Reprinted by permission of American Association for Maternal and Infant Health TKE B~L~I~ OF ~TE~ ANLl INFANT HF.ALTH Vol. VII, No. 2~18-23, 1960 Ih. Vitgtnin Afigar is a member of the Deparlarriit of Itesearch of the National Foundation (March of Ihmrs). lbrmerly she was Professor of Anrslhcstology at Columbia Univcrsi& and active in itre field of perinatal research. Congenital anomalies always will be present in the human race. They are an integral part of every living species. That they need to be present to the ex- tent to which they are now found is by 110 means a foregone conclusion. Some methods are presently at hand to de- crease the frequency of certain anoma- lies, while other factors, if uncontrolled, will cause a theoretical increase. The ap parently relentless increase of population throughout the world will result in more apomalous children who will ne-ed diag- nosis, treatment and care, but it is not a necessary corollary that the rate of mu- tations will also increase. What is the present incidence of con- genital anomalies? The answer to this question involves so many factors that no true answer is possible. What is meant by "congenital anomalies"? The derivation of the word "congenital" sug- gests that its use be confined to the time of generation or fertilization of the egg. This interpretation places great stress on genetic factors and little on environment, except for the biocliemical and physical 18 Congen ita I Anomalies, 1960 environment of the oocyte, spermatozoa, and fallopian tubes. Common usage dic- tates that the term "congenital" refers to "the time of birth." What is meant by "anomaly"? A dictionary definition, which represents the opinion of a cross- section of intelligent people, suggests "a departure from the normal." Thus, a caput succedaneum, or a fractured clav- icle, at birth, is, strictly speaking, a con- genital anomaly, The term "malforma- tion" denotes a morphological anomaly and in this decade is too limited. Al- though chromosomal aberrations would now be included under this morpholog- ical term, the biochemical anomalies of enzyme systems, hemoglobin chains, hap- toglobins and other proteins would nec- essarily be omitted. At what period of life is the incidence figure desired? Almost nothing is known in human beings, as to the survival of every fertilized egg. The data of Hertig and Rock' are the best at present regard- ing the recovery of the product of con- ception after a known date of possible fertilization. Their figure of 30 per cent, for successful recovery of embryos two weeks after coitus in women undergoing hysterectomy, agrees well with other mammalian data. In another 30 per cent, the zygote or early embryo was ap- parently not viable. Abortion specimens should be examined with at least the same care as that expended on autopsies of neonatal deaths. The published data for morphological anoillalies accompany- ing stillbirths of viable age or weight seem quite low: 10.1 per cent according to Potter.2 No published investigation has been made of biocliemical or chro- mosomal anomalies in human stillbirths, a fertile field for research. The series of almost GO00 infants and children reported by McIntosh et UP in 1954 affords the first clue to incidence of morphological anomalies found in an urban American population. They re- port that 43.2 per cent of the anomalies evident after six years of follow-up visits were diagnosed at birth. By the end of the first year, a total of 97.3 per cent of malformations had been diag- nosed. In the study of Wallace et al,4 their data show that 84 per cent of the anomalies occurring in 629 children who had died with congenital malformations, were diagnosed by the end of the first year. Many more studies of this type are needed, with the denominator popu- lation clearly defined. For what population is the incidence of congenital anomalies being described? In Japan, Nee1 and Schull6 ran into dif- ficulties in determining the effect of acute radiation from the Hiroshima and Nagasaki experience because the base- line incidence of congenital anomalies in the Japanese people was unknown. They were surprised to find that this incidence in their control group was dis- tinctly higher than in the United States. Careful epidemiological investigations by Penrose,6 Stevenson,? Record and Edwards8 and others in Great Britain and Ireland seem to indicate an especial- ly high incidence of anencephaly in Ire- land and of congenital dislocation of the hips in Birmingham. In another British study, the biochemical anomaly result- ing in phenylketonuria has been found to stem from grandparents born in Ire- land.