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British Journal of Cancer 24 (3) : 574-587, September 1970. 78 CHAPTER 5 Pregnancy Contents Page Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Effect on Birth Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Effect on the Outcome of Pregnancy . . . . . . . . . . . . . . . . . . . . 83 Congenital Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Cancer in Children Born to Smoking Mothers . . . . , . . , . . . 8'7 Long-Term Effects on Children Born to Smoking Mothers . . 88 Experimental Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 LIST OF TABLES Table l.-Frequency of abortion and cigarette consumption 85 81 INTRODUCTION The 1971 report, "The Health Consequences of Smoking" (23)) summarized the relationship between smoking and pregnancy as follows : Maternal smoking during pregnancy exerts a retarding in- fluence on fetal growth as manifested by decreased infant birth weight and an increased incidence of prematurity, de- fined by weight alone. There is strong evidence to support the view that smoking mothers have a significantly greater num- ber of unsuccessful pregnancies due to stillbirth and neonatal death as compared to nonsmoking mothers. There is insuf- ficient evidence to support a comparable statement for abor- tions. The recently published Second Report of the 1958 British Perinatal Mortality Survey, a carefully designed and controlled prospective study involving large numbers of pa- tients, adds further support to these conclusions. New epidemiological, experimental, and pathologic studies lend support to the foregoing statements. EFFECT ON BIRTH WEIGHT Analysis of data from more than 100,000 births has shown that infants of mothers who smoke during pregnancy have a mean birth weight of 6.1 ounces (173 grams) less than infants born to non- smoking mothers (29). Several recent studies confirm this relation- ship (1,2,6, 7,10,13,15,18,25). EFFECT ON THE OUTCOME OF PREGNANCY New studies have been published concerning the effect of maternal smoking on the outcome of pregnancy. Kullander and Kallen (IS) performed a prospective study in Sweden involving 6,363 pregnant women. These women completed several questionnaires during the course of their pregnancy, and in this manner specific information was obtained on smoking habits for the entire pregnancy. Forty-four percent of the women smoked cigarettes during pregnancy and 97 percent of these smoked during the whole pregnancy. 83 Stillbirths, neonatal deaths, and deaths occurring before one year of age were recorded to determine a "total death risk." This risk was approximately 60 percent higher for children born to smoking mothers as compared to those born to nonsmoking mothers. Deaths occurring before one week of age and also deaths taking place between the age of one week and one year were significantly more frequent in children born to smoking mothers. Among children dying before one week of age, significantly more cases of abruptio placentae were found in smoking mothers than in nonsmoking mothers. The higher level of neonatal mortality in children born to smoking mothers was confined to those weighing more than 2,500 grams. Live-born infants weighing less than 2,500 grams had equally high neonatal mortality rates whether they were born to smoking or nonsmoking mothers. The stillbirth rate was greater in smoking mothers than in nonsmoking mothers, but the difference was not statistically significant. An overall increased risk of spontaneous abortion among smoking women was found, but this was primarily due to an association be tween unwanted pregnancy and smoking. The authors found that significantly (P < .OOl) more women with unwanted pregnancies were smokers than women with wanted pregnancies; in addition, spontaneous abortions were significantly (P < .OOl) more frequent among women with unwanted pregnancies than among women with wanted pregnancies. When correction was made for the mothers' acceptance of pregnancy, the contribution of maternal smoking to spontaneous abortion was of only borderline significance. Also in the Kullander and Kallen study (13)) a decreased fre- quency of preeclampsia among smoking mothers was noted. Mater- nal smoking had no effect on the mean Apgar score of surviving, non-malformed children. A prospective study from Sweden of abortions in 4,312 pregnan- cies was reported by Palmgren and Wallander (17). Only those women who smoked throughout