Prenatal Diagnosis for Pediatricians

Committee on Genetics 0 Prenatal Diagnosis for Pediatricians

This statement is for the pediatrician who may INDICATIONS FOR FETAL TISSUE SAMPLING be called upon to care for the child with a birth defect or genetic disorder. The involved family may Chromosome Analysis wish to know and may benefit from methods that Fetal chromosome analysis should be offered convert probability statements about recurrence when any of the following apply: (1) advanced ma- risks into facts about the fetus. Many families will ternal age11”2; (2) a previous offspring has had one find knowledge and choice better than chance. of the trisomic syndromes and perhaps other chro- Rapid advances in technology have prompted the mosome aberrations”; (3) a chromosome abnor- Committee on Genetics to retire the June 1980 mality is present in either parent, eg, aneuploidy, statement’ and to prepare a new one. The purpose balanced translocation, or clinically significant in- of this revised statement is to inform the pediatri- version; (4) the fetus is at risk for a serious X- cian about the current status of antenatal diagnosis linked condition and specific intrauterine diagnosis as it relates to genetic and family counseling in is not available. Determination of fetal sex may also clinical practice. be appropriate as an initial screen before molecular The pediatrician may be called upon to help genetic studies or fetal blood sampling; (5) a parent address questions about the natural history of the is a fragile X carrier. The mothers are usually disorder under consideration and the possibility of identified by virtue of having a mentally retarded intrauterine treatment. Prenatal diagnosis can give child, brother, or uncle who has the fragile X syn- 0 information that may improve the outcome of preg- drome. Fragile X studies on amniocytes and/or nancy and can be helpful to the obstetrician in the chorionic villi are still considered investigational14; management of labor and delivery. The availability (6) a combination of low maternal serum a- feto- of prenatal diagnosis gives couples options they protein and maternal age in a woman who is might not otherwise have, including termination of younger than those in whom prenatal diagnosis is an affected pregnancy or preparation for the birth considered on the basis of maternal age alone.9 This of an abnormal child. This enables many couples is still considered investigational; (7) ultrasound to have children, when without this information has identified an anatomic abnormality, eg, om- they would have chosen to be childless. phalocele, hydrocephalus, or dysplastic kidney, that The techniques currently in use or under inves- might indicate an increased risk for karyotypic tigation for prenatal diagnosis include (1) fetal tis- abnormalities. Even when these abnormalities are sue sampling: amniocentesis, chorionic villus sam- found in the third-trimester of pregnancy, chro- pling, percutaneous umbilical blood sampling, per- mosome analysis of amniotic fluid cells may be cutaneous skin biopsy, and other organ biopsies27; indicated. The use of percutaneous umbilical blood (2) fetal visualization: ultrasound, fetoscopy, mag- sampling or transabdominal chorionic villus sam- netic resonance imaging, and radiography5; and pling for chromosome analysis in the third trimes- (3) maternal serum a-fetoprotein screening.9”#{176} ter is now also under investigation. Information obtained from these studies can influence decisions regarding the advisability of intrauterine therapy. The findings may also be important to the obstetrician in the management of labor and delivery The recommendations in this statement do not indicate an and to the pediatrician, neonatologist, and geneti- exclusive course of treatment to be followed. Variations, taking into account individual circumstances, may be appropriate. cist in patient management in the newborn period. : Reprint requests to Publications Department, American Acad- I emy of Pediatrics, 141 Northwest Point Blvd, P0 Box 927, Elk Biochemical Studies 0 Grove Village, IL 60009-0927. I PEDIATRICS (ISSN 0031 4005). Copyright © 1989 by the Biochemical studies are indicated when (1) there I American Academy of Pediatrics. has been a previous child affected with a biochem-

