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Am J Perinatol 2025; 42(04): 538-545
DOI: 10.1055/a-2312-8824
Clinical Opinion

Prenatal Screening and Diagnosis: Time for a Paradigm Shift

Yinka Oyelese 
1   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
2   Maternal Fetal Care Center, Division of Fetal Medicine and Surgery, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts
3   Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, Massachusetts
,
Davia Schioppo
1   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
,
Barbara O'Brien
1   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
2   Maternal Fetal Care Center, Division of Fetal Medicine and Surgery, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts
3   Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, Massachusetts
› Author Affiliations Funding None.
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Abstract

Recent advances in genetics and imaging have ushered substantial breakthroughs in screening and diagnosis for chromosomal and structural abnormalities. Thus, it is imperative that health care providers caring for pregnant individuals should reexamine established practices in prenatal screening and diagnosis. In the past, screening for chromosomal abnormalities was based almost entirely on Down syndrome. Pregnant individuals aged > 35 years were considered at “high risk” or of “advanced maternal age” based on age alone; however, the advent of tests with high sensitivity for prenatal detection of chromosomal abnormalities should lead to abandoning that concept, at least from the perspective of chromosomal abnormalities. Given that first-trimester and second-trimester screenings will fail to detect between 5 and 20% of Down syndrome, in most situations, noninvasive testing with cell-free DNA should be the first-line screen for Down syndrome. The fact that over 99% of fetuses with Down syndrome will be detected prenatally with cell-free DNA gives other fetal chromosomal and structural abnormalities increasing prominence. Chromosomal microarray analysis (CMA) permits prenatal detection of several clinically important chromosomal aberrations that cannot be detected by karyotype and may exist in structurally normal fetuses with low-risk cell-free DNA screening. As such, CMA should be more readily conducted when invasive testing is performed, regardless of the presence of a structural abnormality. Isolated sonographic “soft markers” have no clinical significance in patients who have normal cell-free DNA screening, can cause unwarranted anxiety and a negative impact on pregnancy, and perhaps it is time to stop discussing them. Detailed first-trimester ultrasound allows early detection of several severe fetal anomalies and, therefore, in settings with adequately trained personnel and resources, should be used more frequently. This opinion traces the evolution of prenatal screening and diagnosis and advocates for a paradigm shift that aligns with recent developments in prenatal screening and diagnostic capabilities.

Key Points

  • Noninvasive prenatal testing with cell-free DNA should be available to all pregnant individuals.

  • Chromosomal microarray should be available to all pregnant individuals undergoing amniocentesis.

  • Patients >35 years with low-risk screening are not at “high risk” for chromosomal abnormalities.

Keywords

prenatal screening - prenatal diagnosis - chromosomal aberrations - chromosomal microarray - noninvasive prenatal screening - karyotype

Summary

Recent advances in genetics and imaging require that health care providers involved in pregnancy care reevaluate current prenatal screening practices and adopt a paradigm shift.




Publication History

Received: 08 January 2024

Accepted: 17 April 2024

Accepted Manuscript online:
24 April 2024

Article published online:
16 May 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.

 

