325 VfRG.lNIA APGAR, M.D., M.P.H. New Yorlr, New YG&* 9 N TI~J.: operating ;room or interisive care -$: unit, v;e tcnd to take for granted the de- pendahle quality of the fluid.. vvre admiiiistcr to our p'~ticnts. ff the label on the bottle reads Gnstc,r-l'ravenoI, we know we have an extra margin of safety. It is a pleasure to thmk ~IICITI publicly for providing ancsthesi- ologists with this peace of mind, a corn- iriodity often in short supply in thc operat- ing room. We thntik them also for less tan- gible contributions, such as their support of iectrireships and symposia. I haw been perniittcd to select a topic only remotely related to anesthesiology, though less so in pediatric surgery, in which the latge majority of your patients have birth defccts. There is little lif~eiiltood that this nuntber of patients \vi11 decrease. Rather, it will almost surely increase. In a recent study at Johns Ilopkins, the children of parents who theinseIvcs were operated on for congenital heart disease hale been fol- lowed. TiG'hereas the estimate of this condi- tion in the genpral population was 0 3 per cent, those childi i 11 who hnd one pnlcnt with a hi>toi y of succ,escful fmrt sur;c'ry in childhood had congcnital heLx t lesions at the rate of 1.8 per cent, a six-fold increase. There was no appnrcnt relationship between the type of heart defect in the paicnt and in the child. In this particular category of congcnital anomalies, the eternal, nagging problem of classification COI~CS up. I personalfy think that the diagnosis patcnt ductus arteriosus should always be separated cleariy from other cardiac diagnoses. It is not a dcvelop- mental defect, unless ~c~o~~i~)~~ied by an aneurysm of the ductus, but a physiologic defect. fls continued patency is not the xe- sult of hereditary factors, nor oi environ- mcrctal effects before birth, but, in all piob- ability, of environmental effects after birth. 326 ~scsTIiEsr.4 AYD ANALGI:SIA . . . Current Researches VOL. 47, No. 4, JULY- GUST, 1969 Importance of Plinrrnncogeitdics - Also related inore cIosely to a~icst~iesio~o~y is the specialty of phaniiaco~enctics. Errors in the construction of protein molecules arc as much birth defects as cleft lip or palate, which tlieniselvcs prohably occur bccause of molecular niistal~es. After Garrod's pres- cient work at the turn of the last century, the saga of pseudocholinesterase aberration started ~sl~ar~~iacogci~ctics on its merry way. Understanding of ihe relationship of barbi- turates to acute porphyria followed shortly thereafter. G-G-PD deficiency was quickly identified as being related to primaquine sensitivity, intolerance to certain sulfa drugs and fava beans - even to the smoke arising froin burniiig bean pods. A delightful essay by Louis Lasagna. "The Diseases Drugs Cause," in the Summer, 1964, issue of Per- spectices in Biology and nfedicine is highly recommended. I think it likely that niost drug reactions will be found due to some enzymatic quirk, often heritable in nature. Back in 1960, shortly after I joined fhe research staff of the Nations1 Found a t' 1011- March of Dimes, I was coaxed by Dr. Ed- win Gold to write an article, "Congenital Anomalies, 1960." Its rereading gives `me cause for both optimism and ~~cssimism. At that time, the proposed strqcture of the DNA molecule had been before the public for 6 years, and for 4 years it was known 1. hat huli1aii eel Is con tai ned 46 chromosomes, not 45. At scientific meetings, there was hot discussion about the transcription of the hereditary message via RNA to the forma- tion of proteins. Was it a triplet or doublet code? Was it degenerate? Were there non- sense triplets? Was rihosoinal RNA specific? These particular questions have all been answered. Xt is a triplet code; it is degenerate; dl amino acids arc cded by two or more trip- lets. There are no noiiseilse triplefs. All 64 possible coiiil~inations of the four pririne or pyrimidine bases have been assigned to specific amino acids or to "start" or "stop" positions in the reading of the DNA code. Ribosomal RNA is not slxcific. Even E. coli ribosomes can lx niade to niake hemoglobin if fed the right RNA message. But, as expected, new questions have arisen in geo- metric proportions. Jacob and h4onod gave birth to a theory of genetic control iiivolving regulator genes, repressors and derepresors, operator arid structur:il genes, derived from their work with bacteria. It is a brilliant theory, which has given a great impetus to research in this field. Whether or not it applies to marn- mnlian ceIls remains io he proven. White- house recently has divided living organisms into two major divisions, ", . . a chromone- maf kingdom, in which the DNA js not associated with basic protein and no nuclear meinbraiic encloses the UNA (bacteria and blue-grcen algae) ," while all tlie rest is `*. . . a chromoson,aI kingdom in wliicli the "DNA is associated with basic protein and a nuclear niembmne encloses the DNP ex- cept during cell division." 