Downloaded from www.aappublications.org/newsPEDIATRICS by guest on September Vol. 84 26, No. 2021 4 October 1 989 741 ical condition that can be diagnosed prenatally’5; Chorionic Villus Sampling (2) couples are at risk because oftheir carrier status, This is still technically considered an investiga- often related to ethnic origin, eg, Tay-Sachs disease tional procedure for obtaining fetal tissue.4”22 The 0 in Ashkenazi Jews, sickle cell disease in American major advantage of this procedure is that earlier blacks, and thalassemia in those of Italian, Greek, diagnosis is possible. At 9 to 11 weeks of gestation, or Oriental descent’5; (3) neural tube defects are a plastic catheter with a solid flexible stylet is present in a parent or sibling of the fetus’#{176}”6; (4) inserted transcervically, under ultrasonic guidance, couples have been identified as being at increas- to an area of placental development. A sample of ed risk for an offspring with a neural tube defect, villus tissue is removed by aspiration. The villi are eg, as the result of maternal serum a-fetoprotein than dissected from the decidual tissue and can be screening.’#{176}”6 cultured or assayed directly. The disadvantages of this technique are the complications of the proce- Routine and Electron Microscopy dure including fetal loss and the possibility of con- Routine and electron microscopy have been used tamination of the villus sample with maternal de- to diagnose rare genetic diseases, eg, epidermolysis cidua. The safety and accuracy of this procedure bullosa letalis.57 are still being investigated. A promising new investigation procedure is Molecular Genetic Studies transabdominal chorionic villus sampling.23’24 This is also performed at 9 to 11 weeks of gestation. The use of molecular biologic techniques is rap- Transabdominal chorionic villus sampling may also idly increasing.’7 These methods of diagnosis are be performed later in gestation, including the third based upon the fact that the DNA complement is trimester. identical in every cell of the body, and therefore any hereditary defect detectable at the DNA level Fetal Blood Sampling should be found in any nucleated cell from that organism. Enzymes (restriction endonucleases) Fetoscopy for fetal visualization and fetal blood that cleave DNA within a specific base sequence sampling has been largely replaced by percutaneous recognition site are used to identify mutant genes. umbilical blood sampling and better ultrasonic vis- 0 This is currently a clinical tool in the prenatal ualization but still may be useful in selected situa- diagnosis of hemoglobinopathies, hemophilia A, tions.57’25 Duchenne and Becker muscular dystrophy, and A technique for percutaneous sampling of fetal cystic fibrosis. It is being applied experimentally to blood from the umbilical cord or hepatic vein is the prenatal diagnosis of hemophilia B, adult poly- available. Preliminary data suggest, that when this cystic kidney disease, Huntington chorea, and other is done under ultrasonic guidance, there is a lower disorders. New applications are rapidly being made risk of spontaneous abortion than with fetoscopy.25 available. It is often necessary to contact a genetic This technique is still considered investigational. center to determine whether or not this technique For some conditions, fetal biopsy has been replaced is available and accurate for a given genetic disor- by molecular genetic studies of amniocytes or cho- der. rionic villi.

TECHNIQUES FOR TISSUE SAMPLING Fetal Skin Sampling A number of serious skin disorders, eg, epider- Amniocentesis molysis bullosa letalis and harlequin ichthyosis, Transabdominal amniocentesis at 16 weeks of may be diagnosed histologically by skin biopsies pregnancy is the most commonly used technique obtained percutaneously under ultrasonic guidance, for obtaining fetal tissue.2” The results are accurate with or without fetoscopy.57 (more than 99% for most biochemical and cytoge- Organ Biopsies netic studies). Processing of the cultures can take 2 to 4 weeks, but results of cytogenetic analysis are Techniques for biopsy of other fetal organs are routinely available in less than 2 weeks in an in- still considered investigational. creasing number of laboratories. Significant mater- TECHNIQUES FOR FETAL VISUALIZATION nal injury is rare. Although injury to the fetus is also rare, there remains a small, procedurally re- Ultrasound 0 lated risk of fetal loss. Early amniocentesis between 11 and 14 weeks of gestation is currently being This technique is used to monitor fetal growth investigated. and to establish gestational age and placental lo-

742 PRENATAL DIAGNOSISDownloaded from www.aappublications.org/news by guest on September 26, 2021 cation. Many referral centers have ultrasound im- Frank N. Medici, MD aging equipment that provides sharp resolution and Virginia V. Michels, MD detail. Many anatomic lesions can be visualized, Lester Weiss, MD including some genitourinary, gastrointestinal, Liaison Representatives 0 skeletal, and central nervous system abnormali- Felix de la Cruz, MD, National Institutes ties.8’26 Fetal echocardiography may identify some of Health and Human Development cardiac lesions.8’27 Sherman Elias, MD, American College of Obstetricians and Gynecologists Fetoscopy Irene Forsman, MD, Health Resources and Because of the risk of spontaneous abortion as- Services Administration, US Dept of sociated with fetoscopy, it is only used in selected Health and Human Services situations.5 Godfrey Oakley, MD, Centers for Disease Control Magnetic Resonance Imaging

