group. The mean birthweight of infants born to women in the control group was 3.186 g compared with 3,278 g for infants of women in the treatment group. The percentage of low birthweight infants was 8.9 in the control group and 6.X in the treatment group. There were I I stillbirths in the control group and Y in the treatment group. The difference in mean birthweight was statistically significant (~~0.05. two- tailed test); the differences in the percentages of low birthweight and in fetal mortality were not statistically significant. In this trial, 43 percent of the women in the treatment group had ceased smoking entirely by the eighth month of pregnancy. compared with 20 percent of the women in the control group. The intervention was, therefore. highly successful in causing substantial changes in smoking that exceeded changes in the comparison group. The investigators ruled out concomitant changes in consumption of alcohol and coffee as explanations for the increase in birthweight. Weight gain was 1 .O kg greater among the treatment group than the control group. but at least part of the difference in weight gain was a result of the higher birthweight of the infant (Sexton and Hebel 1984). Review of these three randomized trials leads to two conclusions. First, to prevent entirely the adverse consequences of smoking on birthweight, it is necessary for women to cease smoking completely. Second. intensive interventions spanning the entire period of gestation may be necessary to effect large changes among the percentage of women who abstain from smoking entirely. Prevalence of Smoking and Smoking Cessation During Pregnancy and Time Trends in Prevalence and Cessation Introduction Ideally, conclusions about the prevalence of smoking during pregnancy and trends in prevalence would be based on representative samples of pregnant women performed at regular intervals using the same methodology. Assessment of smoking cessation during pregnancy and time trends in smoking cessation should be based on repre- sentative samples of women who start pregnancy as smokers and who are monitored for smoking behavior throughout gestation. Available data fall short of these ideals. Furthermore, available information on smoking and smoking cessation in pregnancy is based almost exclusively on self-reported behavior. Few data on the quality of self-reported smoking specifically in relation to pregnancy have been collected. and it is possible that the societal pressures against smoking during pregnancy would make underreporting more problematic than for other populations (Chapter 2). Similarly, pregnant smokers who admit to smoking might underreport their daily cigarette consumption. perhaps to a greater extent than nonpregnant smokers. The effect of underreporting of smoking and overreporting of cessation would make the data from former smokers more similar to that of continuing smokers with respect to their reproductive health outcomes. Also. smokers who reduce the amount of nicotine in their cigarettes by changing brands or those M ho reduce the number of cigarettes they smoke per day without quittin, ~7 may compensate to maintain the \ame nicotine do\e (US DHHS lY88). Prevalence of Smoking and Smoking Cessation Pertinent data on smoking during pregnancy from the 1985 National Health Interview Survey (NHIS) (NCHS IYXX) are presented in Table IO. The IYXS survey focused on health promotion and disease prevention. The survey involved nearly 35.000 households and more than YO.Ot)O persons. and the response rate was 95.7 percent. Information concerning smoking during pregnancy' vvas obtained from all female household members aged IX to 4-I kears ti ho had had a live birth in the 5 years prior to the survey. The proportion of vvomen u ho had smohed at any time during the year preceding pregnancy ~`a\ 32 percent overall. Of Momen uith less than I? years of education. 46 percent smohed in the year preceding pregnancy. compared with I.3 percent of women with I6 or more years ofeducation. Thirty percent of married women had smoked. compared u ith 10 percent of formerly married u'omen. Patterns of smohing cessation or reduction uere reported in detail for some demographic subgroup\. Overall. 2 I percent of women who smoked prior to pregnancy quit upon learning of their pregnancy. and an addittonal 36 percent reduced the number of cigarette\ they smohed. Cessation (but not reduction) *as strongly related to education and family income. Among uomen with less than 12 years of education. I2 years of education. and more than 12 years of education. 15. 10. and 32 percent quit. TABLE IO.-Smoking and smoking cessation during pregnancy. summary of results of two surveys of national probability samples respectively. The proportions for reduction in smoking were 34. 3X. and 36 percent. respectively. Younger mothers were slightly more likely to quit than older mothers. and white mothers quit slightly more often than black mothers (2 I vs. IX percent ). More married mothers (23 percent) than never married (19 percent) or formerly married ( I3 percent) mothers quit. although the proportions reducing their smoking levels were similar (36. 37. and 35 percent. respectively). Fingerhut. Kleinman. and Kendrick (1990) also reported data on smoking in whites before and during pregnancy based on the Linked Telephone Survey. which reinter- viewed I.550 women aged 20 to 44 years who were respondents to the 1985 NHIS. This analysis confirmed the previous findings that smoking prior to pregnancy and quitting during pregnancy were strongly related to age and educational attainment. Information on amount smoked prior to pregnancy was obtained in this survey. Fifty-nine percent of women who smoked less than I pack per day prior to pregnancy quit smoking. compared with 25 percent of those who smoked I pack or more per day. Of the white women who smoked prior to pregnancy, 3Y percent quit during pregnancy (27 percent when they found out they were pregnant and I2 percent later in pregnancy). This estimate of quitting during pregnancy is higher than the previous estimate of quitting from whites in this survey because it includes as quitters both women who quit upon learning that they were pregnant and those who quit later in pregnancy. Smoking during pregnancy was also assessed in the 1980 NNS (Prager et al. 1983) (Table IO). Questionnaires were distributed to a national probability sample of married women who had had live births in 19X0; the response rate was 56 percent. The restriction to married women severely compromises the generalizability of results. especially for subgroups such as blacks and youth because smoking during pregnancy~ is consistently more common among unmarried mothers (Schramm 1980; Rush and Cassano 19x3) and nearly one-half of black infants are born to unmarried mothers (NCHS IYXZ). The low response rate might have also affected the validity of the study, Prayer and associates ( 19X4) asked women how many cigarettes they smoked per day before and after they found out they were pregnant. Among all married respondents. 3 I percent smoked before pregnancy. Whites were more likely to smoke than blacks (32 vs. 25 percent). These investigators reported a strong association of smoking with age. with younger mothers more likely to smoke than older mothers. There were even more pronounced gradients with education. Among women with less than a high school education. 50 percent smoked before pregnancy, and this percentage diminished monotonically to IS percent among women with 16 or more years of education. Amonp the women in the study (PraLger et al. 19x3) who smoked prior to pregnancy. IX percent quit after realizing they were pregnant. White women were somewhat more likely to quit than black women ( IX vs. I3 percent). Mothers older than 35 years of age were markedly less likely to quit: only 7 percent did. Again. education had a strong association with quitting: IO percent of mothers with less than I2 years of education quit. and the percentage increased monotonically to 33 percent among mothers with I6 or more years of education. The patterns of cessation by amount of smoking are also of interest. Women who were smoking I to IO cigarettes per day at the time of pregnancy recognition were far more likely to quit than women smoking I1 or more cigarettes per dav (3 I v's. I2 percent). Among the heavier smokers. 27 percent reduced their consumption to IO or fewer cigarettes per day even though they did not quit. Williamson and associates ( 19x9) used data from the Behavioral Risk Factor Surveil- lance System in 1985 and I986 to compare smoking patterns among pregnant and nonpregnant women. Data were collected through 19.12-t telephone interviews of a population-based sample of women in 26 States. with ascertainment of current preg- nancy status. smohing history. and current smoking practices. Women pregnant at the time of interview were less likely to be current smokers than nonpregnant women (3 I vs. 30 percent). but had a similar likelihood of ever having smoked (43 vs. 35 percent). The proportion of former smokers was thus greater among pregnant women (?1 v's;. I5 percent). largely accounting for the difference in current smoking patterns. This study, (Williamson et al. I 0x4,) suggests that if 30 percent of women pregnant at the time of the sutvey smoked prior to pregnancy. then 30 percent of smokers would have had to quit after becoming pregnant to account for the reported smoking rate of 1 I percent. Among pregnant women w.ho smoked. the mean number of cigarettes consumed per day was I?. compared M ith 20 cigarettes per day among nonpregnant w otnen who smohed. These data suggest that smokers who do not quit upon becoming pregnant tend to reduce their cigarette consumption (Williamson et al. IYXYI. Patterns ot`smohing were generally similar across demogaphic subgroups. with one important exception. Among unmarried women. smohin, ~7 was slightly more common in pregnant than nonpregnant women (36 vs. 3-t percent,. implying no change in smoking among unmarried pregnant women. The absence ofpregnancy-related reduc- tion in smoking for unmarried women was due exclusively to a markedly higher smoking prevalence for white unmarried pregnant women. The results suggest that data on married mothers cannot be generalized to unmarried mothers. A number of investigators reported smohing patterns in selected populations. such as women delivering in a particular hospital or geographic region or those receiving prenatal care at a specific clinic. Table I I summarizes se\,eral of these studies. Although none are true probability samples. these studies provide an indication of the diversity of smoking and smoking cessation among different populations. The propor- tion quitting during pregnancy ranges from 6 to 3Y percent. Time Trends in Smoking and Smoking Cessation Kleinman and Kopstein ( 19X7) compared the pattern of smohing cessation during pregnancy from the similarly designed IY67 and 1980 NNS. Although there were some changes in the proportion of mothers vv ho were married at the time of each of the 1~ o surveys and the characteristics of nonrespondents might have varied. the surveys provide a unique opportunity to assess temporal trends in smoking and smohing cessation during pregnancy. The percentage of mothers u ho smohed prior to pregnancy decreased markedly during that period. from 55 to 30 percent for white mothers and 40 to 3 percent for black mothers. The percentage of v.hite mothers who quit after pregnancy rose from I I to I7 percent between the two surveys. whereas the percentage of black mothers who quit decreased from I7 to I I percent over that interval. During the interval between the surveys. the diminution of smoking during pregnancy was more pronounced for highly educated women. increasing the differential exposure to tobacco by educational status (Kleinman and Kopstein 1587). Estimates of Attributable Risk Percent Although several measures of attributable risk are commonly used to describe the burden of disease associated with an exposure, the most recent report of the Surgeon General (US DHHS 1989) has focused on attributable risk percent. frequently termed etiologic fraction, as the most relevant measure of the likely public health impact of smoking cessation. Calculation of the attributable risk percent uses the formula as follows: where p is the proportion of persons with the exposure and RR is an estimate of the relative risk of the outcome in those who are exposed compared with those unexposed. At least three different studies (Meyer. Jonas. Tonascia 1976: McIntosh 1983: Kramer 19X7) estimated the relative risk of several pregnancy outcomes after reviewing the research literature. Table I2 summarizes these studies and provides estimates of attributable risk for prevalences of smoking of 20. 30.40. and SO percent based on the relative risk estimates from the three studies. As noted earlier. demographic subgroups of women differ markedly in smoking prevalence. Of those women with less than a high school education, 50 percent smoked during pregnancy: of those women with some college education, 20 percent smoked during pregnancy (NCHS 19X8). Approximate- ly 30 percent of married women and 30 percent of unmarried women smoked prior to `I'AIILE 1 I.--Patterns of smoking cessation during pregnancy among selected populations K~lclcllc~ I.~~c;lll,lll SOlILY YW\ `4 Snrohing iilltially I'jSX 43 3) NK I `M1 (30 I7 II IO I'j5X 3X IX YK NK so NK 1-I I97h- 70 37 4') NK I'JXO 22 3x NK I'JXO NK 2X NK I'MI x1 20 22 NK I')X I -x2 1') h I `1 NK 32 I7 NK TABLE 12.-Summary of studies that estimated relative risk of various pregnancy outcomes for smoking based on a "q nthesis" of the literature, and attributable risk percent based on several estimates of the pre\,alence of smoking during pregnanq P" Prcwrm lklI\~r! RR .AR'r Ile>cr. Joru\. 031 I 2ib 1 TOn;i\LLl 0 Xl h l19?hl 0.10 X 0.w IO Llclnlo\tl 0.3) I.25 I IYX1l o.io I).10 0.50 Kwn1er 0.21) NK /19X7) 0.20 0.10 0.50 i I.81 Y I I 2 12 I,YY" pregnancy (NCHS 198X). The most recent estimates suggest that about 25 percent of U.S. women smoke throughout pregnancy (NCHS 1988). The relative risk estimates forperinatal mortality and preterm delivery are remarkably consistent. especially considering that these authors conducted independent syntheses of the literature. Estimates of the relative risk of low birthweight ranged from 1.81 (McIntosh 1984) to 2.42 (Kramer 1987). probably because ofdifferences in the number of studies used to derive the estimate. For this reason. attributable risk percent for a given prevalence of smoking is more variable for low birthweight than for perinatal mortality and preterm delivery. Based on data that indicate that about 25 percent of U.S. women smoke throughout pregnancy. it can be estimated that 5 to 6 percent of perinatal deaths. 17 to 26 percent of low birthweight births. and 7 to 10 percent of preterm deliveries could be prevented by elimination of smoking during pregnancy. In groups with a SO-percent prevalence of smoking. such as women with less than a high school education. approximately IO to 1 1 percent of perinatal deaths . 29 to 42 percent of low birthweight births. and 13 to 18 percent of preterm deliveries might be prevented by elimination of smoking during pregnancy. These contributions to adverse pregnancy outcome are sizable. and smoh- inp is probably the most important modifiable cause of poor pregnancy outcome among women in the United States (Kramer 1987). Age at Natural Menopause Introduction The significance of menopause extends beyond marking the end of female reproduc- tive potential. The age at which menopause occurs also may have implications for the risks ofosteoporotic fractures. irchemic heart disease. and cancers of the reproductive system. Thus. the effect of smoking on the age of menopause could have potentially broad health implications. In fact. an early natural menopause has been observed consistently among women who smoke cigarette\. As summarized in Table 13. the major studies addressing this topic have indicated that currently smoking women cease menstruating from I to 2 years earlier than otherwise similar nonsmokers. Expressed as relativje risk. women ased 43 to 54 years who \mohe become menopausal at about twice the rate of never smokers (Willett et al. IYX3: Bailey. Robinson. Ves\ey 1977: Hartz et al. 1987: Andersen. Transbol. Christiansen 1983: Baron 1990). Several features of the data suggest that [hi\ is a causal relationship. By using both cohort and cross-sectional methodology with a variety of subject populations. the results have been replicated repeatedly in studies in several areas of the United States and Europe. Dose-response effects have generally been found. with heavy smokers experiencing an even earlier menopause on average than light smokers. HowevJer. these trends have not a1uay.s been assessed with formal test\ of statistical significance in the reports describing the data. Several studie\ demonstrating thi4 association have con- trolled for potential covlariates. That premenopausal smokers may be more lihely than nonsmokers to have a hysterectomy does not appear to explain the relationship (Krailo and Pike 1983). Pathophgsiologic Framework There are at lea\t three way\ in which cigarette smoking could lead to an early natural menopuu\e. Experiments M ith laboratory rodents indicate that the polycyclic aromatic hydrocarbons found in cigarette smoke may be directly, toxic to ovarian follicles (Mattison IYXO). Mattison and colleagues found that intraperitoncal injection of benzo(a)pyrene. .i-meth~lcholanthrene. or 7.12.dimethylbenz(a)anthtracene led to ovarian folliculur atresia (Matti~nl and Thorgcirsson lY7X. lY7Y: Gulyas and Mattison lY7Y). Earlier uncontrolled studic`s of prolonged exposure of mice to cigarette smohe led to similar findings (Es\enbcrg. Fa~an. 5lalerstein IYC I ). which were also seen in a later controlled study of rut\ rsubbarao IYKX). However. other investigator\ failed to find ovarian atrophy in rodent\ chronically rxposcd to cigarette mohe (Haag. Larson. Weatherby 1960: Dontenuill ct al. IY73a). and in most studies. parentersl nicotine or tobacco extract has had minimal effect on the ovaries of experimental animals (Es\en- berg. Fagan. Maler\tein I Y5 I : Thienes I Y60: Lar\on. Haag. Silv ette I Y6 I ; Larson and Silvette 196X). The other two postulated mechanims for premature menopause do not involve direct ovarian toxicity. Cigarette smoking may interfere with IuteiniLing hormone release at TABLE 1X-Summary of studies reporting relationship of cigarette smoking and age at natural menopause Dantell t IY7X1 Lindqui\t and Rell!It\\on t IY7Y) Kaufmm et 21 t I YXO, Adenu and Gtlla~hrr t I `)X2) Willert et al. t IYXi) I O.YYS health \creenrrs McKinlay. Bifano. McKinla) (19X.5) E\er\on et 31. (19X6) Hiatt and Fireman (10X6) Stanford et al. t 19x7 ) Brambilla and McKinlny (19X9) s.350 generul populatton subject\ 261 population wbjcct\ 5.316 HMO health scrrenees I.7 I .3" ?.(I' I P 1i.X' 1.2" 1.7' I .o I .4 I .7 1.I NYS' 0.3 I .s least in rodents exposed to parenteral nicotine or cigarette smoke (Andersson et al. 1980: Andersson et al. 1984; Andersson et al. 1988: Eneroth et al. 1977a.b; Kanematsu and Sawyer 1973: Blake. Norman. Sawyer 1974: Blake 1974: Blake et al. 1971a.b: McLean. Rubel. Nikitovitch-Winer 1977). This effect appears to be due to a nicotinic effect on neurotransmitter release. A return to a more normal function after the end of exposure to smoke or nicotine has not been documented. but it seems likely that such a nicotinic effect on the brain would not be permanent. Therefore. it is possible that in humans. smoking could cause a reversible interference in the pituitary-ovarian axis, which could lead to a cessation of menses. Several investigators found that smoking has been associated with menstrual it-regularity earlier in reproductive life (Wood 1978; Pet- tersson. Fries, Nillius 1973: Brown. Vessey. Stratton 19X8: Hammond 1961). Smoking has also been associated with disturbances of estradiol metabolism. Mich- novicz and colleagues (1986) found that premenopausal smokers tend to metabolize estradiol through pathways producing more catechol-estrogen metabolites than non- smokers. This change would be expected to result in a relative antiestrogenic influence because of the lack ofestrogenic potency of the catechol-estrogens compared with the estrogenic metabolites. such as estriol. which are produced in larger amounts in nonsmokers. There is also evidence that nicotine may inhibit aromatase. an enzyme important in the synthesis of estrogen\ (Barbieri. McShane. Ryan 1986: Barbieri. Gochberg. Ryan 1986). Again. the recovery of normal enzymatic function after cessation of smoking has not been studied. However. it is postulated that these or similar disturbances could result in enough antagonism of estrogen effect to cause an early cessation of menstrual cycling in women already in the perimenopausal years (Baron. LaVecchia. Levi 1990) Studies of Former Smokers Former smoker\ experience menopause only slightly earlier than never smokers (Table 13). In a study of hospitalized women. Jick. Porter. and Morrison ( 1977) found that former smokers had a median age at menopause between that of never smokers and that of women currently smoking half a pack of cigarettes per day. Kaufman and coworkers ( 19X0) reported on hospitalized women aged 60 to 69 years. Data from 10 women who stopped smoking before age 35 indicated that the mean age at menopause was 0.2 year\ earlier than in never makers. after adjustment for parity and body habitu\ (Kaufman et al. 1980). In a cross-sectional study ofwomen attending a screening clinic. Adena and Gallagher (19X2) found ex-smokers to have a median age of natural menopause 0.3 year\ earlier than never makers. Finally. Hiatt and Fireman (1986) found among a group of enrollees in a prepaid health plan attending a screening clinic that es-\moken reached menopause about 0.5 years earlier than never smokers. Thu\. natural menopause appears to occur. at most. 6 month\ earlier in ex-smokers than in never smokers. Limited findings on relative risk of early menopause in former smokers are av,ailable (Willett et al. 1983; Baron. LuVecchia. Levi 1990). From data presented hy, Lindquist and Bengtsson ( 1979) regarding %-year-old women. it can be calculated that compared with never smokers. former smokers had a relative ri& of early menopause of I.8 TABLE Id.-Summary of studies of age at natural menopause among former smokers Vumtxr of COViiKiI~~ Reference ei-rmoker\ considered Fmdllw\ Lmdqw\t and Bengtwn f 1071)) Kaufman et al. I IYXO) Adena and Gallagher IIYX?~ Willett et al. (10X3) 30 I 0 NR I6.034 Age. welght. nulliparity Sib None Pan). reyon. Quetelst'\ Index None Htatt and Fireman (19861 Mean age at menopauw wit\ 0.2 \`rarllrr among e\-moher\ than amcmy never vnohw Odd\ ratto of herng menopausal for current \moher\ v,. never smoker\ ua\ I. IO Mean aFe at menopause u3k 0.5 y earlier among ex-\mohrr\ than among never vnoher\ (95percent confidence interval, (CI), 1.14.7). In a prospective study of American nurses, Willett and coworkers ( 1983) found ex-smokers to have a relative risk of early menopause of I.1 (95percent CI, 0.98-1.23) compared with never smokers after adjustment for age, weight, and nulliparity. In this study, those who stopped smoking in the 2 years previously retained a modest increase in risk of early menopause (RR=1.4); after a longer period of abstinence, there was no effect associated with previous smoking (Willett et al. 1983). All the investigations of smoking and menopause have relied on self-report of menstrual status and smoking history. It is unlikely that misclassification with regard to these features would seriously distort the findings regarding current smoking, but the results for former smoking may be more susceptible to artifact. In particular. some of the study participants who claimed to be former smokers might actually have continued to smoke, or they might have quit for health reasons related to an early natural 399 menopause. Like current smokers. former smoher\ may be more likely to be passively exposed to passive 3mohing than ne\er smokers. thus po\cihly affecting menopaui;al age. These factors would tend to lead to an exaggeration of the apparent impact of former smoking on menopausal age (Chapter 2). Therefore. the results summarized above may overstate the degree to which former smoking is associated with any disturbance in menopausal age. It appears that age at menopause in former smokers is closer to that of never smokers than to current smokers. and the data are consistent with a decline in the risk of early menopause with the cessation of smoking. The effect of smoking on menopausal age may be partly or wholly rever\ible with cessation of smoking during the premenopausal years. However. some pertinent data are lacking. Most of the studies did not consider how long it takes after cessation of smoking for the ri\k of early natural menopause to decrease. Ko studies have verified that the women bho stopped smoking had a lifetime smoking exposure similar to that of women who continued smoking. PART IL MALE Introduction Cigarette smoking has been considered to be associated with impairment of male sexual functioning. and tobacco abstinence has been recommended for men attempting to maximize sexual performance (Larson. Haag. Silvette 1961: Sterling and Kobayajhi 1975: Ochsner I97 1a.b). An association between mokin2 and impaired sexual per- formance among men ha\ been publicized in the lay pre\\ (Reuben 19X8). Althouph some data pro\ ide e\ idcnce for this association. the> are inconclusix e. Pathophysiologic Framework Three general type\ of mechanisms habe been proposed to explain the harmful effect of cigarette 9ilohing on wxtial performance. impotence. and sperm qualit),. First. smoking ma! expose the te\te\ to compounds that are directI! toxic to the 5pern- producing germinal epithelium. to earl! sperm form\. or to the hormone-producing Leydig cell\. The effect\ on sperm rna\~ be ;I manifestation of ;I genotoxic effect of cigarette to the genital\. a\ reflected b! the penile brachial index (PBI) and other 1 atcular mt`a\urement\. A diminished va\cuIar \uppl> to the genitals would compromi\c w~ual performance and spermatogenesis and hor- mone production. Although athero\clero\i5 i\ often considered a fixed lesion. several studie\ ha\,c \ugcsted that :ithcro\clerotic plaque\ ma! regre\\ v, ith approprlatr lifestyle change\ (Barndt et aI. 1077: Nihhil;l 19X0: Kram~h et al. 19X I: Chapter 6). However. no studies ha\e been conducted on the effect of \mohing cessation on regression of atherosclerotic lesion\. Nonatherosclerotic vascular changes may also mediate the effect of smoking on genital function. The vasoconstrictive effects of nicotine in cigarette smohe may impair the complicated vascular processes involved in erection (Benowitz 198X). This may be due in part to disturbances of prostaglandin production in the vascular endothelium or to an enhancement of platelet aggregation noted by several investigators (Nadler. Velasco. Horton 1983; Alster et al. 1986: Taylor et al. 19X7: Lassila et al. 198X: Jeremy et al. 1986: FitzGerald. Oates, Nowak 1 Y8X: Chapter 6). Finally. hormonal effects of cigarette smoking could alter sexual responsiveness and spermatogenesis. Alterations in the secretion of luteiniring hormone releahing hor- mone (Moss, Riskind. Dudley 1979) or catecholamine\ (Patra. Sanyo]. Biswas IY79: Klaiber and Broverman 1988) are two such possibilities. but disturbances in sex hormones. particularly low testosterone or high estradiol. have been suggested more often. In general. men who smoke cigarettes have similar or higher testosterone level\ than nonsmokers: thus. it is difficult to associate low testosterone with sexual dysfunc- tion among men who smoke (Briggs 1973: Shaarawy and Mahmoud 1982: Andersen. Semczuk. Tabor 1984; Handelsman et al. 1984: Deslypere and Vermeulen 1984; Vermeulen and Deslypere 1985: Vogt, Heller. Borelli 1986: Barrett-Connor and Khaw 1987; Dai et al. 1988: Lichtenstein et al. 1987; Meikle et al. 19x7: Klaiber and Broverman 1988). The adrenal androgens (i.e.. androstenedione. dehydroepiandrosterone. and dehydroepiandrosterone sulfate) are elevated in male smokers (Barrett-Connor. Khaw. Yen 1986; Barrett-Connor and Khaw 1987; Dai et al. 1988). Aromatization of these hormones may explain