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Chapter 6 BIRTH DEFECTS AND SELECTIVE ABORTION Until recently, a decision to forego childbearing was the only way in which a couple at risk of having a child with a severe genetic disorder could avoid that possibility.* Within the past decade, however, amniocen- tesis and other diagnostic techniques have been used to identify an increasing number of severe genetic and congenital disorders of the fetus during the second trimester of pregnancy. With prenatal diagnosis, and the opportunity to terminate an affected pregnancy by means of a legal abortion, many women who would otherwise have refrained from becoming pregnant can be helped to bear healthy children. Abortion also can be used with or without prenatal diagnostic procedures in cases for which there is reasonable risk that the fetus is affected or malformed from non-genetic causes. These include exposure of the woman to certain infectious diseases early in pregnancy (e.g., rubella), ingestion of drugs or other substances harmful to the fetus (e.g., thalidomide), or inadvertant exposure of the fetus to x-rays. As knowledge accumulates in this area, the indications for selec- tive abortion will expand. The Use of Prenatal Diagnosis Amniocentesis is a procedure by which a small sample of the amniotic fluid that surrounds the fetus is withdrawn from the uterine cavity via a needle inserted through the abdominal wall after the fourteenth week of pregnancy. (Before that time, there is usually not enough amniotic fluid to obtain an adequate sample and injury to the fetus may be more difficult to avoid.) *There are a number of articles providing data on the reluctance of parents with one genetically defective child to undertake the burden of having a second such child. When the risks were great (more than 10 percent), the majority of the patients interviewed elected not to become pregnant again. (See C. 0. Carter, K. A. Evans, J. A. Fraser Roberts, and A. B. Buck. "Genetic Clinic: A Follow-up," The Lancet 1: 281-285, February 6, 1971; Alan E. H. Emery, Muriel S. Watt, and Enid Clack. "Social Effects of Genetic Counselling," British Medical Journal. March 24, 1973, pp. 724-726; and Claire 0. Leonard, Gary A. Chase, and Barton Childs. "Genetic Counselling: A Consumers' View," New England Journal of Medicine 287: 433-439, August 31, 1972. 103
104 The fluid is analyzed directly for some disorders, such as those relating to certain developmental defects of the central nervous system. In other cases, the fetal cells contained in the fluid are grown in cell culture for two to four weeks to obtain enough cells of unquestioned fetal origin with which to perform diagnostic tests designed to detect the presence of chromosomal or other genetic disorders. Additional prenatal diagnostic techniques now in use include contrast radiography and ultrasonic imaging. Still experimental is direct fetal visualization (fetoscopy), which can be used to diagnose gross anatomical deformities in the fetus, and to facilitate retrieval of fetal tissue, such as blood samples, for diagnosis of other genetic disorders, including sickle cell anemia.I/ Almost two thousand genetic defects have been catalogued. They occur either as chromosomal abnormalities, or as defects at more pinpointed gene locations.2/ Chromosomal abnormalities are estimated to occur about one in every 200 live births. In the United States between 15,000 and 20,000 births with chromosomal disorders occur every year,37 4,000 of them with Down's Syndrome 4/ (once known as Mongolism). The great majority of fetuses with chromosomal abnormalities are spontaneously aborted early in pregnancy; it is estimated that 65 percent of pregnancies in which the fetus has Down's Syndrome terminate in this way.V Types of more pinpointed genetic disorders include X-linked defects, which are located on the female sex chromosome, and autosomal disorders, which are caused by defective genes on one of the other 22 pairs of chromo- somes. With rare exceptions, X-linked defects are expressed only in males. A common example is hemophilia.* In most of these cases, fetal diagnosis of the specific disease cannot be made, but the possibility that a certain X-linked condition might be present can be narrowed through identification of the sex of the fetus; if the woman is known to be a carrier, a male fetus would have a 50 percent probability of having the disease and a female fetus would have an equal chance of being a carrier or a normal infant. Autosomal defects include recessively inherited metabolic disorders, such as Tay-Sachs disease or phenylketonuria (PKU),** in which an abnormal gene has been inherited from each parent, as well as dominant disorders, in which only one defective gene must be inherited to manifest the disease. *In the human, a female has two X chromosomes and a male has one X and one Y. If the female fetus inherits a defective X chromosome from her mother, the normal X inherited from the father usually counteracts the deleterious effects of the defective X. In the male, the one defective X chromosome is expressed because the Y chromosome does not contain genetic material corresponding to that in the X. **See the glossary for a description of these disorders.