'There is inuch discussion about extra-nuclear UNA, found in mitochondria, with a different nucleotide coding than chromosomal DNA. The elusive hereditary pR`rticles of hten- del, named "genes" by Jo1iftnnsc:i over 40 years inter, have finally been translated into chemical terms. `It is estimated that a gene consists of about 1000 nucleotide pairs. The snialIest known organism, the virus X174, which has a single helical DNA molecule, 1 (I I~-~~~~"-U3Vjl---*---~-~ -~--~-~~~,-l-Vl-~~~~~----~--~.~~-~~ V..~,~,s-a--s= ?nc VIRGINIA APGAR, M.D., M.P.H. is the former Chairman of the Department of Anesthesiology, the first Professor of Anesthesiology, and the first woman physician to have been awarded a full professorship at her alma mater, the College of Physicians and Surgeons of Columbia Uni- versity, New York City. Since 1959 she has been Head of the Division of Congenital Malformations of the National Foundation and was recently appointed Vice-President for Medical Affairs. The International Anesthesia Re- search Society was honored to have Dr. Apgar accept its invitation to present the Sixth Annual Baxter-Travenol J;ecture March 20, 1965, at its 42nd Congress jn Sari $hitcisco, Cdifornia. B . : ' j i e f ! t c &--.-==.+- _.. --..."* >-.. *- ---,.. ./ .%=*-,-& _-l-%...* -A*--- w. ~~~~,*~~~~~~-~--~-~=~.~~= -Lo-rs"l -A&&*<*-.-.,-s Huninn Congenital Anomalies . . . 1068 . . . Apgar 327 has five genes or 5000 nucleotide pairs. The lambda virus has 50 genes, T, phage 20,000 ancl .Drosophila 500,~O~ genes on eight chromosomes, only 0.1 pcr cent of which have been mapped. In Iiuman beings with 46 chromosomes, 110 gene locus has ciefinitely been mapped though a number of linkage groups have bcen discovered. In 1960, I mentioned some 35 different human conclitioiis in which chro~noso~~~l abnormalities had been identified. This number is now well over 100 and, in fact, is limited only by methods of cliroinosomc study. The coinmonfy used technics of count- ing the total number of chromosomes, ar- ranging them in order by size and ratio of short and long arms, and their ingestion of tritiated thymidine by autoradiography, are responsible for the increase in positive di- agnoses but leave much to be desired. Ncw technics are needed to study hunian chro- mosomes, especially in meiosis. Electron microscopic photographs of the synaptirnal protein in meiotic chromosomes of corn (Mea zea) give hope that this technic wilf pay off with niainmalian chromosome stud- ies. Does one chromosome fiqve one DNA molecule, or docs it have many? There is evidence 011 both sides. Is tile repressor substance indeed a histone, though nonspe- cific itself, attached to a specific repressor RNA? Chroinosorne "Breaks" - Chromosonie "breaks" are much under discussion, prompt- ed by their discovery in leukocytes of pcoplc using LSD, arid their offspring as well. The offspring, though only a small group are under study, seem to be doing wt~ll, without birth defects or learning disabilities. In the leukocytes of children recovering from ru- beola infection, chromosome brcaIcs are fre- quently found. In fact, in 3 to 6 per cent of controls, such breaks are found. Are they really "breaks"? Tjio thinks not, if they are aligned. One strand of the DNA chain, though presently invisible, is probably in- tact and can reproduce the other strand without difficulty, as has been known for some time in the case of radiation effect on chromosomes. Only occasionally do inver- sions, translocations, or deletions occur. Chromosome breaks in leukocytes have been reported after the use of ninny conimon drugs, such as caffeine, aspirin, and tran- quilizers, but as far as tfic genetic irnplica- tions are coneei ned, chromosome breaks in meiotic cells must be studied. To dafe, only streptonigrin 11:~ been itlentificd as a drug which causes meiotic chromosomal breaks in human oocytes. It comes as no real surprise that the chro- inosonie coniplement of fetal cells in a qua- ter to n half of successful cultures from spontaneous abortion specimens have been found to be abnormal. Trisomies of all seven autosomal groups have been found, as well as several triploid and tetraploid fetusrs. It is a surprise that the most ~G~XT-IO~~ sex chromosome aberration in abortion speci- mens is the deletion of one sex chromosome, a condition which is often compatible with life and even norinal mentality. It is ob- vious in genetic counseling that it is im- portant to obtain an accurate history of spontaneous abortions. Whenever possible, such specimens s ho u 1 d be examined for chromosome analysis. Only about half of attempted cul turcs are presently succcssful, probably because of €ontanii~iation and de- lay in reaching a cylogcrietics laboratory. Problcms of h4ongofisnz - Those working especially with sex chroinosoines report an estimated incidence of sex chromosome ano- malies to be as high as one in 200 births, or 0.5 per cent. Living but abnormal chil- drcn have bmn. identified with chromosomal errors in groups A, B, D, E, aiid G. Only one child has been found with a missing autosome, from group G. Trisomy of pair 21 is