the elevated levels of estradiol among males who currently smoke (Entrican. Mackie. Douglas 1978: Lindholm et al. 1982; Klaiber, Broverman, Dalen 1984: Barrett-Connor and Khan 1987; Lichtenstein et al. 1987: Dai et al. 1988; Klaiber and Broverman lYX8). Elevations in circulating estrogens may interfere with spermatogenesis and sexual behavior (Klaiber and Brover- man 1988); such an explanation remains speculative. Several studies have suggested that the estradiol and testosterone levels of former smokers are comparable with those of never smokers (Deslypere and Vermeulen 1984: Vogt, Heller, Borelli 1986; Barrett-Connor and Khaw 1987; Lichtenstein et al. 1987). This observation implies that smoking cessation is likely to reverse any effect mediated by disturbances of these hormones. Alternatively, former smokers may have had a lower total dose. Androstenedione and dehydroepiandrosterone sulfate levels may be modestly higher in former smokers compared with those of never smokers (Barrett- Connor. Khaw, Yen 1986; Barrett-Connor and Khaw 1987: Lichtenstein et al. 1987). However, the relevance of these findings to sexual capabilities is unlikely to be significant. These hormones appear to have little intrinsic potency, and are important because of their capacity for conversion to more active hormones such as testosterone and estradiol (Baxter and Tyrrell 1987). Sexual Activity and Performance Surveys of the relationship between smokin p and frequency of sexual episodes (intercourse or masturbation) have generally found smokers to be as sexually active as nonsmokers. In two studies of elderly men. sexual activity in smokers was comparable / with that of nonsmokers (Tjitouras. Martin, Harman IYX?: Diokno. Brown. Herzog 1990): in a cross-sectional study of younger men. no difference\ were indicated (Vogt. Heller. Borelli lY86). Adolescent smohers are more sexually active than nonsmokers (Russell I97 I: Malcolm and Shephard 197X ). In contrast. Cendron and Vallery-Mas- son (IY71 ). in study,ing 70 men older than age 45. found that those who reported smoking between ages 25 to 40 al\o reported being less sexually active at those ages than those who denied smoking. Ovrerall. it appean that the relation between current cigarette smoking and the level of male sexual activity is not very strong. Among younger males. personality differences between smokers and nonsmokers may dominate any adverse physiologic effects (Russell 197 I ). If. as the aforementioned studies suggest, current smokers (or ever smokers) are similar in sexual habits to never smokers, then no differences would be expected for former smokers. Vogt, Heller. and Borelli (19X6) evaluated 239 healthy male volun- teers aged 19 to 30 without genital abnormalities or diseases and taking no medications. The study results indicated that the 36 former smokers among them were comparable with both never smokers and current smokers in sexual activity (Vogt. Heller. Borelli 1986). Impotence. the inability to maintain an erection sufficient for intercourse. has been more extensively investigated in relation to smoking. Among treated hypertensives aged 40 to 64. cigarette smoker3 were more likely to report impotence. although the differences were modest and not statistically significant (Biihler et al. IYXX). A statistically significant association was reported among men undergoing radiation therapy for prostatic cancer (Goldstein et al. 1983). However. in both studies. poten- tially important covariates. such as alcohol intake and age. M#ere not considered. Two other studies of men undergoing impotence evaluation indicated a high prev*alence ot smoking and suggested an association between smoking with impotence (Virag. Bouilly. Frydman 1985: Condra et al. IYXh). Unfortunately. neither study included a sexually functional control group. and both studie\ based their conclusions on ques- tionable comparisons ot`the smohing rate in their clinic patients with that of the general population. Vopt. Heller. and Borelli (1986) studied a group of young volunteers vvithout selecting for impotence. These investigators found that smokers reported more difficulties with decrea& libido and erection than nonsmokers (Vogt. Heller. Borelli 19X6). This analysis did not consider former smokers separately. An acute effect ofsmohing on sexual performance is suggested by a study of smokers monitored while viewing erotic films (Gilbert. Hagen. D'.Agostino IYX6). The succes- sive smoking of 2 cigarette\ high in nicotine content significantly impaired the rate of penile diameter change compared with that observed after smoking I cigarette or eating candy. Hovvever. the clinical relevance ofthese oh\enation\ is unhnoan hecauke franh impotence has not studied. An important clinical measurement in the evaluation of impotence is the PBI. v.hich indicates the \y stolic blood pressure in the penis div,ided by systolic blood pres\urc in the arm. A low \,alue i\ considered to be ev idcnce of compromise of the penile blood apply. a factor v+ hich may interfere v+ ith erection. Several \tudie\ of men undergoing evaluation of impotence reported an association between smohing and Ioh PBI (Jacobs et al. IYX3: Condra et al. 1986: Bornman and Du Ples\i\ lYX6: DePulma et al. IYX7). Among impotent diabetics, evidence of nocturnal erections wJas found less in smokers compared with nonsmokers. thus suggesting an increased risk of vascular compromise in smokers (Takahashi and Hirata 1988). However. other studies of impotent men have not reported differences between smokers and nonsmokers in vascular measurements (Wabrek et al. 1983; Virag, Bouilly. Frydman 1985: Kaiser et al. 1988). Most of these investigations did not consider covariates such as alcohol use, although one study suggested that smoking in isolation had little effect and that an association of smoking with an abnormal PBI may be due to the association of smohing with other arterial rish factors (Virag. Bouilly, Frydman 1985). In many of the studies relating smoking and impotence. the investigators did not distinquish nonsmokers as ex-smokers or never smokers. However. two investigations considered former smokers separately (Table 15). Wabrek and associates (1983) studied I20 men who were referred to a hospital-based erectile dysfunction program. The percentage of former smokers vvas approximately the same among men with impaired, borderline. and normal PBI. Condra and colleagues ( 1986) reported on I78 patients also referred for impotence. Former smokers were not separated for analysis. but this study suggests that the PBI for ex-smokers is more normal than in current smokers (Condraet al. lY86). However. neither study considered important covariates. such as age and alcohol use (Wabrek et al. 1983: Condra et al. 1986). Two recent investigations considered the effect of smoking cessation on impotence. Forsberg and colleagues (1979) noted that two smoking men who were impotent improved their functioning after smoking cessation at the same time that measures of penile blood flow improved. However. it is not clear how these two men were selected for this study. and control subjects were lacking. Elist. Jarman. and Edson (1984) reported on the treatment of 60 impotent men. Twenty nonsmoker\ were treated with the vasodilator isoxsuprine. and 40 smokers were either advised to stop smoking or advised to stop smoking and also given isoxsuprine. There was no mention of randomization. and there was no untreated control group. Similar proportions im- proved whether given isoxsuprine. convinced to stop smoking. or both (Elist. Jarman. Edson 1984). Animal data have not elucidated the relation between smoking and either sexual activity or impotence. Soulairac and Soulairac (1972) studied the sexual activity of male rats given either a 0.6 mg/kg or a 1.2 mg/kg dose of nicotine subcutaneously. The sexual activity of the rats after the nicotine administration was compared with that before treatment. Sexual activity was markedly increased with the 0.6 mg/kg dose. and at 1.2 mg/kg there was trembling and twitching and no sexual behavior for 2 to 3 hours. In contrast, exposure to smoke from 1 cigarette has been shown to interfere with the physiology of erection in male dogs (Juenemann et al. 1987). In summary, the level of sexual activity does not appear to be affected by cigarette smoking. Cigarette smoking may be associated with impaired male sexual perfor- mance. Among impotent men, smokers are more likely to have an underlying vascular problem. These associations have been more commonly noted in groups already at high risk of impotence. such as hypertensives and diabetics. However. these associations have not been consistently observed, and the positive findings may be due to the association of smoking with other factors such as alcohol use. Moreover. because the 303 TABLE IS.-Sexual performance among male former smokers studies of PBI are generated entirel) in referral populations. it i\ unclear if these finding\ can be generalired. Because of limited and uncontrolled data. no conclusion\ can be drawn regarding WYLI~I performance or PBI among former makers. Sperm Densit- and Qualit> Measul-ements of sperm den\it!. mr)rpholog . and motilif arc commonI>, uxd assessmcntk of sperm qualit! (Roger\ and Ru\\ell IYX7 I. O\er 20 \tudie\ hare dealt with the relation of cigarette \mohing to sperm den\it!,. motility. and morpholog> (Vicxian lY6Xa: Schirren and Gt'! 1960: Cm~phcll md Harrison lY7Y: Vogel. Braver- man. Klaiber lY7Y: Stehhun IYXO: Nebe and Schirrcn IYXO: EVXII\ t't al. I98 I: Godfre! 19X1: Roclrisuc/-Rigau. Smith. Steinherger IYXI: Shaaraw! and hlahmoud IYX2: Buiatti et al. I YX4: Andervx. Semc/uh. Tabor I YX4: Norden\on. Xbrams\on. Ducheh 19X3: Handcl\man et al. IYX-I: Hoda\ et al. IYX5: Kulihausk. Bluustein. Ahlin IYXS: Ablin IYXh: Rantala and Ko\himie\ lYX7: Vast. Heller. Borelli lYX6: Klaiber et al. lYX7: Dihshit. Buch. Jlansuri lYX7: Sxrrunen et al. IYX7: Klaiberand Bro\erman IYXX: Svaranen et al. I9XY: Rui. Oldereid. Purvi\ IYXY: klar\hburn. Sloan. Hammond IYXY: Oldereid et al. I YXY). Table I6 `rummari/es the finding\ of those studie\ that reported mean values for maker\ and nonsmohcrx In mo\t \tudie\. men smohing cigarette\ had lower sperm Jen\it>. although many ofthe\e \tudie\ indicated differences that \+ere not \tati\tically riynificant. The \moher\' a\`erage sperm density uxs at lea\t X0 percent that of the nonsmohers. In ~\cral studies sperm morphology or motility L\;LS impaired in smokers compared with nonsmokers. but this was a less consistent findincg. Few studies have considered the spermatic chromosomal characteristics of smokers com- pared with nonsmokers. Nordenson. Abramsson. and Ducheh ( 1983) found smokers to have more chromosome breaks than nonsmokers. but Oldereid and couorkers ( I YXY) reported no difference5 in DNA condensation as assessed by flow cytometr\`. Although differences in mean values of any of these measurements suggest an effect of smoking. the most relevant parameter may be the percentage of smokers and nonsmokers who exhibit deficiencies in sperm densit). morpholog\,. or motility. Several researchers have investigated the relative risk ofa/oospermia (no sperm in the ejaculate) or oligospermia (reduced number of sperm) in smokers versus nonsmokers or never smokers (Table 17). Although the ranpe of relative rishs is uide. there is a clear pattern of increased risk among smokers. However. the clinical significance ot oligospermia is uncertain. Most studies have used one cjvculate per man. although the within-man coefficient of variation can be a\ much a\ 60 percent (Schenker et al. 1 YXX ). The available information suggests that current smohins is related to IOU sperm density. However. these data are limited. Many studies investigated men visiting infertility clinics. limiting generalization. Moreover. if male makers with poor sperm quality are most likely to attend these clinics. selection biases may distort the results. Also. many of these studies were relatively informal. Few of the studies accounted for potentially confounding factors such as alcohol use and age. Less than half of the studies documented that a period of sexual abstinence was required for subjects before giving the sperm sample, and few of the studies anstyLed multiple semen specimens as some authorities recommend (Zaneveld and Jeyendran 1988). Most studies have a small number of subjects. and their statistical pouer is limited for this reason. In come of the studies. it is not clear whether former smokers u'ere included in the smoker or nonsmoker group. A few studies investigated ex-smokers (Table IX). One M;IS a case-control stud!, of male infertility in Italy (Buiatti et al. 1984). The cases were a/.oospermic or oiigosper- mic men being treated for infertility at the University of Florence. Controls were University outpatients who had normal sperm counts. There were no significant differences between smoking categories in the percentage of men with Iov. sperm counts. Vogt. Heller. and Borelli (1986) e\,aluated 139 male volunteers. Among former smokers (those who had smoked for at least I year and those who had stopped smoking for at least 1 year). percent normal spermatozoa. percent young forms. percent old forms. and percent degenerate forms were comparable with those of never smokers. Stekhun ( 1980) reported that 42 percent of former smokers had oligospermia compared with I8 percent of never smokers. Schirren and Gel ( 1969) reported that three men with low sperm density and motility showed substantial increases in these parameters 3 to 6 months after smoking cessation. However. there w'erc no control\ defined in this analysis. Because of the limitations of the four studies. no conclusions are possible regarding the effects of smoking cessation on sperm quality in humans. Animal studies have not been particularly informative. In some studies. rodent\ that were heavily exposed to nicotine or cigarette smoke demonstrated testicular atroph!,. but this has not been a general finding (Larson. Haag. Silvette I96 I ; Larson and Silycttc IY6X: Dontenuill et al. lY73b: Essenbq. Fagan. Maler\tein lY.5 I: Thienes IYhO: TABLE 16.-Sperm quality among smokers and nonsmokers Vtcfian I IYhXa, Vogel. Broverman. Klather I IY7YI Nebe and Schlrren I 19x0) Evatx er al (1981) Spira et 31. (I')XI) Rodrtguw-Rteau. Smith. Stetnkryzr (19x7) Andrr\ett. Semcuh Tahor ( I 0X-l I Handel\man et 31. (IYXI) Kulihaukt\. Blaustem. Ahlin i 1985) Rantala and Kokimie\ (10X7) Vogt. Heller. Borellt lnlerttltt! clmtc (71175 1 Volttntwr~ 1 `O/2 I Inferttltt\ cltmc (Xhili7, Semen donor\ (7 I12 3 / Frrttltt) clmic (1351107, Volunteer\ 0.x7 O.ho" I .Ol (1.75" 0.X6 O.Y5 O.Y3 O.YY 0 67 0.43" (I.40 0.x IJ 1).40 lS O.Y7" 0.Y-t O.YJ 0.') I" I (WI 0 h4" I .07 0 YX I .ot) 0.0x I .Ol I) 77 0.x7" O.Y.7~' O.Y)i I .(Hl O.h7" LOX 0.03" 0.7x" O.Y5 0,YY Smohrr\ and non\moLrr~ marched on qxm den\tl) OItgoqwrmtc* men omttted ( may depend on the duration and dose ofexpo~re. a\ well :I\ on the age\ at u hich exposure take\ place. Morco\,er. the relevance to humal> of the large don\ yi\cn to the animals k uncc`rtain. None ofthehe investigation\ considcrcd \pt'rmatogenc\is at'ter exposure ended: thu4. feu conclusion\ may he draun rt,` ~vrding the t'i'fcct of ct's\ation ofcspo~re even within the limitation\ of lhe animal \Iuclie\. TABLE 17.~-Estimated relative risk of azoospermia or oligospermia among smokers versus nonsmokers or never smokers Reference Study population tnumher of non\moher\, number of \moher\) Contra\t Estimated relattve rthk tn \moher\ Comments Schirren and Ge) Andrology clmlc (IYhYl lsxo/ll77l Campbell and Fertility clmic Harrlwn t I Y7Y I (I 19/13-i, Stehhun Uot stated (?3/1051 I IYXII) Rodrtg~r/-Rtyu. Frrtilitk cllnlc Smith. Stetnherger t 101/5X1 I lYX21 Buwtl et 31. Fertillt\ cltmc (14X-I) ,xo;l.G~ Andrr\en. Srmc/uh. T`lhor~ IYX1, ,Ahiln 1 IQXh) l'og. Heller. B~Wlll (14X6) FenlIlt> clonic lX61l-l7) uot \tatwi 1 I .7S/`2iX, Volunteer\ 1.53150, A/oo\permta: \moher\ v\. nonhmohrrs Oligoywmia: \mohen \ `1. non\mohers Ollgo\permta: current \mohrr\ ~5. nexer \mokrr\ OItgo\permta: I<20 x IOh/mLI: current smokers VI. non\mohrr\ Oligoyxrmta (tac)clm formation in human endocxdium 111 \,itr-o. (;c,/rc,c.ci/ /`/ttr~-~~wc o/oy) 170 ):-II I -- 113. 19X6. ALWACHI. S.N.. AL-KOBAISI. M.F.. MAHMOUD. F..1.. Z.AHlD. %.R. Po\\~hlc &`t'cct (It nicotme on the cpermatogene& and wticular activit! of the mature m;tlc ;tlhinc) m~cc. .lof/rnu/ of`Ri/h~ic~o/ S(,iC'f7C c Ke.\eor-(~/r I7(.? 1: I x5- I Y-t. I YX6. ANDERSEh'. A.N.. SEMCZLIK. M.. TABOR. A. Prolacttn and pituita~!-~oliatial ~UIKIIOII 111 cigarette wiokinp infertile patients. .fi\,rcl/-o/,~:iri I h(5 ):iY I -3Y6. I YX4. ANDERSEN. F.S.. TRANSBOL. 1.. CHRISTIANSEN. C. I\ cigarette zmohlnf ;I PI-omotcr 01 the menopau4 Am Mrdiur SC trmliutr~~ic 0 Z 11: I .37-I ?Y. I YX2. ANDERSON. G.D.. BLIDNER. I.N.. MCCLEMONT. 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Modem assessment of semen for diagnostic pur- poses. .Samirzar..r i/r Reprochrc~ri~~e E,~rloc,r.i/lo/o~~ 6(4):123-336. 198X. CHAPTER 9 SMOKING, SMOKING CESSATION, AND OTHER NONMALIGNANT DISEASES CONTENTS Part 1. Peptic Ulcer Disease. .............................. .I Introduction ............................................ Impact of Smoking and Smoking Cessation on Ulcer Occurrence . . Smoking and Gastrointestinal Physiology ................... Trends in Peptic Ulcer Disease ........................... Morbidity From Peptic Ulcers ........................... Mortality From Peptic Ulcers ............................ Effects of Smoking on Ulcer Healing and Recurrence ........... Healing of Duodenal Ulcers ............................. RecurrenceofDuodenalUlcers ........................... Healing of Gastric Ulcers ............................... Recurrence of Gastric Ulcers ............................. Summary ............................................... Part II. Osteoporosis and Skin Wrinkling .................... .~I. Osteoporosis.. .......................................... Introduction .......................................... Pathophysiologic Framework ............................ Bone Mineral Content in Smokers Compared With Nonsmokers Smoking as a Risk Factor for Osteoporotic Fractures .......... Smoking Cessation and Osteoporosis and Fracture ........... Summary ............................................ SkinWrinkling.. ........................................ Introduction .......................................... Pathophysiologic Framework ............................ Smoking and Skin Wrinkling ............................ Smoking Cessation and Skin Wrinkling .................... Summary ............................................ Conclusions .............................................. References ............................................... ........ 429 ........ 429 ........ 319 ........ 429 ........ 430 ........ 431 ........ 432 ........ 331 ........ 331 ........ 433 ........ 440 ........ 440 ........ 441 ........ 433 ........ 443 ........ 443 ........ 443 ........ 444 ........ 449 ........ 453 ........ 453 ........ 453 ........ 453 ........ 453 ........ 455 ........ 456 ........ 457 ........ 457 . . . . . 459 327 PART I. PEPTIC ULCER DISEASE Introduction Numerous studies have demonstrated the association between smoking and the occurrence of peptic ulcer disease. This association was noted in the 1964. 197 I. and 1972 Surgeon General's Reports (US PHS 1964: US DHEW I97 I. 1972). The 1979 Report stated that the evidence of an association between cigarette smoking and peptic ulcer was strong enough to suggest a causal relationship (US DHEW 1979). That Report concluded that cigarette smoking was associated with the incidence of peptic ulcer disease and with increased risk of dying from peptic ulcer disease: the evidence that smoking retards healing of peptic ulcers was regarded as highly suggestive. The 1989 Report (US DHHS 1989) stated that smoking cessation may reduce peptic ulcer incidence and is an important component of peptic ulcer treatment. even with the effective drug therapy presently available. This Section focuses on smoking cessation and the occurrence and course of peptic ulcer disease. Impact of Smoking and Smoking Cessation on Ulcer Occurrence Smoking and Gastrointestinal Physiology Kikendall. Evaul, and Johnson (1984) reviewed the effect of cigarette smoking on aspects of gastrointestinal physiology relevant to peptic ulcer disease. The literature available at the time of their review supported the following concepts. Chronic cigarette smokers have higher maximal acid output than nonsmokers. Smoking I cigarette or more has no consistent immediate effect on acid secretion. Smoking 1 cigarette immediately decreases alkaline pancreatic secretion and immediately results in a pronounced fall in duodenal bulb pH, especially in subjects with gastric acid hyper- secretion. Smoking has a variable effect on gastric emptying, depending on experimen- tal design. Smoking increases duodenogastric reflux. Smoking decreases gastric mucosal blood flow. Smoking during waking hours inhibits the antisecretory effects of a nocturnal dose of cimetidine, ranitidine. or poldine. Subsequent to this review, the two latter concepts have been seriously challenged. Robert, Leung. and Guth ( 1986) found that neither nicotine nor smoking inhibited basal gastric mucosal blood flow in rats. Several investigators could not confirm that smoking antagonized the antisecretory effect of cimetidine or ranitidine (Deakin. Ramage, Williams 1988: Bianchi Porro et al. 1983: Bauerfeind et al. 1987). However, several of the findings from this earlier review (Kikendall, Evaul, Johnson 1984) have been confirmed by more recent reports. Parente and associates (1985) confirmed higher pentagastrin-stimulated acid secretion among chronic heavy smokers than among nonsmokers. Smokers also had higher basal serum pepsinogen-I levels. These differences were statistically significant and large enough to be of clinical importance. Higher maximal gastric acid secretory rates among smokers compared v. ith non\mohers were al\o demonstrated by Whitfield and Hobsley ( 19X5) in a study of 201 patient\ M ith duodenal ulcer. Additionall). Mueller-Lissner ( 1986) noted that chronic smokers M.ho abstained from smohing for I2 hours had more duodenopastric bile retlux than nonsmoher\ and confirmed that smoking cigarettes acutely augments the already elevated rate of bile reflux. Quimby and coworkers (1986) reported that active smoking transiently decreased gastric mucosal prostaglandin synthesis. In summary. the known effects of smoking on gastroduodenal physiology provide multiple potential mechanisms for enhancement of an ulcerdiathesis by active smoking. Several of the effects of smoking, most notably the inhibition of alkaline pancreatic secretion. the reduction of duodenal bulb pH, and the reduction of prostaglandin synthesis. are transient effects that could be reversed quickly by abstinence from smoking. Trends in Peptic Ulcer Disease During the past several decades. the rates of hospitalization for and mortality from peptic ulcer disease in the United States have declined dramatically (Kurataet al. 19X3). Although changes in coding practices and/ordiagnostic procedures could explain some of the decline, the trends in mortality from peptic ulcer have paralleled the decreasing prevalence of smoking. Kurata and coworkers (1986) studied trends in ulcer mortality and smoking in the United States between 1920 and 1980 and estimated that the portion of duodenal-ulcer-related mortality attributable to smoking was between 33 and 63 percent for men and 25 and 50 percent for women. In contrast, Sonnenberg ( 1986) concluded that smoking was not the main determinant of the birth cohort phenomenon of declining peptic ulcer mortality in the United Kingdom. This study descriptively compared the death rates for duodenal and gastric ulcer with the annual cigarette consumption in the United Kingdom according to birth cohorts and found a lack of correlation between ulcer mortality and cigarette consumption (Sonnenberg 1986). Thu\, factors in addition to cigarette smoking may also underlie the recent trends in these indicators of peptic ulcer disease. Two factors that have receivedconsiderable attention in recent years are Hc~lic~ohtrc~tcr~ py/orV gastritis (Graham 1989) and the use of nonsteroidal anti-inflammatory drugs (Griffin. Ray. Schaffner 1988). Martin and associates ( 1989). in an endoscopic stud). found that smoking was a risk factor for peptic ulcer disease among patient\ who had Hc~lic~ohut~er plori gastritis. Willoughby and colleagues ( 1986) found that smoking Was associated wnith peptic ulcer disease among subjects with rheumatoid arthritis. most of whom were taking nonsteroidal anti-inflammatory drugs. Ehsanullah and colleagues ( 1988) and Yeomans and associates ( 1988) also showed an association of smoking with the acute gastric erosions and submucosal hemorrhages induced by these drugs. The\e studies demonstrated that smoking is associated with ulcer disease related to both Helic~ohut~fer./~~/or.i and nonsteroidal anti-inflammatory drugs. 430 Morbidity From Peptic Ulcers In an analysis of prospective cohort data on ulcer incidence in women from the National Health and Nutrition Examination Survey 1 Epidemiologic Follouup Study. the relative risk for developing peptic ulcer was I.3 amon? former smoherc (Y5-percent confidence interval (Cl). 0.7-3.`)) and I.9 among current smoher\ (c)5-percent Cl. 1.2-2.6) compared with lifetime nonsmokers (Anda et al. 1990). In this study. former smokers were defined as persons who had smoked at least IO0 cigarettes in their lifetime but who were not smohing at the time of the baseline interview. The mean length of followup in this cohort was Y years. This analysis used the Cox proportional haLards model to adjust for the potential confoundin effects of age. sex. socioeconomic status. regular aspirin use. alcohol intake. and coffee consumption. Ainley and associates (19X6) surveyed the smoking behavior of I.217 patients undergoing endoscopy. This study did not include "normal" or community controls as all patients had indications for endoscopy. Of the smokers. I I.Y percent had gastric ulcers. a diagnosis shared by 7.7 percent of ex-smohers (pXO% in buth mef~ mtl women: confounding controlled hy marching c" .J TABLE S.--Continued Kt?tNHICC Ahl Kl ill. (IYXX) Picard ct al. (IYXX) Bilhrry. Wcix. Kaplan ( I YXX 1 Slcnlelllh t'l ill. (IYXY) HM hq DPA of ternoral nech, Ward\ trtanglc. trochanterlc regwn ;md 7nd4th lumbar vcrtehrur HM hy SPA ut'did and mdratliu\. DPA of lumbar \pine Fintlmg\ Smoking wa a\soci;tted with Iowcr BM in the rxiiu\ tpI0 tip/day for 3 yr vs. leaz, 4.2" h No control for conlountlerx no \tati\ticsl anslyv\ Caw\: 105 men aged J-l-X3 with vertebral fracture\ Controls: I OS men aged I-LX3 with Paget'\ diebe matched for ape and length of ti~llowup Nonohee. nondrinking. nonsmokers vs. non&x. nondrinking smokers with no underlying chv.3~: aged I ppd v\. never I.27 I.?`) 6.Sh 13.Sh S.4h I .o I.2 Adjusted for ape. Quetelet's Index, months breast feeding. ovariectomy, and estrogen use Smokers and nonsmokers were not directly compared; the comparison group for all analyses was obese nonsmokers who had used estrogen for 2 I yr; controlled for hex and race only TABLE 6.