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Expert commentary on Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders.
Prenatal genetic diagnostic testing is intended to determine, with as much certainty as possible, whether a specific genetic disorder or condition is present in the fetus. In contrast, prenatal genetic screening is designed to assess whether a patient is at increased risk of having a fetus affected by a genetic disorder. Originally, prenatal genetic testing focused primarily on Down syndrome (trisomy 21), but now it is able to detect a broad range of genetic disorders. Although it is necessary to perform amniocentesis or chorionic villus sampling (CVS) to definitively diagnose most genetic disorders, in some circumstances, fetal imaging with ultrasonography, echocardiography, or magnetic resonance imaging may be diagnostic of a particular structural fetal abnormality that is suggestive of an underlying genetic condition.
The objective of prenatal genetic testing is to detect health problems that could affect the woman, fetus, or newborn and provide the patient and her obstetrician–gynecologist or other obstetric care provider with enough information to allow a fully informed decision about pregnancy management. Prenatal genetic testing cannot identify all abnormalities or problems in a fetus, and any testing should be focused on the individual patient’s risks, reproductive goals, and preferences. It is important that patients understand the benefits and limitations of all prenatal screening and diagnostic testing, including the conditions for which tests are available and the conditions that will not be detected by testing. It also is important that patients realize that there is a broad range of clinical presentations, or phenotypes, for many genetic disorders and that results of genetic testing cannot predict all outcomes. Prenatal genetic testing has many benefits, including reassuring patients when results are normal, identifying disorders for which prenatal treatment may provide benefit, optimizing neonatal outcomes by ensuring the appropriate location for delivery and the necessary personnel to care for affected infants, and allowing the opportunity for pregnancy termination.
The purpose of this Practice Bulletin is to review the current status of prenatal genetic diagnostic testing and the evidence supporting its use. For information regarding screening for fetal aneuploidy, refer to Practice Bulletin No. 163, Screening for Fetal Aneuploidy.
COMMITTEE ON PRACTICE BULLETINS-Obstetrics, Committee On Genetics, And Society For Maternal-Fetal Medicine Practice Bulletin #162: Prenatal Diagnostic Testing for Genetic Disorders. Published jointly with the Society for Maternal-Fetal Medicine (Replaces Practice Bulletin Number 88, December 2007). American College of Obstetricians and Gynecologists. Obstet Gynecol. 2016;127:e108-22. Full text of Practice Bulletin #162 is available to ACOG members at aacog.org/Resources-And-Publications/Practice-Bulletins/Committee-on-Practice-Bulletins-Obstetrics/Prenatal-Diagnostic-Testing-for-Genetic-Disorders.
A welcome review of current evidence on prenatal diagnostic testing
by Joe Leigh Simpson, MD
The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have recently revisited and updated clinical information and recommendations on several related documents: Practice Bulletin 162, which will be reviewed in this communication; Screening for Fetal Aneuploidies (Practice Bulletin 163); Microarrays and Next Generation Sequencing Technology (Committee Opinion 682); and Carrier Screening for Genetic Conditions (Committee Opinion 691). In Practice Bulletin 162, Drs. Mary Norton and Marc Jackson are the acknowledged authors on behalf of the ACOG Committee on Genetics and SMFM. Practice Bulletin 162 should be applauded for recommendations and conclusions that previous ACOG bulletins could be accused of obviating in deference to tradition.
In 2007, ACOG boldly stated in Practice Bulletin 77 that all pregnant women should have the option of an invasive procedure (chorionic villus sampling [CVS] or amniocentesis). This statement still holds and reflects sensitivity of detecting fetal abnormalities being greatest with diagnostic tests possible only using tissue obtained from an invasive procedure. New in Practice Bulletin 162 are updated risks for CVS and amniocenteses. The hackneyed and outdated allusions to a loss rate of up to 1% for CVS or 0.5% (“1 in 200”) for amniocenteses are no longer applicable. Pregnancy loss rate following CVS ≥ 10 weeks is now cited as 0.22% (1 in 455).1 The risk of limb reduction defects with CVS is stated to be 6 per 10,000, not significantly different from the general population and as concluded by the World Health Organization in 1994.2
The loss rate following traditional amniocenteses is now stated to be 0.13% (1 in 769) in experienced hands. Practice Bulletin 162 does cite a 1% to 2% rate of amniotic membrane rupture, which seems unduly high in my opinion and based on a 1998 study.3 On the other hand, perinatal survival following often transient membrane rupture is, in my opinion, plausibly stated to be greater than 90%. The long-accepted conclusion that 10- to 13-week amniocentesis is not recommended was confirmed. Loss rates in multiple gestations are said to be 2%, perhaps high in experienced hands.
The most transformative guideline in Practice Bulletin 162 is its recommendation for DNA-based microarrays to determine status of all 24 chromosomes. A karyotype is no longer recommended.