the most coininon error, estimated to occur once in GOO births (mo~i~olism) . The causes for this nondisjunction are probably multiple. Heredity plays only a very ininor role, if any, unlike its role in families with a translocated 21 chromosome. It has been noted from Australian evi- dence that nio~~oljsm occurs in neighbor- hoods and in epidemics. It is suggested that the births of mongoloid infants regularly follow -- about 9 months later - epidemics of infectious hepatitis, as a result of ma- ternal infection early in pregnancy or pos- sibly just before conception. Four other studies in other parts of the world do not corroborate this idea. By 1969, a. definite ansuer should be found, for there is at pres- ent an unusual amount of infectious hepnti- tis in the State of Victoria, Australia. Another clue to the causes of mongolism has received reinforcement. In 19G0, it was reported from Canada thnt the rnottiers of inongoloid children had a history of x-ray exposure to the nbdomm before concept ion four and one-hrllf times greater than their ncigtiborIiooc1 controls. Such an experience was not found in the foilowup of women and 32s ASESTII~XA ASD AS`ALGESIA . . . Current Rescarchcs Vox,. 47, No. 4, JULY-AVCUST, 1968 their infants exposed to the atom boinbs in Hiroshima and Nagasaki. Recently a much larger series of families was examined in Baltiiiiore in which it was found that fluros- copy and radiotherapy were present seven and one-half times as often in mothers of ~iiongoloid children. ,Also, tlicre was a hint of evidence that greater percentage of the fathers had been in radar work in military service. The obvious preventive nicnsure suggested hy these findings is to protect, whenever possible, the future germ cells from tlie effects of x-ray at any age, both in intrauterine and extrauterine life for males and up to the age of genetic death in women. Another theory for the cause of mongo- lism is related to the sexual habits of mar- ried couples. Jt is well liiiown that mongo- loid children are born much more often to woiiicn Iiearing the end of their reproductive life. A wornan of 25 has about 1:2500 chance of giving birth to such a baby. At age 40, these odds are nearer 1:40 or 1:50. (On the hopeful side, a woman of 40 has a 98 per cent chance of not having a mongoloid baby). Studies of reproductive biology in mammals all agree that the sooner an egg is fertilized after ovulation, the better tlie quality of the product. The quality of the manmialiaii egg and possibly the sperm, too, bcgins to deteriorate after 3.1. to 36 hours and, by 48 hours, fertilization is not possi- ble. Ideally, the egg should be received in an environment of fresh, capacitated sperm. A study of the habits of long-married cou- ples shows that the frequency of intercourse, on the average, declines with tlie length of marriage. Prophylactic ineasures, if concep- tion is truly desired, are obvious. One im- portant question which has not yet been answered, either in human beings or sub- human primates, is "when is ovulation?" HopefuIly, future research will hold the answer. Teratogenic Drugs - Thalidoinide is the nost teratogenic drug ever discovered. Its availability to wonien of reproductive age has very properly been made impossible. There is no real evidence why women be- yond menopausal age and men should not have access to it as a tranquilizer or seda- tive, but the unhappy habit of Americans of sharing prescriptions with one another indicates that the decision to remove it from the market was correct. The only other group of drugs which have been dcmon- strated to be occasionally teratogenic are the progestins, frequently given to mothers with bleeding in thc first trimester. Over 200 instances of masculinization of the fe- male fetus have been reported. Fortunately, the changes in the external genitalia can be corrected by plastic surgery. A new con- cern has arisen receiitly about tlie use of these hormones and related steroids. There are rumblings on both sidcs of the Atlantic that the steroids uscd for certain pregnancy tests may be tcratogcnjc. Likewise, a break in the prescribed routine of taking contra- ceptive pills may result in abnoiniality if pregnancy occurs during the break. The present prescription for a better-qual- ity baby with respect to steroids is to stay faithfully with tlie routine prescribed for contraceptive pills; when conccptior, is de- sired, to stay off the pills entirely, have in- tercourse every 24 hours from the 10th to 25th day after the beginning of the last menstrual period, and avoid pregnancy tests which involve the use of ingested or injected steroids. There are very few prospective data about the habits of Anieriun women and their exposure to environmental teratogens. One teratologist considers that the teratogenic period in liurnan pregnancy is the first 40 days, another suggests that it is 60 days. Originally, in the large Perinatal Study of the National Institute for Neurological Dis- eases and Blindness, it was intended that women would be admitted to