pregnancy were considered smokers. The lowest abortion rate was found among nonsmokers, 7.8 percent, while the highest rate was found among heavy smokers, 14.5 per- cent (table 1). The difference is statistically significant (P < .OOl) . Heavier smokers appeared to abort earlier in pregnancy. A history of previous abortion was obtained twice as often in heavy smokers as in nonsmokers. Yerushalmy reported in 1964 on pregnancies occurring in women participating in the Kaiser Health Plan of the San Francisco-Oak- land area (24). The 1971 report, "The Health Consequences of Smoking" (23), commented in detail on that report. Recently, Yerushalmy published data on 13,083 pregnancies occurring in this plan between 1960 and 1967, which included the 6,800 cases pre- viously reported. (24, 25). 84 TABLE L-Frequency of abortion and cigarette consumption. Result of the pregnancy Nonsmokers 510 cigarettes >lO cigarettes Total Abortion 177 148 60 385 7.8% 9.1% 14.5% 8.9% Delivery 2,087 1,486 354 3,927 92.2% 90.9% 85.5% 91.1% Total 2,264 1,634 414 4,312 SOURCE: Palmgren. B., Wallander. B. (17) As in the 1964 study, he again found an increase in the incidence of low birth weight infants (less than 2,500 grams) among smoking mothers. These small infants had a significantly lower neonatal mortality rate and fewer congenital anomalies than the small in- fants born to nonsmoking mothers. The neonatal mortality rate for single, live-born infants born to white, smoking mothers was 11.3/1000, while that for single, live-born infants born to white, nonsmoking mothers was ll.O/lOOO; the difference is not signifi- cant. Taylor analyzed Yerushalmy's data for the probability of fetal death and found no difference between smoking and nonsmoking mothers (22). Some of these findings are different from those reported in the other recent, large-scale prospective studies (5, 13, 17, 19)) and some of the differences may be a consequence of the definition of "smoker" used. In the study of Kullander and KBllen (13), multiple interviews were performed during pregnancy which allowed more precise separation of the pregnant women into smokers and non- smokers. In the study reported by Palmgren and Wallander (17)) only those women who smoked throughout pregnancy were con- sidered smokers. The British Perinatal Mortality Study (5)) which was discussed in the 1971 report, "The Health Consequences of Smoking" (El), defined "smokers" as those women who smoked regularly after the fourth month of pregnancy. The smoking history was obtained shortly after delivery of the infant. In contrast, Yerushalmy (25) defined "smokers" as women who were smoking one or more cigarettes a day during the pregnancy, and "nonsmokers" as women who never smoked and those who stopped smoking either before or during the pregnancy. Because the smoking history was obtained only once, usually early in preg- nancy, some of the women who were classified as smokers could have gone through a significant portion of their pregnancy as non- smokers, and similarly some of the women who were classified as nonsmokers could have gone through a significant portion of their pregnancy as smokers. If smoking by pregnant women increases the risk of an unsuccessful pregnancy, an imprecise separation of preg- nant women into smokers and nonsmokers would tend to diminish the magnitude of any differences found. One Swedish study (13) and the British Perinatal Mortality Study (5) seemed to be at vari- ance in statements about the frequency with which smoking habits vary from one portion of the pregnancy to another. If this is a cul- turally determined phenomenon, there is no way of estimating the extent to which it applies to the patients participating in the Kaiser Health Plan described by Yerushalmy. MacMahon, et al. (14) commented on Yerushalmy's analysis of mortality rates in low birth weight infants. They observed that there are ". . . factors that affect birth weight without influencing mortality ; for example, females have lower birth weights than males but not the higher mortalities that might be predicted for them on that account. If cigarette smoking is another such factor, the explanation of the higher weight-specific mortalities for non- smokers becomes immediately clear : it is an artifact of the analysis. It is meaningful to compare category-specific rates only when the specification of the category has the same implication for each of the populations compared." Perinatal mortality