This conclusion is based first on the 2012 National Institutes of Child Health and Human Development (NICHD) trial of Wapner and colleagues including this author6 followed by replication.7 The NICHD trial report compared accuracy and additional yield of microarray versus karyotype. Given a normal fetal ultrasound and a normal fetal karyotype, chromosomal microarrays identified clinically significant (chromosomal) abnormalities in 1.7% additional cases over that detected by karyotype alone. The additional abnormalities involved genomic material smaller than the 5 to 7 million base pair resolution possible with a high-resolution karyotype. If ultrasound had revealed a fetal anomaly, the yield catapulted an additional 6%. The take-home message is that an invasive prenatal procedure performed for any reason warrants a chromosomal microarray, and not simply a karyotype.
Chromosomal mosaicism is stated to occur in 0.25% of amniocenteses and in 1% of CVS samples. In amniotic cells and in chorionic villi analysis, providers have long applied algorithms to clarify the clinical significance of abnormal, non-modal cells. If a non-modal cell line in chorionic villi is believed confined to trophoblasts (placenta), the embryo itself should theoretically be normal: confined placental mosaicism (CPM). Extant recommendations for determining clinical significance remain.
Practice Bulletin 162 was prepared, however, prior to generation of new information derived from next generation sequencing (NGS). With NGS, mosaicism is unavoidably encountered, given its greater sensitivity, more often than with chromosomal microarrays. If NGS has been recently introduced into a lab to which prenatal samples are being sent, the provider should inquire if altered criteria for prenatal diagnosis of CVS or amniotic fluid cell mosaicism is being applied. NGS is now widely used in preimplantation genetic diagnosis (PGD), for which Practice Bulletin 162 was presumably not intended.
Chromosomal microarrays have also replaced karyotypes as the recommended diagnostic test in evaluating tissue from a fetal demise. In addition to greater sensitivity, chromosomal microarrays do not require cultured cells. This has long been a major problem in studying miscarriages, as witnessed by a disproportionate number of 46, XX results, a reflection of unwitting laboratory analysis of maternal cells. It is difficult to avoid maternal admixture (decidua) in cultures of products of conception. With chromosomal microarrays, however, DNA alone from identifiable fetal tissue (villi) will suffice to generate results, without need for cell culture; thus, the percentage of informative cases has greatly increased (90%).
ACOG recommends that if only a karyotype were possible, cell culture should be initiated from amniotic fluid obtained by amniocentesis. This should maximize the rate of successful cell culture required for a karyotype.
Practice Bulletin 162 appropriately counsels that transmission of chronic maternal infection to the fetus is increased if an invasive procedure is performed in a mother who has hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). However, risks can be mitigated. The once prohibitively high rate of maternal to fetal transmission in HIV is now greatly decreased when affected women receive combination antiretroviral therapy. In the study on which Practice Bulletin 162 recommendation was based, 30 of 2528 fetuses (~1% of ART-treated HIV) women were infected.8 Notwithstanding this 1%, Practice Bulletin 162 states that the risk of “newborn infection is not increased after amniocenteses, maternal viral load is low or undetectable.” A recommendation is made, however, to perform the necessary invasive procedure once viral loads are undetectable.
Practice Bulletin 162 states that loss rates following an invasive prenatal diagnostic procedure should now be communicated to be 1 in 769 for amniocentesis and 1 in 455 for CVS. For most practitioners, these new numbers will be more in sync with their clinical impressions. Also transformative in Practice Bulletin 162 is that chromosomal microarrays and not a karyotype should be ordered whenever an invasive prenatal procedure (CVS, amniocenteses) is performed. This holds whether evaluation is for a miscarriage or stillbirth.
1. Akolekar R, Beta J, Picciarelli G, Ogilvie C, D’Antonio F. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2015;45:16–26.
2. Kuliev A, Jackson L, Froster U, Brambati B, Simpson JL, Verlinsky Y, et al. Chorionic villus sampling safety. Report of World Health Organization/EURO meeting in association with the Seventh International Conference on Early Prenatal Diagnosis of Genetic Diseases, Tel Aviv, Israel, May 21, 1994. Am J Obstet Gynecol 1996;174:807–11.
3. Botto LD, Olney RS , Mastroiacovo P, Khoury MJ, Moore CA, Alo CJ, et al. Chorionic villus sampling and transverse digital deficiencies: evidence for anatomic and gestational-age specificity of the digital deficiencies in two studies. Am J Med Genet 1996;62:173–8.
4. Odibo AO, Gray DL, Dicke JM, Stamilio DM, Macones GA, Crane JP. Revisiting the fetal loss rate after second-trimester genetic amniocentesis: a single center’s 16-year experience. Obstet Gynecol 2008;111:589–9
5. Borgida AF, Mills AA, Feldman DM, Rodis JF, Egan JF. Outcome of pregnancies complicated by ruptured membranes after genetic amniocentesis. Am J Obstet Gynecol 2000;183:937–9.
6. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012;367:2175–84.
7. de Wit MC, Srebniak MI, Govaerts LC, Van Opstal D, Galjaard RJ, Go AT. Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature. Ultrasound Obstet Gynecol 2014; 43:139–46.
8. Mandelbrot L, Jasseron C, Ekoukou D, Batallan A, Bongain A, Pannier E, et al. Amniocentesis and mother-to-child human immunodeficiency virus transmission in the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales French Perinatal Cohort. ANRS French Perinatal Cohort (EP F). Am J Obstet Gynecol 2009;200:160.e1–9.