105 Approximately one percent of all infants are born with definable metabolic disorders^/ although not all are of a serious nature and some can be treated with varying degrees of success.* More than 20 metabolic disorders have been identified by prenatal diagnosis and nearly 40 more are potentially discoverable in utero.7/ Prenatal diagnosis is increasing for the detection of developmental malformations of the central nervous system, which may represent some of the most common types of congenital abnormalities.8/** Between 1972 and 1974, 211 amniocenteses were performed at a laboratory in Cardiff, Wales, of which 104 were performed for suspected neural tube malformations,*** 88 for suspected chromosomal disorders including 49 for high maternal age, and the rest for other reasons.1^0/ In Edinburgh, 58 percent of 217 pregnancies monitored by prenatal diagnosis were suspected at risk of neural tube defects; only 36 percent were for chromosomal defects.ll/ More than six thousand pregnancies have been monitored in the United States and Canada by means of amniocentesis and prenatal diagnosis, most of them for suspected chromosomal disorders related to advanced maternal age. A survey by Milunsky of American and Canadian experience with amniocentesis for prenatal genetic diagnosis is summarized in Table 18. Of 1,663 cases studied, 1,368 were examined for chromosomal disorders, 115 for X-linked disorders, and 180 for other metabolic disorders. Of those performed for possible chromosomal defects, 485 were requested because a Down's Syndrome child had already been born to the pregnant woman. Affected fetuses were found in five of these pregnancies. An additional 602 cases were examined because the pregnant woman was more than 35 years old. Among these, 13 affected fetuses were diagnosed and 10 of the pregnancies were terminated by abortion.12/ *Diagnosis of an inherited metabolic disorder requires biochemical tests to determine whether there is a deficient activity of a specific enzyme or an abnormal concentration of certain substances in the tissue. **The combined incidence of neural tube defects in Britain is 4-5 per 1,000 births. After the birth of one child with these defects, the risk of the second child also being affected is one in twenty, and after two such births, the risk becomes one in ten. Infants delivered with this type of defect usually are stillborn or die within a day.9/ ***Neural tube defects, such as spina bifida, often cause an increased concentration of alpha-fetoprotein in the amniotic fluid, permitting diagnosis of the malformation.
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107 Noteworthy in Table 18 is that at the time of publication of the Milunsky survey 893 normal births had occurred from the original group of 1,663 cases studied (643 births had not yet been accounted for). This supports the view that a major advantage of prenatal genetic diagnosis is its preservation of normal fetuses that might otherwise be aborted because of a feared genetic risk.13/ All pregnant women are not considered candidates for screening for genetic disorders in the fetus, but only those who can be identified at risk of giving birth to an infant with a severe genetic disorder and who would consider an abortion if an affected fetus were identified. Logical candidates for amniocentesis if they so choose are pregnant women who 1) previously had a child with a severe genetic defect if it is recognizable in utero; 2) have been identified as carriers of a chromosomal aberration or whose husbands have been identified as such; 3) have been identified as carriers of a severe metabolic disorder and whose husbands are also carriers; 4) have been exposed to infectious diseases, drugs, or radiation that might be harmful to the fetus; and 5) are beyond 35 or 40 years of age and therefore run a greatly increased risk of having a child born with Down's Syndrome or other defects. At age 40-44, a woman's risk of having a Down's Syndrome baby is 23 times greater than the risk faced by a woman less than 20 years of age. After age 45, the relative risk becomes 51 to 1, and the probability of a Down's Syndrome child becomes one out of every 50 births,\A_I Generally, as maternal age increases, the risk of one or another type of chromosomal aberration also increases. The Economics of Prenatal Diagnosis Prenatal diagnosis in combination with selective abortion could help reduce severe childhood morbidity resulting from genetic defects and the financial costs associated with it. Approximately 10 percent of all admissions to U.S. pediatric services are due to genetic defects; of patients currently in institutions for the mentally retarded, five percent have inherited metabolic disorders, more than 10 percent have Down's Syndrome and 25 percent have central nervous system defects, many of which may be inherited.^5_/ Some of the disorders suffered by these children could now be detected with prenatal diagnosis. The financial outlays associated with the care of children with severe genetic disorders are in the millions of dollars. It takes about $5,000- $6,000 per year to pay the costs of institutional care for retarded individuals. The 50,000 persons now receiving institutional care for Down's Syndrome alone represent an expense of some $250-$300 million per year.16/