the Study only if they were in the eighth week of pregnancy or earlier. Now that 60,000 couples are under study, it is found that fewer than one third entered in the first 3 months of preg- nancy, or 90 days. There are almost no data about the first 40 to 60 days following conception. Two other studies, one in New York City and one in Oakland, California, are in prog- ress, but only prescription drugs are en- tered for analysis. It seems imperative to enlist a group of women who are planning to have children in a prospective study which will involve daily reporting of a iiuniber of parameters. Such a study is being planned by The National Foundation, which will be extended to a large group of couples if found to be feasible. Congenital Aiiornalies Not Remote from Anesthesiology Znfcrests - This subject of congenital anomalies is not so rcmote from anesthesiology in still another respect. No longer are birth defects thought of as coiidi- tions which are prcsent and diasnosed only at birth. In over 57 per cent of the babies, Human Congenital Anomalies . . . 1968 . . . Apgar 329 the condition is diagnosed long after the usual 48 hours after birth, when a birth cer- tificate must be filed. Between 65 and 95 per cent of significant birth defects are diag- nosed by the end of the first >'ear of life. In the broader view of this field, many birth defects are "expressed') in adolescents and adults, many of whom come under your care. A recent paper surprisingly reported the occurrence of congenital pyloric stenosis in a man of 40 who had had gastrointestinal symptoms all his life. Diabetes is probably the most common biochemical defect in man. One in four of LIS has one gene for diabetes, while one in 20 has two genes - one for each parent - and if we live long enough, we shall have this genetic defect expressed. Yet, this con- dition is a most complex one. Recent tech- nics show that juvenile diabetes is quite different from the middle-aged type. A true deficiency of insulin production seems to IX present in the former, while hyperinsulinism may exist in the older age group. The anes- thetic management may be quite different in these two types of diabetes. Congenital cerebral aneurysm is the most common diagnosis in strokes occurring in young people. Polycystic kidneys and other urologic abnormalities, such as those pro- duced by vascular aberrations, are frequent iii adults. Intestinal obstruction from a vari- ety of gastrointestinal anomalies, colonic polyposis, and diverticula are all evidenccs of late expression of hereditary conditions. The classic book, "The Mendelian Inlieri- pational therapists, and clinical psycholo- gists. Medical students and nurses are ex- posed to this interdisciplinary approach. The individual patient and his family are offered all these services at one visit. This great number of patients offers an oppor- tunity to set up birth defects registries, spc- cia1 genetic and environmental studies, and a comparison of therapeutic measures. This review has touched only on the high spots in the field of human birth defects. No mention has been made of what has been learned from the recent rubella epidcmic. Its occurrence has led to the identification of the virus, positive identification of anti- bodies and, shortly, to the production of an effective vaccine which will protect that 10 to 15 per cent of young women still suscep- tible to infection from the rubella virus. Neither has mention been made of the imminent eradication of erythroblastosis due to the Rh factor. Some 5000 deaths annually of liveborn infants, let alone many thousands of stillborn infants, will soon be averted by administration of a special vac- cine to Rh-negative women with Rh-positive husbands at the time of the first delivery. Many dozens of other immunologic de- fects, most of them fatal to the child who inherits them, are under study. Recently, two conferences on immunology have been held at Sanibel Island in Florida, sponsored by the United States Public Health Service and The National ~oundation- arch of Dimes. tance of Man," now in its second edition, You, as anesthesiologists, will, I am sure, catalogs 1487 inherited traits, many of which keep abreast of the literature especially you are already treating as anesthesiologists. dealing with inborn errors of metabolism. You have my synipathy when you are called upon to determine someone "legally dead" for cardiac transplant. I trust your efforts to change the legal usage of "death" from cardiac arrest to neurologic arrest will be successful in the near future. Fortunately, there are many advances on the therapeutic front. Augmenting the State Crippled Children's Clinics, 100 Birth De- fects Centers have been established by The National Foundation-March of Dimes, where specialists in many disciplines are concentrated. The associated medical spe- cialties are represented in full force: physi- cal therapists, medical social workers, occu- May I assure you of my continuing in- terest and great optimism in new develop- ments in anesthesiology.