Fetal Aneuploidy: Screening and Diagnostic Testing


Am Fam Physician. 2020 Apr 15;101(8):481-488.

  Patient information: See related handout on fetal aneuploidy.

Author disclosure: No relevant financial affiliations.

Aneuploidy is the presence of one or more extra chromosomes or the absence of one or more chromosomes. The risk of fetal aneuploidy rises with increasing maternal age. Because fetal aneuploidy can affect any pregnancy, all pregnant women should be offered screening. First-trimester combined screening performed between 10 and 13 weeks' gestation detects 82% to 87% of trisomy 21 (Down syndrome) cases. Second-trimester serum quadruple screening performed between 15 and 22 weeks' gestation detects 81% of trisomy 21 cases. Combinations of these tests include integrated or serum integrated, stepwise sequential, and contingent sequential screenings, all of which improve detection rates compared with each test alone. Fetal cell-free DNA testing (noninvasive prenatal testing) performed at or after 10 weeks' gestation detects more than 99% of trisomy 21 cases, with a lower false-positive rate than traditional first-or second-trimester screening methods. Fetal cell-free DNA testing has similar detection rates in high- and low-risk populations but has lower positive predictive values in younger women. It may be performed as primary screening or as a follow-up test to abnormal findings on first- or second-trimester screenings. Second-trimester ultrasonography has limited utility in aneuploidy screening in women who have already been screened with a first- or second-trimester serum test. Diagnostic tests following a positive screening result include chorionic villus sampling performed between 10 and 13 weeks' gestation or amniocentesis performed after 15 weeks' gestation.

Chromosomal abnormalities affect approximately one in 150 pregnancies1 and are responsible for 50% of early pregnancy losses.2 Aneuploidy is the presence of one or more extra chromosomes or the absence of one or more chromosomes.3 The consequences of fetal aneuploidy vary from incompatibility with life to intellectual and physical disability. Prenatal screening aims to detect the most common forms of aneuploidy compatible with survival beyond early embryologic development into viability. The risk of fetal aneuploidy rises with increasing maternal age. For example, the risk of a woman giving birth to a live newborn with trisomy 21 (Down syndrome) increases from one in 1,480 at 20 years of age to one in 85 at 40 years of age.1 Although the overall birth rate in the United States has declined, the portion of first births to women older than 30 years increased from 23.9% in 2000 to 30.2% in 2014.4,5 Because fetal aneuploidy can affect any pregnancy, all pregnant women should be counseled and offered aneuploidy screening regardless of age.1,6,7


Although the overall birth rate in the United States has declined the portion of first births to women older than 30 years increased from 23.9% in 2000 to 30.2% in 2014.

Fetal cell-free DNA testing (noninvasive prenatal testing), which is generally performed at or after 10 weeks' gestation, can be used to determine the likelihood of trisomies 21, 18, and 13, as well as fetal sex and sex chromosome aneuploidy.

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Clinical recommendationEvidence ratingComments

All pregnant women should be counseled and offered aneuploidy screening regardless of maternal age.1,6,7


Expert consensus guidelines

Fetal cell-free DNA testing (NIPT), which is generally performed at or after 10 weeks' gestation, is superior to first- or second-trimester serum screenings with fewer false positives and higher positive predictive values for trisomies 18 and 21.1,7,17,2332


Systematic reviews and meta-analyses of high-quality diagnostic accuracy studies; NIPT performs similarly in high- and low-risk populations, although positive predictive values are lower in low-risk populations

First-trimester nuchal translucency, NIPT, and first- or second-trimester serum testing can be performed in twin pregnancies.1,7,38


Meta-analysis of diagnostic accuracy studies with limitations; detection rates are lower in twin pregnancies

Women with positive results on aneuploidy screening should be offered referral for invasive diagnostic testing.1,7


Expert consensus guidelines; no screening test, including cell-free DNA, is considered diagnostic

NIPT = noninvasive prenatal testing.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

The Authors

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NICHOLAS M. LEFEVRE, MD, is a faculty physician at the John Peter Smith Hospital Family Medicine Residency Program and Maternal-Child Health Fellowship, Fort Worth, Tex., and an assistant professor in the Department of Family Medicine at the Texas Christian University and University of North Texas Health Science Center School of Medicine, Fort Worth....

RICHARD L. SUNDERMEYER, MD, FAAFP, is program director of the HealthONE/Sky Ridge Family Medicine Residency Program, Denver, Colo. At the time this article was written, he was a faculty physician at the John Peter Smith Hospital Family Medicine Residency Program and director of the Maternal-Child Health Fellowship.