108 There have been efforts to estimate and compare the direct financial costs of widespread prenatal diagnosis and selective abortion with the lifetime costs of treatment and care for individuals with severe genetic disorders born to women who might have elected to abort the fetuses if screening had been made available .1^7/ Some argue that the high costs of amniocentesis, laboratory testing, and selective abortion for certain groups (such as pregnant women over 35 years) are offset by the even greater costs associated with medical and institutional care for those individuals born with severe genetic disorders. All of these sets of costs are known to be large, but there are no adequate data from which to develop accurate estimates of cumulative annual outlays over time.* Also, changes are taking place in the way that society treats mentally retarded individuals; many children who once might have ended up in institutions for the rest of their lives are being cared for today in their homes or day-care centers where they are much less of a financial burden to their families and to society as a whole.1^/ Shifting patterns of care make it difficult to develop cost estimates based on "average lifetime" costs of children disabled by genetic disorders. Furthermore, a fiscal balance sheet for rearing a child with a severe genetic defect does not take into account the non-monetary considerations that will be faced by the individual family making its own decision whether or not to undergo amniocentesis and selective abortion. Procedural Problems and Medical Risks of Prenatal Diagnosis Limits on the use of prenatal diagnosis are based not only on its costs and the relative scarcity of medical personnel skilled in performing it, but also on the incompletely defined medical risks associated with amniocentesis. To obtain the kind of comprehensive information needed to identify and evaluate these risks, the National Institute of Child Health and Human Development is sponsoring a collaborative project in nine medical centers. One thousand women undergoing second-trimester amniocentesis will be matched with pregnant women not undergoing the procedure. The pregnancies in both sets will be monitored until completion, and children born to these women will receive follow-up examination for up to one year. One potential risk is that amniocentesis will not be successful on the first attempt. The needle inserted in the uterine cavity may not remove sufficient fluid for analysis or for adequate culture of fetal cells, which would necessitate a re-sampling and a consequent increase in possibility of injury. However, the success rate of experienced obstetricians has been reported as greater than 95 percent, and in some major centers the success rate on the first attempt is nearly 100 percent.19/ *Mass screening for all pregnant women over thirty-five, for example, would entail screening of more than 180,000 women each year at an average cost that may exceed $200 per patient, or $36 million per year.
109 There also is a risk of faulty diagnosis following amniocentesis and cultivation of the fetal cell mass. In Milunsky^ survey of 1,663 cases, only three diagnostic errors were made. (An additional seven errors of incorrect sex determination were made but in none of these cases was the possibility of an X-linked disorder the basis for the amnio- centesis.) In one pregnancy for which the prenatal diagnosis had specified a normal fetus, an infant with a metabolic defect was born. Of the total pregnancies in which the prenatal diagnosis could be confirmed, however, the diagnostic accuracy was very high (greater than 98 percent).20/* Diagnostic errors can also be made in attempting to identify the presence of neural tube defects. High concentrations of alpha-fetoprotein will not be found in the amniotic fluid when the neural tube lesions are closed. This may occur in 10 percent of disabling neural tube malformations in which the infants survive.21/ Direct medical risks of amniocentesis can be classified into three categories. Immediate or early complications are defined as those occurring within two weeks, i.e., vaginal bleeding, infection, abdominal pain, leakage of amniotic fluid through the vagina, ruptured membrane, spontaneous abor- tion, or fetal death. In Milunsky's survey there were four fetal deaths, three spontaneous abortions, and a variety of lesser complications.22/ Short-term or intermediate complications are defined as those occurring later than two weeks after the amniocentesis and prior to the third trimester. These include spontaneous abortions and vaginal bleeding followed by spontaneous abortion. Sixteen spontaneous abortions during this period were reported in MilunskyNs survey and two abortions occurred after vaginal bleeding .Z3_/ Kaback would also include premature birth as a possible short-term complication,^/ although Milunsky classified this as a late complication of the third trimester. Other short-term risks faced by the woman are those associated directly with a second-trimester abortion (See Chapter 3). *Accurate laboratory results are heavily dependent on a laboratory^ experience in cell cultivation for certain disorders. Centralization of amniocentesis labs may enhance diagnostic accuracy.