--Continued Hip and/or fwxrm frnctutw Kcfcrence Population (`ompariwn E\tlmated relative rl\i\ Smohcr\ v\. nonmoher\ I.3 large samples from the Framingham Heart Study, the Nurses Health Study, and the first National Health and Nutrition Examination Survey. In the largest study by Hemenway and colleagues (1988) 96,508 nurses reported 975 hip or forearm fractures during an average 4 years of observation. The relative risk of fracture was 1 .O in each smoking category (former smokers, smokers of I-14 cigarettes/day, 15-25 cigarettes/day. and >25 cigarettes/day) compared with never smokers. Smoking Cessation and Osteoporosis and Fracture No studies have evaluated the effect of smoking cessation on osteoporosis and fracture, nor are there studies of the risk of osteoporosis or fracture in former smokers compared with continuing smokers. Summary There is insufficient evidence to conclude that smoking decreases bone mineral content and the risk of osteoporotic fractures. Some studies have found lower bone mineral content in smokers compared with nonsmokers, but others have not. Some. but not all, case-control studies have found a higher risk of osteoporotic fracture among smokers. Most negative studies were limited by small sample size, and most positive studies were not designed to control for potentially strong confounding variables. Analysis of data in five cohort studies has found no association of smoking with increased risk of fracture. Skin Wrinkling Introduction Although wrinkling of the facial skin is nearly universal among elderly persons, it is rarely mentioned in textbooks of dermatology or medicine, and little research has been published concerning its etiology or risk factors. Skin wrinkling is associated with sun exposure (Kligman 1969; Allen, Johnson, Diamond 1973; Daniel1 197 1; Knox. Cockerell, Freeman 1962; Rook, Wilkinson, Ebling 1979). Wrinkling occurs with increasing age (Daniel1 1971; Knox, Cockerell, Freeman 1962: Rook, Wilkinson. Ebling 1979), but even among the elderly, wrinkling usually is confined to sun-exposed areas (Kligman 1969; Allen, Johnson, Diamond 1973; Knox, Cockerell. Freeman 1962). There is limited evidence that dramatic weight loss is associated with skin wrinkling (Daniel1 1971). Pathophysiologic Framework It is not clear how cigarette smoking may promote skin wrinkling. Some investigators have concluded that a localized finding such as wrinkling of the face and hands could not be caused by a systemic factor such as the absorbed components of cigarette smoke. TABLE 7.--Summary of cohort studies of smoking and fractures Keference JeflV31 (14X6) Populatlon/out~on~~ Population-bawd study of 70-year-old women in Copenhrigen. Denmarh: 77 smohed daily for 220 yr: 103 never \mohed 0utc0111r: all fractures Hemenway et al. (IYXX) 0630X nurwb aged 35-50 31 hahellnc ( IYXO) followed fur 4 yr. Outcome: self-report of Y7S fracture\ of hip or fwxrm Felson et al (IYXX) Holbrook. Barrett-Connor. Wingard (IYXX) Farmer et al. (19X0) 52OY men and women m the Framingham Heart Study followed retrr)qxxtively for about 30 yr. Outcome. ? I7 documented hip fracture5 Y7S men and women aped S(b7Y at haaeline followed for I4 yr, Outcome: 33 documented hip fractures 3,595 white women in NHANES-I aped 4&77 at baseline ( lY71-75) followed fur an uvernge of IO yr, Outcome: X4 documcntrd hip fractuw Comparison `% smoker\ with fracture vs. % nonsmokrr~ with fracture: All po\tmenopauwl fractures O~troporot~c frscturesh Age-adjusted fracture rate compared to: never smoher\ Ex-smokrrx Smokers I I4 tip/day IS-24 c@day 23 cig/d/dny Bawd on ciglday Smohrrs vs. nonsmoker\ I.1 Bawd on number of yr smoked at huwlinr exam Relative risk Comments All wbject\ were 70.yr-old women: no control for other confounders I .o I .o I .o I .o No incrrase No mcreasr A very large cohort study producing narrow Cl3 (upper hmn I .2.5). hut most women were mlddlr-aged or younger; controlled for age only Cox re@re%ion model. adJusted for age. wx. body ma\\ Index, dietary calcium. and alwhol conwmptwn No data given. hut reported no significant 35wiation: ilnaly~a adJusted for age. body muss Index. menopausal Qtuh. citlcium conwmption. and activity However. facial skin, and to a lesser extent, the skin of the hands contain an intradermal elastic tissue mesh that is denser and more complex than in other areas (Shelley and Wood 1974). Thus. the toxic effect of both sunlight and smoking may be most damaging in these more susceptible areas. Alternatively. damage from sunlight and smoking may simply be additive. and the threshold for clinically apparent changes from smoking may not be reached in sun-protected areas of the skin. Histopathologic examination of sun-exposed skin commonly shows abnormalities of collagen in the dermis that decrease the elastic properties of the skin. a condition known as elastosis (Marks 1976: Shelley and Wood 1974). However. the mechanism by which sunlight might cause these changes is uncertain, and there is no evidence that smoking is associated with elastosis. Cigarette smoking has been shown to decrease capillary and arteriolar blood flow in the skin acutely (Klemp. Staberg. Thomsen 1982: Reus et al. 1984: Richardson 1987). and hence. may cause tissue hypoxia. However. there is no evidence that this causes changes in skin transparency and turgor or produces wrinkles. Smoking and Skin Wrinkling Several studies have reported that smoking is associated with prominent skin wrin- kling, particularly in the periorbital or "crow's foot" area of the face. lppen and Ippen (1965) defined "cigarette skin" as appearing pale. grayish. and wrinkled. especially on the cheeks. with thick skin between the wrinkles. In an examination of women aged 35 to 84.66 of the 84 .;mokers had cigarette skin compared with 27 of the 140 nonsmokers (relative risk=4. I. pltr.,ia/ oJ`Gtrsrr.oerlre,.~~/~J,~~ (Supplement X3):6 l-68. 1983. CONSENSUS CONFERENCE. Osteoporosis. .lorw/7c~/ of/he Anler-iwn Mrdir u/ Assoc~iutior7 252(6):799-X02. Augubt IO. 19X-t. COOPER. C.. BARKER. D.J.P.. WICKHAM. C. Physical activity, muscle stren_eth. and calcium intake in fracture of the proximal femur in Britain. Bri/i.sh Mdicd Jo7o~nul 297:1443-1446. December 3. 19Xx. CRAWFORD. F.E.. BACK. D.J.. L'EORME. M.. BRECKENRIDGE. A.M. 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January 1982. 468 CHAPTER 10 SMOKING CESSATION AND BODY WEIGHT CHANGE CONTENTS Introduction ..................................................... ..47 3 Amount of Weight Gain After Smoking Cessation and-Likelihood of Gaining Weight ....................................................... ..47 3 Causes of Postcessation Weight Gain ................................... 483 Food Intake ................................................... 4x4 Physical Activity .............................................. 486 Energy Expenditure ............................................... 487 Relationship Between Overweight and Adverse Medical and Psychosocial Outcomes .................................................... Change in Weight-Related Health Risks After Smoking Cessation ......... Strategies to Control Postcessation Weight Gain ....................... Behavioral Methods for Reducing Postcessation Weight Gain .......... Pharmacologic Methods for Reducing Postcessation Weight Gain ....... Conclusions .................................................... ... References ..................... ................................ 490 497 -500 500 502 SOS so7 INTRODUCTION Cigarette smoking is associated with decreased body weight. and many smokers report that a major reason they smoke is to reduce body weight (Grunberg 1986: Klespes et al. 1989; US DHHS 19gXa). However. as documented in this Chapter. the weight gain associated with smoking cessation is generally small and poses a minimal health risk. This Chapter is organized into six sections. Drawing from prospective investigations meeting specific criteria. the first section of this Chapter determines average weight gain following smoking cessation compared with continued smoking. assesses the percentage of continuing smokers and quitters gaining weight. and calculates the risk of gaining weight after smoking cessation versus continued smoking. The next section of this Chapter discusses the mechanisms responsible for weight gain after mohing cessation. The available literature is reviewed on dietary,. activity. and metabolic changes after smoking cessation The third section reviews the relationship between body weight and adverse medical and psychosocial outcomes. The fourth section examines whether weight-related health effects accompany weight gain in ex-smokers. The fifth section presents potential treatments for reducing postcessation weight gain. including pharmacologic (e.g.. nicotine polacrilex gum. phenylpropanolamine. and d-fenfluramine) and nonpharmacologic approaches. The sixth section presents con- clusions regarding smoking cessation and body weight change. AMOUNT OF WEIGHT GAIN AFTER SMOKING CESSATION AND LIKELIHOOD OF GAINING WEIGHT To evaluate postcessation weight gain and to determine the likelihood or relativ,e risk of gaining weight after smoking cessation, longitudinal investigations after 1970 of postcessation weight gain were examined. Only studies that included a control group of continuing smokers were evaluated. Requirements for studies in this review included a minimum followup period of 1 month and at least IO smokers who quit. Studies were excluded if a weight loss component or severe caloric restriction was part of the intervention or if an agent known to affect body weight (e.g., nicotine polacrilex gum) was used; however, placebo conditions within drug trials were considered. A few studies were excluded for methodologic or interpretive reasons, such as relapsed subjects included in data analysis along with quit subjects or whenever a weight change could not be calculated. Table I summarizes the IS studies that fulfilled the\e inclusionary and exclusionary criteria. The following information is included for each study listed in Table 1: the study reference, the followup or period of abstinence. the mean weight gain among in dividuals whoquit smoking, the mean weight gain of subjects whodid not quit smoking. the percentage of subjects quitting smoking who gained weight from baseline to the followup period, the percentage of nonabstinent subjects who gained weight during the same period, and the relative risk of gaining any weight after smoking cessation versus continued smoking. Adjusted averages of weight gain are provided to summarize across all studies. These adjusted averages control for differing sample sizes and assign 173 TAHIX I.--Summary of prospective studies on smoking and body weight 5 yr ! yr I qr I Yr h yr 6.3.5 7.5 5.15 I I.1 3.1X (1. I I .h (1.94 7.7 2.01 - 2.2 0.04 76.9 JO.3 I.66 7.3 x7.0 60.7 I .a3 0.r) - 0.3 0.9 - - 7x.0 Sh.0 I ..I9 0.44 - - 2.4 X0.6 61.7 1.31 TABLE I.--Continued Krference Sample Number of \i7c quitters Quit period Mean weight % continuing Relative ri\h gain (lb) `2 quitter\ who gain \moher\ who of gaining Qumer\ Continuing \moher5 weight gain weight weight Puddry et al. (IYXS) zx Kabhin ( lYX4h) 107 Kotlin 42 (lYX7) Scltfrr (l'J73) 31X Tuomilehto et al. ( IYX6) 3Yh I..( mn 3 mo I .5 mo 5 yr s yr 2.Y7 4.4 3.1x 7.`) 6.02 Median l'ollowup period=7 yr Avcragc ~elght gain among quitter\=l.h: N=J.h47 0.44 0.7 0.70 5X.3 33.3 I .75 33 I .57 Avcragc wclght gain among continumg w~oker\=O.X: N= 15.046 Averq!e Average Average `I$ of quitter\ % ot cclntirlulng relntive rlah uho gain \mcrher\ who olgaming wcighk7Y";: gain \cright=Wk: weight= I.451 Numhcr ot Numhcrot Numher ot \tudie\ reportlng=5: dud~c\ \tudie\ N=714 reporting=5: rcpwmg=S: N=l,l I3 N= I.77 more weight to large versus small samples. Table 2 provides more detailed information (e.9.. Y-percent confidence intervals for weight gain and relative risk) regarding each of these investigation<. As indicated in Tables I and 2. the average sample sire of these investigations was I .34X (range=ZX-9.539). The followup period ranged from I month to 5 years. with a median followup period of 7 years. Consistent w'ith previous reviews of the smoking and body weight literature (Klesges et al. 19X9: US DHHS I9XXa). the adjusted average weight gain among smokers u ho quit was approximately 5 pounds (mean=4.6: range= I .&I I .2 pounds). The weight gain among smokers who quit was considerably greater than the adjusted average gain of 0.X pounds observed among subjects who continued to smoke (range=0 to +3.S pounds). Thus. although variability of wseight gain is quite marked (Tables I and 2). smoking cessation produces approximately a l-pound greater weight gain thail that associated with continued smoking. A commonly reported, but erroneous. estimate regarding postcessation weight gain is that one-third of smokers gain weight after smoking cessation. one-third maintain body weight. and one-third lose weight after cessation (US DHEW 1977). In the five investigations providing detailed information regarding changes in body weight. the actual percentage of quitters gaining weight appears to be much greater than previously estimated. Considering the results of all five studies and adjusting for sample size, 79 percent of those who quit smohing experienced a weight gain (range=%-87 percent). Over the same followup period, an adjusted average of 56 percent of continuing smokers experienced an increase in body weight (range=33-62 percent) and. as presented above. the average amount of weight gain was less among continuing smokers. Data allowing computation of a relative rish estimate of weight gain after smohing cessation w'ere available from five investigations. This relative risk estimate compares the likelihood of weight gain in quitters versus continuing smokers. That is. a higher relative risk ratio indicates that the percentage ofquitters who ssined wright was higher compared with that of corresponding continuing smokers. Overall. the risk of n,eight gain after cessation was 45 percent greater for quitters (mean=l.35. ranFe=I .3 l-l .7S) than for continuing smokers. This increased rish of weight gain was consistent across differing follow up periods. appearin, _ (7 as earlv as 6 weeks (Rodin 19X7: relative rish (RR)=I.75) and lasting up to 6 bears after smohinf cessation (hoppa and Bengtsson 19x0: RR=I 3 I ). Additionall) _ one investigation found the relative risk ofgaining more than 1 pounds after smohin, (7 cessation to he I .3X (Bosst!. Carve!. Costa 19X0). In another investigation. the rish of gaining more than IO pounds was XX percent higher for quitters than for continuin g smohers (RR= I .XX) (Friedman and Sieselaub 19X0). Although the rish of yining more than IO pounds appears to be almost 90 percent greater among quitter\ than con1lnuin, `7 smohcrs (Friedman and Siegelaub IYXO). actual occurrence of I ()-pound L\ eight fains uas reluti\el\ Iou (20.3 ~4. 10.X percent amonp quitters and conlinuin, `7 smohers. respccti\el\ 1. Frkman and Siegelaub (19x0). with a large sample of quitters (`1:=7.7.3X) xid continuin g smohers (N=6.X() I ). presented the percentage\ of those gaining 20 pounds or mow o\ t`r ;I median I X-month follow up. Among males. 3.7 percent of those i\ ho quit smohin, 17 gained more than 20 pounds compared 14 ith 0.9 percent of those u ho continued to smohe. Amon females, 3. I `I'AHLE: 2.--Continued Kclallvc IWh ol ~;IIIlIn~ >I0 Ih=I.XX `)5'/; (`I ( t .70-1.0X) TABLE 2.--Continued TABLE 2.--Continued Quit period Average gain +SD (lb) Re\ult\ Rwl~n t tYX7) Sctl/er t lY7-t) Quitters: 3.1+3.Y (?.I-S.7) Males: S.Y+4. I (3.X-X. I ) Fcmalrs: 3.2f3.0 (2.04.h) Continuing >mohera: 0.753.7 (60.2-1.5) M&x 7 `+3 1 A.___. (O.Y-3.5) Femalw 4.4k3.0 t-1.34).4) Quitters: 3. IX (`ontinumg smohrrs: 0.30 Quitters: 7.Y No chance or Io\t 41.7'/;(10) 66.7% ( I?) ucight=l.75 TABLE 2.-Continued percent of those who quit smoking gained more than 20 pounds compared with 1.6 percent of those who continued to smoke. In summary. while approximately four-fifths of smokers who quit will gain weight after cessation. average weight gain is approximately 4 pounds greater than that expected among continuing smokers. The risk of weight gain after cessation is 45 percent greater than the risk associated with continued smoking. although individual weight gains of 20 pounds or more are rare. Although weight gain is common after cessation. little is known concerning the types of individuals at risk for substantial increases in body weight. Researchers have concluded that women. moderate smokers. and older smokers have the greatest weight control effect from smoking (US DHHS 1988a). although the tremendous variability in body weight changes after cessation has yet to be explained. That is. while the average weight gain after smoking cessation is approximately 5 pounds. individual responses range from weight loss to a weight gain exceeding 20 pounds. Studies are needed that focus carefully on individuals at risk of excessive weight gain after smoking cessation and the differences between these individuals and those who do not gain weight. Additionally. investigators hypothesize that the relationship between smoking and body weight is attenuated by other health behaviors (Marti et al. 1989). Although the effects of smoking to reduce body weight are acknowledged, individuals who smoke are more likely than nonsmokers to have unhealthy lifestyles associated with increased body weight (e.g.. lower levelsof physical activity and higher dietary intakes)(Klesges. Eck et al. 1990: Chapter I I ). CAUSES OF POSTCESSATION WEIGHT GAIN Cross-sectional and longitudinal studies clearly indicate the inverse relationship between smoking and body weight in humans and between nicotine and body weight in animals (Grunberg 1986: Klesges et al. 1989: US DHHS 1988a: Winders and Grunberg 1989). However, no study has included a simultaneous evaluation of the long-term changes in all of the variables that may account for this relationship. including food intake. physical activity. and energy expenditure. Of the currently published investigations, the longest followup period evaluating all three aspects of the energy balance equation has been 8 weeks (Stamford et al. 1986). A recent study evaluated food intake and physical activity changes over a 26-week followup but did not include metabolic measures (Hall et al. 1989). Short-term evaluations do not allow for an adequate determination of predictors of weight gain. This review focuses on those studies that have directly evaluated either food intake, physical activity, and/or meta- bolic rate as a function of smoking cessation. nicotine administration. or nicotine deprivation. The available data on changes in the energy balance equation that result from smoking cessation are summarized below. Food Intake Most short-term evaluations (e.g.. 3 days or less) found that food intake, particularly the consumption of sweet foods and simple carbohydrates, increases after smoking cessation. For example in a I -day experiment. Grunberg ( 1982a) reported that smokers who were allowed to smoke ate fewer sweet foods, but consumed similar amounts of non-sweet foods. compared with nonsmokers and smokers not allowed to smoke. This between-subjects laboratory study was short term and did not measure body weight changes. In another short-term study. Hatsukami and colleagues (1984) hospitalized 27 smokers for 7 days. After a 3-day baseline, 20 of the subjects were deprived of smoking for 4 days while the remaining 7 served as a control group. During this 4-day abstinence. caloric intake increased significantly in the abstinence group and was accompanied by a I .76-pound increase in weight compared with baseline. Recently, Duffy and Hall ( 1988) assessed smokers who differed in degree of eating disinhibition. defined as eating that occurs in situations in which self-control behaviors are disrupted (e.g.. binge eating). Smokers who were allowed to smoke before eating ice cream did not show food consumption differences as a function of level of disinhibition. How- ever, results for smokers who had abstained from smoking for 24 hours showed a different pattern. Abstaining smokers who scored high on eating disinhibition ate more than three times (273.6 g) as much ice cream as those who scored low (86.4 g) on eating disinhibition. The results from this investigation indicate that dietary changes follow- ing smoking cessation may vary as a function of dieting history. use of cigarettes to curb appetite. and other wei_pht history variables. Some prospective investigations have qualitatively ashed participants who quit smoking if they believed that their dietary intake had changed. These studies also reported that food intake increases after cessation. For example. Manley and Boland (19X3) examined the side effects experienced by 94 subjects quitting smoking and whether these side effects varied as a function of relapse. On a withdrawal rating system. those whoquit smoking rated themselvesas furthest from"optimal"at followup on general appetite and overeating. On a separate rating scale. abstainers also ga1.e higher ratings than relapsers at followupon "eating more." In astudy of 53 self-quitters. Black and coworker\ ( IYXX) found that of those reporting that they ate more. average weight gain uas 6.9 pounds. In contrast. of those reporting that they ate the same or less. average Mcifht gain ua'r I .-I pounds. Unfortunately. there are few prospective human investigations that have attempted to quantify carefully food intahe changes over time among subjects after quitting smohing. The\e 5tudies penerally indicate that food intahe increases after cessation; however, result\ v'ary greatly across investigation\. Of eight studies to date. t&o reported clear increases in food consumption after cessation (Leischow and Stitzer IYXY: Stamford et al. 19X6). four provided qualified support for increased food consumption after cessation (Hall et al. 1989: Kles,_ges et al.. in press: Perkins. Epstein. Pastor I YYO: Rodin 19x7). and tv+ o reported no changes in food intake after cessation (Dallosso and James 19x3: DiLorenTo et al. 1988). In what may be the most comprehensive evaluation to date of change in energry balance. Stamford and colleagues ( 1986) analy.zed changes in food intake. physical activity, and resting metabolic rate in 13 sedentary females who quit smoking for 48 days. Mean daily food intake increased by 177 kcal and explained 69 percent of the variance in changes in weight (3.85 pounds). No changes in physical activ,ity or resting metabolic rate were observed. To evaluate dietary changes after cessation. Leischow and Stitzer ( 1989) assigned subjects, in an inpatient setting, to either smoke-ad-libidum (N=6) or quit-smoking (N=9) conditions for at least I4 days after a 4-day baseline period. Results revealed a significant difference in weight gain (pI40 Total dtxiths MA I .2s I .os I .oo I.15 I 27 I .4b I .x7 F~lll~k 1.1') 0.Yc-J I .oo 1.17 I .2Y I .Jh I .XY CIiD 420 Male o.xx O.YO I .oo I .73 1.32 I .ss I .YS Femalr I .o I 0.x9 I .oo I .2i LAY I.54 1.07 CXKW. I4tk20.5 Mdr I .33 I.13 I .oo I .07 I .OY I.13 I ..11 011 \ite\ Frm:ilr 0.96 0.02 I .oo I.10 I I 0 I .23 I.55 Diabetes 260 Male o.xx 0.x4 I .oo I .hS 2.X-l 3,s I S.IY Female O.hS O.hl I .oo I .Y2 3.3-l 2.7x 7.00 Dlgative S4ObS42 Male I.3Y 1.2x I .oo I .-Is .XX 7.X') 3.w tliw~w~ 570-57x 5X4-5X6 Femalr 1.5X O.Y2 I .lK) I .hh h I 7.1s 7.3 C`errhrovawulnr 330-3.34 Mb I.21 I .OY I .oo I.15 .I7 I .SJ 1.17 diwaw F~lll~k 1.33 O.YX I .oo I .OY I.10 1.40 I.52 Nol`E. (`llD=co~ w.q he;w d,\~il\~! "C`;il~ul.~trd hy ~hvdin~ a t"r\,m`\ .~ctuid wc,gt,t hy the ~orrc\,,w,d,n~ ;,vcr.,g' welghl t,,r Ihc .~,,,mqm.w wx-IIICII 01 thaghl-5.!r ;I~C ~"`L,,`. n~d~,t~t,cd II> 11Kl SOI XC'E: 1.w id (;artinkl ( lY7Y I. TABLE 4.-Mortality ratios for all ages combined according to smoking status in relation to those 90-1099'~ of average age Weight index" Never vwkd o.xx 20 cig/dny I .6X Other I.77 Ncvcr \n~kxi 1.10 x0 q/day I .YH Other I..53 0.75 I .40 1.01 o.xx 1.5') I.13 0.75 I.34 O.Y3 O.Y3 1.64 I.12 0.98 I .76 1.1s I .20 2.22 I .42 1.16 I .6Y 2.00 2.21 I.29 I .66 1.37 I .74 2.30 2.73 I .62 2.04 Coronq artery dwax (ICD 420) Never wwked t20 clg/day Other Never smohed X0 cig/duy Other 0.72 I .Oh 0.`) t O.Y3 t 3 I 1.54 0.66 0.76 I.13 1.33 0.90 0.93 ox 0.92 I .70 2.12 I.14 I.IX 0.96 t .66 1.12 I.10 2.20 I .xx I .04 I.81 1.1') I .2Y 3.4x I .44 1.24 2.1 I t 37 t .3Y 3.79 2.01 1.73 2.1 I 1.x4 I.86 4.74 2 .3 3 Cancer, at1 slteh ( ICD I-K-205) Malt' Fcmule Never mohrd 220 cydday Other Never welled 220 cigiday Other 0.60 2.07 I.20 0.x.5 t .4Y I.1 I 0.60 I.71 I .03 0.x5 t .x1 O.YX 0.66 I .43 I .YO O.Yh I.34 I .03 0.69 I .46 0.89 t .Oh t .x1 I .Oh 0.7Y t 5s t .05 I.th I.34 I.16 0.90 I.71 0.87 1.1') I .70 I.1 I 0.76 2.00 I .22 t .so I .4Y I.60 elevated premature mortality compared with maintaining a more stable weight ov'er time. In a study by Hamm. Shekelle. and Stamler ( IYXY). for example. CVD and cancer mortality and total mortality were compared among individuals who reported either having gained significant weight (N=l33). having remained at the same weight (N=l7X), or both having gained and lost significant weight (N=YX). Both gainers and cyclers had significantly elevated total mortality experience. relative risks of 1 .S and I .4. respectively. compared with individuals whose weights remained constant. Three recently published abstracts (Lissner et al. l9XY: Lissner. Collins et al. IYXX: Lissner. Odell et al. 19X8) have reported even Freater health risks of weight cycling. Using prospective data from the Multiple Risk Factor Intervention Trial (MRFIT) (Lissner. Collins et al. IYXX). two prospective studies from Goteborg. Sw,eden (Lissner et al. 1987). and the Framingham Study (Lissner. Odell et al. 19Xx). weight cycling vvas defined as the variability of vveights recorded at repeat examinations. Controlling for a variety of possible confounding variables, weight cycling was independently predic- tive of total premature mortality and CVD mortality. In the analyses based on MRFIT. premature mortality among men with the most variable weights was 36 to X9 percent higher than among men with the most stable weights. An additional issue to consider in the relationship between body weight and health is the distribution of body fat. Individuals differ in the location of stored adipose tissue. Research data show that individuals who store greater amounts of body fnt in the abdominal region rather than in the hips or limbs have elevated cardiovascular risk factors (Gillum 19X7; Selby. Friedman. Quesenberry l9XY ). CVD. and diabetes rates (Freedman and Rimm 19X9: Lapidus and Bengtsson 198X) as well as reproductive system cancers among women (Bjomtorp 198X ). Usually measured by the ratio of abdominal circumference to hip circumference or the ratio of trunk versus peripheral skinfolds. a central body fat distribution is positively correlated with absolute body weight. However. in several studies, the centrality of fat distribution has proven to be a much stronger predictor of disease than body weight. A landmark study in this area was conducted by Larsson and colleagues (1984) who reported on I3 years of followup for 792 Swedish men aged 54 years at the time of first observation. Outcome measures were stroke. ischemic heart disease. and all-cause mortality. None of these health outcomes was significantly related to measures of adiposity (body mass index weight/height', the sum of several skinfold measurements. and body circumferences). However. the ratio of waist to hip circumference (WHR) was significantly and positively related to all three measures of illness and death. The relevance of this finding for ex-smokers, as discussed below, is that smoking is positively related to WHR and that smoking cessation is associated with a reduced WHR (Shimokata. Muller. Andres 1989). Compared with pathophysiologic health risks, social and psychological pathologies associated with overweight are not as well established. This situation may reflect the relative absence of research in this area, but it may also indicate the absence of a strong relationship. Obesity is strongly disapproved of and discriminated against in this society (Allon 1973: Grunberg 19X2b; Wadden and Stunkard 19X5). Overweight individuals are falsely stereotyped as having a variety of undesirable characteristics. including self-indulgence, laziness. lack of self-control, and lack of intelligence. The perception in this culture of obesity as unattractive has been documented in various populations. For example Richardson (1971). in a study of IO- and I l-year- olds' perception of the likableness of children with a variety of handicaps. found that obese children were judged less attractive than were children with amputations and facial disfigurement or children confined to wheelchairs. Similar biased impressions have been documented among adults and among physicians and medical students (Allon 1973; Maddox and Liederman 1969). Canning and Mayer ( 1966) found that the prevalence of obese students in college was less than the prevalence of obese students in high school despite no difference in academic performance in high school or in college application rates. A survey of employers indicates that many profess not to hire obese individuals (Roe and Eickwort 1976). and at least one survey of business executives suggests an inverse association between obesity and salary (Indrrst~:\ We& 1974). In a survey of college students, Kallen and Doughty ( 19X4) found lower rates of reported dating in overweight