AMERICAN ACADEMY OF

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 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 . 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 . 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 , 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 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, ; 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 for carriers for autosomal recessive or X-linked recessive 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, 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’ . 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 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 no family history of a disorder but prenatal ultra- direct fetal injury. The risk of fetal loss in most large sonographic findings are suggestive of a biochemical series is less than 0.5%, and many prenatal diagnostic disorder. For example, in a pregnancy in which cleft centers have a lower loss rate. To prevent Rh iso- palate and abnormal genital findings are identified immunization, Rh immune globulin is administered by ultrasonography, biochemical testing for Smith- at the time of the procedure to nonsensitized Rh- Lemli-Opitz syndrome, a disorder of cholesterol bio- negative women. genesis, should be considered, because these are In recent years, amniocentesis performed at 11 to characteristic features of this syndrome. 13 weeks’ gestational age has gained increasing at- tention. Some investigations have suggested that this Molecular Genetic Studies technique carries similar risks to amniocentesis at 15 Similar to biochemical studies, molecular genetic to 18 weeks’ gestational age.9 In a large multicenter studies almost always are undertaken because there randomized trial, however, investigators found a is a positive family history of a specific genetic dis- higher risk of fetal loss, a greater number of amniotic ease or prenatal findings point to a possible single- fluid culture failures, and an increased risk of tali- gene disorder that can be diagnosed by molecular pes.10 Additional investigations have also identified techniques. The list of available molecular genetic an increased risk of foot deformities in the offspring studies has grown dramatically in the last several of women who undergo early amniocentesis.11,12 Al- years, and many of the common single-gene disor- though it is desirable to complete prenatal diagnostic ders can be diagnosed rapidly and conclusively by tests as early as possible, the American College of

890 PRENATAL SCREENINGDownloaded AND from DIAGNOSIS www.aappublications.org/news FOR PEDIATRICIANS by guest on September 24, 2021 Obstetricians and Gynecologists does not recom- spontaneous abortion is reported in approximately mend early amniocentesis because of higher rates of 1% to 2% of cases, making the risk associated with pregnancy loss and other complications compared this procedure higher than that with amniocentesis with amniocentesis after 15 weeks’ gestation.13 or CVS.24

CVS PGD The advantage of CVS is earlier diagnosis. Earlier In some circumstances, specific genetic diseases diagnosis provides additional time for counseling can be diagnosed before implantation of the blasto- and decision-making, and in the circumstance in cyst after in vitro fertilization. PGD provides pro- which termination of pregnancy is elected, termina- spective parents the possibility of establishing a tion can be performed more safely for the mother. pregnancy in which the fetus is unaffected with the CVS is usually performed at 10 to 12 weeks’ gesta- disorder for which it is at risk. In this procedure, a tional age. The procedure involves transcervical single cell is taken from the early and ana- placement of a or transabdominal placement lyzed by molecular techniques after DNA amplifica- of a needle, under ultrasonographic guidance, into tion by polymerase chain reaction. For this technique the developing placenta. The transcervical and trans- to be useful, it is essential to know the precise abnor- abdominal approaches seem to have comparable mality being sought, which usually means that both safety and accuracy.14 A sample of the chorionic the genetic locus and the mutation have been iden- villus is removed by aspiration. Once removed, the tified in a previous child or another family member. fetal villi are dissected from the maternal decidual PGD is performed in a limited number of prenatal tissue. Cytogenetic, molecular, and some biochemi- diagnostic centers, and systematic outcome analyses cal studies can be performed on CVS samples, but of large groups of patients are not available. It has amniotic fluid is not obtained for protein analysis. been used to detect such disorders as cystic fibrosis Therefore, women who have had CVS should also and Tay-Sachs disease.25 have maternal serum ␣-fetoprotein (MSAFP) screen- ing at 15 to 20 weeks’ gestational age to screen for TECHNIQUES FOR PRENATAL DIAGNOSIS BY fetal NTDs. FETAL VISUALIZATION Although CVS loss rates are slightly higher than Ultrasonography those associated with amniocentesis in some clinical Ultrasonography has become the primary method trials,15,16 other studies have suggested that the pro- for fetal anatomic imaging. This technique may be cedure-related loss rates are comparable between used in pregnancy to monitor fetal growth, move- CVS and second-trimester amniocentesis.17,18 The ment, position, and morphology; assess amniotic success of cytogenetic diagnosis is slightly lower for fluid volume; and establish gestational age and pla- CVS versus amniocentesis. In particular, CVS is as- cental location. In some countries, it has become sociated with an increased frequency of placental standard practice to perform ultrasonographic exam- mosaicism, which is a cytogenetic abnormality de- ination at some time in the second trimester. In many tected in the CVS sample but not found in the fetus other countries including the United States, ultra- or newborn. Placental mosaicism is found in approx- sonography is performed at some time during preg- imately 1% of CVS samples,19,20 and although the nancy for a wide range of clinical indications. During fetus is chromosomally normal, placental mosaicism the early second trimester, ultrasonographic exami- is associated with an increased risk of non–proce- nation is used to date the pregnancy, identify twins, dure-related, spontaneous fetal loss. An additional diagnose some fetal structural anomalies, and exam- concern for CVS is the reported association of CVS ine the placenta and the amount of amniotic fluid. and limb-reduction defects, especially when the pro- Improvements in the technical quality of ultrasono- cedure is performed before 10 weeks’ gestational graphic equipment and increasing skill levels of ul- age; although some investigations have shown an trasonogram operators have led to an ever-increas- association21 and others have found none,22 the ing identification of fetal structural abnormalities of American College of Obstetricians and Gynecolo- the genitourinary, gastrointestinal, cardiac, and cen- gists has recommended that CVS not be performed tral nervous systems. before 10 weeks.23 Ultrasonography has become the mainstay for pre- natal diagnosis of structural abnormalities, particu- Sampling of Fetal Blood larly when used in the mid– to late second trimester. In some circumstances, it may be useful to obtain a As a modality used to follow-up on abnormal ma- sample of fetal blood. This technique, referred to as ternal screening results, ultrasonographic examina- cordocentesis or percutaneous umbilical blood sam- tion can identify most associated abnormalities such pling, may be used to assess fetal blood disorders, as ventral abdominal wall defects and NTDs. Almost fetal infections, or isoimmunization or may be used all cases of anencephaly are detectable by ultra- for rapid fetal karyotyping. It also has been used to sonography, and more than 90% of open spina bifida supply fetal treatment such as transfusions. Percuta- is detectable when ultrasonography is used for a neous umbilical blood sampling is usually per- high-risk population such as those with abnormally formed with a 20- or 25-gauge spinal needle inserted high serum ␣-fetoprotein concentrations.26,27 With into the umbilical vein or artery, preferably near the the advent of improved image quality of ultrasono- insertion of the cord into the placenta. Fetal loss or graphic examinations, a number of minor abnormal-