110 Finally, there are long-term complications associated with amniocentesis, usually defined to include permanent damage to the fetus, such as injury, deformity, or long-term mental impairment.25/ The woman also may face certain long-term risks from second-trimester abortion, as discussed in Chapter 3. Beyond this limited information, however, the long-term risks of amniocentesis are not known. In a study of 100 pregnancies examined by amniocentesis at the Prenatal Detection Center, University of California Medical Schoo1, San Francisco, early and short-term complication rates were comparable to those of the Milunsky survey.^6/ To determine long-term complications, follow-up examinations were made soon after birth on 62 of the 78 infants delivered of the original 100 pregnancies. Three of these infants (plus another examined only from a photograph) had small linear scars, possibly from having been scratched by the amniocentesis needle.2^7_/ Although complications were minor, the complexity of the entire process from both a technical and social point of view led these authors to conclude "that prenatal diagnosis should be carried out only in centers where there are adequate facilities and trained personnel to handle the special techniques and gain the experience necessary to provide this service."28/ Recognizing that the evidence is still very preliminary, Kaback concludes that, "it is...too early to give an absolute answer to the overall risks but we can say that the serious complication rate of amniocentesis, at least the immediate or short-term frequency, is not greater than one percent," provided it is performed at medical centers with experience in the procedure.29/ Alternatives to Abortion At the present time there is a limited number of alternatives to selec- tive abortion for couples faced with the prospect of a severely disabled child. A few metabolic diseases such as methylmalonic aciduria can be treated while the fetus is still in the uterus.30/ This disease can also be sucessfully treated with doses of Vitamin B-12 after birth,31f PKU and galactosemia are examples of diseases that can be treated with diet restrictions to limit the amount of mental retardation suffered by those children. Other potential techniques, including organ transplants to pro- duce a deficient enzyme, may turn out to be successful means of therapeutic intervention.3_2_/ However, parents still may elect to abort an affected child rather than cope with major treatment programs.^3/ And for couples who choose not to risk an affected pregnancy, adopting a child or obtaining artificial insemination with donor sperm are possible options.
Ill In the present state of medical practice, prenatal genetic diagnosis and selective abortion will probably continue to be used by families to prevent the birth of children with severe genetic disorders and to help ensure the birth of unaffected children. Pending the availability of techniques for earlier detection of a fetus with severe genetic disorders, prevention of the birth of children with these disorders will remain an important reason for second-trimester abortions. Summary Recent developments in the techniques of amniocentesis and cell culture have made an increased number of genetic defects and other congenital dis- orders detectable in the second trimester of pregnancy. The possibility of prenatal genetic diagnosis with selective abortion may encourage families at risk of having a child with a severe genetic disorder to become pregnant with the likelihood that their child will not suffer from that disorder. More than 6,000 such pregnancies have now been monitored in the United States and Canada. There are significant limitations on the use of amniocentesis. It is still a relatively expensive procedure with a smal1, but growing group of medical personnel qualified to administer it and to carry out necessary tests on fetal fluid and cells. Personnel and facilities are too limited for mass screening. There is also some degree of risk in the procedure, and only those women who can be identified as having a high possibility of an affected pregnancy should be considered candidates for the procedure. And, although about 60 genetic disorders can now be identified before birth, other defects exist for which there is yet no prenatal diagnosis to confirm or deny a suspected risk. The possibility of obtaining a legal abortion expands the options available to a couple who face known risks in becoming pregnant.