subjects. although no less satisfaction with intimate relationships. Although it is obvious that many overweight individuals are dissatisfied with their personal appearance. desire to lose weight. and frequently make efforts to lose weight (Wadden et al. 19X9: Polivy, Gamer. Garfinkel 1986: Adams 19X0: Guggenheim. Poznanski. Kaufmann 1973: Dwyer. Feldman, Mayer 1975: Dwyer and Mayer 1970: Stewart and Brook 1983; Jeffery et al. 19X4), evidence for severe psychological or social impairment in all but the most severe cases of obesity is generally lacking. Moore. Stunkard. and Srole ( 1962), reporting data from the Midtown Manhattan Study. found higher scores on three measures of psychological disability in the obese compared with the nonobese. Data from the Rand Health Study and a Dutch population-based study indicated that obese individuals report that their weight imposes some restrictions on their everyday activities and causes them more pain and worry compared with the nonobese (Stew*art. Brook, Kane 19X0: Stewart and Brook 19X.1: Seidell et al. 19X6). However. Stewart and Brook ( 19X3) also reported that obese persons are less depressed than normal- woeight persons. a finding corroborated in a study of British citizens by Crisp and McGuiness ( 1976). These mixed and inconsistent findings from studies of obese adults also have characterized studies of obese children (Wadden et al. 1989: Wadden et al. 19X4). In extremely obese individuals presenting themselves for treatment (i.e.. those 75 percent or more overweight). higher levels of psychological disturbance have been reported (Halmi et al. 1980: Atkinson and Ringuette 1967). Even here. it has been questioned whether such pathology is greater than that oh\erved in normal-weight individuals pre\enting for medical or surgical procedures (Wise and Fernandez 1979: Swenson. Pearson. Osborne 1973). It has been su,, CToested that unwarranted concerns about vveight gain mav contribute to eating disorders such as anorexia and bulimia (Wooley and Wooley 19X-l). Data supportin, (7 this idea. however. are largely anecdotal (Wadden and Stunkard 19X5 ). Prospective studies on the effects of weight gain on psychosocial functioning have not yet been reported. Studies of psychological changes accompanying weight loss generally show positive effects. even when weight loss is modest and not well main- tained (Wing et al. 19X-t). Therefore. consistent with intuition. many people feel better about themselves when they lose weight. However. the extrapolation of these findings to weight gain lacks empirical support. In summary. although adverse psychological and social consequences of overweight have been much discussed in both lay and professional circles. \uch effect\ have not been well documented. Moreover. to the extent that associations have been reported. the direction of causation is unclear. More research in this area is warranted. particu- larly because the available research is not extensive and much of it is methodologically weak. At this time. data suggest that only the most extreme forms of obesity, the upper I or 2 percent of the weight distribution in this domain. pose significant hazards. However. it is important to emphasize that these conclusions reflect the lack of evidence for serious psychosocial problems resulting from modest weight pains. Nevertheless. many persons want to lose weight. many persons seek ways to lose height. and many persons feel better about themselves when they lose weight. CHANGE IIV WEIGHT-RELATED HEALTH RISKS AFTER SMOKING CESSATION As documented earlier in this Chapter. smoking cessation is associated with weight gain. An important question is the extent to which this weight gain might lead to elevations in blood pressure. cholesterol. glucose intolerance, or other factors that would offset the benefits of smoking cessation discussed in detail throughout this Report. Relatively few studies have specifically examined the effect of smoking cessation on weight-related health risks. Seven studies were reviewed for this Report. Gordon and coworkers ( 1975) reported changes over an I S-year period in weight and related risk characteristics among individuals in the Framingham Study. At entry into the study, 61 percent of men and 40 percent of women smoked cigarettes; at the I S-year followup. 37 percent of men and 3 I percent of women continued to smoke. Analyses of changes were restricted to men because of the small numbers of women who quit smoking in this sample. Male quitters were similar to those who continued to smoke in baseline characteristics except that the former group contained more diabetics. The authors interpret this finding as suggesting that ill health is an incentive to stop smoking. Short-term effects of smoking cessation, defined as the change between the last examination at which smoking was reported and the first examination at which nonsmoking was reported (I-year intervals). included a weight gain of 3.8 pounds. an increase in systolic blood pressure of I .6 mm Hg. and an increase in serum cholesterol of0.2 mg/dL. Continuing smokers had an average weight gain of 0.3 pound. increased systolic blood pressure of 0.7 mm Hp. and decreased serum cholesterol of 0.2 mgjdl. For the same time period, nonsmokers had an average weight gain of 0.5 pound. increased systolic blood pressure of 0.7 mm Hg, and increased serum cholesterol of 0.3 mg/dL. Differences among groups in blood pressure and cholesterol changes were not statistically significant. Long-term changes associated with smohing cessation were evaluated by comparing changes between the fourth and the tenth examination. a period of 11 years. among continuing smokers. nonsmokers. and individuals smoking at entry but not smoking from the fourth to the tenth examination. Trends in weight. blood pressure, serum cholesterol. and blood glucose did not differ significantly among these three groups. Schoenenberger (19x2) reported the relationship between smoking cessation and changes in body weight. blood pressure, and serum cholesterol over 3 years among men in the special intervention group in MRFIT. All men in the study were at high risk for heart disease and were being counseled throughout the study in smoking cessation and dietary changes to effect cholesterol reduction. When necessary. the men were also treated pharmacologically for elevated blood pressure. Results indicated significantly less weight loss in quitters (-0.6 pounds. i.e.. a gain of 0.6 pounds) compared with nonsmokers and continuing smokers (5.7 and 3.6 pounds, respectively), no differences in blood pressure change (-9.6, -8.7. and -9.4 mm Hg, respectively, for systolic blood pressure among men not on medication). and greater reductions in serum cholesterol among quitters (-I 3.4 mg/dL) than in the other two groups (-10.0 and -8. I mg/dL). The latter effect was interpreted as possibly reflecting a higher level of generalized motivation to reduce risk in the quitting group. In a S-year followup study of 2.383 persons with mild hypertension in eastern Finland, Tuomilehto and colleagues (1986) found that 26 percent of men and 35 percent of women who smoked at the time of the initial examination had quit. Among men, smoking cessation was associated with a 7.9-pound weight gain compared with 0.2- pound and 2.2~pound weight gains among nonsmokers and continuing smokers. respec- tively. Among women. weight loss after smoking cessation averaged 0.7 pound compared with gains of 0. I pound and 2.2 pounds among nonsmokers and continuing smokers, respectively. Smoking cessation was not associated with a significant in- crease in blood pressure or serum cholesterol compared with continuing smokers or nonsmokers. Mean arterial pressure fell by 5.0 and 13.1 mm Hg in male and female quitters. respectively. compared with decreases of 6.9 and 8.7 mm Hg among non- smokers and of 7.0 and 9.6 mm Hg among continuing smokers. Serum cholesterol fell between 0.63 and 0.66 mmol/L across the various subgroups. Two papers relating smoking cessation to weight-related risks have been published based on data from the Normative Aging Study. The first report examined change over 5 years among 2 14 continuing smokers and 103 quitters (Garvey. Bosse, Seltzer 1973). An average weight gain of 4.2 pounds. which was accompanied by a 3.6 mm Hg increase in diastolic blood pressure. was observed among quitters compared with continuing smokers. The second report examined the relationship between smoking and body fat distribution. both cross-sectionally and longitudinally between examina- tion visits scheduled 7 years apart (Shimokata, Muller. Andres 1989). Central body fat distribution. which poses increased health risks. as assessed by WHR was positively associated u ith making. Moreover. among smokers. daily cigarette consumption was positively associated with central adiposity. Smoking cessation was associated with increased body weight. However. despite the weight gain. the change in WHR among ex-smohers was small and. in hct, decreased slightly because hip circumference increased. Therefore. based on WHR data only. smoking rather than smoking cessation may pose a wjeight-related health risk. Stamford and coworkers ( 19X6) studied the short-tern1 effects of smoking cessation on lipoprotein fractions. Amon I3 women who successfully quit smoking for a period of 48 days, these investigators observed a weight increase of 4.9 pounds. This weight change was accompanied by a nonsignificant increase in total cholesterol of 9 mg/dL and a significant increase in HDL-C of 7 mg/dL. Over the subsequent year. these favorable HDL-C changes were maintained in three individuals continuing to abstain from smoking, but were lost in nine individuals who returned to smoking. One randomized trial of smoking cessation and weight-related health risks was located for this review. Rabkin (1984a) randomized I07 smokers to smoking cessation and 33 to continued smoking in a comparative study of smoking cessation strategies. A battery of physiologic measures was obtained at baseline and repeated 2 to 3 months following randomization. No differences were found in cessation rates among the different quitting strategies. Physiologic changes observed in the smoking cessation group as a whole (i.e., all those randomized) included a significant increase in weight (I .8 pounds) and skinfold thickness (6.6 mm) compared with the control group (0.4 pound and -7.0 mm). but no significant change in lipid profiles, fasting glucose, or blood pressure. Only 35 subjects in the cessation groups were successful in quitting smoking. Successful quitters gained significant amounts of weight compared with individuals who did not quit (4.4 vs. 0.7 pounds, respectively). Successful quitters also experienced significant increases in HDL-C compared with nonquitters (4.2 vs. 0.1 mg/dL). Changes in other weight-related risk factors did not differ among groups. The studies reviewed above are consistent in their findings. Individuals who quit smoking andgain weight appearto experience relatively small changes in health-related risk factors such as blood pressure. serum cholesterol, and blood glucose. Moreover. some of the potentially adverse effects of weight gain on health risks are mitigated by changes in lipid profiles and in body fat distribution in a direction predictive of improved health outcomes. It seems likely that only those smokers who have large weight gains after smoking cessation would experience important changes in weight- related risk factors. The characteristics of individuals most likely to gain harmfully large amounts of weight after smoking cessation merit additional investigation. Bosse, Garvey. and Costa (1980) have reported relevant findings from the Normative Aging Study. Over a S-year period these investigators found that factors most predictive of weight gain among recent quitters were younger age, leanness of body build. and greater amounts of smoking. The latter finding is confirmed by other studies (Blitzer. Rimm. Giefer 1977; Gordon et al. 1975). There are no data available on specific predictors of excessive weight gain among ex-smokers. Research on predictors of weight gain suggest that those persons most likely to gain weight after smoking cessation may be those who can best afford it because they are relatively lean. They also may be those who need smoking cessation most because they smoke the most. Quantitatively estimating the extent of health risk associated with weight gain after smoking cessation is a complex process. The health risks of obesity vary with age, the temporal patterning of weight changes. type of obesity, and other risk factors. Moreover, smoking cessation itself appears to have independent effects on some weight-related risk factors that may actually be beneficial. It has been estimated that the health risks posed by regular smoking double overall mortality rates compared with never smoking (US DHHS 1989). Moreover. as detailed elsewhere in this Report. there are clear health benefits associated with smoking cessation. The amount of excess body weight that would have to occur to offset the benefits of smoking cessation would have to be considerable. Yet. average weight gains after smoking cessation are only about 5 pounds. bringing most individuals to a weight level similar to that of their nonsmoking peers. As discussed in this Chapter. the proportion of ex-smokers who are likely to gain large amounts of weight (e.g.. more than 20 pounds) is small. Therefore. although some individuals may experience these large weight gains. the number of individuals likely to gain enough weight to offset the benefits of smoking cessation is negligible. Also, the likelihood of adverse psychoso- cial consequences because of small weight gain seems remote for most people. Although further research in this area is w)arranted. there is little reason to expect weight gain to pose a substantive medical or psychosocial hazard to the vast majority of smokers who are quitting. For those persons wsho do pain excessive amounts of weight after smoking cessation. the health benefits of cessation still exist. and weight control programs rather than smoking relapse should be implemented. In conclusion, the clear reduction in health risks that results from smoking cessation overshadows any health risks that may result from smoking cessation-induced body weight gain. STRATEGIES TO CONTROL POSTCESSATION WEIGHT CAIN Because weight gain after smoking cessation commonly occurs and because many people, particularly young women, report smoking to control weight gain (Klesges and Klesges I9XX: US DHHS 1990). strategies that successfully moderate postcessation weight gain ma) encourage weight-conscious smohers to attempt cessation and ma) facilitate the efforts of successful quitters to remain abstinent. Only a few controlled investigations have examined interventions for reducing wjeight gain after smoking cessation. Currcntl! existing behavioral and pharmacologic intervention\ are sum marized belo\ Behavioral Methods for Reducing Postcessation Weight Gain Smoking cessation programs that include a M eight control component have not successfull! increased \mohing cessation. In one study. 79 women Here randomly assigned to a 7-h eek smohing cc\sation program either u ith or u ithout @eight control information (Mermrlsrein 19x7 ). At po\ttreatmt'nt and at thllowup. there Mere no significant differences in \mohing ct`\\ation rate\ bet\rren the tuo groups. Participant\ in both groups gained Meight during treatment: ho\\tc\,er. the weight increase for the smohing-ce\~;ltic,n-plLi~-~\ei~ht-colitr~)l - c'roup ~3s \ignit'icantl) le\s than the increase for the \rnokin~-cc~~ati(~~i-~)~ll~ group ( I .f \ s. 2.4 pound\). Several \reight control \tratcgie\. as adjunct\ to smohing cessation. were evaluated b> Grinstead ( 19X I ). Fort>-fi\,e \ub.jects were randomly a\\ifned to ;I I-weeh smohing a\,er\ion pr+ram LI ith one of three height control intt'r\,cntions. No difference\ in smohing cc\sation rate\ wcrc observed. and there were no \\cight change differences among the group\. Suh,ject\ in all groups gained iheight during treatment. 500 In another smoking cessation stud). Bowen. Spring. and Fox (submitted for publica- tion) randomly a\\iged 3 I participant\ to either a high- or low -carbohydrate diet. Sub.jects in the high-carbohydrate group uere given specific dietary ad\,& encouraging the use of carbohydrates: they v,ere also given tQ,ptophan a\ a dietar! supplement. In the low-carhohydrutc proup. dietary advice focused on consumption of food\ IW in carbohydrate\. Each group attended four Z-hour meeting\ per Mech. Scs\ions for both group\ $tres\ed information about the effect\ of tobacco. self-m~tnalreni~lit \trategit'\. rapid smoking. and relapse prevention techniques. The rationale for this treatment approach i\ haed on a IYXZ report that smohing ce\\ation is accompanied by an increase in preference for \ueet-ta\ting high car- bohydrate food\ (Grunberg 1YXZa). Grunberg ( IYX6) suppe\ted that carbohydrate\ act through \erotonergic mechanism\ to attenuate L\ ithdraual. Tqtophan is thou@t to increase the production of \erotonin in the brain. At the end of treatment. I3 of 16 subjects (XI percent) in the high-carbohydrate group were abstinent (confirmed by CO assessments) compared with Y of 15 subject\ (60 percent) in the low-carb(~h~,dr~lte group. Thi\ difference M';I\ in the hypo;he\iLed direction but was not \tatisticall> sifniticant. Also consistent uith the hypothesis. nonab\tainers in the high-car- bohydrate group were smoking significantly fen,er cigarettes than nonabhtainers in the low-carbohydrate group. In both group\ sub.ject\ gined ueight after quitting smohing. No significant differences were observed between experimental group\ in the number of subject\ who gained weight or in the average amount of weight gain per subject. Ofthe three investigations that have evaluated the impact of a weight-control program on weight gain and cessation (Bowen. Spring. Fox. submitted for publication: Crin\tead I YX I : Mermelstein I YX7). none were successful in preventing weight gain and only one (Mermelstein IYX7) reported a significant between-groups difference in the amount of weight gain. None of the smoking-plus-weight-control programs were clearly succe\\- ful in significantly enhancing cessation rates. At least three investigations have indicated that individualscan stop smoking without significant w(eipht gain. However, these studies have been limited to subjects typicalI\ at h&h risk of CVD who participated in multicomponent CVD rich factor reduction trials. In ;1 study involving MRFIT participants at the upper 10 to IS percent on a measure of CVD risk. Schoenenberger (IY81) reported that continuing smokers had lost an average of4.6 pounds at a J-year followup. but that those who quit \mohin$ had gained less than 1 pound. All subjects participated in several treatmentc that focused on stopping smoking and improving diet. III a h-vex followup of these participants. quitters had gained4.7 pounds compared with a I .3-pound weight lo\4 among nonquit- ters overall (Gerace et al.. in press). However. weight gained after cessation varied as a function of baseline daily ciparette consumption. For those H ho had smohed 1 to IY cigarette\ per day. quitters averaged a O.S-pound weight gain compared uith ;I 2.1. pound weight loss among continuing smokers For those who had smoked 20 to 3Y cigarettes per day. quitters avetqed ;I -If-pound weight gain compared with ;I I .I- pound weight loss among continuing 5mohers. For those who had smohed more than 40 cigarettes per day. quitters averaged ;i 7.2.pound weight gain compared \rith a I .()-pound weight toss amoncg continuing smokers. Thus, weight gain after cmohiny cessation was positively related to daily cigarette consumption before quitting (Gerace et al.. in press). Hickey and Mulcahy (1973) reported on 124 male smokers who survived a myocar- dial infarction and participated in a lifestyle modification program. At I-year followup. these investigators found an average weight gain of I .6 pounds (change not significant) among the 60 individuals (4X percent) who quit smoking. Those individuals who continued to smoke averaged a small. but nonsignificant weight loss (0.8 pound). In a study of CVD risk factor assessment in Paris. Ducimetiere and colleagues (197X) randomly assigned 271 smokers to either a cessation-plus-diet advice group or a smoking cessation-only group. The two groups did not differ in weight at pretest, but at Z-year followup. subjects in the cessation-plus-diet group had significantly lower weights than subjects in the cessation-only group. However, the two groups did not differ in smoking cessation. and the large degree of attrition in the cessation-plus-diet group must be noted when evaluating treatment outcome. Thus, it appears that for individuals at high risk for CVD participating in intensive, multicomponent risk factor trials, smoking cessation can occur without significant increases in body weight. Future research needs to focus on whether similar results can be obtained with the typical smoker in a more cost-effective intervention. Pharmacologic Methods for Reducing Postcessation Weight Gain Three pharmacologic approaches have been evaluated as potential treatments for reducing postcessation weight gain: nicotine polacrilex gum. d-fenfluramine. and phenylpropanolamine (PPA). The available information on pharmacologic interven- tions for reducing postcessation weight gain is summarized below. There is substantial evidence that nicotine is the agent in tobacco that causes changes in body weight (US DHHS I9XXa) Therefore. the most obvious pharmacologic approach that may prove useful in reducing postcessation weight gain is nicotine replacement. The least hazardous vehicle currently available to deliver nicotine is nicotine polacrilex gum. As literature documenting the use of the gum to aid in quitting smoking has grown (Schwartz 19x7; US DHHS 1988a). several correlational studies have reported that use of the Furn reduces postcessation weight gain (Emont and Cummings 1987: Fagerstrom 19X7: Hajek. Jackson. Belcher 198X). although this effect is not observed uniformly (Hjalmarson IYX4: Tonnesen et al. IYXX). In one study. Fagerstrom (19X7) conducted a followup of 2X patients who were still abstinent at b-month posttreatment after attending a smoking cessation clinic. These subjects received 7 mg of nicotine gum. Subjects were divided at the median (263) number of pieces of gum chewed. Six months after treatment. less frequent gum users had gained an average of 6.X pound\. whereas the body weight of more frequent gum user\ had increased by 3.0 pounds. Fagerstrom (1987) hypothesized that higher nicotine pola- crilex gum use was necessary' to produce blood nicotine levels approaching the effective dosages achieved by smoking. Emont and Cummings ( 1087) also found that nicotine polacrilex gum use reduced postcessation weight gain and that this effect was related to the amount of gum chewed. These investigators studied 103 participants of a 2.5week stop-smoking clinic. Of the subjects who were either abstinent at 1 month or had smoked fewer than 5 cigarettes in the month since treatment. 20 had used nicotine polacrilex gum in their attempts to quit. Use of nicotine polacrilex gum in general was not significantly related to weight gain. However. when number of pieces of gum chewed per day was considered. there wa\ a significant inverse correlation (r=O.37) between nicotine polacrilex gum use and increase in body weight. When broken down by initial daily cigarette consumption. the relationship between nicotine polacrilex gum use and weight pain held only for individuals who had smoked more than 26 cigarettes per day. Neither the Fager\trom ( 1987) nor the Emont and Cummings ( 1987) studies biochemically verified smoking status or measured blood nicotine levels. In the only controlled investigation ofthi\ hind. Gro\s. Stitzer. and Maldonado ( 1989 1 examined the relationship between nicotine polacrilex gum u\e and body weight. Subjects were randomly assigned in a double-blind study either to a nicotine polacrilex gum or a placebo condition. Smohing and nicotine polacrilex gum use were verified with CO. thiocyanate, and cotinine measurements. Of the original 117 subjects. 40 completed the IO-week abstinence trial. In this period. abstinent subjects in the placebo group gained an average of 7.X pounds. 4.0 pounds more than the abstinent nicotine polacrilex gum users. There was also evidence for a nicotine dose effect on weight gain. Users of fewer than 6.5 pieces of gum per day gained 5.0 pounds over the IO weeks. whereas more frequent nicotine polacrilex gum users gained I .S pounds. Gro\s. Stitzer, and Maldonado (198Y) present strong support for nicotine polacrilex gum's suppression of postcessation weight gain in this rigorous study. Once nicotine polacrilex gum use was discontinued. weight gain in both active gum and placebo conditions was comparable (6.8 vs. X.7 pounds at 6-month followup). Thus. in this study. nicotine replacement delayed rather than prevented postcessation weight gain. A recent controlled study (Spring et al.. in press) evaluated the effects of d- fenfluramine on postcessation changes in food intake and weight gain. D-fenfluramine. which releases and blocks re-uptake of serotonin. is a prescription drug that has anorectic qualities without stimulating the central nervous system (CNS). For this study. 31 overweight female smokers were placed either on placebo or 30 mg d- fenfluramine per day in a double-blind assignment. Subjects then quit smoking and were observed for4 weeks. Although the numbers of subjects remaining abstinent were small (five in the placebo group and eight in the d-fenfluramine group), significant differences in food intake between the two groups were observed over time. By 4X hours after discontinuing smoking, placebo-treated subjects consumed approximately 300 cal more per day than during the baseline measurement period. This increase resulted largely from increased consumption of carbohydrate-rich meal and snack foods. The difference in weight gain between the two groups was significant. with the placebo-treated subjects gaining an average of 3.5 pounds and the d-fentTurdmine- treated subjects losing an average of I .X pounds. No significant differences in smoking cessation were observed, although statistical power to detect a difference was low. A recently completed. placebo-controlled investigation evaluated the effects of phenylpropanolamine (PPA). which is an over-the-counter sympathomimetic agent that has weak CNS effects and more pronounced peripheral effects. on weight gain a\- sociated with smoking cessation (Klesges. Klesges et al. I990). It is used both LS an anorectic agent and as adeconge\tant. Subjects vvere S7 adult female cigarette smokers who were randomly assigned, in a double-blind procedure. to either gum with PPA. (7-S mg tid). placebo gum. or no gum. After a baseline assessment, subjects were paid to quit smoking for 2 weeks. Smoking cessation was verified by weekly as well as by random (spot), CO assessments. Of the 57 subjectsenrolled in the study. 