Downloaded from www.aappublications.org/news by AMERICANguest on September ACADEMY 24, 2021 OF PEDIATRICS 891 ities have been recognized. Studies of these abnor- defects of the genitourinary and gastrointestinal sys- malities in high-risk populations have shown that tems. MSAFP screening results are abnormal in ap- some of these markers may be seen more commonly proximately 90% of cases of anencephaly and ap- in pregnancies with fetal chromosome abnormalities proximately 80% of cases of open spina bifida. It is than in unaffected pregnancies. Nuchal translucency, recommended that MSAFP testing be offered to all thickened nuchal fold or cystic hygroma, choroid prenatal patients, and in some states it is mandated plexus cysts, fetal echogenic bowel, intracardiac by law.31 Because elevated MSAFP concentrations echogenic foci, and renal pyelectasis have all been have also been associated with adverse pregnancy suggested as possible markers for fetal chromosome outcomes such as low birth weight and , abnormalities.28 Although these features are associ- pregnancies in which concentrations are elevated ated with increased fetal risk, they are not used as may be monitored more closely than those with primary screening methods. When they are identi- normal concentrations. Most of those who have fied, however, additional investigation may be war- increased MSAFP concentrations even after repeat ranted on the basis of a number of factors such as testing will have a normal outcome. When concen- maternal age and associated abnormalities. The pe- trations are increased, ultrasonography is used to diatrician may encounter newborn infants in whom confirm gestational age, exclude multiple gestation, one of these markers has been detected prenatally. and assess for recognized causes (primarily NTDs Because these infants have an increased risk of an- and ventral wall defects) of the increase. A normal euploidy such as trisomy 13, 18, or 21, neonatal ex- result of an ultrasonographic examination performed amination should be directed toward identification in a specialized center decreases the probability of a of clinical features associated with one of these tri- fetal NTD by 95% or more.32 If ultrasonographic somies. If the clinical examination is not suggestive examination does not identify a cause, amniocentesis of one of these conditions and there are no major is offered for measurement of amniotic fluid ␣-feto- anomalies, it is reasonable to observe the infant and protein and acetylcholinesterase concentrations, both perform no additional diagnostic testing. of which are increased with open NTDs.