@ There are no data for the vast majority of population groups. What degree of anomaly should be in- cluded? The slightly webbed toes of the Dionne quintuplets were of no signifi- cance to them but are singularly impor- tant to the geneticist. This leads to other questions. For whom or what dis- cipline is the incidence figure requested? What time in an individual's life is being considered? How serious an effect is produced by the anomaly? What is the source of information regarding in- cidence? The anatoniic classifications of anom- alies have long been existent and have been useful to a certain degree. Below are listed many other factors to be con- sidered in classifying anomalies and re- lating them to estimates of incidence: Effect of Anomaly Fatal Seriously disabling Moderately disabling Of little consequence Of no consequence Time in Life of Individual 1st trimester of pregnancy zygote embryo fetus 2nd trimester of pregnancy 3rd trimester of pregnancy Neonatal period (0-28 days) Infancy (28 days to 1 year) Childhood (1 year to 12 years) Adolescence (12 to 18 years) Adulthood (18 years and older) Observer Patient Relatives of patient General practitioner Medical specialist General Pediatric internist surgeon Pediatric surgeon Gynecologist Physiatrist Metabolic Psychiatrist Neurologist Public health Obstetrician officer Pathologist specialist Plastic surgeon Anatomist Biochemist Dental specialist Geneticist Government organizations National Office of Vital Statistics U. S. Public Health Service War Department Psychologist Public Health nurse Rehabilitation workers Social service workers Statisticians Veterinary specialist Voluntary health organizations 19 Source of Information Autopsy Clinical record Hospital Outpatient clinic Private practice record Patient Patient's family et cetera Available incidence figures indicate that severely disabling anomalies which are often fatal are present in 0.9 to 3.1 per cent of live births,lO, 11 that there is approximately a 7.0 per cent incidence of anomalies of significance to the pedia- trician in the first six years of life,3 and if minor dermal, dental and skeletal anomalies are included, almost half the population have anomalies. The causes for congenital anomalies are much more elusive than figures for incidence. The extremely complicated interrelation of genetics and environ- ment impatiently awaits further inter- est, and further skills of able people with a background in genetics, medicine, epidemiology, biochemistry, radio bio 1- ogy and even unnamed specialties. With present knowledge, it has been suggest- ed that genetic influence is mainly re- sponsible for congenital anomalies in 20 per cent of patients.l2 As suggested by Runner,l3 every anomaly involves a "genetically permissive" individual, and an environment which is "permissive." There can be no complete separation of environmental and genetic effects. Neell2 has indicated that another 10 per cent or so of congenital anomalies in human beings are related to antenatal viral infections of the mother. There is definite evidence of effects of rubella infection especially in the first eight weeks of pregnancy, which results in cataracts, deafness, or congenital heart lesions in the infant, depending on the week of infection. There is some evi- dence for fetal death following polio- myelitis in early pregnancy, but none to date for the production of congenital anomalies. Mumps also is under sus- picion as being related to the production of human malformations. Data on the effect of the influenza virus are conflict- ing. While it is logical to associate 20 viremia in the mother with adverse ef- fects on the fetus, it is possible that toxic by-products of virus infection may be responsible for anomalies, even without proven viremia. At any rate, it is most likely that anomalies resulting from virus infection of the mother during early pregnancy are not heritable, and should be classified as environmental effects, with no stigma of possible future anomalies in siblings, nor in the next generation. There is a remainder of 70 per cent of congenital anomalies for which a proper cause is not known. Chromosome aberrations and enzyme deficiencies may account for another ten per cent, but such investigations are only recently un- der way. What can be done about serious anom- alies found at birth, today? The first line of attack is to expect them, in cer- tain conditions. A thorough prenatal history should reveal the presence of anomalies in pr e v i o u s pregnancies, while in many instances, such as viral infections early during the previous preg- nancy, these anomalies have no known relation to an abnormal second preg- nancy; other anomalies do have a small, but definite relation to their occurrence in subsequent pregnancies. Their chance of doing so depends on the type of in- heritance, if it is known, Le., dominant, sex-linked