rates were similar in infants born to smoking and nonsmoking mothers in a recent prospective investigation of 1,300 pregnancies from New Zealand (1) . Women were classified as smokers or nonsmokers during their first `booking" at an ante- natal clinic, and this was not later amended. This method of classi- fication is similar to that used in the Yerushalmy study. Comstock, et al. (6, 7) have reported in 1967 and 1971 on the relationship of maternal smoking to the outcome of pregnancy. In their studies, all perinatal deaths and samples of live births occur- ring during a lo-year period among children whose mothers were residents of Washington County, Maryland, were matched against the records of a special census based on a household interview taken in 1963. Maternal smokers were defined as women who were smok- ing in 1963 and who had started to smoke prior to the pregnancy in question; maternal nonsmokers were women who denied ever hav- ing smoked. When this study is compared to previously cited studies (5, 13, 17')) the data on the smoking status of the mothers during pregnancy are imprecise, which limits their value. In the 1967 study (6), maternal smoking was associated with an increased risk of mortality for the child, both in the neonatal period and for several years thereafter; however, this effect was thought to be related to factors such as adequacy of prenatal or postnatal environment and care, rather than a direct effect of maternal smok- ing. Stillbirth rates were similar for smokers and nonsmokers. The more recently published study (7) includes a 32 percent sample of live-born, low birth weight infants and a 3 percent sam- ple of live-born, larger infants born during the lo-year period pre- ceding the census. The total births represented by these samples were 4,641 to smokers and 7,646 to nonsmokers. The neonatal mor- tality rate, when adjusted for environmental and socioeconomic factors, was approximately one-third higher among infants born to smoking mothers than among those born to nonsmoking mothers (7). The categories of asphyxia, atelectasis, and immaturity ac- counted for the greater neonatal mortality among infants born to smoking mothers as compared to those born to nonsmoking mothers (7) * CONGENITAL MALFORMATIONS As noted in the 1971 report, "The Health Consequences of Smok- ing" (zS), the possible teratogenic effect of maternal smoking has not been adequately evaluated. Additional studies have been pub- lished in the interim, but rather than investigating congenital mal- formations in both stillborn and live-born infants, most of the recent studies have dealt only with live-born infants. Fedrick, et al. (8) analyzed data from the large British Perinatal Mortality Study for the incidence of congenital heart disease in still- born and live-born infants of smoking and nonsmoking mothers. An incidence of 7.3/1000 births was found in infants born to smoking mothers as compared to 4.`7/1000 births for infants born to non- smoking mothers, a statistically significant difference (P < .OOl ) . Kullander and Killen (IS) noted no teratogenic effect of maternal smoking in children dying before one year of age or in children surviving one year of age. However, they observed that published studies have been too small to exclude this possibility. In a study of perinatal death occurring in infants weighing more than 1,000 grams, Bailey (1) found that maternal smoking did not lead to an increased incidence of congenital anomalies. Yerushalmy (25) reported only on live-born infants weighing less than 2,500 grams and found significantly fewer (P < .02) anomalies among infants born to smoking mothers. Comstock, et al. (7) found fewer than the expected number of Congenital anomalies among live-born infants of smoking mothers. CANCER IN CHILDREN BORN TO SMOKING MOTHERS Neutel and Buck (16) studied the relationship between maternal Smoking during pregnancy and the development of cancer in the off- spring. The ba+se population was obtained from the British and Ontario Perinatal Studies and consisted of 89,302 babies who sur- 87 vived at least seven days. There were 65 cancer deaths and 32 can. cer survivors in the period from birth to a minimum of 7 and a maximum of 10 years of age. For cancer of all sites, the children of smokers had a relative risk of 1.3. The authors concluded: "Al. though these results make it most unlikely that in utero exposure to tobacco smoke has a broadly carcinogenic effect