  • References

  • 1 Case JT. Anencephaly successfully diagnosed before birth. Surg Gynecol Obstet 1917; 24: 312
    PubMedSearch in Google Scholar
  • 2 Turnbull AC, Gregory PJ, Laurence KM. Antenatal diagnosis of fetal abnormality with special reference to amniocentesis. Proc R Soc Med 1973; 66 (11) 1115-1118
    PubMedSearch in Google Scholar
  • 3 Resta RG. Historical aspects of genetic counseling: why was maternal age 35 chosen as the cut-off for offering amniocentesis?. Med Secoli 2002; 14 (03) 793-811
    PubMedSearch in Google Scholar
  • 4 Ferguson-Smith ME, Ferguson-Smith MA, Nevin NC, Stone M. Chromosome analysis before birth and its value in genetic counselling. BMJ 1971; 4 (5779) 69-74
    CrossrefPubMedSearch in Google Scholar
  • 5 Nadler HL, Gerbie AB. Role of amniocentesis in the intrauterine detection of genetic disorders. N Engl J Med 1970; 282 (11) 596-599
    CrossrefPubMedSearch in Google Scholar
  • 6 Tjio JH. The chromosome number of man. Am J Obstet Gynecol 1978; 130 (06) 723-724
    CrossrefPubMedSearch in Google Scholar
  • 7 Lejeune JGM, Turpin R. Le chromosomes somatique des enfants mongoliens. Comp Rendus Acad Sci 1959; 248: 1721-1722
    PubMedSearch in Google Scholar
  • 8 Jacobson CB, Barter RH. Intrauterine diagnosis and management of genetic defects. Am J Obstet Gynecol 1967; 99 (06) 796-807
    CrossrefPubMedSearch in Google Scholar
  • 9 Nadler HL, Gerbie A. Present status of amniocentesis in intrauterine diagnosis of genetic defects. Obstet Gynecol 1971; 38 (05) 789-799
    PubMedSearch in Google Scholar
  • 10 Penrose LS. Mongolian idiocy (mongolism) and maternal age. Ann N Y Acad Sci 1954; 57 (05) 494-502
    CrossrefPubMedSearch in Google Scholar
  • 11 Dashe JS. Aneuploidy screening in pregnancy. Obstet Gynecol 2016; 128 (01) 181-194
    CrossrefPubMedSearch in Google Scholar
  • 12 Oyelese Y, Vintzileos A. Interpretation and communication of medical evidence: room for improvement. Obstet Gynecol 2012; 120 (03) 650-654
    CrossrefPubMedSearch in Google Scholar
  • 13 American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics, Committee on Genetics, Society for Maternal-Fetal Medicine. Screening for fetal chromosomal abnormalities: ACOG Practice Bulletin, Number 226. Obstet Gynecol 2020; 136 (04) e48-e69
    CrossrefPubMedSearch in Google Scholar
  • 14 Hook EB. Rates of chromosome abnormalities at different maternal ages. Obstet Gynecol 1981; 58 (03) 282-285
    PubMedSearch in Google Scholar
  • 15 Snijders RJ, Sundberg K, Holzgreve W, Henry G, Nicolaides KH. Maternal age- and gestation-specific risk for trisomy 21. Ultrasound Obstet Gynecol 1999; 13 (03) 167-170
    CrossrefPubMedSearch in Google Scholar
  • 16 Seller MJ. Alpha-fetoprotein in anencephaly. Lancet 1972; 2 (7779) 716-717
    CrossrefPubMedSearch in Google Scholar
  • 17 Leek AE, Ruoss CF, Kitau MJ, Chard T. Raised alpha-fetoprotein in maternal serum with anencephalic pregnancy. Lancet 1973; 2 (7825) 385
    CrossrefPubMedSearch in Google Scholar
  • 18 Brock DJ, Sutcliffe RG. Alpha-fetoprotein in the antenatal diagnosis of anencephaly and spina bifida. Lancet 1972; 2 (7770) 197-199
    CrossrefPubMedSearch in Google Scholar
  • 19 Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol 1984; 148 (07) 886-894
    CrossrefPubMedSearch in Google Scholar
  • 20 DiMaio MS, Baumgarten A, Greenstein RM, Saal HM, Mahoney MJ. Screening for fetal Down's syndrome in pregnancy by measuring maternal serum alpha-fetoprotein levels. N Engl J Med 1987; 317 (06) 342-346
    CrossrefPubMedSearch in Google Scholar