recessive gene.14 Although nothing definitive can be done for these conditions in the immediate postnatal period, a somewhat guarded prognosis on the part of the obstetrician and pedia- trician before delivery may spare the parents the shock of a second abnormal pregnancy. A few conditions which are operable at birth have been reported in more than one child, i.e., tracheo- esophageal fistula. The pediatrician, knowing of a previous anomaly in the family, will look especially for the anom- aly in the next child, and institute prop- er therapy promptly. There is on rec- ordl6 a report of a woman, who herself had a congenital heart lesion of the cya- notic type, and who had had two anen- cephalic children. Surgical repair of her heart lesion resulted in normal oxygena- tion. Her next cliild was entirely nor- mal. Altliougli iioi coiidiisive, this rc- port fits in with cxpcrimental data oL' Ingalls and others.'" If polyhydramnios is present in tllc mother, anomalous children also shou Id be expected. The high association of this condition with anomalies in the off- spring has been known for years. Esti- mates of the association range from 4 to 59.5 per cent.". 18 The anomalies which are found, following pregnancv with polyhydramnios are associated with in- terruption of the normal circulation of amniotic fluid during the last trimester. A variable, but appreciable amount of amniotic fluid is actively swallowed by the fetus, absorbed from its upper intes- tinal tract, and returned to the placenta by the mesenteric and umbilical circula- tion. Any interruption of this flow may lead to polyhydramnios. Several defi- cienciq in the central nervous system have been cited by Prindle as a cause.19 All infants with anencephaly involving a functionally absent medulla are de- livered from mothers having polyhy- dramnios, while the mothers of those with an occipital bone, or remnants thereof, which have a minimally func- tioning medulla do not have polyhy- dramnios since the fetus can swallow amniotic fluid. Many of the mothers of infants with tracheo-esophageal fistula and esophageal atresia have polyhydram- nios.20 Indeed, the diameter of the fis- tula can be predicted from this symptom. All mothers of infants with complete in- testinal obstruct ion, whether from atresia, volvulus, constriction by an an- nular pancreas, or peritoneal bands have polyhydramnios. One mother of an in- fant who had suffered antepartum per- foration of the ileum with tremendous hydroperitoneum had polyhydramnios.21 It is indeed true that in many cases of polyhydramnios, anomalies are not found in the infants at birth, but they are often missed because of inadequate examination. In pediatric teaching, em- phasis should be placed on the impor- tance of questioning whether there was excessive amniotic fluid in the mother, when a newborn child is admitted as an emergency, or an excessive gain of wciglit (over 25 pinds). If the mother is not ;I\ ailablc, die lather accompany- ing he child olten knows the correct answer, or better yet, a conversation with the obstetrician will reveal polyhy- dramnios in the mother before delivery. Thus, the diagnosis of the anomaly in the infant can quickly be narrowed to those in wliich reparative surgery will be lifesaving. The second line of attack is to ex- amine all newborn infants routinely in the first fifteen minutes for anomalies. Aside from the obvious gross malforma- tions, many hidden anomalies can be diagnosed with nothing more than a stethoscope, a flashlight or laryngoscope and a catheter, by an inquisitive physi- cian or nurse. The catheter is used to rule out choanal, esophageal, anal, and rectal atresia, and to measure the con tents of the stomach. Over 25 cc should suggest partial or complete intestinal ob- struction. Observation for appearance of bowel sounds, and rectal swab exami- nation for squamous cells should lead to a definitive diagnosis. The stethosocpe is used to rule out the presence of dia- phragmatic hernia, which causes a shift of the heart sounds away from the hernia, and absent respiratory sounds over the site of the hernia. The light is used to rule out cleft palate due to bony or soft tissue defects. Surgery, as soon as the infant has re- covered from tlie normal birth asphyxia, and possible additional antenatal as- phyxia, is indicated in tlie following con- ditions: tracheo-esophageal atresia, per- foration of the stomach, intestinal obstruction, anorectal atresia, omphalo- coele, and diaphragmatic hernia. Auscultation of the various heart sounds will not yield diagnostic infor- mation unless their site of maximum in- tensity is distinctly misplaced. Murmurs and abnormal sounds are not diagnostic. Angiocardiography and phonocar d iog- raphy from within