on the fetus, a re- sponse confined to one tissue or expressed over a narrow age range cannot be ruled out." LONG-TERM EFFECTS ON CHILDREN BORN TO SMOKING MOTHERS Goldstein (9) analyzed data from the British Perinatal Mortality Study to determine factors influencing the height of 7-year-old children. In the 1958 study, information was collected on 16,994 singleton births. In 1965, heights were measured "to the nearest inch" on 13,127 of these children who could be followed up. The dab were analyzed for the influence of parity, birth weight, length of gestation, maternal age, maternal height, social class, number of younger siblings, and maternal smoking habits during pregnancy. Allowance was made for the sex and age of the child at the time of measurement. The author's conclusions included the following: "After allowing for the other variables, the children of mothers who smoked 10 or more cigarettes a day after the 4th month of preg- nancy, are on average about 1.0 cm shorter at age seven than the children of mothers who did not smoke." EXPERIMENTAL STUDIES Becker and Martin (3) continued their experiments concerning the effect of nicotine on pregnant rats. Offspring of rats given nico- tine weighed significantly less at birth than saline-injected controls. There were fewer live births among the nicotine-injected rats. Kelly and Roy (12)) using cinephotomicrography, demonstrated that nicotine crosses the mouse placental barrier in amounts ade- quate to produce a measurable cardiovascular response. Stalhandske, et al. (21) studied the in vitro metabolism of nico- tine in livers of fetal, young, and adult mice. Cotinine was found to be the major metabolite at all ages investigated. Using radioactive compounds, Sieber and Fabro (20) identified a variety of drugs in the preimplantation blastocyst and in uterine secretions of pregnant rabbits. In animals receiving dose levels of nicotine comparable to that encountered in man, significant amounts of radioactivity were found in the preimplantation blastocyet. A markedly higher concentration of radioactivity was observed in uterine secretion than in maternal plasma. Juchau (11) studied the levels of benzpyrene hydroxylase in the placentas of smoking and nonsmoking women obtained both early in pregnancy and at term. This enzyme hydroxylates benzo (a) pyrene, a carcinogenic hydrocarbon found in tobacco smoke. Previous stud- ies had shown that placentas, obtained at term from smoking women, have a greater ability to hydroxylate benzo (a) pyrene than the placentas from nonsmokers (23). Juchau corroborated this, but also found very low levels in placental tissues obtained from healthy smokers during first trimester dilatation and curettage or hystero- tomy for therapeutic abortion. This lack of significant placental drug metabolizing activity during the first trimester was in- terpreted as a possible hazard to the fetus, particularly if the sub- stance were active in the unmetabolized form. Enzyme levels were undetectable in placental homogenates of nonsmokers at 8 to 16 weeks gestation. The carcinogenic effect on the newborn of rats receiving benzo- (a) pyrene during the latter half of pregnancy was studied by Bulay and Wattenberg (4). An increased incidence of pulmonary adenoma and skin papilloma was observed. SUMMARY Maternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birth weight and an increased incidence of prematurity, defined by weight. There is increasing evidence to support the view that women who smoke during pregnancy have a significantly greater risk of an unsuccess- ful pregnancy than those who do not. PREGNANCY REFERENCES (1) BAILEY, R. R. The effect of maternal smoking on the infant birth weight. New Zealand Medical Journal 71(456) : 293-294, May 1970. (2) BEAL, V. A. Nutritional studies during pregnancy. Journal of the Amer- ican Dietetic Association 58(4) : 321-326, April 1971. (3) BECKER, R. F., MARTIN, J. C. Vital effects of chronic nicotine absorption and chronic hypoxic stress during pregnancy and the nursing period. American Journal of Obstetrics and Gynecology llO(4) : 522-533, June 15, 1971. (4) BULAY, 0. M., WATTENBERC, L. W. Carcinogenic effects of subcutaneous administration of benzo(a)pyrene during pregnancy on the progeny. Proceedings of the Society for Experimental Biology and Medicine 135(l) : 84-86, October 1970. (5) BUTLER, N. R., ALBERMAN, E. D. (Editors). Perinatal Problems. The Second Report of the 1958 British Perinatal Mortality Survey. London, E. and S. Livingstone Limited, 1969. 