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Prenatal genetic evaluation of the anomalous fetus

Neeta Vora, MD
Sarah Harris, MS, CGC
Section Editor
Louise Wilkins-Haug, MD, PhD
Deputy Editor
Vanessa A Barss, MD, FACOG


Approximately 3 percent of live births are affected by a major structural malformation [1]. With advances in prenatal ultrasound, many of these anomalies are now identified before birth. The etiology is diverse and includes environmental factors, genetic factors, or a combination of both.

As the landscape of genetic testing rapidly evolves, clinicians are often left with many questions about the most appropriate testing methods to use for their patients. This topic will provide a reasonable approach to the genetic evaluation of an anomalous fetus. Postnatal evaluation of the anomalous infant is reviewed separately. (See "Birth defects: Approach to evaluation".)


The finding of a fetal structural anomaly increases the possibility of a chromosome abnormality or genetic molecular defect and should prompt further evaluation into genetic etiologies. The frequency of a chromosome abnormality depends on the specific anomaly, the number of anomalies, and the combination of anomalies identified [2]. In several retrospective series of prenatally detected anomalies on ultrasound that prompted genetic studies, an isolated fetal anomaly was associated with fetal chromosome abnormalities in 2 to 18 percent of cases; multiple anomalies were associated with a fetal chromosome abnormality in 13 to 35 percent of cases [2-7].


Our approach — We offer a diagnostic procedure to patients with structural fetal abnormalities on ultrasound examination (algorithm 1) [8]. The goal is to determine whether there is a genetic etiology of the abnormalities that would enable well-informed counseling about prognosis, reproductive options, obstetric and pediatric management, and recurrence risks.

The decision to undergo invasive testing is personal and must be based on the individual patient's values and goals. Pretest counseling by a provider familiar with the suspected fetal diagnoses and with genetic testing options is necessary for patients to make informed decisions. Alternatives to prenatal diagnostic testing include prenatal screening and postnatal diagnostic testing.