the paracardial blood vessels may give useful informa- tion, but at the present, these are tech- nics demanding highly trained person- nel. It is now known that tliere may be a flow of blood in either direction, or 21 both, for some days or weeks after birth through the dwtus, without abnormal- ity. Persistence of flow may be associ- ated with other cardiac lesions. In some, maintenance of Bow through the ductus is lifesaving. Ligation is fatal. A pedi- atric cardiorespiratory team is the best hope for this group of patients. In a few newborn infants, surgery is imperative to prevent death. Tracheos- tomy for complete laryngeal stenosis or for choana1 atresia is occasionally indi- cated. The latter condition may be treat- ed successfully by inserting an infant pharyngeal airway, or pulling the tongue away from the posterior pharyngeal wall with a suture through the midline near the tip. Operations on the bony atresia itself are being developed.22 A third line of attack is presented by exciting new diagnostic opportunities during the first week of life. These are concerned with biochemical abnormali- ties. The mental deficiency accompany- ing phenylketonuria can be completely prevented by early diagnosis and appro- priate therapy. The same is true for galactosemia, Rh incompatibility is the anomaly of blood groups most widely recognized and treated, but many others exist. Abnormal amounts of fetal hemo- globin, abnormal hemoglobin chains, ab- normal haptoglobins and other serum proteins can be diagnosed by new metii- ods of protein analysis. Routine blood grouping of the infant for the common AB0 groups may point out incompati- bilities with the parents so that kernic- terus may be avoided by exchange trans- fusion, or even newer therapeutic methods. Practical human genetics is in its in- fancy. The mapping of gene loci on human chromosomes is just beginning, while in mouse chromosomes, it is far advanced. The discovery of three poly- morphic loci on human chromosomes may lead to unexpected diagnoses and thus appropriate treatment: (1) The Lutheran blood group and the AB0 secretor loci, (2) the Rh locus and that for elliptocytosis, and (3) the AB0 locus and that for the nail-patella syndrome, in which the finger and toenails are var- iously deformed, the patellae are abnor- mal, the iliac crest shows unusually bony growth and the radius and ulna are fre- quently fused at the proximal end.** In the last four years, technics. to de- termine chromosome abnormalities have been developed. Over 35 different con- ditions have already been identified in human beings. Many of these involve diagnosis of sex. It is not surprising that human populations appear to have as many intersex variations as other mam- mals. A smear of the buccal mucosa, suitably stained, can be used to identify the presence or absence of sex chroma- tin, or the diagnosis of double sex chro- matin. Tissue cultures of minute sam- ples of skin or bone marrow can be harvested, and the infant's karyotype defined in detail. Certain entities are already apparent. All mongols have chromatin material equivalent to '47 chromosomes. However, not all persons with 47 chromosomes are mongols. In general, individuals with any number of chromosomes other than the usual 46, are not normal. Most are mentally de- ficient. What are the prospects for the future? To date, there is no suggestion as to what can be done about abnormal chro- mosomes. It is not known whether the extra chromosome in mongolism con- tains normal nucleic acid, or an abnor- mal type. Most individuals with such abnormal chromosomes are not fertile, but the record of seven marriages involv- ing one or both partners who were mon- gols shows that 50 per cent of the off- spring were mongols.z* Cytologists at present are advancing knowledge of heredity by surgery of the cell, micrurgy. In lower forms of life, nuclei are being t~~planted from one cell to another. The next step will be to transplant or delete chromosomes and observe the ef- fect on the organism. Following this, anatomy and chemistry of genes and gene particles will have been defined, and their transpiantatio~ may be ef- fected. For several years, mammalian eggs after fertilization have been transferred to foster mothers (rabbits) and the rela- 22 tive etfect of heredity and environment persons trained in these special methods, noted.25 Many more such experiments and able to discover new metliods are in niany species are needed to properly needed. Ten years from now, many of interpret the results. the current problems will be solved and Only recently, it has been reported36 new and different problems will present that it is possible to distinguish from. themselves, only to be met by better- each other spermatozoa wl&h carry the trained, more experienced investigators. male, and those which carry the female Pessimism is impe~issible. chromosomes. So far, it has not been possible to separate these two types of spermatozoa, but such a time is not far off. All these seemingly tinrefated experi- merits have a bearing on human abnor- BlBLlOGRAPHY 1. Hertig, A. T. and Rock. J. Series of potentially abor- tiye ova recovered from fertile women prior to first mid 2. Potter. E. L. and Adair. F. L. Fetal and Neouatal 3. McIntosh, R.. Merritt. K. K.. Richarda, M. It.. spmucfi. M. H. and Bellows, M. T. The incidence of congenital malformations: A rtudy of 5,964 pregnancies. Pediatrics J4: 505-522, November, 1954. 