395 pp. (6) COMSTOCK, G. W., LUNDIN, F. E., JR. Parental smoking and perinatal mortality. American Journal of Obstetrics and Gynecology 98 (5) : 708-718, July 1, 1967. 09 (7) COMSTOCK, G. W., SHAH, F. K., MEYER, M. B., ABBEY, H. Low birth weight and neonatal mortality rate related to maternal smoking and socioeconomic status. American Journal of Obstetrics and Gynecology 111(l) : 53-59, September 1, 1971. (8) FEDRICK, J., ALBERMAN, E. D., GOLDSTEIN, H. Possible teratogenic ef- fect of cigarette smoking. Nature 231: 529-530, June 25, 1971. (9) GOLDSTEIN, H. Factors influencing the height of seven year old children -results from the National Child Development Study. Human Biol- ogy 43: 92-111, February 1971. (10) GOUJARD, J., ETIENNE, C., EVRARD, F. Caracteristiques matemelles et poids de naissance. (Maternal characteristics and birth weight.) Revue du Praticien 19(28, Supplement) : 54, 59-62, 65, November 1, 1969. (11) JUCHAU, M. R. Human placental hydroxylation of 3,Pbenxpyrene duri ing early gestation and at term. Toxicology and Applied Pharmacology lS(3) : 665-675, March 1971. (12) KELLY, M., ROY, F. H. Microcirculatory response of fetal mice to ma- ternal nicotine. (Abstract.) Clinical Research 19( 2) : 322, April 1971. (13) KULLANDER, S., KLLLEN, B. A prospective study of smoking and preg- nancy. Acta Obstetricia et Gynecologica Scandinavica 50(l) : 8%94, 1971. (14) MACMAHON, B., ALPERT, M., SALBER, E. J. Infant weight and parental smoking habits. American Journal of Epidemiology 82(3) : 247-261, November 1965. (15) MURPHY, J. F., MULCAHY, R. The effect of age, parity, and cigarette smoking on baby weight. American Journal of Obstetrics and Gyne- cology 111(l) : 22-25, September 1, 1971. (16) NEUTEL, C. I., BUCK, C. Effect of smoking during pregnancy on the risk of cancer in children. Journal of the National Cancer Institute 47 (1) : 59-63, July 1971. (17) PALMGREN, B., WALLANDER, B. Cigarettriikning oeh abort. Konsekutiv prospektiv undersokning av 4312 graviditeter. (Cigarette smoking and abortion. Consecutive prospective study of 4312 pregnancies) Llkarrtidningen 60 (22) : 2611-2616,197l. (18) PETTERSSON, F. Medicinska skadeverkningar av tikning. Rijkning och gynekologisk-obstetriska tillstand. (Harmful clinical effects of smok- ing. Smoking and gynecological-obstetrical condition.) Social-Medi- cinsk Tidskrift Z(Special No.) : 78-82, February 1971. (19) RUSSELL, C. S., TAYLOR, R., LAW, C. E. Smoking in pregnancy, maternal blood pressure, pregnancy outcome, baby weight and growth, and other related factors. A prospective study. British Journal of Pre- ventive and Social Medicine 22(3) : 119-126, July 1968. (20) SIEBFX, S. M., FABRO, S. Identification of drugs in the preimplantation blastocyst and in the plasma, uterine secretion and urine of the preg- nant rabbit. Journal of Pharmacology and Experimental Therapeutics 176 (1) : 65-75,197l. (2.2 ) STALHANDSKE, T., SL~~NINA, P., TJALVE, H., HANSSON, E., SCHMITERL~W, C. G. Metabolism in vitro of 14C-nicotine in livers of foetal, newborn and young mice. Acta Pharmacologica et Toxicologica 27(5) : 363- 380,1969. (22) TAYLOR, W. F. The probability of fetal death. IN: Fraser, F. C., McKusick, V. A. (Editors). Congenital Malformations. Proceedings of the Third International Conference, The Hague, The Netherlands, September 7-13, 1969. New York, Excerpta Medica, August 1970. pp. 307-320. 90 (28) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of the Surgeon General: 1971. Washington, U.S. Departr ment of Health, Education, and Welfare, DHEW Publication No. (HSM) 71-7513, 1971. 458 pp. (Z4) YEBUSHALMY, J. Mothers' cigarette smoking and survival of infant. American Journal of Obstetrics and Gynecology 88 (4) : 505-518, February 15, 1964. (25) YERUSRALMY, J. The relationship of parents' cigarette smoking to out- come of pregnancy-implications as to the problem of inferring causa- tion from observed associations. American Journal of Epidemiology 93(6) : 443-456, June 1971. 91 CHAPTER 6 Gastrointestinal Disorders Contents Page Highlights of Current Gastrointestinal Information . . . . . . . 