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Literature review current through: Nov 2017. | This topic last updated: Nov 13, 2017.
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  1. National Center for Health Statistics. Birth defects monitoring program. www.marchofdimes.org/peristats (Accessed on February 29, 2016).
  2. Staebler M, Donner C, Van Regemorter N, et al. Should determination of the karyotype be systematic for all malformations detected by obstetrical ultrasound? Prenat Diagn 2005; 25:567.
  3. Halliday J, Lumley J, Bankier A. Karyotype abnormalities in fetuses diagnosed as abnormal on ultrasound before 20 weeks' gestational age. Prenat Diagn 1994; 14:689.
  4. van Zalen-Sprock MM, van Vugt JM, Karsdorp VH, et al. Ultrasound diagnosis of fetal abnormalities and cytogenetic evaluation. Prenat Diagn 1991; 11:655.
  5. Nicolaides KH, Snijders RJ, Gosden CM, et al. Ultrasonographically detectable markers of fetal chromosomal abnormalities. Lancet 1992; 340:704.
  6. Rizzo N, Pittalis MC, Pilu G, et al. Distribution of abnormal karyotypes among malformed fetuses detected by ultrasound throughout gestation. Prenat Diagn 1996; 16:159.
  7. Bijok J, Massalska D, Kucińska-Chahwan A, et al. Complex malformations involving the fetal body wall - definition and classification issues. Prenat Diagn 2017; 37:1033.
  8. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 88, December 2007. Invasive prenatal testing for aneuploidy. Obstet Gynecol 2007; 110:1459.
  9. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics, Committee on Genetics, Society for Maternal–Fetal Medicine. Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders. Obstet Gynecol 2016; 127:e108.
  10. Shaffer LG, Bui TH. Molecular cytogenetic and rapid aneuploidy detection methods in prenatal diagnosis. Am J Med Genet C Semin Med Genet 2007; 145C:87.
  11. Tepperberg J, Pettenati MJ, Rao PN, et al. Prenatal diagnosis using interphase fluorescence in situ hybridization (FISH): 2-year multi-center retrospective study and review of the literature. Prenat Diagn 2001; 21:293.
  12. de Wit MC, Srebniak MI, Govaerts LC, et al. 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.
  13. Hillman SC, Pretlove S, Coomarasamy A, et al. Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2011; 37:6.
  14. Hillman SC, McMullan DJ, Hall G, et al. Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysis. Ultrasound Obstet Gynecol 2013; 41:610.
  15. Bernhardt BA, Soucier D, Hanson K, et al. Women's experiences receiving abnormal prenatal chromosomal microarray testing results. Genet Med 2013; 15:139.
  16. Innes J, Reali L, Clayton-Smith J, et al. CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing. J Med Genet 2017.
  17. Tyreman M, Abbott KM, Willatt LR, et al. High resolution array analysis: diagnosing pregnancies with abnormal ultrasound findings. J Med Genet 2009; 46:531.
  18. Committee on Genetics and the Society for Maternal-Fetal Medicine. Committee Opinion No.682: Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology. Obstet Gynecol 2016; 128:e262.
  19. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med 2015; 17:444.
  20. Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med 2009; 11:127.
  21. Xue Y, Sun A, Mekikian PB, et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med 2014; 2:497.
  22. Croonen EA, Nillesen WM, Stuurman KE, et al. Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings. Eur J Hum Genet 2013; 21:936.
  23. Rabbani B, Tekin M, Mahdieh N. The promise of whole-exome sequencing in medical genetics. J Hum Genet 2014; 59:5.
  24. Carss KJ, Hillman SC, Parthiban V, et al. Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Hum Mol Genet 2014; 23:3269.
  25. Drury S, Williams H, Trump N, et al. Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. Prenat Diagn 2015; 35:1010.
  26. Farwell KD, Shahmirzadi L, El-Khechen D, et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med 2015; 17:578.
  27. ACMG Board of Directors. Points to consider in the clinical application of genomic sequencing. Genet Med 2012; 14:759.
  28. Benn P, Cuckle H, Pergament E. Non-invasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound Obstet Gynecol 2013; 42:15.
  29. Benachi A, Letourneau A, Kleinfinger P, et al. Cell-free DNA analysis in maternal plasma in cases of fetal abnormalities detected on ultrasound examination. Obstet Gynecol 2015; 125:1330.
  30. Oneda B, Steindl K, Masood R, et al. Noninvasive prenatal testing: more caution in counseling is needed in high risk pregnancies with ultrasound abnormalities. Eur J Obstet Gynecol Reprod Biol 2016; 200:72.
  31. Beulen L, Faas BHW, Feenstra I, et al. Clinical utility of non-invasive prenatal testing in pregnancies with ultrasound anomalies. Ultrasound Obstet Gynecol 2017; 49:721.
  32. Committee Opinion No. 640: Cell-Free DNA Screening For Fetal Aneuploidy. Obstet Gynecol 2015; 126:e31. Reaffirmed 2017.
  33. Mennuti MT, Cherry AM, Morrissette JJ, Dugoff L. Is it time to sound an alarm about false-positive cell-free DNA testing for fetal aneuploidy? Am J Obstet Gynecol 2013; 209:415.
  34. Yaron Y, Jani J, Schmid M, Oepkes D. Current Status of Testing for Microdeletion Syndromes and Rare Autosomal Trisomies Using Cell-Free DNA Technology. Obstet Gynecol 2015; 126:1095.
  35. Yaron Y. The implications of non-invasive prenatal testing failures: a review of an under-discussed phenomenon. Prenat Diagn 2016; 36:391.
  36. Palomaki GE, Kloza EM, Lambert-Messerlian GM, et al. Circulating cell free DNA testing: are some test failures informative? Prenat Diagn 2015; 35:289.
  37. Breathnach FM, Fleming A, Malone FD. The second trimester genetic sonogram. Am J Med Genet C Semin Med Genet 2007; 145C:62.
  38. Committee on Practice Bulletins—Obstetrics and the American Institute of Ultrasound in Medicine. Practice Bulletin No. 175: Ultrasound in Pregnancy. Obstet Gynecol 2016; 128:e241.
  39. Shaffer LG, Rosenfeld JA, Dabell MP, et al. Detection rates of clinically significant genomic alterations by microarray analysis for specific anomalies detected by ultrasound. Prenat Diagn 2012; 32:986.
  40. Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012; 367:2175.
  41. Society for Maternal-Fetal Medicine (SMFM). Electronic address: pubs@smfm.org, Norton ME, Biggio JR, et al. The role of ultrasound in women who undergo cell-free DNA screening. Am J Obstet Gynecol 2017; 216:B2.
  42. Fonda Allen J, Stoll K, Bernhardt BA. Pre- and post-test genetic counseling for chromosomal and Mendelian disorders. Semin Perinatol 2016; 40:44.