4. Wallace. H. and Sanders. D. Mortality experiena in children with congenital anomalies. J.Pediat. 5f: 801-808, June, 1959. 5. Schull, W. J. and Ned. J- V. Atomic bomb explooion aud the pregnancies of biologicaIly related parents. Amer. 6. Pen-. L. S Genetics of anencephaly. J.Ment.Dcf.Ra I: 4-15. 1957. chance for transmission, First cousins 7. Stevenson, A. C. The load of hemxitary defec~ in hu- man populations. Radiat.Res. Suppl. 1: 306-325, 1959. fluences related to the etiology of congenital dirloation Of menstrual wid. A=r.J.Ol=teLGyncc. 558: 96s. 1949. tkath. 154. Thtr University of Chicago prar. ~9. Even more* the of a true social conscience among human ture generations, is within reach bein@, and a real desire to improve fu- ~~OZU.'~ The few, well-proven genetically quenTe should not be permitted the should not consider reproduction unless their genetic history is marked by ab- sence of expression OE delterious genes. Young married women should not have eIective x-rays for diagnosis in the pelvic determined diseases of serious conse- J.Pnb~.Hlth. 19: 1621-1629, December, 1959. 8. Record. R. G. and Fdwardq J. H. Environmental in- ihe hip. Brit.J.prev.m.Med. 12: 8-22. January. 1958. 9- genetics. University c- of Utah. May, on methodofogy 1960. in humvl ~it~~~~o~a~~~~ ~~m~~~~~j~~~ $;$yFk zy: Pediatrics 12: 525, 1953. 11. Tholen, A.. cited by Logan. W. P. D. Incidence of regions, except in the first two weeks congenital malformations and their relation to vim infm- after menstmation, for the very early tions during pregnancy. Brit.med.J. 2: 641. 1951- 12. Neel. J. V. International Medical Congress on Congcn- embryo is especially sensitive to radia- ita1 Malformations. London. July. 1960. 13. Runner, M. Course in Medical Chetia. Bar Harbor, tion. Young married males, who have M~I~. st, 1960. had accidental doses of radiation to their ~~a~~~~ 6~~U~v~~~~~~~~~o~~~g~et~ testes, should not consider attempts at 15. Olim. C B. and Turner, H. 8. Anenccphafy in fanam of a mother with tetralogy of Fallot. J.Amer.med.As8. 119: fertilization for at least two months. Re- 932, July 5, 195% 16. In& T. H. and Philbrook. F. R. Monaroritia in- covery of spermatozoa from radiation duced by hypo& New Ewl.J.Med. 259: 558.564, seprrm. damage occupies about that period of 2 t&:58&. H. Dircus*w of cw: repoRl by I)r. E. E. time, but at least it is known that B;nzeI. Aker.J.Obuet.Gynec. 21: 784-786, November. 19%. Giud by Moya F Am V Jam- L. S. and Bemen. C. spermatozoa can recover born such an Hydrasmnios ah '&gcn:tal ';-alkh J.A==.A assault. 18. Polck, E. LIL expectancy with hydramniok Mrhr. Gebunrch.GynUk. 63: 203-210. July. 1933. Cited by Mwa, Although chemotherapeutic control of F.. et d. 19. Prindle, R. A., Ingalls, T. H. and Kirkwmd, S. B. viral infections has been relatively un- Materod hydnunniol. and congenital momalien of antd successful thus far, there is considerable zy w-* Chance for SUCCeS along this line. pm- 20. Humphw8, G. H.. Hasp. B. M. and F-r, J- Coa- genital atda of esophagus. J.ThoraC.Surg. 32: 539-3M. sibly, the intentional exposure of young 1s. 21. Penonai Communication. C. Marshal Lee. Jr. cfndn- women of high school age to various nati,Ohio. 1954. 22. &infield. H. H. Wayr and meam to h-t mortality due to suffocation. J.Anu?r.mcd.Aa. 170: 647450. June 6, 1959. 23. Penroae. L. S. Outline of Human Genetkr Pp. 79-81, infections during early pregnancy. There is a new awakening of interest JO~U wilcy and Sow. NM York. 1959. 24. Lebmann. 0. and Forsunan. 8. Chmmomme compk- in the future of human beings. There is mutt in a moogdoid mather, b chiid ond the child's father. Lvlar 1/71% 498. Febniaq M, 1960. thought as to the improvement in their 25. Chang M-C, Transplantation d feailired rpbbit ova. mental and physical attributes. Means p&f&,Ts* ~&~~~~~b,w rd ,prrmoto- are at hand to diagnose and study defi- ciencies in these attributes. Many more 173: 1552-1556. AU~US~ 6. 1960- Engl.J-Med. z12: 555-561D AprU viruses may lead to diminution of such 265f54;:g6=; ;yknetic change. American seientiu 47: 551-562. December. 1959. 23