MRI Detection of Chromosome Abnormalities MRI has received limited use, primarily because fetal movement prevents optimal resolution. Ultra- After the advent of MSAFP screening for NTDs, it fast MRI scanning has improved its utility. MRI may was recognized that low second-trimester MSAFP be especially useful for the evaluation of fetal central concentrations were associated with an increased 33,34 abnormalities, when oligohydram- risk of Down syndrome. Since that time, addi- nios is present, or when ultrasonography is diffi- tional serum markers that increase the detection rate cult.29 MRI generally is not recommended during the for Down syndrome have been identified. When sec- first trimester. ond-trimester MSAFP testing is combined with mea- surement of human chorionic gonadotropin and un- Fetal Echocardiography conjugated estriol concentrations (these 3 proteins constitute the “triple screen” for fetal aneuploidy), Fetal echocardiography is usually performed after up to 80% of fetuses with Down syndrome can be 20 weeks’ gestation. When used together with du- identified.35,36 Decreased concentrations of all 3 ana- plex and/or color-flow Doppler ultrasonography, it lytes are associated with an increased risk of fetal can identify a substantial number of major structural trisomy 18. Some screening programs have added cardiac defects and rhythm disturbances.30 Fetal inhibin A to the triple screen to improve the sensi- echocardiography is considered when there is an tivity and specificity of the test.37 Clinicians should increased risk of congenital heart disease because: 1) be aware that MSAFP screening for Down syndrome there is an extracardiac malformation identified by has a positive screening rate of approximately 5% ultrasonographic examination; 2) there has been pre- and a positive predictive value of approximately 3% natal exposure to a teratogenic agent; 3) there is a to 5%, which means that the great majority of those family history of congenital heart defects, especially who have a positive screening result have a normal in a parent or sibling; 4) a fetal chromosome abnor- outcome. mality or genetic disease associated with heart de- Over the last several years, techniques for effective fects is suspected; 5) a maternal disease associated first-trimester screening for Down syndrome have with fetal structural heart defects, such as diabetes or been explored. Although a number of concerns about phenylketonuria, or maternal disease associated with the appropriateness of adopting these techniques on fetal cardiac arrhythmia, such as lupus erythemato- a population basis have been raised,38 many perina- sus, has been identified; 6) a cardiac defect is sus- tologists are already using fetal ultrasonography pected by findings on routine ultrasonography; or 7) and/or screening for maternal serum markers in a fetal arrhythmia has been detected on auscultation clinical practice.39 Measurement of nuchal translu- or examination. cency (a sonolucent space at the back of the fetal neck) can be performed between 10 and 13 weeks’ MATERNAL SERUM SCREENING STUDIES gestation. The fetus with Down syndrome tends to Detection of NTDs have a larger area of translucency when compared MSAFP concentrations are increased in many ab- with the chromosomally normal fetus. The nuchal normal fetal conditions including open NTDs and translucency measurement is used in combination

892 PRENATAL SCREENINGDownloaded AND from DIAGNOSIS www.aappublications.org/news FOR PEDIATRICIANS by guest on September 24, 2021 with 2 serum analytes, pregnancy-associated plasma John B. Moeschler, MD protein A and the free ␤ subunit of human chorionic Howard M. Saal, MD gonadotropin, to adjust the risk for Down syndrome based on maternal age alone. The detection rates are Liaisons comparable to second-trimester serum screening. James D. Goldberg, MD American College of Obstetricians and Gynecologists Detection of Other Abnormalities James W. Hanson, MD There are a number of conditions associated with National Institute of Child Health high or low MSAFP concentrations. In addition to and Human Development/ abdominal wall defects such as omphalocele and American College of Medical gastroschisis, high concentrations are also associated Genetics with renal anomalies, congenital nephrosis, gastroin- Michele A. Lloyd-Puryear, MD, PhD testinal tract obstruction, and low birth weight.40,41 Health Resources and Services Administration In addition to these conditions, high MSAFP concen- Cynthia A. Moore, MD, PhD trations may also be seen with multifetal gestation, Centers for Disease Control and underestimated gestational age, and some maternal Prevention conditions such as low maternal weight. Low MSAFP concentrations are associated with adverse Staff outcomes other than chromosomal trisomies, includ- Paul Spire ing fetal death and gestational trophoblastic dis- 42 ease. As with high MSAFP concentrations, low con- REFERENCES centrations may be seen in nonpathologic conditions 1. Creasy RK, Resnik R, eds. Maternal-Fetal Medicine. 4th ed. Philadelphia, such as overestimated gestational age or high mater- PA: Saunders; 1999 nal weight. 2. Cunningham FG, ed. Williams . 21st ed. New York, NY: McGraw-Hill; 2001 CONCLUSIONS 3. Simpson JL, Elias S, eds. Genetics in Obstetrics and Gynecology. 3rd ed. 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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/114/3/889 References This article cites 39 articles, 2 of which you can access for free at: http://pediatrics.aappublications.org/content/114/3/889#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Fetus/Newborn Infant http://www.aappublications.org/cgi/collection/fetus:newborn_infant_ sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 24, 2021 Prenatal Screening and Diagnosis for Pediatricians Christopher Cunniff Pediatrics 2004;114;889 DOI: 10.1542/peds.2004-1368

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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 © 2004 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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