Address correspondence to Nicholas M. LeFevre, MD, 1500 S. Main St., Fort Worth, TX 76104 (email: nlefevre@jpshealth.org). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.


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1. Committee on Practice Bulletins—Obstetrics, Committee on Genetics, and the Society for Maternal-Fetal Medicine. Practice bulletin no. 163: screening for fetal aneuploidy. Obstet Gynecol. 2016;127(5):e123–e137....

2. ACOG practice bulletin no. 200: early pregnancy loss. Obstet Gynecol. 2018;132(5):e197–e207.

3. Dashe JS. Aneuploidy screening in pregnancy. Obstet Gynecol. 2016;128(1):181–194.

4. Martin JA, Hamilton BE, Osterman MJK. Centers for Disease Control and Prevention. NCHS data brief no. 318. August 2018. Births in the United States, 2017. Accessed May 2019. https://www.cdc.gov/nchs/data/databriefs/db318.pdf

5. Mathews TJ, Hamilton BE. Centers for Disease Control and Prevention. NCHS data brief no. 232. January 2016. Mean age of mothers is on the rise: United States, 2000–2014. Accessed May 2019. https://www.cdc.gov/nchs/products/databriefs/db232.htm

6. Benn P, Borrell A, Chiu R, et al. Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. 2015. Accessed March 15, 2019. https://www.ispdhome.org/docs/ISPD/Society%20Statements/PositionStatement_Current_8Apr2015.pdf

7. Audibert F, De Bie I, Johnson JA, et al. No. 348-Joint SOGC-CCMG guideline: update on prenatal screening for fetal aneuploidy, fetal anomalies, and adverse pregnancy outcomes [published correction appears in J Obstet Gynaecol Can 2018;40(8):1109]. J Obstet Gynaecol Can. 2017;39(9):805–817.

8. Johnston J, Farrell RM, Parens E. Supporting women's autonomy in prenatal testing. N Engl J Med. 2017;377(6):505–507.

9. Committee opinion no. 693 summary: counseling about genetic testing and communication of genetic test results. Obstet Gynecol. 2017;129(4):771–772.

10. Beulen L, van den Berg M, Faas BH, et al. The effect of a decision aid on informed decision-making in the era of non-invasive prenatal testing: a randomised controlled trial. Eur J Hum Genet. 2016;24(10):1409–1416.

11. Anderson CL, Brown CE. Fetal chromosomal abnormalities: antenatal screening and diagnosis. Am Fam Physician. 2009;79(2):117–123. Accessed December 5, 2019. https://www.aafp.org/afp/2009/0115/p117.html

12. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion. Fertil Steril. 2018;109(3):429–436.

13. Malone FD, Canick JA, Ball RH, et al.; First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med. 2005;353(19):2001–2011.

14. Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome based on tests performed during the first and second trimesters. N Engl J Med. 1999;341(7):461–467.

15. Benn PA, Campbell WA, Zelop CM, et al. Stepwise sequential screening for fetal aneuploidy. Am J Obstet Gynecol. 2007;197(3):312e1–312e5.

16. Wright D, Bradbury I, Benn P, et al. Contingent screening for Down syndrome is an efficient alternative to non-disclosure sequential screening. Prenat Diagn. 2004;24(10):762–766.

17. Gil MM, Accurti V, Santacruz B, et al. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2017;50(3):302–314.

18. Reddy UM, Mennuti MT. Incorporating first-trimester Down syndrome studies into prenatal screening: executive summary of the National Institute of Child Health and Human Development workshop. Obstet Gynecol. 2006;107(1):167–173.

19. Alldred SK, Takwoingi Y, Guo B, et al. First and second trimester serum tests with and without first trimester ultrasound tests for Down's syndrome screening. Cochrane Database Syst Rev. 2017;(3):CD012599.

20. Committee on Obstetric Practice, the American Institute of Ultrasound in Medicine, and the Society for Maternal-Fetal Medicine. Committee opinion no 700: methods for estimating the due date. Obstet Gynecol. 2017;129(5):e150–e154.

21. California Department of Health Services. Midtrimester risk for chromosome abnormalities by maternal age. Accessed April 1, 2019. http://perinatology.com/calculators/ama.htm

22. Dugoff L; Society for Maternal-Fetal Medicine. First- and second-trimester maternal serum markers for aneuploidy and adverse obstetric outcomes. Obstet Gynecol. 2010;115(5):1052–1061.