4 1 (72 percent) were successful in quitting smoking. Of subjects receiving PPA, 94 percent quit smoking. whereas 63 percent of the two control groups quit smoking. Of those subjects remaining continuously abstinent over the 2 weeks. dietary intake decreased 630 kcal on average in the PPA group, whereas intake in the other two groups remained unchanged. Decreases in intake of all major nutrients (carbohydrate. fat. and protein) were observed in the PPA group. Abstinent subjects receiving PPA gained significantly less weight (mean change=0.09 pounds) compared with either the placebo gum group (mean change=l.S9 pounds) or the no gum group (mean change=I.W pounds). To summarize this Section, additional minor weight control modifications to smoking cessation programs do not generally yield beneficial effects in terms of reducing postcessation weight gain or increasing cessation rates. However, aggressive weight control programs, perhaps offered after individuals have quit smoking (Wittsten 1988). may be able to produce smoking cessation without unwanted weight gain. Nicotine polacrilex gum, d-fenfluramine. and PPA all have promise as adjuncts for reducing postcessation weight gain, but research to date is extremely preliminary. Focus needs to be on more effective behavioral methods for reducing unwanted postcessation weight gain and on combination therapies that include behavioral and pharmacologic strategies. High priority must be given to the development and evalua- tion of effective programs that can be offered in a cost-effective manner. Given the probable role of metabolic rate on postcessation weight gain, weight programs may need to focus on reduction of dietary intake rather than dietary maintenance. Addition- ally. aggressive weight management programs may not be necessary, or even wanted. for many subjects who quit smoking (Gritz. Klesges. Meyers 1989). Future inve5tiga- tions need to determine. of those who quit smoking. the individuals best suited for weight management programs without compromising smoking cessation. Studies on the effects of nicotine polacrilex gum. d-fenllurdmine, and PPA on postcessation weight gain yield some cautious optimism. However. longer followup periods and larger. more heterogeneous sample\ must be utilized in future investiga- tions. It al\o appears. at lea\t with nicotine polacrilex gum (Gross. Stitzer. Maldonado 19X9). that weight gain can occur rapidly after gum use is discontinued. This delayed weight gain . and it\ possible role on post-drug relapse .needs to be investigated. Future research also needs to focus on specifying the influence of moderator variables. such as initial daily cigarette consumption. age. gender. and level of drug use on the effectiveness of the\c pharmacologic agents in preventing weight gain. 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SIS CHAPTER 11 PSYCHOLOGICAL AND BEHAVIORAL CONSEQUENCES AND CORRELATES OF SMOKING CESSATION 517 CONTENTS Introduction ..................................................... ..52 1 Short-Term Effects of Smoking Cessation: Nicotine Withdravval ............. 511 Brief Review of Previous Worh ...................................... 57 1 Craving as a Withdrawal Symptom ................................... 523 Changes in Alcohol and Caffeine Use ................................. 51-I Withdrawal Relief Versus Enhancement Models of the Effects of Smohinp on Performance ................................................... 53 Variability in Withdrawal .......................................... 526 Timecourse of Withdrawal .......................................... 529 Withdrawal as a Cause of Relapse .................................... 530 Summary ........................................................ 531 Long-Term Psychological and Behavioral Consequences and Correlates of Smoking Cessation ........................................... 532 Introduction ................................................ 5.32 Mood. Anxiety. Perceived Stress. and Psychological Well-Being ...... 533 Research Results .......................................... s3-l Self-Efficacy and Locus of Control .............................. 541 Self-Efficacy ............................................. S-11 LocusofControl .......................................... 541 Coping and Self-Management Skills ............................. 513 Social Support and Interpersonal Interactions ...................... s-is Summary ................................................... 5-w Health Practices of Former Smokers .................................... 516 Introduction ........................................ Physical Activity .................................... Dietary Practices. .................................... Use of Other Substances .............................. Other Tobacco Products ............................. Alcohol .......................................... Studies of Multiple Health Habits ....................... Summary ........................................... Participation of Former Smokers in Health-Screening Programs Summary ............................................ Conclusions .......................................... References ................... ..~ ..................... . . . . . INTRODUCTION Former smokers often describe quitting smoking as a tuminy point in their lives. For many individuals, cessation leads to an improved sense of well-being and often $erve\ as a catalyst for other positive health-related lifestyle changes (Finnegan and Suler 1985: Knudsen et al. 1984: Suedfeld and Best 1977). These improv,ement\ in psycho- social functioning and health-related lifestyle behaviors may contribute to and reinforce continued abstinence. However, some smokers may hesitate to try to quit because they fear negative changes in mood and vvell-being (Gritz IYXO: Hall IYX1: Tamerin lY77). In addition. relapsers often attribute their return to smohing to unwanted changes in mood or to a strong desire for a cigarette (Baer 1985: Chapman. Smith. Lay den 197 I: Marlatt and Gordon 1980; Russell 1970: Shiffman 1982). This Chapter reviews findings on short-term withdrawal effect\ and the longer term psychological and behavioral effects related to abstinence from smoking. Short-term withdrawal effects are described in the 1988 Report of the Surgeon General on nicotine addiction (US DHHS 1988). The first Section of this Chapter updates this review by examining recent studies in six areas: cravin_p as a withdrawal symptom. changes in alcohol and caffeine use. withdrawal relief versus enhancement models of the effects of abstinence on performance. variability in withdrawal. timecourse of withdrawal. and nicotine withdrawal as a cause of relapse. The second Section reviews lonser term changes. such as changes in the use of alcohol. illicit drugs. and other tobacco products as well as increases in other health-related practices and preventive health behaviors. including participation in cardiovascular and cancer screening. A major portion of this Section reviews the relationship of long-term abstinence to psychological factors such as mood, coping with stress, self-efficacy, and locus of control. Because the long-term psychological and behavioral effects of smoking abstinence have never been sum- marized, this Section will include a more indepth review of studies than will be provided in the Section on short-term effects. Providing smokers with information on transient adverse withdravval effects and the distinction between these and the longer term psychological and behavioral benefits of abstinence may allay fears and help remove barriers to quitting or to maintaining abstinence. This information may also help to develop more effective programs that help the smoker plan and cope with the effects of cigarette abstinence. For example. education about the signs and symptoms of withdrawal from tranquilizers appears to help long-term users stop using tranquilizers (Lader and Higgitt 1986). SHORT-TERM EFFECTS OF SMOKING CESSATION: NICOTINE WITHDRAWAL Brief Review of Previous Work Over the last decade, several reviews have been published on nicotine withdrawal (Hatsukami, Hughes, Pickens 1985: Henningfield 1983; Hughes. Higgins, Hatsukami 1990; Murray and Lawrence 1984; Shiffman 1979: US DHHS 1988: West 1984). Perhaps the most widely-accepted description of nicotine withdrawal i\ that which appears in the Dia,~/ros/ic~ ulrtl Stotistiol Mutl~rul (!f` Mcutul Di.sodo~.s (DSM-III-R. American Psychiatric Association 1987) (Table I ). In addition to the signs and symptoms listed in DSM-III-R. depression. disrupted sleep. impatience. and perhaps increased pleasantness of sweets are common and valid indicators of nicotine withdrawal (Hughes. Higgins. Hatsukami 1990). However, an especially important effect not included in DSM-III-R is impaired performance. particularly on vigilance and rapid information processing tasks (Snyder. Davis. Henningfield 1989: Wesnes and Warburton 1983). Other consequences of withdrawal. which may not be clinically evident. include slowin_g ofthe electroencephalogram. changes in rapid eye movement during sleep. decreased levels of catecholamines. decreased thyroid function. increased levels of medications. decreased orthostatis. and increased skin temperature (American Psychiatric Association 1987: Hughes. Higgim. Hatsukami 1990). TABLE I.-Diagnostic categorization and criteria for nicotine withdrawal- nicotine-induced organic mental disorder The e\wntial feature ofthi\ d~wrder I\ a characterl\ttc withdrawal syndrome due to the abrupt ce\\ation of or reduction in the we of nicotine-contatninf wbamces (e.g.. ciparette\. ctfarx. ptprr. cheuing tobacco. or nlcotlne sum) and that has been at lest moderate in duratton and amount. Among many heavy ciyrette smoker\. change\ in mood and performance that are related to \slthdraual can be detected withm 7 hr after the kt tobacco we. The `ewe of cravmg appear\ to reach ;L peah u ithm the first 23 hr after ce\\atlon of tobacco u\e and pradually decline\ thereafter ovrr a few day\ to several week\. In an) eiven caw it i\ dtfftcult to di\tinyut\h a withdrawal effect from the emergence of p~ychologicsl twit\ that are wppre\\ed. controlled. or altered h) the effects of nicotine or from a behaworal reaction (e.g.. fru\trstton) to the In\\ of a remforcer. Mtld symptom\ of H ithdraual ma) occur after \H ttchtnp to low-tar (ntcorine) cigarette\ and after \toppmg the we of \mohelr\\ (chewing) tobacco or nicotme polacrilex ym. Dqno\ttc criteria for nicotine H ithdrawnl: A. Dally we of nlcotinr for at lea\1 several wreh\ 6. Abrupt cesttion ot nwtms u\e or reduction in the amount of mcotine wed folIoned wtthin 24 hr b> at least four of the following \ipn\: ( II crav~np for nicotine (2) irrnability. frustration. or anger (31 anale (41 dtfficult) concentrattng (5) restle\we\\ 161 decreased heart rate (7) increased appetite or weight gain The signs and symptoms of nicotine withdrawal are observable: they are often of clinically significant magnitude and occur in self-quitters as well as those who attend smoking cessation clinics (Hughes. Higgins, Hatsukami 1990). Most withdrawal symptoms are opposite to those produced by administration of nicotine. occur for a specified period of time, and with continued abstinence. return to levels similar to those experienced by a smoker. Relief of withdrawal by use of nicotine polacrilex gum. occurrence of withdrawal upon cessation of nicotine polacrilex gum. and occurrence of withdrawal upon switching to Low-nicotine cigarettes indicate that a lack of nicotine is responsible for most withdrawal effects (Hughes, Higgins Hatsukami 1990: We\t 1984). Craving as a Withdrawal Symptom Recent articles have attempted to clarify the role of craving in cigarette smoking (Kozlowski and Wilkinson 1987a: West and Kranzler 1990: West and Schneider 19X7). The term "craving" has been used loosely and interchangeably by both smokers and investigators to indicate a strong desire or urge to smoke. The problems associated with this terminology and the advantages to using the term "strong desire" have been outlined (Hughes 1986a; Kozlowski and Wilkinson 1987a; Kozlowski and Wilkinson 1987b: Marlatt 1987; Rankin 1987; Shiffman 1987; Stockwell 1987: West 1987: We\t and Schneider 1987: Kozlowski, Mann et al. 1989). Although an increased desire for a cigarette is a common consequence of abstinence, part of the craving may result from the desire to relieve other withdrawal symptoms by having a cigarette. For example. a review by West and Schneider (1987) demonstrated that withdrawal effect\. such as irritability and restlessness, are positively associated with craving. They noted that drugs such as clonidine may alleviate craving because these agents reduce the other symptoms. Thus, craving might be alleviated by reducing other withdrawal symptoms (Kozlowski and Wilkinson 1987a). An urge to smoke may be due to several factors, such as response to environmental stimuli associated with cigarette smoking or deprivation, onset of withdrawal symptoms, and protracted withdrawal. That such effects are physiologically. be- haviorally, orcognitively mediated has been debated widely (Kozlowski and Wilkinson 1987a. b; West and Kranzler 1990; West and Schneider 1987). The desire to smoke as indicative of nicotine withdrawal has been a subject of some controversy for five reasons. First, the referent for the terms craving and desire is unclear. In 1955, the World Health Organization (WHO) stated. "a term such as `craving' with its everyday connotations should not be used in the scientific literature . . . if confusion is to be avoided" (WHO 1955, p. 63). On the other hand, craving for a cigarette is the most commonly reported postcessation symptom (Hughes. Higgins, Hatsukami 1990); and therefore, it is difficult to ignore these self-reports. Second, craving readily occurs even when smokers are not trying to abstain (Hughes, Higgins, Hatsukami 1990; Hughes and Hatsukami 1986). However, many other withdrawal symptoms, such as irritability. are also experienced by smokers (Hughes, Higgins, Hatsukami 1990). Third, several factors other than abstinence. such as sensory cues associated with smoking (Rose 1988). the "behavior" of smoking (Hajek et al. 19X9). and expectancy (Hughes et al. 1989; Gottlieb et al. 1987). can intluence craving. However. these factors can also affect other withdrawal symptoms (Francis and Nelson 19x4). In addition. demonstrating that a symptom is influenced by a nonabstinence variable does not mean that the symptom cannot be induced by abstinence: it simply suggests nonspecificity; that is, abstinence is only one of many causes. Fourth, nicotine polacrilex gum does not predictably reduce the desire for a cigarette (Hughes 1986b; West 1984; West and Schneider 1987). However, one possibility is that more cigarette-like (i.e., more bolus-like) routes of administration of nicotine, such as aerosols. nasal sprays, and vapors, would decrease desire to smoke (Pomerleau et al. 1988). Fifth. managing craving may be critical to cessation of smoking. Recent prospective studies have indicated that postcessation self-reports of craving are predictive of later relapse (Gritz, Carr, Marcus 1990; West, Hajek, Belcher 1989; Killen et al. 1990). Also, the ubiquity of smoking cues and the availability of cigarettes may make craving especially prevalent and difficult to resist. Recent research contradicts the commonly held notion that the desire for cigarettes is less than that for prototypic drugs of abuse (Kozlowski, Wilkinson et al. 1989). Persons presenting for treatment of alcohol and drug problems compared the strongest urge they had for cigarettes with their strongest urge for the alcohol or drug for which they were seeking treatment. Among alcohol-dependent persons, 50 percent reported that their strongest urges for cigarettes were greater than their strongest alcohol urges. 32 percent reported that the strongest urges were about the same for both cigarettes and alcohol, and I8 percent reported that their strongest urges for alcohol were greater than for cigarettes. Among drug-dependent persons, 25 percent said their strongest urges were for cigarettes. 27 percent said their strongest urges were about the same, and 48 percent said their strongest urges were for their drug of choice. In the treatment of drug dependencies. such as alcohol, use of the term craving has been historically associated with theories of loss of control (Ludwig and Wikler 1974). Typically, tobacco researchers are not implying loss of control over smoking when they use the term craving (Kozlowski and Wilkinson 1987a). Smokers may or may not be implying loss of control when they use the term. In summary. although the desire to smoke may have a more complex origin than other withdrawal symptoms, it is a predictable and important withdrawal effect. The occur- rence of craving after cessation has several implications. It suggests that nicotine delivered in a cigarette-like system may be the best method to relieve the desire to smoke because the delivery would mimic some of the sensory cues associated with smoking (Rose 1988: Hajek et al. 1989). Also. it suggests that for smokers who wish to avoid medication, behavioral strategies could be used to combat even pharmacologically mediated desires to smoke. Changes in Alcohol and Caffeine Use Initial short-term changes in alcohol and caffeine intake upon smoking abstinence are of increasing interest. It is unclear that smoking cessation impedes abstinence or prompts relapse back to drinking among those with alcohol dependence (Kozlowski, Ferrence, Corbit 1990). Such changes in alcohol and caffeine use were not reviewed extensively in the 1988 Surgeon General's Report on nicotine addiction (US DHHS 524 1988). Long-term effects of abstinence on alcohol intake are reviewed later in this Chapter. Two prospective studies found that among smokers trying to stop smoking per- manently. alcohol use significantly decreased, by about 75 percent per drink per day in one study, during the first week after abstinence (Hughes and Hat\ukami 1986: Puddey et al. 1985). A third study reported that subjects who had a larger decrease in the number of cigarettes smoked postcessation had a larger decrease in alcohol use (Olbrisch and Oades-Souther 1986). However. a recent study suggested the opposite: that is. alcohol use increased among females who stopped smoking temporarily for I week for the duration of an experiment (Perkins. Epstein. Pastor 1990). This discrepancy across experiments may be due to gender or motivational differences in the populations. In the latter case. an increase in alcohol consumption may occur when smokers in an experiment do not try to control their alcohol intake during temporary smoking abstinence; however, when smokers are trying to stop permanently they may decrease alcohol use voluntarily as an aid to smoking cessation. Abstinence does not appear to change short-term caffeine intake (Benowitz, Hall. Modin 1989: Hughes and Hatsukami 1986; Hughes 1990: Hughes et al. 1990: Koz- lowski 1976; Puddey et al. 1985: Rodin 1987). Smoking increases the elimination of caffeine, probably through non-nicotine-related mechanisms (Benowitz 1988): thus, when smokers stop, their rates of elimination of caffeine decrease (Benowitz, Hall. Modin 1989: Brown et al. 1988). With no change in caffeine intake, blood levels of caffeine increase 2.5-fold (Brown et al. 1988). Because several of the symptoms of caffeine intoxication are similar to those of nicotine withdrawal (e.g.. anxiety, restless- ness. and irritability), it has been suggested that these increased levels of caffeine may mimic or potentiate symptoms attributed to tobacco withdrawal (Sachs and Benowitz 1990). Withdrawal Relief Versus Enhancement Models of the Effects of Smoking on Performance The effects of abstinence on performance were reviewed in the Surgeon General's Report on nicotine addiction (US DHHS 1988). This review and others (Hughes. Higgins. Hatsukami 1990) have concluded that abstinence impairs performance on attention tasks, especially those labeled as rapid information processing, selective attention. sustained attention, or vigilance tasks. This impairment may persist for at least 7 to 10 days (Snyder, Davis, Henningfield 1989) and is reversed by nicotine replacement (Snyder and Henningfield 1989). However. it is not clear that abstinence impairs learning, memory, performance on more complex tasks, problem solving, or reaction time. In the prototypic procedure for studying the effects of smoking on performance, smokers abstain overnight; performance is then measured before and after smoking a cigarette. A possible result would be that performance on a vigilance task was better after smoking than before smoking, Some researchers might interpret this difference as an indication that smoking enhances performance (Wesnes. Warburton. Matz 1983). However, another interpretation is that the presmoking performance level was poor 525 because of tobacco withdrawal and that the improvement in performance occurred because smoking relieves tobacco withdrawal (Schachter 1979; Silverstein 1982). This latter interpretation assumes that overnight deprivation induces withdrawal; although this assumption has not been tested directly, withdrawal effects can occur after only 12 hours of deprivation (Hughes, Higgins, Hatsukami 1990). Ideally, studying smokers before initiation would allow comparison of this baseline with before and after a smoking episode. As this is impractical, one solution has been to add a control group of nonsmokers (Hughes, Higgins, Hatsukami 1990). For example, smokers performed better after smoking and the same as nonsmokers in several studies of errors on a vigilance task (Taylor and Blezard 1979; Hughes, Keenan, Yellin 1989; Lyon et al. 1975; Heimstra et al. 1980; Tong et al. 1977; Tarriere and Hartmann 1983; Keenan, Hatsukami, Anton 1989) and a tracking task (Lyon et al. 1975) (Figure 1, upper panel). The effect was attributed to relief of withdrawal. One study provided evidence for enhancement of performance from smoking inde- pendent of reversing withdrawal. Wesnes and Warburton (1978) reported a pattern consistent with enhancement when errors on vigilance tasks were studied (Figure I, lower panel). Other indirect evidence can be used to test the withdrawal relief versus enhancement models. Two studies reported enhancement of tracking or motor skills when smokers were not deprived (Parrott and Winder 1989; Hindmarch. Kerr, Sherwood 1990; Larson, Finnegan, Haag 1950; Pomerleau and Pomerleau 1986). Several studies have examined the effect of cigarette smoking or nicotine administration on the performance of nonsmokers (Dunne, MacDonald, Hartley 1986; Hindmarch, Kerr, Sherwood 1990; Wesnes, Warburton. Matz 1983; Wesnes and Revel1 1984; West and Jarvis 1986: Wesnes and Warburton 1984). In two studies, the improvement in nonsmokers was similar to that of deprived smokers (Wesnes, Warburton, Matz 1983; Wesnes and Revel1 1984). One study reported performance to be similar between deprived smokers and nonsmokers (Warburton 1990). Finally, nicotine appears to improve the perfor- mance of animals not previously exposed to nicotine (Clarke 1987; Emley and Hutchin- son 1984). In summary, the results of studies to assess if smoking increases performance through withdrawal relief or by direct enhancement appear contradictory. One possible ex- planation of this discrepancy is that smoking may increase performance through both withdrawal relief and direct enhancement. The specific mechanism that is operative may vary not only among smokers but also within smokers across situations. Variability in Withdrawal Whereas the necessary and sufficient condition to establish dependence is repeated exposure to the drug, other factors may exacerbate nicotine withdrawal symptoms. Although several investigators have commented on the variability of postcessation symptoms, it is unclear that this variability is greater than with other drug withdrawal syndromes (Hughes, Higgins, Hatsukami 1990: US DHHS 1988). The results of retrospective and postcessation studies on self-reported withdrawal symptoms (e.g., hunger, restlessness, or inability to concentrate) among smokers who have a greater 526 60 50 - 2 NONSMOKERS 2 $j 40 - c- 5 3 e 30 I I I I I I 1 2 3 4 5 6 HOURS 0.9 r NONSMOKERS 2 DEPRIVED SMOKERS F: VJ 0.6 1 1 I I I I I I 10 20 30 40 50 60 70 80 MINUTES FIGURE I.-Uppc~ pu~wl: Performance on a meter (i.e., visual) vigilance task SOURCE: Heinhm CI al. IW). f,o~~~r~puwI: Performance on the continuous clock task, a visual vigilance task nicotine intake are inconclusive (Goldstein, Ward, Niaura 1988; Hughes, Higgins, Hatsukami 1990: Shiffman 1979: US DHHS 1988; Williams 1979). Withdrawal effects. including weight gain, have not been found to differ consistently by gender or age (Hughes, Higgins, Hatsukami 1990). Several studies have suggested that expectancy influences the effects of abstinence; that is, some individuals may amplify. deny, or misattribute their withdrawal symptoms (Barefoot and Girodo 1972; Gottlieb et al. 1987: Hughes and Krahn 1985; Hughes et al. 1989). According to the misattribution model, at times the individual can "mistake" withdrawal symptoms for other possible events. For example, in one study a labeling mistake was made when individuals were told that a placebo they were taking was alleged to have side effects similar to the effects of cigarette withdrawal (Barefoot and Girodo 1972). Three direct tests of expectancy have been published (Gottlieb et al. 1987; Hughes and Krahn 1985; Hughes et al. 1989). In one study, subjects in a double-blind trial of nicotine polacrilex gum were asked if they thought they had received nicotine or placebo gum. Those who believed they had received placebo gum had more abstinence discomfort than those who could not differentiate what they had received; this latter group had more discomfort than those who thought they had received the nicotine polacrilex gum (Hughes and Krahn 198.5). Because this study used post hoc ratings, it is unclear that the belief in which gum had been received modified the level of abstinence effects, or that the level of abstinence effects modified the belief of which gum had been received. Two experimental trials have manipulated instructions and thereby directly tested if expectancy influences abstinence effects. The first study randomly assigned smokers to a 2x2 design of contrasting instructions; subjects were told that they received either nicotine polacrilex gum or placebo gum, and actually received either nicotine polacrilex gum or placebo gum (Gottlieb et al. 1987). Most of the measures of abstinence effects were unchanged by instructions or by actual drugs. The physical symptoms and stimulation scores on the Shiffman-Jarvik Withdrawal Scale were less only on some days in the group told they were receiving nicotine than in the group told they were receiving placebo. A second study used a similar design and found that abstinence symptoms were fewer among those who received nicotine polacrilex gum than among those who received placebo gum. but found no effect of instructions (Hughes et al. 1989). In summary, the seemingly valid proposition that abstinence effects are in- fluenced by expectancy has not been completely supported by empirical tests. Abstinence effects have been hypothesized to be greater in more dependent smokers. However, the scales for dependence used to test this hypothesis vary according to whether they are quantifying physical dependence (withdrawal), behavioral depen- dence (desire for tobacco or tendency to relapse), or dependence on tobacco or on the nicotine in tobacco (Hughes 1984). The Fagerstrom Tolerance Scale (TQ) is the most widely used dependence scale (Fagerstrom 1978). TQ consists mostly of items that refer to behavioral dependence on tobacco. The total TQ score predicted total abstinence discomfort in one study (Fagerstrom 1980) and weight gain in another study (Tonnesen et al. 1988). However, two detailed studies failed to indicate that TQ 528 predicted weight gain (Emont and Cummings 1987) or self-reported withdrawal symptoms. The Reasons for Smoking Scale has two scales relevant to the dependence con- struct-the addiction scale and the negative affect scale (Ikard, Green. Horn 1969). Neither of these has been shown to predict weight gain (Boss& Garvey. Costa 1980). self-reported withdrawal (Hughes and Hatsukami 1986). or relief by nicotine polacrilex gum (Hughes and Hatsukami 1986). Russell's Smoking Motivation Questionnaire has a subscale for dependence (Russell, Peto. Pate1 1974). In one study, the scale predicted total abstinence discomfort and irritability but did not predict restlessness, depression. hunger. or inability to con- centrate (West and Russell 1985). Another measure somewhat related to dependence includes the sevoerity of abstinence discomfort in the past, which appears to predict self-reported abstinence (Hughes and Hatsukami 1986). Other generic scales, such as the MacAndrews Scale for Addiction (MacAndrew 1979) and Eysenk Personality Questionnaire (Eysenk and Eysenk 1975). do not predict abstinence discomfort and weight gain (Bosse. Garvey. Costa 1980). Although one study found that self-reported smoking for stimulation predicted abstinence effects (Niaura et al. 1989), an earlier study had found no such relationship (West and Russell 1985). In summary, the evidence that any dependence scale predicts abstinence effects is quite limited. Further tests that use scales that more specifically determine physical versus behavioral dependence and dependence on nicotine versus tobacco may provide more