AMERICAN ACADEMY OF PEDIATRICS CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care Christopher Cunniff, MD; and the Committee on Genetics Prenatal Screening and Diagnosis for Pediatricians ABSTRACT. The pediatrician who cares for a child ital adrenal hyperplasia. These procedures may be with a birth defect or genetic disorder may be in the best important to couples at increased risk of having chil- position to alert the family to the possibility of a recur- dren with genetic disorders, because without this rence of the same or similar problems in future offspring. information they might be unwilling to attempt a The family may wish to know about and may benefit pregnancy. from methods that convert probability statements about A number of well-studied techniques are used for recurrence risks into more precise knowledge about a specific abnormality in the fetus. The pediatrician also prenatal diagnosis. For many of these techniques, the may be called on to discuss abnormal prenatal test results accuracy, reliability, and safety of the procedures are as a way of understanding the risks and complications positively correlated with operator experience. Pro- that the newborn infant may face. Along with the in- cedures such as amniocentesis, chorionic villus sam- crease in knowledge brought about by the sequencing of pling (CVS), fetal blood sampling, and preimplanta- the human genome, there has been an increase in the tion genetic diagnosis (PGD) allow analysis of technical capabilities for diagnosing many chromosome embryonic or fetal cells or tissues for chromosomal, abnormalities, genetic disorders, and isolated birth de- genetic, and biochemical abnormalities. Fetal imag- fects in the prenatal period. The purpose of this report is ing studies such as ultrasonography, magnetic reso- to update the pediatrician about indications for prenatal nance imaging (MRI), and fetal echocardiography diagnosis, current techniques used for prenatal diagno- sis, and the status of maternal screenings for detection of identify structural abnormalities and provide defin- fetal abnormalities. Pediatrics 2004;114:889–894; prenatal itive diagnostic information or suggest additional diagnosis, amniocentesis, chorionic villi sampling, genetic evaluation. In addition to these techniques, maternal screening, chromosome aberrations, prenatal ultrasonog- serum screening is used to identify pregnancies that raphy, neural tube defects, genetic counseling, preimplan- are at increased risk of adverse outcomes, such as tation diagnosis, ␣-fetoproteins. neural tube defects (NTDs), chromosome abnormal- ities, and fetal abdominal wall defects. This report ABBREVIATIONS. CVS, chorionic villus sampling; PGD, preim- focuses on the techniques that are most commonly plantation genetic diagnosis; MRI, magnetic resonance imaging; used and provides an outline of pertinent informa- NTD, neural tube defect; MSAFP, maternal serum ␣-fetoprotein. tion that the practicing pediatrician may find useful. For more in-depth discussions of these techniques, a INTRODUCTION number of comprehensive texts are available.1–3 The hen a genetic or potentially genetic disor- GeneTests Web site (www.geneclinics.org) also pro- der is diagnosed prenatally, the pediatri- vides extensive information about testing for many Wcian may assist the family in addressing chromosomal and genetic disorders. questions about the natural history of the disorder and in planning for care of the affected newborn. The INDICATIONS FOR PRENATAL DIAGNOSIS information gained from prenatal diagnosis is help- Prenatal diagnosis is indicated whenever there is a ful to the obstetrician or family practitioner in the familial, maternal, or fetal condition that confers an management of pregnancy, labor, and delivery and increased risk of a malformation, chromosome ab- in some circumstances may improve pregnancy out- normality, or genetic disorder. Some prenatal diag- come. The availability of prenatal diagnosis gives nostic studies are prompted by abnormal results of couples options they might not have otherwise, in- tests such as ultrasonographic examinations or ma- cluding preparation for the birth of a child with an ternal serum screening. In other circumstances, par- abnormality, termination of an affected pregnancy, ents may be affected with a genetic disorder, may be or use of fetal treatment such as fetal surgery for carriers for autosomal recessive or X-linked recessive spina bifida or use of maternal dexamethasone to disorders, or may be a member of an ethnic group prevent virilization of affected females with congen- with an increased risk of a specific genetic disease. The guidance in this report does not indicate an exclusive course of treat- Chromosome Analysis ment or serve as