23. Royal College of Obstetricians and Gynaecologists. Non-invasive prenatal testing for chromosomal abnormality using maternal plasma DNA: scientific impact paper no. 15. March 2014. Accessed March 15, 2019. https://www.rcog.org.uk/globalassets/documents/guidelines/scientific-impact-papers/sip_15_04032014.pdf

24. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372(17):1589–1597.

25. Nicolaides KH, Syngelaki A, Ashoor G, et al. Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am J Obstet Gynecol. 2012;207(5):374.e1–374.e6.

26. Iwarsson E, Jacobsson B, Dagerhamn J, et al. Analysis of cell-free fetal DNA in maternal blood for detection of trisomy 21, 18 and 13 in a general pregnant population and in a high risk population - a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2017;96(1):7–18.

27. Taylor-Phillips S, Freeman K, Geppert J, et al. Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. BMJ Open. 2016;6(1):e010002.

28. Mackie FL, Hemming K, Allen S, et al. The accuracy of cell-free fetal DNA-based non-invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta-analysis. BJOG. 2017;124(1):32–46.

29. Malan V, Bussières L, Winer N, et al.; SAFE 21 Study Group. Effect of cell-free DNA screening vs direct invasive diagnosis on miscarriage rates in women with pregnancies at high risk of trisomy 21: a randomized clinical trial. JAMA. 2018;320(6):557–565.

30. Norton ME, Jelliffe-Pawlowski LL, Currier RJ. Chromosome abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol. 2014;124(5):979–986.

31. García-Pérez L, Linertová R, Álvarez-de-la-Rosa M, et al. Cost-effectiveness of cell-free DNA in maternal blood testing for prenatal detection of trisomy 21, 18 and 13: a systematic review. Eur J Health Econ. 2018;19(7):979–991.

32. Society for Maternal-Fetal Medicine Publications Committee. #36: Prenatal aneuploidy screening using cell-free DNA. Am J Obstet Gynecol. 2015;212(6):711–716.

33. Palomaki GE, Kloza EM, Lambert-Messerlian GM, et al. Circulating cell free DNA testing: are some test failures informative? Prenat Diagn. 2015;35(3):289–293.

34. Palomaki GE, Kloza EM. Prenatal cell-free DNA screening test failures: a systematic review of failure rates, risks of Down syndrome, and impact of repeat testing. Genet Med. 2018;20(11):1312–1323.

35. Ashoor G, Syngelaki A, Poon LC, et al. Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks' gestation: relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol. 2013;41(1):26–32.

36. Carlson LM, Hardisty E, Coombs CC, et al. Maternal malignancy evaluation after discordant cell-free DNA results. Obstet Gynecol. 2018;131(3):464–468.

37. Bianchi DW, Chudova D, Sehnert AJ, et al. Noninvasive prenatal testing and incidental detection of occult maternal malignancies. JAMA. 2015;314(2):162–169.

38. Liao H, Liu S, Wang H. Performance of non-invasive prenatal screening for fetal aneuploidy in twin pregnancies: a meta-analysis. Prenat Diagn. 2017;37(9):874–882.

39. Committee on Practice Bulletins—Obstetrics and the American Institute of Ultrasound in Medicine. Practice bulletin no. 175: ultrasound in pregnancy. Obstet Gynecol. 2016;128(6):e241–e256.

40. Smith-Bindman R, Hosmer W, Feldstein VA, et al. Second-trimester ultrasound to detect fetuses with Down syndrome: a meta-analysis. JAMA. 2001;285(8):1044–1055.

41. Weisz B, Pandya PP, David AL, et al. Ultrasound findings after screening for Down syndrome using the integrated test. Obstet Gynecol. 2007;109(5):1046–1052.

42. Norton ME, Biggio JR, Kuller JA, et al.; Society for Maternal-Fetal Medicine. The role of ultrasound in women who undergo cell-free DNA screening. Am J Obstet Gynecol. 2017;216(3):B2–B7.

43. 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(5):e108–e122.

44. Sundberg K, Bang J, Smidt-Jensen S, et al. Randomised study of risk of fetal loss related to early amniocentesis versus chorionic villus sampling. Lancet. 1997;350(9079):697–703.

45. Alfirevic Z, Navaratnam K, Mujezinovic F. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database Syst Rev. 2017;(9):CD003252.



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