informative data. Timecourse of Withdrawal Several recent studies produced concordant results on the timecourse of nicotine withdrawal. Most signs and symptoms of nicotine withdrawal are readily detected within 24 hours (Hughes, Higgins, Hatsukami 1990). Previous studies have suggested that abstinence effects can occur even sooner. for example, within 2 hours (US DHHS 1988). These studies have measured effects during smoking and 2 to 6 hours post- smoking: it was noted that 2 to 6 hours after smoking. self-ratings of performance were worse than during smoking. Several investigators have interpreted the scores during smoking as representing baseline and the postsmoking scores as representing withdrawal. However. as discussed earlier. an alternate interpretation is possible: the scores 2 to 6 hours po\tsmoking represent baseline scores and the scores during smohing represent the acute effects of smoking (Hughes et al. 1990). The results of several prospective studies indicate that the \ignj and symptoms of nicotine withdrawal peak in the first I to 2 days following cessation (Gumming\ et al. 1985: Hughes and Hatsukami 1986: West et al. 1983: Shil`fmun and Jarvik 1976: Schneider. Jarvik. Forsythe 19X3) and la\t about I month (Grit/. Carr. Marcus 1990: Cummings et al. 1985: Gross and Stitrer 1989: Hughe\ 1990: Hughes t`t al. 1990: Lawrence. Amoedi. Murray 19x2: West. Hajek. Belcher 19X7). For each of IO weehs. Gross and Stitzer ( 1989) recorded symptoms of quitters and found a peak during the first week and a return to bu\eline 3 to 4 ueeh\ po\tcessation. Snyder. Davi\. and Henningfield ( I YXY) trached perfomiance on several ta\h\ over IO day\. Impairment in performance peahed at I to 2 da) \. and performance on mo\t ta\h\ I-eturned to baseline during the IO day\: however. performance on mne task\ &;I\ still impaired after IO days. A study by Gumming\ and colleague\ ( IYXS) included 33 subject\ uho hept a daily record oCX withdrawal symptoms. AI 21 days. few subjects were reporting withdrawal symptoms. with the exception of a11 occasional desire for a cigarette. A fourth study (Hughes IYYO) provided a less-detailed timecour\e but included group\ of never smokers. ex-smokers. and continuing smokers. The withdrawal scores ot abstinent smokers at I month were equivalent to their baseline score4 and to those of never smokers and continuin g smokers (Hughes IYYO). Although the average withdrawal symptom score returned to baseline at I month, 45 percent of \ub,jectr reported symptoms still above precessation levels at I -month followup (Hughe\ IYYO). Further followup of these subjects indicated that their withdrawal score\ had returned to baseline or below baseline by 6 month\ postcessation. Craving. hunger. and ueight gain are exceptions to the I -month duration: they may continue at least through the first h-months after cessation (Gritz. Carr. Marcus 1990: Hughe\ 1990; Hughes et al. IYYO: West. Hajek. Belcher 1987). With cessation of other drugs. a prolonged withdrawal syndrome has been postulated (Martin and Jasinski IY69). There is no evidence of a prolonged nicotine withdrawal syndrome. In fact, scores on withdrawal scales appear to decrease below prece\\ation levels at followup (Figure 2): that is. positive mood changes occur after Ions-term abstinence from smoking (Chapter I I. see section on long-term psychological and behavioral consequences and correlates of smoking cessation) (Grit/. Carr. Marcus 1990: Gross and Stitzer 1989: Hughes IYYO: Hughes et al. IYYO). Withdrawal as a Cause of Relapse Seven recent studies have examined nicotine withdrawal as a predictor of rclap\e. that is. whether smokers with severe withdraual are more likely to relapse. Five studies found that some withdrawal symptoms predicted relapse at some points in time (Gritz. Carr. Marcus IYYO; West. Hajek. Belcher IYYO: Hughes IYYO: Killen et al. IYYO: Swan et al. IYXX). The two studies that did not indicate such a relationship examined the ability of withdrawal to predict abstinence at very earl!, followup (Hughes and Hut- sukami 19X6) or very late followup (Hughes et al. IYYO). In the five positive studie\. mood changes. such as depression and anxiety. were the more common predictors. However, both across and within the studies. there \va\ no con\i\tent or clear grouping of symptoms predicting wlithdrawal at specific points in time. One common findin? wa\ that the number of symptoms appeared to be a predictor (Gritz. Carr. Marcus I YYO: Hughes 19YO). For subgroups of smokers. such ;I> more dependent mohers. withdrawal may be an especially important factor in relapse. hut this relationship ha\ not been demonstrated. Postcessation weight gain ha$ often been hypothesized to be a major cause of relapse. especially among women (Hall. Ginsberg. Jones 1986). Contrary to several (I /~/`ior.i hypotheses. three prospective studies have found that more weight gain predicted les\ relapse (Duffy and Hall I Y90: Hall. Ginsberg. Jones I YX6: Hughes et al. 1990). There 8 6 I I I I I I I I I I I BL 1 2 3 4 5 6 7 8 9 10 0 l- 24 WEEKS FIGURE 2.-Self-reported withdrawal discomfort among abstinent smokers SOURCE: Groa and St~trer I YXL): Hughe\ I IWO). was no gender difference in this prediction in any of the three studies. This finding is further supported by a study in which women who reported eating more in the first 4 days ofcessation were more likely to be abstinent at 6-month followup (Guilford 1966). One explanation for the weight gain-relapse finding is that food deprivation increases the reinforcing effects of drugs (Carroll and Meisch 1984). Cessation of smoking may decrease metabolic rate (Perkins, Epstein, Pastor 1990); if this is true, to avoid weight gain, smokers may deprive themselves of food and thereby increase the reinforcing effects of cigarettes smoked during periods of relapse. In summary, this recent evidence shows that smokers with more severe withdrawal symptoms are more likely to relapse. However, these results should not be misinterpreted. First, prediction is not equivalent to causality: withdrawal symptoms may predict relapse, not because they cause relapse, but because they are associated with some other variable, such as degree of dependence. Second, those symptoms that predict the occurrence of relapse and the timing of relapse-very early (<2 days), early (2-10 days), or later (IO-30 days)-vary across studies. Third. although studies have shown that withdrawal is an early predictor of relapse, these studies have not shown that withdrawal predicts eventual outcome (i.e., long-term abstinence). Summary Strong evidence indicates that smokers who stop smoking experience a nicotine withdrawal syndrome that includes the short-term consequences of anxiety, irritability. frustration, anger. difficulty concentrating, and restlessness. These symptoms general- ly occur within 24 hours and subside after about 1 month. Smokers also report strong cravings or urges to smoke when they are not smoking; this symptom will persist among some former smokers. Hunger and weight gain may also persist longer than I month. Abstinence does not appear to affect short-term caffeine intake. However, it does increase caffeine metabolism, which may mimic or potentiate symptoms of nicotine withdrawal. There are conflicting data on the short-term effects of smoking abstinence on alcohol intake. However, the data suggest that smokers attempting permanent smoking abstinence experience decreased alcohol intake. Research on the effects of smoking abstinence on performance indicates that abstinence impairs performance on attention tasks. This impairment may persist for at least 7 to IO days and is relieved by nicotine replacement. Other more complex types of tasks as well as memory and learning have not been clearly shown to be impaired by abstinence. The relation of improvement in attention tasks with nicotine may be due either to withdrawal relief or to performance enhancement; findings are consistent with both models. However. evidence more strongly suggests withdrawal relief from receiving nicotine. Variability in tobacco withdrawal symptoms resembles that observed for other drug withdrawal syndromes. Several studies have suggested that expectancy influences withdrawal effects. However, this has not been completely supported by empirical tests. Although abstinence effects have been hypothesized to be greater in more dependent smokers, the evidence is conflicting. Recent data indicate that smokers with more severe withdrawal symptoms are more likely to relapse. However, no symptoms or groups of symptoms consistently predict relapse at any given point in time. LONG-TERM PSYCHOLOGICAL AND BEHAVIORAL CONSEQUENCES AND CORRELATES OF SMOKING CESSATION Introduction Most long-term studies of self-quitters or smokers taking part in treatment programs only include data on smoking behavior or smoking status (Adesso 1979: Gordon and Cleary 19X6; Orleans and Shipley 1983; Shipley. Rosen. Williams 1982); followup measures of psychological and behavioral consequences are rarely included. Thu\. although former smokers represent a large and growing segment of the U.S. population (Volume Appendix). the long-tern1 psychological and behavioral consequences of smoking cessation have not been well studied. Very few studies of former smoker-j have employed prospective or longitudinal designs: rather. most have used retrospective or cross-sectional designs. In the typical retrospectivse study. subjects are asked whether after quitting or during their experience of trying to quit, they were more or less nervous. irritable. depressed. sedentary. or health conscious than before quitting. While relevant to the experience of a person abstaining from tobacco, retrospective studies potentially suffer from several limita- tions, including the absence of information about baseline group similarities or differ- 532 ences and the problem of recall bias. (See Chapter 2 for a discussion of methodologic problems.) Successful former smokers may minimize or fail to recall their difficulties or exaggerate their prowess (Heinold et al. 1982): recidivists may exaggerate withdrawal problems to justify their relapse (Graham and Gibson 1971). Cross- sectional studies do not permit the establishment of comparability at baseline. Con- clusions from the data are therefore limited, often identifying the correlates of cessation rather than the consequences. Both consequences and correlates of cessation will be discussed in this Section. Most prospective studies of smoking cessation sequelae have been conducted with smokers participating in formal treatment programs rather than with smokers quitting on their own (Hughes, Higgins. Hatsukami 1990). Treatment participants may differ in several ways from self-quitters. In a recent review of findings concerning short-term withdrawal effects, Hughes, Higgins. and Hatsukami ( 1990) noted that self-quitters had fewer and less severe withdrawal symptoms than treated quitters; they noted. as did Schachter (1982), that clinic populations may include a higher proportion of hardcore, highly dependent smokers. On the other hand, treated quitters may learn new coping skills such as relaxation, self-reward, or exercise and gain additional support for their initial quitting efforts. Therefore, their short-term postquitting experiences may not be representative of the 90 percent of former smokers who quit on their own (US DHHS 1988; Fiore et al. 1990). Thus. in drawing conclusions from studies of participants in treatment programs, it is important to be aware of the possible differences between these two populations of abstainers. Mood, Anxiety, Perceived Stress, and Psychological Well-Being Tobacco use has often been described as a maladaptive response to. or a way to cope with, life stress and a way to regulate negative affect (Tomkins 1966: Billings and Moos 1981: Ockene et al. 1981: Orleans 1985; Abrams et al. 1987). Smokers often believe that smoking helps them cope with stress and anxiety (Ikard, Green, Horn 1969). Thus. in addition to the stress of separation from cigarettes (Tamerin 1972). abstaining from cigarettes potentially could make the smoker feel less able to cope with stress (Abrams et al. 1987: Marlatt and Gordon 1985) and thereby constitute a biologically based source of stress (Grunberg and Baum 1985). If the quitter feels unable to cope with stress without cigarettes, perceived stress may increase, and self-efficacy may decrease. resulting in heightened anxiety and an overall negative shift in well-being. Alterna- tively, Cohen and Lichtenstein (in press) have hypothesized that for smokers who want to quit smoking, continued smoking may prove more stressful than cessation. and quitting smoking may result in a more positive self-appraisal and heightened feelings of self-esteem and personal competence. Similarly, other researchers have proposed that smoking may cause negative self-evaluations and feelings of guilt and helplessness among smokers who want to quit. so that quitting would result in an overall long-term improvement in mood, self-image, and 5elf-esteem (Frerichs et al. I98 I : Knudsen et al. 1984: Schwartz and Dubitzky 1968). Possible long-term changes in anxiety levels after quitting might also reflect quitting- related changes in physiologic stres\ reactivity (Abrams et al. 1987). To the extent that smoking contributes to excess physiologic stress reactivity and more ready arousal to anxiety (Emmons et al. 1986; Williams, Hudson, Redd 1982: US DHHS 1988). cessation might lead to stable reductions in general anxiety. Several models have been proposed to understand the possible long-term conse- quences of smoking cessation for depression or dysphoria (Frerichs et al. I98 I ; Hughes 1988; Hughes, Higgins, Hatsukami 1990; Tamerin 1972). Studies of withdrawal effects have found depressed mood or dysphoria to be a common, transient withdrawal effect, partly reflecting multiple pharmacologic effects of nicotine abstinence (Backon 1983; Hughes, Higgins, Hatsukami 1990; US DHHS 1988). Covey, Classman, and Stetner (in press) found that smokers with a history of major depression had more severe symptoms of depression 2 weeks after a behavioral treatment for smoking than those without such a history. However, some theorists have proposed that for smokers who want to quit, quitting could result in improved mood. well-being, and self-esteem (Frerichs et al. 198 1). Research Results Five cross-sectional studies have compared former smokers with continuing smokers or relapsers on measures of mood, affect. anxiety, and psychological well-being (Abrams et al. 1987; Giannetti, Reynolds, Rihn 1985; Orleans et al. 1983; Pederson and Lefcoe 1976; Pomerleau, Adkins, Pertschuk 1978). Of these live studies, three found no differences between these groups, and two found differences demonstrating more healthy outcomes for former smokers. Pederson and Lefcoe ( 1976) compared 46 former smokers, mostly self-quitters who had not smoked cigarettes for 1 year or longer, with 46 current smokers volunteering for treatment. These researchers found no differences on Jackson Personality Inventory scales that included measures of anxiety and self-esteem. Likewise, Pomerleau, Adkins. and Pertschuk (1978) used the Symptom Checklist (SCL-56) as a 2-year followup measure of dysphoria among 60 smoking cessation treatment participants and found no differences between quitters and continued smokers. Mean duration of smoking abstinence was not reported. Giannetti, Reynolds. and Rihn ( 1985) compared 47 former smokers who had been abstinent for at least 6 months with 35 current smokers hospitalized for cardiovascular disease and found no differences in "habits of nervous tension." In the only study to employ multiple self-report, physiologic, and observer measures, Abrams and colleagues (1987) found no significant differences between 22 former smokers (mean abstinence approximately 2 years) and 22 relapsers on the State-Trait Anxiety Inventory, but did find that former smokers reported significantly less anxiety and had significantly lower heart rates in response to simulated smoking-related stressors. In a study of worksite health screen participants, Orleans and colleagues (1983) compared 525 long-term former smokers who had been abstinent for more than I2 months (mean abstinence = approximately 9 years) with 856 current smokers and found that the long-term former smokers had significantly better age- and sex-adjusted scores on the Health and Nutrition Examination Survey (HANES) General Well-Being Index, including its anxiety and depression subscales, and on the Framingham measures of anger symptoms and anger internalization. However, there were no'differences on 534 these measures between current smokers and recent ex-smokers, those who had been abstinent for less than 12 months. Prospective longitudinal studies of smokers who become former smokers or remain continuing smokers are needed to establish whether any differences between former and current smokers existed prior to quitting, especially since baseline or "prequitting" measures of psychological well-being and self-esteem have been found to predict success in quitting smoking (Hall et al. 1983; Ockene et al. 1982: Schwartz and Dubitzky 1968; Straits 1970; West et al. 1977). The few prospective studies (Table 2) that have been conducted have either documented no significant change in psychologi- cal factors from baseline among former smokers. or no difference in the magnitude of change for former and continuing smokers. or have indicated improvements for former smokers. None of these studies demonstrated long-term negative psychological chan- ges for former smokers. Two of the prospective studies found no significant changes in a variety of mood and psychological measures from a prequitting baseline to long-term followup among former smokers and no significant differences between quitters and continuing smokers in the magnitude of such change. Pertschuk and coworkers ( 1979) asked 24 participants in a nonaversive cognitive-behavioral treatment to complete pretreatment and 2month followup ratings of psychological functioning. These researchers found no significant changes in stress, affect, symptoms of psychological distress, or utilization of psychiatric treatment as indicated by need for psychotropic medication or mental health services, Changes from baseline to followup were not evaluated separately for quitters and nonquitters. but these groups did not differ on 4-month followup ratings. Emmons and associates ( 1986) studied the effects of smoking cessation on cardiovascular reactivity to stress among quit-smoking clinic participants and found no significant changes from baseline to a 6-month followup among 16 abstainers or 8 relapsers. However, this study noted that an average weight gain of 5 pounds among abstainers may have masked improvements in reactivity scores. Because weight was related to baseline and followup cardiovascular measures, it is possible that in each of these studies, treatment assisted quitters in avoiding persistent unwanted side effects. Two studies of nicotine withdrawal effects that extended measurement beyond 4 weeks of abstinence have yielded no evidence for a withdrawal syndrome beyond 4 to 5 weeks (Hughes, Gust, Pechacek 1987; Gross and Stitzer 1989). These studies, reviewed in detail by Hughes. Higgins, and Hatsukami (1990). found that adverse postquitting changes in levels of anxiety. restlessness. impatience, irritability, and dysphoria peaked during the first 2 weeks after quitting. returned to baseline or below-baseline levels by 4 weeks. and remained at those levels at IO- to 36-week followups. Gross and Stitzer ( 1989) studied 40 smokers who quit after a j-session cessation class and maintained biochemically validated smoking abstinence for 10 weeks while using nicotine polacrilex gum or a placebo. Subjects completed weekly ratings of withdrawal symptoms, including symptoms of psychological distress such as irritability. anxiety. and impatience. Weekly followup ratings were adjusted for baseline ratings and baseline smoking rate. For the 20 placebo subjects. mean ratings for irritability. anxiety . and impatience increased from baseline to the first postquit weeh. returned to baseline TABLE 2.-Prospective studies of quitting-related changes in mood, anxiety, stress reactivity, perceived stress, self-image, and psychological well-being Reference Sample 5ile Type of study Findings Strengths or limitation\ Pertachuk CI al. (IY7Y) 24 smokmg cessation clinic participants Emmons et al. ( IYXh) Groaa and Stiller (IYXY) 24 smoking cessation clinic participant\ 40 abstamer5 using nicotine polacrilex gum or n placebo following a 3-sesston treatment Stress. affect. psychological distress. and utilization of psychiatric treatment were assessed at the start of treatment and 2 mo posttreatment Cardiovascular reactivity No significant pre- to poattreattnent (SBP. DBP. HR) in response to change for abstainers (N=16) in cognitive and physical stressors mean SBP, DBP. or HR. and no were assessed I wk prior to difference in amount of change treatment and 6 mo after between abstainers and recidivist\ treatment (N=U) A IS-item withdrawal symptom measure was completed weekly for 10 postquit weeks For placebo subjects. rated symptoms of psychological distrtx (irritability, anxiety. impatience) increased from baselme to first postquit week. returned to baseline by week 4. then declined below baseline initially, stabilizing after 5 wk; scores for active gum u\erh declined below baseline initially. stabilizing after 3 wk at below-baseline levels No significant pre- to posttreatment change in self-reported anxiety. depression, anger, irritabiltty, appetite loss, msomnta, hopelessness. dtfficulty concentrating, apathy, use of psychotropic medication Although pohttreatment scores did not dtfferentlnte abstainer\ (N=l6) and recidivists (N=X). thebe groups were not compared on pre- to posttreatment changes Only abstainen had a significant weight increase during the following period: thih may account for lack of reductton in cardiovascular reactivity Self-reported abstmencr biologically confirmed and baseline score\ and baseline smokmp rate uxd as covariates, but no control for repeated measurement TABLE 2.--Continued Sample we Typr of study Findings Strength\ or limitation\ I'dlacKh (IW7) after :I contact trc:ttmcnt with phyhictan xivicc and active nicotine polacrilex or placebo gum subject\ mted 5 withdrawal \ymptomh relevant to mood and psychological functioning (anger. anxiety, difficulty concentrating, impatience. restlehsnrsh) Among abstinent suhtects. these ratings peaked at l-7 wk postquttting, returned to bawlme by I mo. and declined further to below-baseline at 6 mo Below-baseline 6-mo ratings among nonquitters suggest a drift in mensures due to il repeated testing effect 35 participant5 m u whsation clinic for mokw with chronic cardiopulmonary diwaw 72 ex-\moher\ (N=7 mo ab\tinrnt) who had quit during the year follwinp a worhde health wreen (49 at comp;mie\ with health promotion programs, 73 at control companir\) POMS was adminiwred before md h mo after treiltmrnt HANES well-being, anxiety, and deprr\\ion scalc~ and the Framingham anger symptom 4c;ilc'~ wcrc ximinl5terrd 31 ;L hawlinc health scrrrn and I-4 r followup A meuwx of total mood di\turhancr (anger/irritability + tension + anxiety + fatigue + confusion + d~pr~\\ion/dejectiotl - vigor) at 6 mo w;t\ \ignificmtly negatively correlated with mohing reduction: parallel Ggnificant relations were noted for the ~caics anger/irritability and ten\ion/vnxiety Significant hawline to I-yr improvements in the HANES well-being and deprewon wale\ werr observed for new cx-wwher\ at treatment \ttes only: no changes tn Framingham anger mwwrc~ were ohwrved Analy\e\ controlled for pretrcatmcnt mwhurc~ Analyws controlled for uyz. wx. burlme UIUCI. and tlurntion of nhatinrnce: compxiwn\ with never moher\. long-term fommcr \mohtw. or reciclivlst\ at twittment \ite\ were not cwdKtrd levels by week four, then continued to decline, stabilizing at below-baseline levels by week six. There were significant interactions between use of the gum and the weeks during which it was used for each of these symptoms, with nicotine polacrilex gum significantly suppressing postcessation ratings only during the first 4 to 5 weeks after quitting. The authors concluded that several of the most disturbing aspects of the tobacco withdrawal syndrome appear to resolve within 4 to 5 weeks after quitting (Gross and Stitzer 1989). Although findings suggest positive changes over baseline for these recent quitters, below-baseline 6- to IO-week scores may reflect the effects of the initial treatment or a repeated-testing effect. In a similar study of the effects of nicotine polacrilex gum on tobacco withdrawal. Hughes, Gust, and Pechacek (1987) studied 3 15 smokers for 6 months after a minimal contact treatment involving brief physician counseling, instruction in nicotine polacrilex gum use, and prescription of nicotine polacrilex gum or a placebo. At a pretreatment baseline, and again at I- to 2-week. l-month, and 6-month followups, subjects rated six withdrawal symptoms related to mood and psychological functioning including anger, anxiety, difficulty concentrating, impatience, and restlessness in addition to four others--craving. hunger, insomnia, and physical symptoms. For 75 subjects abstinent at 6 months, of whom 57 used nicotine polacrilex gum and I8 used a placebo. ratings for anger, anxiety, difficulty concentrating. restlessness, and im- patience peaked at the I- to 2-week followup, returned to baseline at 1 month, then dipped to below-baseline levels at 6 months. Subjects receiving nicotine polacrilex gum compared with those using placebo reported smaller increases from baseline to I- to 2-week and I -month ratings for most withdrawal symptoms, but nicotine polacrilex gum effects were not explored at the 6-month followup because too few subjects continued using the gum. However, 6-month ratings were lower on many symptoms even among 240 nonquitters, suggesting a drift in ratings due to a testing effect. In fact, the only symptom change from baseline, which differentiated quitters and nonquitters at 6 months, was that quitters had a greater increase in hunger than did nonquitters (p I2 months) scored significantly higher on personal control than current smokers (~~0.01). A followup conducted 1 year later showed a significant (~~0.0 I ) increase toward internal control among 72 smokers who had quit since baseline (mean abstinence, 7 months). 