a standard of medical care. Variations, taking into account The most commonly cited reason for prenatal di- individual circumstances, may be appropriate. DOI: 10.1542/peds.2004-1368 agnosis is advanced maternal age, which in the PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- United States is considered to be 35 years or greater emy of Pediatrics. at the time of delivery. Amniocentesis or CVS is Downloaded from www.aappublications.org/news byPEDIATRICS guest on September Vol. 24, 114 2021 No. 3 September 2004 889 offered to such women because of the increased risk molecular techniques. The description of the meth- of aneuploidy (an abnormal number of chromo- ods used to make a molecular diagnosis is beyond somes in the fetus). Amniocentesis or CVS also is the scope of this report, but several useful resources used commonly to evaluate pregnancies in which an are available for this purpose.4–6 Examples of disor- ultrasonographic examination or a maternal serum ders that are diagnosed by molecular methods in- screening result has identified a possible fetal prob- clude fragile X syndrome, cystic fibrosis, Duchenne lem. In addition to advanced maternal age or an and Becker muscular dystrophy, and hemophilia. In abnormal screening result, other indications for chro- each case, it is important that the clinician first know mosome analysis include: 1) a chromosome abnor- the specific mutation that is being sought in the case mality in a previous offspring, a parent, or a close of a positive family history or that the detection rate relative; 2) a previous offspring with multiple mal- for the mutation be known if there is no family formations in whom no chromosomal study was ob- history. The consultation of a geneticist, genetic tained; and 3) fetal sex determination in pregnancies counselor, or other clinician familiar with the utility at risk of a serious X-linked disorder for which spe- of these prenatal tests may be particularly helpful. cific prenatal diagnostic tests are not available. For the child with a normal prenatal chromosome anal- ysis but with signs of a possible chromosome abnor- TECHNIQUES FOR PRENATAL DIAGNOSIS BY mality such as multiple malformations, growth defi- CELL OR TISSUE SAMPLING ciency, or developmental disabilities, repeat testing Amniocentesis should be considered, because the quality of a post- Transabdominal amniocentesis is the most com- natal study is usually superior to one obtained pre- monly used procedure for obtaining fetal cells that natally, and some cases of chromosome mosaicism can be analyzed for cytogenetic, biochemical, or mo- may only be diagnosed postnatally. lecular abnormalities. In addition, amniotic fluid can be analyzed separately for ␣-fetoprotein and acetyl- Biochemical Studies cholinesterase concentrations associated with open Biochemical studies are undertaken most often NTDs and for other analytes that are diagnostic of when a known abnormality is present in a family and specific genetic diseases. The procedure is most com- the disorder can be diagnosed by a specific biochem- monly performed at 15 to 18 weeks’ gestational age. ical test. The number of biochemical disorders that Amniocentesis in the second trimester is associated can be diagnosed prenatally is growing rapidly, so with a low rate of complications and provides an that many common inborn errors of metabolism can accurate sample for analysis in more than 99% of be diagnosed through biochemical testing for en- cases.7,8 Fetal chromosome analysis is the most com- zyme deficiency or an abnormal metabolite. Condi- mon laboratory study performed on samples ob- tions such as Tay-Sachs disease, mucopolysacchari- tained by amniocentesis. Results are usually avail- doses, and peroxisomal diseases may be diagnosed able 1 to 2 weeks after the procedure and sooner in by biochemical tests on amniotic fluid, amniocytes, some circumstances. Fluorescence in situ hybridiza- or chorionic villi. Before proceeding to evaluation of tion studies are performed increasingly for rapid the fetus, there should be biochemical confirmation detection of fetal aneuploidy or for microdeletion of the diagnosis in the index case, one or both parents syndromes such as 22q11 deletions in fetuses with should be a confirmed carrier for an autosomal re- conotruncal heart defects. Risks of amniocentesis in- cessive or X-linked recessive disorder, or a family clude fetal loss, chorioamnionitis, fetal injury, and history of a diagnosable disorder and indeterminate maternal Rh sensitization, each of which is very un- carrier status should be established. In a few circum- common. Amniocentesis is performed under ultra- stances, biochemical testing may be used when there sonographic guidance, which minimizes the risk of is