As a fetal imaging technique, magnetic resonance

imaging is being actively investigated.8 REFERENCES

1. Scriver CR, Feingold M, Holtzman NA, et al. Prenatal Radiography diagnosis for pediatricians. Pediatrics. 1980;6:1185-1186 2. Tabor A, Philip J, Madsen M, et al. Randomized controlled Although radiography has been largely replaced trial of genetic amniocentesis in 4000 low-risk women. Len- by ultrasonography for the detection of anatomic cet. 1986;1:1287-1293 lesions, it may still be indicated for specific disor- 3. Hanson FW, Zorn EM, Tennant FR, et al. Amniocentesis before 15 weeks’ gestation: outcome, risks, and technical ders and selected cases, particularly after the first problems. J Obstet Gynecol. 1987;156:1524-1531 trimester. 4. Ward H. A source of fetal cells: chorionic villi sampling its promise and its problems. Contemp Obstet Gynecol Tech. 1984;1983:31-38 SERUM a-FETOPROTEIN 5. Elias S. Fetoscopy in prenatal diagnosis. Semin PerinatoL 1980;4:199-205 Detection of Neural Tube Defects 6. Golbus MS. Special report: the status of fetoscopy and fetal tissue sampling. Prenat Dtagn. 1984;4:79-81 Please refer to the statement on maternal serum 7. Dale BA, Perry TB, Holbrook KA. Biochemical examination of fetal skin biopsy specimens obtained by fetoscopy: use of a- fetoprotein screening by the Committee on Ge- the method for analysis of keratins and filaggrin. Prenat netics.’#{176} Diagn. 1986;6:37-44 8. Romero R, Pilu G, Jeanty P, et al. Prenatal Diagnosis of Congenital Anomalies. Norwalk, CT: Appleton & Lange; Identification of Trisomy 21 1988 9. DiMaio MS, Baumgarten A, Greenstein RM, et al. Screening Results of recent studies have suggested that low for fetal Down’s syndrome in pregnancy by measuring ma- maternal serum a-fetoprotein concentrations may ternal serum alpha-fetoprotein levels. N EngI J Med. be associated with an increased risk for trisomy 21 1987;317:342-346 10. Holtzman NA, Leonard CO, Medici FN, et al. a-Fetoprotein and perhaps other chromosomal aneuploidies in the screening. Pediatrics. 1987;80:444-445 fetus.9 11. Schreinemachers DM, Cross PK, Hook EB. Rates of trisom- ies 21, 18, 13 and other chromosome abnormalities in about 20 000 prenatal studies compared with estimated rates in RECOMMENDATIONS live births. Hum Genet. 1982;61:318-324 12. Hassold T, Chiu D. Maternal age-specific rates of numerical Pediatricians should be familiar with the princi- chromosome abnormalities with special reference to tn- pies of antenatal diagnosis and know how to apply somy. Hum Genet. 1985:70:11-17 13. Stene J, Stene E, Mikkelsen M. Risk for chromosome ab- them to specific problems in genetic counseling, normality at amniocentesis following a child with a nonin- diagnosis, and management in clinical practice. At herited chromosome aberration. Prenatal Diag. 1984;4:81- the same time, pediatricians should be familiar with 95 resources available in their region. The technology 14. Shapiro LR, Wilmot PL. Prenatal diagnosis of the Fra(X) syndrome. Am J Med Genet. 1986;23:325-340 of prenatal diagnosis is changing particularly rap- 15. Scriver CR, Beaudet AL, Sly WS, et al. The Metabolic Basis idly, and pediatricians may find that their genetic oflnherited Disease. New York, NY: McGraw-Hill Book Co; 1988 consultants can assist them in keeping their infor- 16. Laurence KM, Dew JO, Dyer C, et al. Amniocente8is carried mation and practice current in this field. out for neural tube indications in South Wales 1973-1981: outcome of pregnancies and findings in the malformed abor- COMMITTEE ON GENETICS, 1987-1988 tuses. Prenant Diagn. 1983;3:187-201 17. Beaudet AL. Molecular genetics and medicine. In: Peters- Edward, R. B. McCabe, MD, Chairman dorf RG, Adams RA, Baumwald E, et al, eds. Harrison’s Claire 0. Leonard, MD Principles of Internal Medicine. New York, NY: McGraw-

Downloaded from www.aappublications.org/newsAMERICAN by guest ACADEMYon September 26, OF 2021 PEDIATRICS 743 Hill Book Co; 1987:296-310 Obstet GynecoL 1987;70:827-830 18. Simoni G, Brambati B, Danesino C, et al. Efficient direct 23. Bovicelli L, Rizzo N, Montacuti V, et al. Transabdominal chromosome analyses and enzyme determinations from cho- versus transcervical routes for chorionic villus sampling. rionic villi samples in the first trimester of pregnancy. Hum Lancet. 1986;2:290 Genet. 1983:63:349-357 24. Lilford RI, Linton G, Irving HC, et al. Transabdominal 19. Ward RHT, Modell B, Petrou M, et a!. Method of sampling chonion villus biopsy: 100 consecutive cases. Lancet. chonionic villi in first trimester ofpregnancy under guidance 1987;1:1415-1416 of real time ultrasound. Br Med J. 1983;286:1542-1544 25. Hobbins JC, Grannum PA, Romero R, et al. Percutaneous 20. Gatti R, Lombardo C, Filocamo M, et al. Comparative study umbilical blood sampling. Am J Obstet GynecoL 1985;152:1- of 15 lysosomal enzymes in chorionic villi and cultured 6 amniotic fluid cells. Prenat Diagn. 1985;5:329-336 26. Daffos F, Forestier F, MacAleese J, et al. Fetal curarization 21. Hogge WA, Schonberg SA, Golbus MS. Chorionic villus for prenatal magnetic resonance imaging. Prenat Diagn. sampling: experience of the first 1000 cases. Am J Obstet 1988:8:311-314 GynecoL 1986;154:1249-1252 27. Huhta JC. Uses and abuses of fetal echocardiography: a 22. Cashner KA, Christopher CR, Dysert GA. Spontaneous fetal pediatric cardiologist’s view. J Am Coil CardioL 1986;8:451- loss after demonstration of a live fetus in the first trimester. 458

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1989 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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