542 Conversely, Orleans and colleagues (1983) found a significant shift toward more external health locus of control of similar magnitude among 30 individuals who had been former smokers at baseline. but who had relapsed by the l-year followup. A similar pattern was reported by Horwitz, Hindi-Alexander. and Wagner (1985) who followed 2 19 participants in a single-session hypnosis treatment over a I -year period. These researchers found a significant shift (p. There is some support to suggest that treatment method may have a differential effect on an increase in internal locur, of control orientation. Coping and Self-Management Skills The relation of abstinence from cigarettes to a generalized improvement in the extent and use of coping and self-management &ills has not been studied. To the extent that stopping smoking results in an individual'\ acquirin g or strengthening general]! ap- plicable stress-coping and temptation-copin g &ill\. long-term benefit4 of ab\tinnics might be expected to include the gencrali/ed use of such skills. Ho\se\er. no \tudic\ have assessed whether increases in feneralilrd \tre+copin, ~7 \hill\ occur ;I\ ;\ cons- quence of cessation. Longitudinal studies have not included prequitting and postquit- ting measures of generic copin p strategies. A brief review of the relation of coping to smoking cessation and maintenance of abstinence may help to provide direction for this line of needed research. Shiffman and Wills (1985) have developed a conceptual framework of coping that distinguishes stress-coping skills, that is. skills used to cope wnith general life stressors. and temptation-coping skills, or skills relevant forcoping with a situation in which there is a specific temptation for substance use or an urge to smoke. Folkman and Lazarus ( 1988) defined stress-coping as constantly changing cognitive and behavioral efforts to manage specific external and internal demands that are appraised as taxing or exceeding the resources of the person to maintain an appropriate balance between environmental demands and resources available to the individual to meet those demands. Temptation coping can be separated into what smokers do when faced with the immediate tempta- tion to smoke and anticipatory coping or the strategies smokers use to maintain commitment to abstinence and prevent temptation (Shiffman and Wills 1985). To the extent that smoking constitutes a maladaptive response for coping with stress and negative affects such as anxiety, depression. anger, frustration, loneliness. or boredom (Abrams et al. 1987: Marlatt 198Sb.c: Ockene et al. 198 I ), the former smoker must find alternative strategies for coping. The use of healthy all-purpose coping strategies such as self-reinforcement. assertive behavior, social support, relaxation, and exercise has proven important to success in maintaining abstinence in some studies (Ashenberg, Morgan. Fisher 1984: Grunberg and Bowen 1985; Marlatt 1985~: Shif- fman 1982). However, two large worksite studies demonstrated no differences between current and former smokers in the self-reported use of healthy and unhealthy techniques for coping with stress (Blair et al. 1980; Orleans et al. 1983). In support of the importance of coping skills. Katz and Singh ( 1986) found that 77 former smokers who had abstained for 6 months or more (mean 6.7 years) had significantly higher scores on the Rosenbaum Self-Control Schedule (a self-report measure of individual differences in applying \elf-control or coping methods) than 52 smokers recruited for a quit-smoking treatment. "Self-cured" and treated former smokers did not differ on this measure. The inves- tigators concluded that former smokers may have succeeded because they possessed better self-coping skills initially. The same interpretation could be applied to the study by Abrams and associates (1987) in which 22 former smokers (mean abstinence 22 months) exhibited better observer-rated skills to resist the temptation to smoke than did 22 recidivists in simulations involving interpersonal smoking triggers. Shiffman ( 1982) found that former smokers w,ho reported using cognitive and behavioral strategies to cope with smoking temptations vvere less likely to relapse. These few studies support the conclusion that use of skills to cope with stress and with temptations or urges to smoke seem to be more prevalent among former smokers compared with current smokers. 544 Social Support and Interpersonal Interactions Research has not addressed how smoking cessation influences the level of general or quitting-relevant social support available to the quitter or how cessation affects the quality of the individual's interpersonal interactions. Research on social support processes has focused on examining baseline or posttreatment measures of social support as predictors of quitting success (Graham and Gibson 1971: Lichtenstein. Glasgow, Abrams 1986; Mermelstein et al. 1986; Ockene et al. 1982: US DHHS 1989). Several studies have demonstrated that successful quitters had significantly fewer smokers in their social networks at baseline than did continuing smokers (Eisinger I97 I ; Graham and Gibson 197 I ; Ockene et al. 1982). Others have demonstrated that the quitter's success stimulated quitting by others. especially spouses (Suedfeld and Best 1977). A few studies are relevant to the investigation of cessation effects on social support. A large-scale. cross-sectional and longitudinal worksite study (Orleans et al. 1983) found no differences among current smokers, former smokers. and never smokers at baseline in satisfaction with personal relationships and interpersonal communication or in satisfaction with coworker relationships. However, at l-year followup. 72 baseline smokers who had quit (mean abstinence, 7 months) showed a significant decline from baseline in satisfaction with coworker relationships (p 3 meals/day on weekdays 3 meals/day on weekends Avoid\ wachs weekday\ Avoid\ wackh weehends Haa changed dret for health 220% above desirable weight Preventive care 6.1 1% h 36.3 30.5' h I.3 3.1dh 12.9 Il.h"h 1.7 4.X" h 30.3 25.x" h 48.6 14.3 24,s 21.0 35.0 21.9 Digital rectal exam (ever) Blood stool test (ever) Proctov2opic exam lever) WOMEN Alcohol conwmptlon Drink\ beer tS/wk Drinks 23 heers/epiwde Drinkc wine tS/wk Drink\ 23 glasse\ wme/epi\ode Drinhr liquor ZS/wk 23 drmks/epi\ode Dietary practices 3 meals/day on weehdays 3 meaNday on weekends Avoids bnacks weekdays *Avoids snack!, weekend\ Has changed diet for health 20% above desirable weight Preventive care Digital rectal exam (ever) Blood stool test (ever) Proctoscopic exam (ever) Pap smear (within year) Breast self-exam (withm yr) Breast exam (monthly) Mammogram lever) SY.5 3X.6 24.0 0.9 17.1 1.3 7.0 0.7 13.7 so. I 14.2 26.6 22.6 3x.7 `1.3 .56.X 67.4' h 37.9 36.2" h 20.x 27.2" h 39.7 13.5" h 34.x 30.3" h 51.5 57. 3X.5 16.7" h Former \moher\ Current smoker\ % % 17.1' 51. IL 1.7` `0.2' 1.1' 15.1' 32.X' 3S.l' `6.SL 33.6' 26.3' 33.X' 66.X" h 4-l.Yd h 27.7" h 2.3" h 17.zh 1.3" h IO.`)" h 2.7" 14.1h 4Y.Sh 4 I .x* h 76.9 `3.4" Cl 49.0" h ?4.Xh s9.4 33.`)' 2 I S)' 3.0' 32.7' I .9' 17.X' 2.7' x.0' X.5' 29.4' 26.X 23.6 34.5' 20.3' 60.6' 35.7' `I.1 40.7' 31.0 52.1 35.1' TABLE K-Summary of data from 1987 BRFSS, behaviors of former smokers and current smokers aged 18 and older .AdJu\ted odd\ ratio\ Behavior Former \mvhrr\ relatl\,e to never \moher\ Current \mohen relative to never \moher\ Former smoker\ relative to current \mokerr MEN .Alcohol conwmptwn Any alcoholimo 2.5 drinks/episode 260 drmk\/mo Drinkmg and drivmg I .75" 2.1 IJ 0.82" I .67" 2.63' 0.63' I .7S" 3.0?" 0.58" I .4-v' I .YY" 0.71' Weight/diet/exerci\e Obese (BMI)' Obese (Met. Llfe)d Trying to lose pounds More exercise Eating fewer kcal Physical actwity Sedentary I .os 0.63" I .6x" I .06 0.6-1" 1.63" I.??' 0.63" 1.92" O.YX 0.X3" l.l7h 0.x+ O.XZh I .w l.lOh 0.69" 1.57" 0.9 lb I .43" 0.64" Preventive care ~_- Cholesterol te\t Flu shot part month 1.77.' 0.04 1.34" I .OY o.X7h I .Ih" Other Use ST l.7JJ o.84h `.OYJ Use seatbelt O.YZh OX" I .60" WOMEN Alcohol consumption Any alcohollmo 25 drmks/epi\ode 260 drmk\/mo Drinhing and drivmg 2.07" I .X6' 2.xX" I .X7" 2.w 3.35" s .w' 1.92" 0.87" OX" 0.52 0.65" Weight/diet/exercr\e Obese (BMI)' Obese (Met. Life 1" Trymg to lose pounds More exercise Eating feuer kcal Physrcal activity Sedentary O.YX 0.96 1.19" I .07 0.97 1.17" 0 X6" 0.63" 0.65" 0.75" 0.72" 0.96 0.X1" 1.7-t.' 1.59" 1.52" I .60" I .4x" 0.99 I .JS'l 0.69" Preventive care Cholesterol test Flu shot past month I.15 0.95 I.1 I" O.Ylh 1 .os I .os 550 TABLE 5-Continued Ad,ju\ted odd\ ratw\ Behavior ______ Other Former \moher< rrliltive to nevrr \mokrrr Current \moherr relative to fnexer \moher\ U\e ST 0.73 0.16" I 53 U\e \eatbelt I .03 0.6? I .h3" Physical Activity Evidence from the 1985 NHIS. the 1987 BRFSS, and other cross-sectional studies suggests that smokers are less likely than nonsmokers to make regular exercise part of their lives (Goldbourt and Medalie 1975: Schoenborn and Benson 1988: Martin and Dubbert 1982). These differences may be the consequence of cessation and result partly from changes in physiologic function, such as lung function, that make exercise more pleasurable or tolerable for former smokers compared with current smokers (Castro et al. 1989). They also may retlect the former smokers' efforts to maintain abstinence. Blair and colleagues (1980) found mixed results in their studies of workers in a South Carolinacompany. Among men living within a 0.5 mile of work, current smokers were less likely than never smokers to walk to work. Among women, former smokers were more likely than either never smokers or current smokers to walk to work. (Mean duration of abstinence for former smokers was not reported.) There were no significant differences between smoking categories in other measures of physical activity, such as time spent sitting, use of stairs versus elevator, level of leisure time versus physical activity. and participation in a company exercise program. However. many measures for former smokers were between those of current smokers and never smokers. The 1985 NHIS used 2 measures of physical activity, the perception of being less physically active than others and a more rigorous definition of sedentary behavior based on subjects' reports of participation in 23 leisure activities during the preceding 2 weeks (Schoenbom and Benson 1988). The perception of being less physically active was significantly more common among current smokers than former smokers and never smokers (Table 3). When separated by sex. these differences appear to be greater for men than for women. Men who were former smokers were significantly less likely to report being sedentary than current smokers and not significantly different from never smokers. Among women. former smokers were significantly less likely than current smokers and never smokers to be sedentary. In two studies among Navy personnel. Conway and Cronan (1988a.b) studied the relationship among smoking. exercise. and physical fitness. The first study (Conway and Cronan 1988a) included 3.035 Navy personnel randomly selected from a group who volunteered to participate in an evaluation of physical fitness and health. Both TABLE 6.-Summary of data from 1987 BRFSS, behaviors of former smokers aged 18 and older by duration of abstinence Behavior MEN Alcohol consumption Any alcohol/ma >5 drinks/episode 260 drinks/m0 Drinking and driving Weight/diet/exercise Obese (BMIJh Obese (Met. Life)' Trying to lose pound\ More exercise Eating fewer kcal Physical activity Sedentary Preventive care Cholesterol test Flu shot past month Other Use ST Use seatbelt WOMEN Alcohol consumption Any alcohol/ma i1S drinks/episode %Odrinks/mo Drinking and driving Weight/diet/exercise Obese (BMIjh Obese (Met. Life)' Trying to lose pounds More exercise Eating fewer kcal Physical activity Sedentary Preventive care Cholesterol test Flu shot past month Adjusted odd\ ratlos by duration of abrttnence 13-21 mo relative to I-12-moquitters 1.01 I .02 I .03 I .os I 00 I .26 1.27 I.14 l.51d 1 .16L I .45" 1.38" I .02 I.18 0.85 I .06 0.92 I .16 0.98 1.13 I .02 0.88 0.94 I .03 0.88 0.96 0.64" I .02 I .02 I .2R" 0.97 I .03 1.30 I .03 I .55 0.60 1.28 1.31" 1.07 1.16 1.17 1.15 0.97 I.10 1.10 1.01 I .os 1.06 0.95 0.95 0.89 I .05 1.26 0.97 25-60 mo relative to 261 mo relative to I-1 2-mo quitter\ I-I?-moquitters 0.97 0.73" I .09 I .22" 1 .09 0.95 I .09 I.17 I .13" I .39" I .08 0.86 1.37 I .25* O.Sd 0.98 0.95 I .22" 0.83 1.15 0.72 I .42" 1 .30d I .w 0.98 0.90 I.1 I 0.90 0.88 I .04 552 TABLE 6.-Continued Adjusted odds ratios by duration of abstinence Behavior Other 13-24 mo relative to 25-60 mo relative to l-l 2-mo quitters I-I?-moquitten 261 mo relative to I-I?-moquitter\ Use ST Use seatbelt 0.49 0.27 I .07 I .28" I.14 1.24. NOTE: BRFSS=Beharlordl Ri\k Factor Survetllance Syrtem: ST=\mokelev tobacco `Signtticantly different from I-12.mo quttten lp4.051. There were no significant difference\ nmung the three categories of cesmon >I yr. "BMI=body ma\\ index. `Met. Life=Metropohtan Life hetght and weight Index. SOURCE: Samet and W&t\. unpublished analye\ of the 19X7 BRFSS. never smokers and former smokers engaged in significantly more exercise sessions per week than did current smokers. Current smokers exercised for significantly less time per session and had significantly lower overall physical fitness scores compared with never smokers or former smokers. In a second study. the same authors examined the association between physical fitness and smoking among 1,357 Navy men (Conway and Cronan 1988b). Again, current smokers had poorer levels of physical fitness with lower scores than former smokers or never smokers on tests of cardiorespiratory and muscular endurance. Overall, never smokers performed better than former smokers and current smokers. In both studies, participants were young, with an average age of 26 years (study 1) and 28 years (study 2). suggesting that both decrements associated with smoking and improvements associated with quitting can appear at an early age. A cross-sectional study of 78 1 runners found that as mileage increased, the percentage of self-defined former smokers also increased (Macera, Pate, Davis 1989). These investigators suggested that high-mileage runners seemed to quit smoking at a higher rate than low-mileage runners. Although the sample size was probably too small to show significant differences and the data were cross-sectional, the results support both empirical and anecdotal data about the relationship between abstinence from smoking and increased participation in exercise. Gordon and Polen ( 1987) studied 1,061 men and women who participated in smoking cessation clinics at Kaiser Permanente medical facilities from 1980 to 1983. Men and women who had increased their exercise after program participation were more likely to be abstinent from smoking 7 to 12 months later. These studies suggest that increasing exercise may be part of a former smoker's efforts to remain abstinent, a direct consequence of cessation, or both. The study by Gordon and Polen ( 1987) lends support to the first hypothesis. The 1987 BRFSS allows a comparison among current smokers, never smokers, and former smokers on a range of health practices (Table 5). Two measures of physical activity were used. One asked a very general question about any physical activity in the past month, including nonaerobic activities, such as gardening. as well as major aerobic activities. The second identified sedentary lifestyle as the lowest category on a complex scale of life activities. On both measures. men and women who had quit smoking were more active than nev'er smokers. who were in turn more active than current smoLer\. Among men, those who had been smoke-free for more than 5 years here significantly more active and less sedentary than neu quitters, those who had been abstinent less than I year. This difference was not significant among women. Prospective investigations of changes in physical activity after smoking cessation have indicated either no change or an increase in activity (Chapter IO). An additional prospective study focusing on exercise specifically. rather than weight changes, also found increased exercise among quitters. In a l-year study of a large worksite population, Orleans and associates ( 1983) found that 71 recent ex-smokers (mean abstinence, 7 months) significantly increased their self-rated levels of activity compared with 347 continuing smokers (~~0.01) and that the ex-smokers achieved significant increases (p smohers smoher5 Total smokers wwkers smokers Total Chewing tobacco Never Former Current Snufl Never Formrr Current Pipe Never Former Current Cigars Never Formrr Current 100.0 IWO 93.X 96.7 4.2 I .x 2.0 I .s Y5.Y Y3.3 2.4 I.1 1.7 I .6 01.1 Yl.4 7.3 I .7 I .6 0.x 8Y.X 02.0 X7.6 02.5 7.3 5.x x.3 4. I 2.`) 2.2 4.0 3.4 04.3 94.x 02.3 Y4.6 3.x 3.5 4.7 2.4 I .Y I .6 3.0 3.0 79.3 x0.7 8 I.5 Y3.Y IX.5 7.0 15.2 4.4 2.2 2.3 2.3 2.2 x03 x0.7 Xl.7 Y2.S 16.3 6.2 13.1 4.4 3.2 3.1 5.2 3. I I(w).0 Ion.0 100.0 x3.s X.5.3 YY.3 I I.Y IO.6 0.4 3.6 4. I 0.3 00.9 Y0.S YY.2 YY.0 h. I 6.4 0.4 0.3 3.0 3.1 0.5 0.7 x5.`) x03 YY.7 30.4 IS.1 0.3 3.7 4.4 (HP x7.x x0.x YY.6 YY,X 2h.Y I I.5 0.3 O.ll' 5.3 7.X 0. 1,' 0.0" loo.0 09.3 0.3 0.4 lot).0 00" I00.0 Iwo YY.2 YY.2 0.6 0.6 0.2" 02 00.2 YY.4 0.5 0.5 0.3" 0. I" YY.2 YY.5 0.x 0.4 0.0:' 0."' 09.4 YY.2 0.6 0.6 0.0" 0. I" Never Fommr Iand smohing recidivism: A prospective assessment. Paper prshented at the SBM Fifth Annual Conference. Philadelphia. Pennsylvania. 1984. BACKON. J. Prostaglandins. depression and not smohlng. (Letter.) A!?ro-ic ((I( .I(~ccr-rlctl of P.~whiut,~\~ I30(5):645. May 1983. BAER. J.S. Patterns of relapse after cessation of smoking. Unpublished doctoral dissertation. University of Oregon. Eugene. 1985. BANDURA. A. Self-efficacy mechanibm in human agency. r\r?ic,r.ic,tr~r P~~c~/ro/o,q!s! 37t3 1: I??- 147. February lY82. BAREFOOT. J.C.. GIRODO. M. The miasttribution of smoking cessation symptoms. Cur~~rlior~ ./owr~~/ o~Belic~~~ioru/ .Sci~wt~ 4(3):35X-363. 1972. BARRIOS. F.X.. NIEHAUS. J.C. 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ROTTER, J.B. Generalized expectancies for internal versus external control of reinforcement. P.s~c~ho/qicu/ Motmgrunlrs 80( I ). 1966. RUSSELL. M.A.H. Effect of electric aversion on cigarette smoking. Briri.c/l Merliwl Jorrmcrl I :X2-86. 1970. RUSSELL, M.A.H., PETO. J., PATEL. U.A. The classification of smoking by factoral structure of motives. Jollrjru/ r$r/re Ro~ul Sfufisfic tr/ Soc.ic!\ 137(Part 3):3 13-333. 1974. SACHS. D.P.L.. BENOWITZ. N.L. The nicotine withdrawal syndrome: Nicotine absence or caffeine excess'? In: Harris. L.S. (ed.) Proh/enr.c of` DIX~ L)c,/x,~x/~~/xx,. NIDA Research Monograph Series, 1990. SAMET. J.M.. WIGGINS, C.L. Unpublished analyses of the 1987 Behavioral Rish Factor Surveillance System. SCHACHTER, S. Regulation. withdrawal, and nicotine addiction. In: Krasnegor. N.A. (ed.) CiRarrtte Smoking us CI Dcpr,zd~rrc,e PI-oc~c,s.c. NIDA Research Monograph 23. U.S. Depart- ment of Health. Education. and Welfare. Public Health Service. Alcohol. Drug Abuse. and Mental Health Administration. National Institute on Drug Abuse. January 1979. pp. 123-l 33. SCHACHTER. S. Recidivism and self-care of smoking and obesity. Amrrit un P.swldqi.rf 37(4):336-444, April 1982. SCHNEIDER. N.G.. JARVIK, M.E.. FORSYTHE. A.B. Nicotine vs. placebo gum in the alleviation of withdrawsal during smoking cessation. Addictiw Brhu~~iors 9~1): 149-156. 19x4. SCHOENBORN, CA.. BENSON. V. Relationships between smoking and other unhealthy habits: United States, 1985. Vim/ ar7d He&h Sfurisfics. No. 154. U.S. Department of Health and Human Services, Public Health Service, DHHS Publication No. (PHS) XX- 1250. May 27. 1988. SCHOENBORN, C.A.. BOYD. G.M. Smoking and other tobacco use: United States. 19X7. Viful und Heuhh Sfutisfics. No. I69 (Series 10). U.S. Department of Health and Human Services, Public Health Service, DHHS Publication No. (PHS)89-1597. September 1989. pp. l-78. SCHOENENBERGER. J.C. 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Orlando, Florida: Academic Press. 1985. 57.5 SHIFFMAN, S.M. The tobacco withdrawal syndrome. In: Krasnegor. N.A. (ed.) Ci\ ......................... Office on Smoking and Health Survelh .............................. Measures of Quitting Behavior ...................................... Percentage of Former Smokers in the Entire Population Percentage of Ever Smoher\ Who Are Former Smokers ("Quit Ratio") The Smoking Continuum ......................................... Other Measures ................................................. Trends in the Proportion of Ever Smoker\ Who .,\rc F'~~wI~ Smoker\ ("Quit Ratio") .................................................. Trends by Gender ............................................... Trends by Race.. ............................................... Trends by Age ................................................. Trends by Level of Educational Attainment .......................... Long-Term Abstinence and Relapse .................................. National Health and Nutrition Examination Sur\,e! Epidemlolo~ic FollowupStudy ............................................... The Smoking Continuum ........................................... Percentage of Ever Smokers Who Have Never Tried to Quit Percentage of Those Smohing at I? Month\ Prior to ;I Sur\,c! Inter\ ieu Who Quit for at Least I Day During Those 12 blonth~ ................ Percentage of Ever Smokers Who Had Been Ah\tincnt for Lc\\ Than I YLYII Percentage of Ever Smokers Who Had Been Ah\tinent for I to 1 Year\ Percentage of Ever Smokers Who Had Been Ah\tincnt for at Least 5 Year\ Interpretation of Continuum Findings ............................... 5x3 5x3 5x3 5x-t 5x-l 5x5 sxs sxs sxx 606 606 606 607 A07 Other Measures Related to Smoking Cessation . 60X Intention to Smoke in 5 Years .-. .................................. Receipt of Advice to Quit From a Doctor ............................ Conclusions ..................................................... References ...................................................... 60X hOC) 610 63 INTRODUCTION This volume appendix discusses national trends in smoking cessation over the last 25 vears. specifically updating and expanding descriptions of the national trends in quilting activity presented in previous Surgeon General's reports (US DHHS 1980. 1983, 1988, 1989a). This Section does not provide a detailed discussion of psychoso- cial, pharmacologic, and behavioral factors known to be related to cessation, because this information is available from other sources (US DHEW 1979; US DHHS 1980, 1988. 1989a). Data are utilized from 5 national cross-sectional surveys on adult tobacco use that were performed by the Office on Smoking and Health (OSH) (formerly the National Clearinghouse for Smoking and Health) and the I2 National Health Interview Survey (NHIS) supplements and the National Health and Nutrition Examination Survey (NHANES) Epidemiologic Followup Study (NHEFS), both performed by the National Center for Health Statistics (NCHS). The surveys were conducted between 1965 and 1987. The national surveys and the measures of quitting activity are described below, followed by a discussion of the data. Information on smoking cessation during pregnancy is also included in Chapter 8. Information on smoking behavior was obtained from these surveys by means of self-report(i.e., without biochemical validation). Asdiscussed in Chapter 2. self-report is considered a valid measure of smoking status in cross-sectional surveys. although some underreporting of daily cigarette consumption likely occurs. SOURCES OF DATA National Center for Health Statistics Surveys Survey data collected by NCHS and available for inclusion in this Report were derived from the 1965, 1966.1970, 1974, 1976, 1977, 1978, 1979. 1980,1983. 1985. and 1987 supplements to NHIS and the 1982 to 1984 NHEFS. Cigarette smoking status (current, former, and never) is assessed in the same manner in all surveys. The constructs assessed on the NHIS supplements vary from survey year to survey year. Variables assessed include attempts to quit smoking among current smokers, duration of abstinence among former smokers, and receipt of advice to quit from a doctor. NHIS, a cross-sectional household interview survey, samples the civilian, noninstitu- tionalized population of the United States (NCHS 1958, 1985. 1989). Weighting procedures are used to provide national estimates. Sample sizes for the smoking supplements (ages 20+) vary from approximately 9,700 in 1980 to over 80,000 in 1966. NHEFS was a followup study of persons enrolled in NHANES-I, which assessed lifetime patterns of cigarette smoking behavior among current and former smokers. Whereas NHANES-I participants were drawn from a national probability sample of the civilian, noninstitutionalized population, NHEFS participants included only those who underwent the medical examination in NHANES-I. Personal interviews with each participant or a proxy (for deceased NHANES-I participants) were completed for 12,200 of the 14,407 original examinees. Proxy interviews were conducted with I.697 583 representatives of deceased NHANES-I examinees. The interval between NHANES-I and NHEFS was about 10 years (Madans et al. 1986: NCHS 1987). Office on Smoking and Health Surveys OSH has commissioned five national surveys of tobacco use among adults in this country, referred to as the Adult Use of Tobacco Surveys (AUTSs). The surveys ask detailed questions designed to assess the knowledge. attitudes, and practices of adults regarding all forms of tobacco use. These cross-sectional surveys were conducted in 1964,1966, 1970. 1975, and 1986 (US DHEW 1969,1973,1976; US DHHS 1989b). The similar or identical wording of several standard questions for all five surveys facilitates comparisons. Constructs assessed included tobacco use behavior, intentions regarding future smoking behavior among ever smokers. and receipt of a doctor's advice to quit smoking. Some differences in the conduct and design of the studies occurred. The mode of interviewing changed with time. The 1964 survey obtained data solely from personal household interviews. Whereas personal household interviews were the major mode of data collection in the 1966 survey. telephone interviews and mailed questionnaires were also used to collect data from eligible household members not available when the interviewer was present in the house. The 1970 and 1975 surveys conducted telephone interviews when possible and personal household interviews in nontelephone households. The 1986 survey was conducted entirely by telephone. The I964 and 1966 surveys drew samples only from the contiguous United States. Other AUTSs collected data from residents of all SO States. The actual number of respondents for each survey was 4,635 in 1964,4,06 I in 1966, 5.191 in 1970, 12,029 in 1975, and 13.031 in 1986(US DHEW 1969. 1973, 1976: US DHHS 1989b). In each survey, weighting procedures were used to adjust for an oversampling of ever smokers in the original study population. Comparisons between the 1986 AUTS and the others will not be exact. because the 1986 AUTS weights to an estimate of the adult U.S. population. whereas the other surveys weight to their respective sample sizes. MEASURES OF QUITTING BEHAVIOR As documented in several previous Surgeon General's reports (US DHEW 1979; US DHHS 1988. 1989a) and discussed in Chapter 2 of this Report. smoking cessation is a multifactorial process for overcoming an addictive behavior. One model characterizes this process as having several stages-precontemplation. contemplation, action, and maintenance (Prochaska and DiClemente 1983: Chapter 2). People frequently cycle and recycle through the various stages (marked by frequent relapse episodes) on their way to becoming long-term ex-smokers (Prochaska and DiClemente 1983; Cohen et al. 1989). This analysis of national trends in smoking cessation will use several measures to describe the quitting process. The 1989 Surgeon General's Report (US DHHS l989a) discusses three measures of quitting behavior. These interrelated parameters are discussed below. 584 Percentage of Former Smokers in the Entire Population This measure of quitting behavior has been used to calculate the number of former smokers in the population. Based on data from the 1987 NHIS. for example, 23.6 percent of the 162.6 million civilian, noninstitutionalized adults 20 years of age and older were former cigarette smokers. There were. therefore, approximately 38.5 million former smokers 20 years old or older in the United States in 1987. The percentage of former smokers in the entire population is limited as a measure of quitting activity primarily because it does not take into account the percentage of the population that has ever smoked (and thus is "at risk" of quitting). It also does not differentiate between people who have been abstinent for a short period and people who have maintained abstinence for several years (US DHHS 1989a). Percentage of Ever Smokers Who Are Former Smokers ("Quit Ratio") By dividing the number of ever smokers into the number of former smokers. perspective is given to the magnitude of quitting in a population. The term "quit ratio" has been used to describe this measure (CDC 1986: Pierce. Aldrich et al. 1987; US DHHS 1988. 1989a: Fiore et al. 1989) and is the term used below; this measure has also been termed the "quit rate" (Kabat and Wynder 1987) or the "cessation rate" (Jarvis 1984). The term "ratio" is mostly used in sciences when the numerator and the denominator are two separate and distinct quantities (Elandt-Johnson 1975). "Quit ratio" is used here, even though the numerator is included in the denominator. because of its repeated use in the literature as well as in previous Surgeon General's reports. The percentage of ever smokers who have discontinued smoking indicates the prevalence of abstinence (Ossip-Klein et al. 1986). In 1987, 23.6 percent of the population were former cigarette smokers and 29.1 percent of the population were current smokers. The quit ratio among ever smokers was 44.8 percent; that is, nearly one-half of all living adults who ever smoked cigarettes had quit. Quit ratios by gender and age were recently published for 36 States and the District of Columbia based on 1988 data from the Behavioral Risk Factor Surveillance System (Anda et al. 1990) (Table I). The measure is limited because it treats all former smokers equally, regardless of duration of abstinence. It also classifies current smokers who had never tried to stop smoking in the same manner as it does current smokers who had been abstinent for a long period of time and relapsed shortly before the time of the survey (US DHHS 1989a). The Smoking Continuum The I989 Surgeon General's Report defined a 1 O-category smoking continuum based on data from the 1986 AUTS. This continuum expanded on the smoking status variable (current, former, and never) to incorporate the timing and duration of quit attempts (US DHHS 1989a). Respondents were asked whether they had ever made a serious attempt to quit, and if the response was affirmative, they were then asked about the timing of TABLE I.