98 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 95 GASTROINTESTINAL DISORDERS The 1971 report, "The Health Consequences of Smoking" (4), summarized the relationship between smoking and peptic ulcer as follows : Cigarette smoking males have an increased prevalence of peptic ulcer disease and a greater peptic ulcer mortality ratio. These relationships are stronger for gastric ulcer than for duodenal ulcer. Smoking appears to reduce the effectiveness of standard peptic ulcer treatment and to slow the rate of ulcer healing. Studies of the effect of smoking on gastric secretion in patients with peptic ulcer and normal controls have produced conflicting re- ports (4). Recently, Wilkinson and Johnston (5) reported a sig- nificant inhibition of pentagastrin-stimulated gastric acid secretion after cigarette smoking by normal volunteers, while Debas, et al. (1) found no significant overall change. Wilkinson and Johnston also studied patients with gastric and duodenal ulcers in whom a sig- nificant inhibition of pentagastrin-stimulated gastric secretion was observed after the patients smoked one or two cigarettes over a Period of 10 to 15 minutes. A study by Konturek, et al. (3) suggests that alterations in pancreatic and biliary secretion may be responsible for the relation- ship between smoking and peptic ulcer. Nicotine was infused in mongrel dogs in doses corresponding to amounts absorbed from smoking up to four cigarettes in one hour. In the pancreas, nicotine inhibited the secretin-stimulated secretion of both fluid and bi- carbonate, and the degree of inhibition was dose-related. Spontane- OUs biliary secretion of bicarbonate was also depressed by the drug. Nicotine had no effect on gastric secretion of acid, gastric mucosal blood flow, or the mucosal barrier to hydrogen or sodium ions. This inhibition of pancreatic and hepatic bicarbonate secretion may de- prive the duodenum of sufficient alkaline secretion to neutralize gas- tric acidity and may be one biomechanism linking cigarette smoking and peptic ulcer. Dennish and Caste11 (2) noted the clinical association between cigarette smoking and heartburn. To investigate the biomechanism of this relationship, lower-esophageal sphincter pressure determi- nations were made before and after smoking in six normal male volunteers. All of the volunteers were cigarette smokers. In each 97 subject after the onset of cigarette smoking, there was a rapid d+ crease in lower-esophageal sphincter pressure from the basal level. This diminution in sphincter pressure persisted until smoking was stopped, at which time the pressure returned rapidly toward nor. mal. Mean basal pressure was 19.6 -C 2.1 (C 1 S.E.) mmHg. and mean pressure during smoking was 11.4 2 2.2 mmHg. The differ. ence between these pressures is statistically significant (P < .OOl), No changes were noted when volunteers puffed on unlit cigarettes. Variable responses were noted when volunteers smoked cigars and pipes. The investigators concluded that cigarette smoking decrease the effectiveness of the lower-esophageal sphincter as a barrier against gastroesophageal reflux. HIGHLIGHTS OF CURRENT GASTROINTESTINAL INFORMATION In addition to the summary statement cited at the beginning of this section, the following observations have been made: 1. A possible link between cigarette smoking and peptic ulcer has been demonstrated in dogs in which nicotine was found to in- hibit pancreatic and hepatic bicarbonate secretion. This could lead to peptic disease by depriving the duodenum of suf- ficient alkaline secretion to neutralize gastric acidity. 2. An investigation in human volunteers has suggested that cigarette smoking decreases the effectiveness of the lower- esophageal sphincter as a barrier against gastroesophageal reflux. GASTROINTESTINAL DISORDERS REFERENCES (1) DEBAS, H. T., COHEN, M. M., HOLUBITSKY, I. B., HARMKIN, R. C. Effect of cigarette smoking on human gastric secretory responses. Journal of the British Society of Gastroenterology 12: 93-96, 1971. (2) DFNNISH, G. W., CASTELL, D. 0. Inhibitory effect of smoking on the lower esophagea! sphincter. New England Journal of Medicine 284(20) : 1136-1137, May 20, 1971. (9) KONTUREK, S. J., SOLOMON, T. E., MCCREICHT, W. G., JOHNSON, L. R., JACOBSON, E. D. Effects of nicotine on gastrointestinal secretions. Gastroenterology 60 (6) : 1098-1105, June 1971. (4) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of the Surgeon General: 1971. Washington, U.S. Depart- ment of Health, Education, and Welfare, DHEW Publication No. (HSM) 71-7513, 1971. 458 pp. (5) WILKINSON, A. R., JOHNSTON, D. Inhibitory effect of cigarette smoking on gastric secretion stimulated by pentagastrin in man. Lancet Z(`7725) : 628-632, September 18, 1971. 98 CHAPTER 7 Allergy