112 REFERENCES 1. Michael M. Kaback, Jaakko T. Leisti, and Marshall D. Levine. "Prenatal Genetic Diagnosis," Endocrine and Genetic Disorders of Childhood. L. Gardner, ed., Philadelphia: W. B. Saunders, 1975. 2. Ibid; Richard W. Erbe. "Therapy in Genetic Disease," The New England Journal of Medicine 291: 1028, November 7, 1974; U.S. Department of Health, Education, and Welfare, Public Health Service, National Institute of Child Health and Human Development. "Mental Retardation: The First Decade," (A Report prepared by the Mental Retardation Program for Presentation to the National Advisory Child Health and Human Development Councils, March 26, 1973), p. 1; and V. A. McKusick. Mendelian Inheritance in Man. Baltimore: The Johns Hopkins Press, 3rd ed., 1971. 3. Aubrey Milunsky. The Prenatal Diagnosis of Hereditary Disorders. Springfield, Illinois: Charles C. Thomas Publisher, 1973, p. 21. 4. Theodore Friedman. "Prenatal Diagnosis of Genetic Disease," Scientific American, November 1971, p. 38. 5. M. R. Creasy and J. A. Crolla. "Prenatal Mortality of Trisomy 21," The Lancet 1: 473, March 23, 1974. 6. A. G. Motulsky, G. R. Fraser and J. Felsenstein. "Public Health and Long-Term Genetic Implications of Intrauterine Diagnosis and Selective Abortion," Birth Defects: Original Article Series 7: 22, April 1971. 7. Personal Communication from Michael Kaback, March 1975. 8. Harry Harris. Prenatal Diagnosis and Selective Abortion. London: Nuffield Provincial Hospitals Trust, 1974, p. 33. 9. Ibid. 10. K. M. Laurence. "Fetal Malformations and Abnormalities," The Lancet 2: 940, October 19, 1974. 11. D. J. H. Brock. "Changing Pattern of Antenatal Diagnosis," The Lancet 2: 1077, November 2, 1974. 12. Milunsky, p. 37. 13. M. Neil Macintyre. "Genetic Risk, Prenatal Diagnosis, and Selective Abortion," Abortion, Society and the Law. David F. Walbert and Douglas Butler, eds. Cleveland: Case Western Reserve University Press, 1973, p. 236.
113 14. Curt Stern. Principles of Human Genetics. 3rd ed., San Francisco: W. H. Freeman & Co., 1973, p. 112. 15. National Institute of Child Health and Human Development. "Mental Retardation: The First Decade," pp. 26-27. 16. Gene Bylinsky. "What Science Can Do About Hereditary Diseases," Fortune, September 1974, p. 156. 17. See for example, Milunsky, pp. 165-168; Norman Glass. "Economic Aspects of the Prevention of DovrrTs Syndrome, (Mongolism)," Systems Aspects of Health Planning. N. T. J. Bailey and M. Thompson, eds., Amsterdam: North-Holland Publishing Company, 1975; and Zena Stein, Mervyn Susser and Andrea V. Guterman. "Screening Programme for Prevention of Down's Syndrome," The Lancet 1: 306, February 10, 1973. The latter does not provide financial data but deals with the structure of the problem. 18. National Association for Retarded Citizens. The Right to Choose, Achieving Residential Alternatives in the Community, Arlington, Texas, October 1973. 19. Kaback, Leisti, and Levine. 20. Milunsky, pp. 40-41. 21. Harris, p. 34. 22. Milunsky, pp. 41-42. 23. Ibid. 24. Kaback, Leisti, and Levine. 25. Kaback, Leisti, and Levine; and Orlando J. Miller. "Discussion," Birth Defects: Original Article Series 7: 33, April 1971. 26. Mitchell S. Golbus, Felix A. Conte, Edward L. Schneider, and Charles J. Epstein. "Intrauterine Diagnosis of Genetic Defects: Results, Problems and Follow-up of One Hundred Cases in a Prenatal Genetic Detection Center," American Journal of Obstetrics and Gynecology 118: 902, April 1, 1974. 27. Ibid., p. 903. 28. Ibid., p. 905. 29. Kaback, Leisti, and Levine.
114 30. M. G. Ampola, M. J. Mahoney, E. Nakamura, and K. Tanaka. "la Utero Treatment of Methyl Malonic Aciduria with Vitamin B-12," Pediatric Research 8: 387, 1974. 31. Leon E. Rosenberg. "Vitamin-Dependent Genetic Disease," Medical Genetics. Victor A. McKusick and Robert Claiborne, eds., New York: H P Publishing Co., Inc., 1973, pp. 75-76. 32. R. Rodney Howell. "Genetic Disease: The Present Status of Treatment," Medical Genetics, p. 275. 33. Arno G. Motulsky. "Brave New World?" Science 185: 659, August 23, 1974.