-Quit ratio" in selected States, by age group and gender-BRFSS, 1988 I x-34 3544, S(L64 25s MW Wonlrn Total SlLlk (h (fYS% Clhl % l+Ys% (`I) % (+Ys% Cl, % (+Ys% Cl) % (*OS% CI) `k (WS'/i <`I) % (It').S'ir (`I) Ald%l~~~;l Arimm California Connecticut District of Columbia Florida Georgia Hawaii Idaho Illinoi\ Indiana Iowa Kentucky Maine Maryland Massachusetts Michigan Minnesota Misouri Montana 143 4.5,s 40. I 3X.6 37.2 43.7 3Y.S 33.7 43.6 2s. I 23.1 30.0 22.6 3x.3 41.1 35.2 37.4 41.2 3.5.x 45.7 (7.0) (7.Y) (5.7) (7.4) (8.X) (7.4) (S.6) (7.1) (7.1) (6.7) (5.5) (Y.2) (S.b) (7.2) (Y.0) (6.6) (7.0) (4.4) (7.1) (9.6) `II.3 54.2 54.3 40.0 45.4 45.3 40.3 45.0 4Y.2 42.6 41.2 503 33.h so.4 45.6 50.x s0.s ss.2 43.`) 5X.X (7.3) (X.0) (5.h) (7.3) (Y.9) (7.2) (X.7) (7.6) (6.`)) (6.6) (S.X) (10.5) (6.9) (7.4) (X.3) (7.0) (7.3) (4.3) (73) (7.7) 54.3 (X.3) 61.2 (9.`)) 64.3 (6.Y) 60.7 (Y.3) 56.5 ( I I .h) S2..? (7.7) S2.1 (12.7) 61.5 (Y. I ) sx.3 (X.3) S3.h (X.0) 51.`) (6.7) 55.4 (12.3) 4x.2 (7.0) 65.3 (X.4) S7.Y (Y.9) X).X (Y.5) 5.5.0 (10.7) 64.6 (5.4) 57.5 (X.41 5x.x (X.2) 65.X 67.0 65.6 74.`) SY.4 77.6 70.2 7O.Y 77. I 64.1 79. I 71.1 63.6 72.7 70.`) 75.5 b.5 .Y 76.0 79.1 7Y.O ( IO. I ) (X.8) (7.X) (X.0) (12.5) (5.7) (17.2) (9.Y) (6.2) (X.3) (5.`)) ( IO.`)) (7.0) (X.7) (Y.3) (7.1) ( 13.4) (S.0) (7.0) (7.1) 47.4 (5.6) 37.3 60. I (6.2) 40.x 56.4, (4.4) 49.3 ss. I (6.4) so.4 52.0 (X.0) 43.4 5x.5 (4.X) so.4 44.2 (7.2) 4h.6 49.6 (5.X) 44.3 61.3 (S.5) 44.2 4x.9 (5.3) 42.4 51.6 (4.4) 41.2 60.2 (X.1) 3Y.l 42.6 (4.`)) 31.1 h0.S (5.Y) 44.5 s3.0 (7.1) 4x.0 56.2 (6.3) 47.6 52.0 (6.4) 45.5 60.4 (3.4) 49.2 54.7 (6.1) 43,s 62.0 (6.4) s4. I (S.9) (6.0) (45) (.5.X) (7.3) (S.2) (6.X) (6.3) (5.5) (5.2) (4.6) (7.1) (4.5) (5.5) (h.5) (5.2) (5.X) (3.X) (5.4) (6.2) 43.2 5.5.4 53 7 52.x 47.6 s4.x 4S.3 47.3 s4.0 3.5.x 47.0 so.7 27.x 53.2 SO.6 51.`) 4X.Y 5.5.4 4Y.b SX.6 (4.1 ) (4.3) (3.1) (4.3, (5.5) (3.5) (5.2) (3.3) (7.Y) (3.h) (7.2) (S.X) (3.4, (4. I ) IS 0) (4.2) (43) l3.5) (4. I ) (4.S) TABLE l.-Continued state 1 X-34 3549 so-64 265 Men Women Total % (2995% CI) % w50/, CI) % (+9s%cI) % (H58 Cl) % (k9sx CI) % ( f')S%, CI % (FWE Cl) Nebraska New Hampshire New Mexico New York North Carolina North Dakota Ohio Oklahoma Rhode Island South Carolina South Dakota Tennessee Texas Utah Washington West Virginia Wisconsin Median prevalence 39.6 (7.4) 57.6 35.2 (7.0) 53.0 3x.4 (X.7) 47.0 29.8 (7.4) 42.7 37.0 (6.X) 47.5 3x.7 (7.1) so.9 30.6 (6.5) 42.3 37.1 (9.1) 43.6 34.7 (6.4) 44.x 2x.9 (5.X) 41.5 37.4 (9.2) 52.3 29.0 (4.X) 40.9 3X.X (X.6) 45.7 33.5 (7.5) 50.9 37.7 (7.3) 54.X 3X.S (7.1) 43.4 35.0 (6.9) 92.0 37.2 47.0 (8.3) 57.6 (7.4) 60.3 (9.2) 53.4 (8.1) 66.3 (6.7) 47.9 (6.X) 62.2 (7.6) 57.4 (8.6) 55.9 (6.X) 55.6 (6.6) 58.7 (8.6) 60.8 (5.7) 49.5 (8.4) 53.7 (X.1) 6X.3 (7.5) 53.7 (6.5) 49. I (7.3) 62.2 57.5 (9.0) (9.9) (9.X) (X.9) (8.5) (7.9) (9.0) (10.2) (X.5) (7.6) (9.2) (6.X) (10.5) (I 1.3) (X.7) (7.2) (X.5) 74.5 (7.X) 74.2 (9.2) 64.7 (I 1.7) x0.3 (X.2) 72.3 (7.0) 73.3 (7.4) 67.3 (X.4) 62.9 (13.4) 60.X (7.2) 72.2 (X.X) 71.1 (X.7) 67.2 (7.9) 69.3 (12.5) x0. I (Y.2) x2.5 (7.9) 69.4 (7.2) 76.0 (9.1) 71.1 59.0 (9.9) s3.x (6.1) 40.4 (7.3) 54.2 (6.X) so.4 (5.7) 5x.3 (5.1) s-2.0 (h.2) 53.4 (7.0) 51.1 (5.h) 46.0 (5.1) 55.6 (5.X) 43.4 (4.S) 52.5 (6.7) 65.2 (5.X) 5x.2 (5.X) 54.5 (5.2) 63.X (S.6) 94.2 47.2 (6.1) 54.0 4X.6 (6.0) 51.5 46.3 (7.0) 4x.0 46.X (6.5) SO.5 43.4 (5.2) 47.3 45,s (5.6) 53.1 31.4 (5.7) 44.9 3Y.b (6.7) 47.5 44.6 (51) 47.x 42. I (S.4) 44.4 SO.5 (6.7) 53.4 3Y.4 (4.1) 4 I .x 41.4 (6.X) 47.9 40.5 (X.6) 5h.h 46. I (5.X) 53.0 3X.4 (5.0) 47.6 46.3 (6.7) 56.5 44.6 so.5 (4.3) (4.6) (5.2) (4.7) (3.9) (3.X) (4.2) (S.1) (3.X) (3.8) (4.3) (3.2) (4.X) (5.0) (4.2) (3.7) (4.4) NOTE: BRFSS=Behavioral Rl\k Factor Survedlance System. "Ddmed as the percentage ofever vnokcn who were former amoken at the time ot the survey hConfidrncr interval. SOURCE: BRFSS IYXX (Anda et al. IYYO) z -4 their most recent quit attempt. This measure provides information on the recent quitting history of the population (Pierce, Giovino et al. 1989: US DHHS 1989a). The trend analyses presented below will use an eight-category continuum (Table 2) among ever smokers to incorporate data from the 1978, 1979. 1980, and 1987 NHISs. As opposed to the 1986 AUTS, the questions asked in these NHISs do not permit a dichotomous classification of current smokers who had never tried to quit according to interest in quitting. In addition to a description of the overall smoking continuum, several segments of the continuum, or measures derived from the continuum, will be described separately. These measures include the following: o The percentage of ever smokers who have never tried to quit; o The percentage of people smoking at I2 months prior to a survey interview who had been abstinent for at least I day during those 12 months: o The percentage of ever smokers who had stopped smoking for less than 1 year: o The percentage of ever smokers who had stopped smoking for I to 4 years: and o The percentage of ever smokers who had stopped smoking for at least 5 years. Other Measures Respondents to AUTSs were asked to estimate the possibility that they would be smoking 5 years after the survey. This question gives a measure of intention to smoke. Finally, respondents to several NHISs and to all OSH tobacco use surveys were asked if a physician had ever advised them to stop smoking. TRENDS IN THE PROPORTION OF EVER SMOKERS WHO ARE FORMER SMOKERS ("QUIT RATIO") Using data from NHISs for I965 to 1987. trends in the proportion of ever cigarette smokers in the U.S. adult population who have stopped smoking cigarettes (quit ratio) are presented by gender and by race in Figures 1 and 2. respectively. Trends for the total adult population. as well as trends by age and by education, are shown in Table 3. These data, with the exception of the age-specific estimates. are age-adjusted to the 1985 population. In thes,e analyses. the quit ratio was regressed on the calendar year of data collection. The R- statistic. supplied for each trend analysis. is a measure of the strength of the linear relationship. R' values may range from 0 (no linear trend) to 1 .O (a perfect positive or negative linear relationship). Trends by Gender As shown in Figure 1. the quit ratio for both genders has been increasing in an approximately linear fashion (R-=0.94 for males and 0.97 for females) since 1965, and 5X8 TABLE d.-Cigarette smoking continuum by year, percentage of ever cigarette smokers, NHISs, United States, 1978-87, adults aged 20 and older Cigarette smoking continuum I. Current smokers who had never tried to quit 2. Current smokers who had quit previously but not in past year 3. Current smokers who had quit for <7 days in past year 4. Current smoker5 who had quit for >7 days in past year 5. Former smoker\ who had quit within past 3 mo 6. Former smokers who had been abstinent for 3-12 mu 7. Former smokers who had been abstinent for I-S yr X. Former smokers who had quit 25 yr earlier Percentage of those smoking during the year prior to the survey who tried to quit during that year (Categories 3+4+5+6 divided by 1+2+3+4+.5+6) Percentage of those smoking during the year prior to the survey who quit during that year and were still abstinent at the time of the survey (Categories S+6 divided by 1+2+3+4+5+6) 197x I979 IYXO 10x7 25.9 26. I 25.4 1X.Y 22.7 2 I .4 23.1 20.0 6.6 6.0 5.9 7.0 KS X.6 7.x x.4 I.3 1.6 I .4 1.x 2.7 2.6 2.7 2.X Y.0 IO.0 Y.5 IO.4 23.3 23.6 24.1 20.7 -___ .- 2X.2 2x.4 26.X 34.0 6. I 6.3 6.7 7.x NOTE: NHIS=NAonal Health Interview Survey SOURCE: NHlS\ IY7X. 197'). 19X0. 1987. z 0 60 MALES FEMALES Slope of Regression Line 0.70 0.76 -........_._..__________________________--------------.------.-.--....-..-..---- !f -----....____ !E! __________ !!L?! _________ I 1 I I I I I I I I I I I I I I I I I I I I I 1964 1969 1974 1979 1984 YEAR FIGURE I.-Trends in the quit ratio, United States, 1965-87, bv gender NOTE: Quit ratio ib the proportion of ever \mohers who are former \moher\. NH`IS=N;it ionnl Health Intreview Survey; OSH=Office on Smoking ond Health. SOURCE: NHIS!, IOhS. IYhh. lY70. 1974, lY7h. 1077. lY7X. 1979. IYXO. lYX3. IYXS. IYX7: OSH. 1. 1 1. 40 30 20 3 10 s E z E 0 Whites Blacks Slope of Regression Line 0.72 0.45 I32 0.96 0.86 ______________---__-____________________~--~--------------------~----~--------------------~..~~~~-~~~~~-~~-~.~~~~~~-~-~.~~~-~--- I I I I I I I I I I I I I I I I I I I I I I I I 964 1969 1974 1979 1984 YEAR FIGURE 2.Trends in the quit ratio, United States, 1965-87, by race NOTE: NHlS=National Health Interview Survey; OSH=Office on Smoking and Health. SOURCE: NHISs 1965. 1966, 1970, 1974, 1976, 1977, 1978, 1979, 1980. 1983, 1985, IYX7: OSH, 22 unpublished data. TABLE .X-Trends in quit ratio ( %) (percentage of ever cigarette smokers who are former cigarette smokers), by age and by education, NHISs. United States, 1965-87, adults aged 20 and older Year I Y65" I YM 20-2-l 17.x 17.0 Age (yr) Educational level Lr\s than Hngh school Some h!gh school (`allege 25-u 4SA4 xl5 graduate praduatc college graduate 22.6 30.0 1x.7 `3.4 30.0 SO.5 33.3 2x.0 28.7 30.1 1070 3s.1 20.x 3.X 36.1 S6.Y 3x. I 33.6 34.9 3x.2 1974 7h.J 2O.Y 3.3 3Y.7 57.x 3X.0 35.2 36.6 47.') I Y7h 37.1 22.0 X4 JO.4 5Y.h 3Y.S 35.0 37.' 36. I 1077 36.X 22.0 ?Y.fl 3.5 5x.7 3x.3 34.0 36.X 4X.6 197x 3X.5 22.x 7 I .Y 40. I 62.4 3x.7 36.3 4 I .o 4Y.7 I Y7Y 34.0 27.h 3 I .x 32.4 61.7 30.x 36.7 37.5 SO.6 I YXO NO 73 7 --.- 33.0 40.0 hl .o 3Y.3 36.5 40.6 4x.7 3x.7 `II.2 S4.Y 40.5 46.0 61.1 `Il.1 4.5.5 SC). I 0.5s 0.74 0 xx 0.0s 0.0x 0. I3 0.92 O.YO 0 x3 the rates of increase for both are also similar (0.70 percentage points/year for males and 0.76 percentage points/year for females). The quit ratio has been consistently higher for males than for females. Using data from the 1970 and I975 AUTSs. Jarvis (1984) reclassified as current smokers males who gave up smoking cigarettes but who con- tinued to smoke cigars and/or pipes. When the use of other forms of smoking tobacco was considered, the difference between males and females in the quit ratio (termed as the "cessation rate" by Jarvis) was reduced by more than two-thirds. Data from the 1987 NHIS Cancer Epidemiology and Control supplement (Schoen- born and Boyd 1989) were analyzed to update the work of Jarvis (Table 4). The weighted percentage of ever cigarette smokers who were former cigarette smokers among males was 48.7 percent. The corresponding number among females was 40. I percent. When former cigarette smokers who smoked cigars and/or pipes were reclas- sified as current smokers (without changing the denominator). the prevalence of cessation among ever smokers became 45 percent for males and 40 percent for females. Furthermore, when former cigarette smokers who used any other form of tobacco (cigars, pipes, snuff, and/or chewing tobacco) at the time of the survey were classified as current tobacco users, the figures became 42. I percent for males and 39.9 percent for females (OSH, unpublished data). Thus, reclassification of former cigarette smokers who were smoking cigars and/or pipes as current smokers reduced the difference in the quit ratio between males and females from 8.6 to 5.0 percentage points. Former cigarette smokers who were using any other form of tobacco were reclassified as current tobacco users, and this reclassification further reduced the difference to 2.2 percentage points. Trends by Race Trends by race are presented in Figure 2; The quit ratio among both whites and blacks has been increasing steadily since 1965 (R&=0.96 for whites and 0.86 for blachs). While the change per year since 1965 is higher for whites (0.72 percentage points/year) than it is for blacks (0.45 percentage points/year), the lines have been essentially parallel since 1974 (Fiore et al. 1989). Use of the 1987 NHIS data to reclassify as current smokers all former cigarette smokers who were smoking cigars or pipes reduced the quit ratio from 46.4 to 44.2 percent among whites and from 3 I .S to 30.2 percent among blacks. Further reclassification, as current tobacco users, of former cigarette smokers who were using any other form of tobacco reduced the numbers to 42.5 percent for whites and 29.1 percent for blacks (OSH, unpublished data). Trends by Age Table 3 provides information on the quit ratio stratified by age. For all age categories. the quit ratio increased from 1965 to 1987. The rate of change was highest in the age categories of 45-64 years and 65 years and older. Reclassification of the I987 data to account for cigar and pipe smoking and for any other tobacco use lowered the numbers from 23.8 percent to 23.4 and 22.2 percent. respectively. among the 20-24-year-olds: from 37.2 percent to 35.6 and 34.3 percent. respectively.among 25-G-year-olds; from 4Y.2 percent to 46.4 and 35.0 percent. respectively. among 4%64-year-olds; and from 69.1 percent to 66.2 percent and 62.8 percent, respectively, among those 65years-old and older (Table 4) (OSH. unpublished data). A detailed analysis of trends in the quit ratio by age for the period 197-I through I087 has been completed (Novotny et al., in press). Differences in quit ratios between age groups may reflect actual differences in quitting activity by age-that is. older persons may be more prone to quit and maintain abstinence than younger smokers, perhaps because of the occurrence of smoking- related symptoms or illness. However, continuing smokers are less likely than former smokers to survive to old age (Chapter 3): this selective mortality will artifactually increase the quit ratio among older age groups. TABLE 4.-Effect of adjusting for use of other tobacco products on quit ratio (percentage of ever cigarette smokers who are former cigarette smokers), 1987, NHIS, United States Quit ratio (%) Adjusting for UnadyNed" Adjustmg for cigar\/pipe\h ciE"r"/pipe\/~nuff/~hewin@ tobacco` Gender Males Females Race White5 Black> .Age (yr) xb-21 7.5-4-I 35-64 265 Education (yr I : Educational difference\ are increasing. ./ortrxtr/ I!/. rl~c~ Anwric utt Medic u/ .&s.s~~c~rtrtro,t 26 I ( I ):56-60. January 6. I YXY. PIERCE. J.P.. GIOVINO. G.. HATZIANDREL'. E.. SHOPLAND. 0. National age and hey differences in quitting smoking. ./err,-/OCR/ r!f'P\~(,/~~~t(.tt).(, Drrrg 21(3):`93-`98. Julb-Scp- tember 19X9. PROCHASKA. J.O.. DICLEMENTE, C.C. Stages and proces\e\ of \eIf-change of \mohinl: Toward an integrative model of change. .lolrt-t~trl of' Cotr.srrlrltl,~ cltltl c/ill/c C;rncer Pre\,ention Studyll. 1X. 7X-7Y. I IO. 124. 1 `Y. 1.32. I SC). 171. `lS.`11.`15 350 `5' 75X, _. -- . -- -. -. iox. 34s Anal cancer. 172-l 76 Analytic issues of consequence assessment. SS-S7 Anxiety. 5.33-51 I Aortic aneurym. 2-I I Arrhythmias. 195 Arteriosclerosis obliterans. 244 A\ses\ing smohing cessation. see Chapter 2 .4\thma (4ee also Airway respomiveness) nosology. 27Y-3X0 respiratory symptom\. 36 Atherowlerosis CHD development. IYl-lY3 severity. IYY-200 .L\ttrihutahle ri4h. pregnancy outcome. 3Y3-3% R Behav ioml consequence\ of ceskon. we Chapter I I Behavioral measures. 15-J I Bias. 36.18. 53-55 Biochemical marherr. 33-37 Birth&eight cessation after conception. 383-3X7 ce\Wion before conception. 382-3X.3 continued smohins. 3X 1-3X2 loIt. attributable rik N-3YS mohing and cessation. 379-3237 Bladder cancer. 159-l 65 Blood oxygen deliwry. CHD development. IYS-lY6 Body fat di\trihution. lYS Body height. we Chapter IO Bogw pipeline. 37 Bone 104s. WC Osteoporosis Bone mineral content. W&UC) Breast cancer. I69 Breathlessnes\, see Respiratory symptoms British Physicians Study. 7Y. I 10. 118. -70s. 30x. 33 I Bronchitis (see also Rcbpiratory infections) mortality. .?J2-315 nosology. 27Y Caffeine we. cessation. S23-525 Cancer\. nonrespirutory. see Chapter 5: \ee also specific bites Cancers. respiratory. \ee Chapter 1: see alw specific \ite\ Carbon monoxide. M-35 C'rrrdiovawular disease risk. estimated cessation effects. I97 Cardiovavzular diseases. see Chapter 6 Carotid artery plaques. 216 Cas+ontrol study design. 39-50 Cerebral blood flow. 216. 25 I Cerebrovascular disease abstinence duration. 37-15X age factors. 3 I ca\e-control studie4. 2KP24Y cross-\ectional \tudie\. 2-16 de\ elopment. I Y6 inter\,ention \tudie\. 3 I oral contraceptives. 75X-260 prospective cohort \tudit'\. 21Y-750 wiohing and cc\wtion. 215-260 vmohing hi\tor\. 3 l-252 wmmarv of ob\ervstional qudiet. 151 Cervical cancer. 165-l 60 Ceswtion consequence\ a\\essment. 16-57 proces\ and heha\,ior a\w\vnent. `216 rate. \ee Quit ratio xtaze modsl. 22-2-I c time trend\. pregnanq. 393 timing. bil-thweight. 3X3-386 Chapter conclusions. Y- I1 Chronic obstructive pulmonary disease FEVI decline. 33X-333 mortality. 3-l l-338 nosologj,. 27Y-25 patients. 31534X Cigar smoking 3s cigarette replacement. 555-556 lung cancer. 12-LI25 trend\. 593 Cigarette consumption bladder cancer. I61 cerebrovascular di\ea\e. 25 I-752 FEVI decline. 329-333 lq ngc;il cancer. I.32 lung cancer. 11-l MI ri\h. 703 oral cancer. I.5 I - IS2 overall mortality. 7X-M). X6 pancreatic wicer. 15.5 prefnanc! . 3YO-393 LIttight gain. 501-501 Cohort \tud! de\ifn. 1X-4Y Conclusion\ chapter. YP I1 1 olume. x Contextual i4w3. biochemical ~l\w\\nlt`nt. 17-k Coping shill\. 513-S4-l Coronary arty sp;~wl. CHD dcwlopment. I OS Coronar! heart divzrhe (CHD) cro\5-wclion;il Gudiek 1 YY-200 cc'\\ation. 147-730 development. lYLlY6 niortal~t!. 3JS-2I!4. 227-220 patwnt\. 72%23Y rich factors. 1Y71YY Cotinine. 36-37 Cough. see Rrqiratory synptoms Craving. 573-524 Cro4~+ectional stud!, de\ign. 171X 0 D-fentluramine. weight control. soi-so1 Demographic factor\ prqnanc! outcomc~. attributable rich. 3Yi-3YS \mohing and ccs\ation during pregnant> 3YOk3Y.J Deprc\sic,n. 5.73%51 I Diahetlc\. CHD mortalit!. 22 I-222 Diet. SOO-502 Dietar! ch;mge\. 4X-L-M I>ict:rr! prxtiLy\. 554-555 Dlt`fuslnp capacity. former wiohcrs. F 327-3'8 Disease developnicnt. Atinence duration. 129 DNA adduct lwels. IN- I IO Duodenal ulcers (see also Peptic ulcers) healing. 132-133 recurrence. -133-439 Duration of abstinence. see Abstinence duration Dyspnea. see Respiratory symptoms E Ecologic study design. 47 Ectopic pregnancy. 375-376 Educational attainment abstinence duration. 606608 quit ratio. 595 smoking continuum. 5999608 Emphysema mortality. 342-345 nosology. 179 Endometrial cancer. 169- I71 Energy expenditure. 487l90 Enhancement models, performance. 52-526 Esophageal cancer. 153-l 55 Estrogen metabolism osteoporotic fractures. 44334-t premature menopause. 398 Ethnic factors abstinence duration, 606608 quit ratio. SO3 smoking and cessation during pregnancy. 39 i-393 smoking continuum. 599%608 Ex-smokers. see Former smokers Fertility female. 372. 373-37s male. 304-409 Fetal growth. 373. 379-387: see also Birthvveight Fetal mortality. 376-379 Forced expiratory volume in I second (FEVI) cross-sectional population studies. 308-3 I6 decline. 328-337.345-347 longitudinal population studies. 318-337 Fibrinogens. former smokers. I94 Food intake. 484386 Former smokers absenteeism, 89 anal cancer. 172-l 76 atherosclerosis severity, 199-200 bladder cancer, I64 breast cancer, 169 cerebrovascular disease, 246260 cervical cancer, 166-169 dietary practices, 554-555 diffusing capacity, 327-328 early menopawe risk, 30X-400 endometrial cancer. I69- I72 esophageal cancer, 15% IS5 established COPD. 355-348 fibrinogen levels, I94 health practices. 546-56 I health screening. 56 l-564 health status. 87-9 I hepatocellular cancer. 176 HDL-C levels. 192-193 kidney cancer. I72 Ieukemi;l. I76 lung cancer ri& pattern\. I IO- I27 medical care utilization. X7 Ml wr\,i\ 31 200-771 ` . oral cancer. 117-l S2 ovarian cancer. I72 over311 mortalit!. 7X-X0 pcnilc c3nccr. 172-l 76 phq\ical xtivit!. SS l-554 population pcrccntafe. CXS pulmonary function. 30X-337 re\pir;~toq \\mptoni\. 2X.5-305 stomach cancer. I76 Fractures. see O\teoporosi\ Framingham Heart Stud!. X0. 2 I X-22 I. 30-23s. 250. 25x. 453,1Y71YX Frequency issue\. \elf-reports. 27-7X G Gastric secretion. smohinp. J2Y430 Gastric ulcer4 (\ee alw Peptic ulcers) healing. 440 recurrence. 3301-l I Gastrointestinal physiolog . wioking. 42Y3.30 Gender factors abstinence duration. 606-60X alcohol consumption. 556-S% bladder cancer. I61 diet. 1X53X6 dietary practices. SSA-555 esophageal cancer. I S2- IS5 MI survi\xl. 237 oral cancer. I17 o\~er3ll mortalit>. X0 pancreatic c3nccr. IS5 physical activit>. 55 l-551 H Health practlc'e\. tormcr \mohcrs. S-K-S6 I Health rish ch;mgc\,. -4Y7-500 Health \creenlng. former wohers. S6l-S6-l Htxlth \t;rtu\. X7-Y I Hemorrhagtc \trohc. WC Cerehro\ascular diwacc Hepatocellular cancer. I76 High-densit) lipoprotein chole\terol (HDL-CJ Ic\el\. former smokers. ICI?-IYi Hormones. male reproduction. 10 I I Imn~unc \steni. respirator\ infection\. 305-30x ImpotcYlc~. malr. -102-w Infertilit! female. 372. 371-375 male. 1OS-4OY I~lflue~l~;~. we Respirator! infection\ Inhalation practice\. lung cancer. 12-l IntentIon to cmohe. SXX. 60X-hoc) Intermittent claudication. 213-714 Intcrpcrwnal intfxiction~. 545-516 Intrr~tsntion trial\. \tudJ dc~i~n. 50-Y I Inter\ it3 \. 15-29 Ii Kidnc! cancer. 172 1, Laryngeal cancer. Ii I - 132 Leukemia. I76 Locus of control. 542-513 Long-term p\ychologicul and beha\ ioral consequence\ and correlates. 532-546 Lung c;mccr abstinence duration. I IO-I 31. a E e at cessation. 125-l 76 airs ay histopatholosy. I OX- I OY wiohing and cessation. lO7- I3 I cigar smoker4. I25 cigarette consumption. I24 DNA adduct levels. I OY- I IO diagnosis. I2Y-I 3 I inhalation practice\. 12-l multl\tqe models. 126-l 3X nonfilter cigarettes. 124 12.5 pathophbsiologic mechanisms ot \mokinf. 107-l IO pipe smohcw I25 \mohincy duration. 122-l 23 2 smohino hi\tor\ I Z7-1 26 C . - Major conclusions. X Measures of cessation. 2216 Measures of quitting beha\,ior. 5X4-SXX Medical care utilization. X7 Clcnopause. premature. 3Y6400 Zletabolic rate. 4X71YO `Llethodologic i\\ues of consequence ;I\\c`sslllcllt. 5 l-57 Mrthodologie\. cexttion a\eswicnt. \ec Chapter 3 Mi\clas~ificntion of smoking st;ltu\. 4Y. 5 I. 52-55 Mood. 533-5-l I Morbidity (\ee alw Chapter 3: specific caLl\es) peptic ulcers. 13 1332 respiratory. 2X5-30X Mortality (see alw Chapter 3: specific causes) bronchitis. 331-33.5 COPD. 31 1-315.347-34X cohort studies. 75-X3 emphysema. 341-335 fetal. neonatal. and perinatal. 371. 376-37Y overall. intervention studies. X&X6 peptic ulcers. 332. weight. 4Y l3YS Mouth c;mcer. jee Oral cancer Multiple health habit\. 559-561 Multiple primary cancer\. 176-l 77 Multiple Rish Factor Intervention Trial. 34. 2X. SO-S I. 53. X6. 227-`2X. 333-33s. 4%. 3YX. 560-56 I. SYS Multistage models. lung cancer. 136-11X Myocardinl infarct (MI) risk ca\exontrol studies. 200-20-l cigarette consumption. 203 cohort studie\. 20S-393 -- healthy persons. 200-379 624 intervention trials. 223-220 Ml patients, 22Y-23Y recurrent. 230-73Y N National Health and Nutrition Esamination Sur\e>,. 21. 30. 4.3 I. 1s3.sx3-sx1 National Health Interview Sur\e>. 3. 390-39 I. 537-561.5X3-5x4 National trend5 in smohing ce\\ation. we Appendix Neonatal mortality. 379-3X I Neoplasms. see Cancer\: we LIIW specific sites Nicotine polacrilek gum weight control. 502-503 lvithdraual \)mptorn\. 518. 53Y Nicotine M ithdraival. 52 l-532 Nonbehavioral measure\. 3 116 Nonfilter cigarettes. lung cancer. 134-1'5 0 Obesity. 3Y0497 Obstructive airways divzase\. see Chapter 7 Occupational factors. respirator! symptoms. 2Y6-2YY Oral cancer kohol conwmption. IS I - I32 cigarette consumption. I5 l-l 51 former smoLer5. I-$7- I57 gender facton. I.47 5nioAing xld ce\s;ition. I17- 152 Oral contrucepti\ e\. cerebra\ ;I\CLI~:II diwaw. 25X-700 Osteoporosis. 44.345; O\teoporotic fractures. 44YL-453 Oi arian cancer. I72 O\ eweight. xl\ crw nicdical and p\>cho\ocial outcomes. 4YO4Y7 P Pxncreatic caiccr. I55- I30 Pathoph! \iolofic nicchaii\m\ ot wlohln~ cartlio\ ;I\~LII:II. diw;rw\. I Y I - I Y7 I;ir> ycal C~IIlCt'l'. I3 I lung cwccr. 107-l IO male reproduction. 40040I preyancb. 37 l-371 premature ~iienop;~uw. 396-39X osteoporo\l\. I-ii-444 respirator> di\e;iw. 77Y-2X.5 shin ~rinhling. 4531.56 Penile c;uiccr. 171-l 76 Peptic ulcer di\e;iw. 17%41~ Peptic ulcer\ morbidit!,. -Ii ILL32 mortalit>. 4.32 Pcrfomwicc. aktinencc. 525-526. 5.30 Perinatal mortalit! attrihutahlc ri4. iY.JLWS \niohing and ceswtion. 376-37Y Pei-ipheral ;irtc'l-ial occItisi\e dixe;l\e. 2-l I-211 Peripheral artel-! diw,tw dC\ clopllkwt. I%. 21.3 progno\i\. T-13-744 PIlen\ I~~rop~inolanlirle. ~4 tight control. 503.-504 Phleynl production. \c`c Ke\pirator! `! lllp,loln\ f'h! \ic;il ;ii,ti\ 11) 4S6. .i5 I --554 f'ti! SICI;II~ .id\ ic,c`. 5%. 6tN Kac~al t`ac,tor.\. \c'c E!I~IIIC Factor, Kccidi\ i\m. 595--5YX: \c`c AIYO Kclapc Kcducrion 01' ~tnok~n~. prcy;tnc>. 7X7-.3X9 R~lapw. 23-21. 53Ok53 I. 5Y5-5YX Report coticlu4ion~. X de\ cloptlletlt. x-9 05 ervich . 5-7 Reproduclion fetnale. 37 IL-W male. 10010v Reproduction. see Chapter X Ropiratory cancers. we Chapter 4 Respirator!, diwuw\. \ec Chapter 7 Respiratory function te\th. we Spirometric parameter\: Stii~ill airway\ function Respiratory infection\. 305-30X Respiratory morbidit!,. mohing cr\\at;on. 2X5-308 Re\piratorl symptotn~ ah\tinence duration. 303 asthmatic\. 1X6 ce\3ation clinics. 2X5-7X7 cro3\-sectional population studic\. 2Xx-296 longitudinal Gudiw 7YY-305 occupational !yoiip\. 7061YY rc\ awl. pooihlr mechaniwi\. 301 w-tohing anti ct`\\ation. 1X5-305 wiohinp hi\lor! . 3Y-3Oi Self-report tneawres. 3-2Y Self-monitoring. 29 Sexual acti\ ity. male. IOI-U)4 Sexual behavior. cervical cancer. I66 Shorme\s of breath. see Re\ptratorl symptoms Skin urinhling. 153456 Small airways function. smoking cessation. 323-327 Stnohing and ce\ation wrveys. methodoio~~\ 5X'-.5X4 t- . Smoking behavior chanc7e "-21 t .-- Smohin~ charucteri~tic~. see Inhalation practice\ Smohing continuum abstainers for lesh than I Jear. 606 abstainer\ for I to 1 years. 606-607 ab\taitwr\ for 5 \`ear\. 607 defir,ition. 5X5-58X smokers never trying to quit. SYY smoker\ quitting for at least I day during I ?-month period. 606 Smoking duration. lung cancer. 122-123 Stnoking history cerebrovascular disease. 25 l-252 FEV I. 30X-3 16.328-337 lungcancer. I??-126.13%12X respiratory symptom\. ZYY-303 Smoking interventions cerebrovaxular dizea\e. 25 I CHD mortality. 22&2?Y overall mortality. X3-86 pregnancy. 3X7-.3X9 &eight control. SOO-502 Social wpport. 535-516 Spam. coronary arter! I Y5 Sperm qualit!. JO-l-lOY Spirometrtc p;tr;lmeter~. smohing cessation. 3 IY-32.2 Spontaneou\ abortion. 372. 376 Statistical coti~ider3tiotis. 52 Stomach c:tncer. I76 S1re\4. 533-S-I I Strobe patients. ce\\;ttion. 760 Studv design. 16-S I Subaruchnoid hemorrhage. 2IY. 150. `.5X-260 Surrogate ;i\w5wxnt\. JO-3 I Survival progtiwi\ lung cancer. l2Y- I3 I MI patients. 7iO-33Y T T lymphocyte\. 306-307 Temporal i\we>. wit`-report\. 77-7X Tertninolog\~. ahse\stnent. 33-31 Thiocyanate. 35-36 Thrombosi\. CHD de~~loptncnt. lY3-I95 Time trend\ in mohing and ce\\;ttion. pregn;inc>. iY3 Tobacco conwt~~p~iot~. e\oplugr~~l cancer. I52- I S-l Tracheal mttcou\ \.elocit>. 304 U.S. Veteran\ Stud!. 10. 7Y. I IO. 12-t. 12s. I'X. l2Y. 132. IS I. 15'. 155. IM. l71-17h.217-`IX. 2s I-25'. 345.112 Lllcrr healing ;tncl recurrence. 4321-i I lilcer occurrt'nc`c'. -17%4.3~ L;lccr\. 4et' 21~ kpiic ulc`t`t-\: Ga\trtc ulcer\: Duotlen~tl LIICC`I-\ Weight control \trategie\. SOO-SO-1 Weight c\cling. 197195 , Weight gain (we ;1lx~ Chapter IO) pregnancy. 373 rish and amount. 473483 c;1use5.483190 Weight. mortality. 19 I495 Weigh-rclattxl health rid>. 497-500 Well-being. psychological. 533-511 Whesre. \ee Respiratory \ynptoms Withdraual symptoms relapse. 5X-53 I relief. performance. 525-526 timecourse. S? I. 519-530 variability. 526-529 Wrinhlinp. skin. 453456