  • 21 Haddow JE, Palomaki GE, Knight GJ, Canick JA, Wald NJ, Cuckle HS. Maternal serum unconjugated estriol levels are lower in the presence of fetal Down syndrome. Am J Obstet Gynecol 1990; 163 (4 Pt 1): 1372-1374
    CrossrefPubMedSearch in Google Scholar
  • 22 Haddow JE, Palomaki GE, Knight GJ. et al. Prenatal screening for Down's syndrome with use of maternal serum markers. N Engl J Med 1992; 327 (09) 588-593
    CrossrefPubMedSearch in Google Scholar
  • 23 Heyl PS, Miller W, Canick JA. Maternal serum screening for aneuploid pregnancy by alpha-fetoprotein, hCG, and unconjugated estriol. Obstet Gynecol 1990; 76 (06) 1025-1031
    PubMedSearch in Google Scholar
  • 24 Sheldon TA, Simpson J. Appraisal of a new scheme for prenatal screening for Down's syndrome. BMJ 1991; 302 (6785) 1133-1136
    CrossrefPubMedSearch in Google Scholar
  • 25 Nicolaides KH, Azar G, Byrne D, Mansur C, Marks K. Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy. BMJ 1992; 304 (6831) 867-869
    CrossrefPubMedSearch in Google Scholar
  • 26 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
    CrossrefPubMedSearch in Google Scholar
  • 27 Wald NJ, Hackshaw AK. Combining ultrasound and biochemistry in first-trimester screening for Down's syndrome. Prenat Diagn 1997; 17 (09) 821-829
    CrossrefPubMedSearch in Google Scholar
  • 28 Prabhu M, Kuller JA, Biggio JR. Society for Maternal-Fetal Medicine (SMFM). Electronic address: pubs@smfm.org. Society for Maternal-Fetal Medicine Consult Series #57: Evaluation and management of isolated soft ultrasound markers for aneuploidy in the second trimester: (Replaces Consults #10, Single umbilical artery, October 2010; #16, Isolated echogenic bowel diagnosed on second-trimester ultrasound, August 2011; #17, Evaluation and management of isolated renal pelviectasis on second-trimester ultrasound, December 2011; #25, Isolated fetal choroid plexus cysts, April 2013; #27, Isolated echogenic intracardiac focus, August 2013). Am J Obstet Gynecol 2021; 225 (04) B2-B15
    CrossrefPubMedSearch in Google Scholar
  • 29 Bahado-Singh RO, Mendilcioglu I, Rowther M. et al. Early genetic sonogram for Down syndrome detection. Am J Obstet Gynecol 2002; 187 (05) 1235-1238
    CrossrefPubMedSearch in Google Scholar
  • 30 Benacerraf BR. The role of the second trimester genetic sonogram in screening for fetal Down syndrome. Semin Perinatol 2005; 29 (06) 386-394
    CrossrefPubMedSearch in Google Scholar
  • 31 Benacerraf BR, Gelman R, Frigoletto Jr FD. Sonographic identification of second-trimester fetuses with Down's syndrome. N Engl J Med 1987; 317 (22) 1371-1376
    CrossrefPubMedSearch in Google Scholar
  • 32 DeVore GR. Is genetic ultrasound cost-effective?. Semin Perinatol 2003; 27 (02) 173-182
    CrossrefPubMedSearch in Google Scholar
  • 33 Vintzileos A, Walters C, Yeo L. Absent nasal bone in the prenatal detection of fetuses with trisomy 21 in a high-risk population. Obstet Gynecol 2003; 101 (5 Pt 1): 905-908
    PubMedSearch in Google Scholar
  • 34 Yeo L, Vintzileos AM. The use of genetic sonography to reduce the need for amniocentesis in women at high-risk for Down syndrome. Semin Perinatol 2003; 27 (02) 152-159
    CrossrefPubMedSearch in Google Scholar
  • 35 Bromley B, Lieberman E, Shipp TD, Benacerraf BR. The genetic sonogram: a method of risk assessment for Down syndrome in the second trimester. J Ultrasound Med 2002; 21 (10) 1087-1096 , quiz 1097–1098
    CrossrefPubMedSearch in Google Scholar
  • 36 Hobbins JC, Lezotte DC, Persutte WH. et al. An 8-center study to evaluate the utility of mid-term genetic sonograms among high-risk pregnancies. J Ultrasound Med 2003; 22 (01) 33-38
    CrossrefPubMedSearch in Google Scholar
  • 37 Nicolaides KH, Snijders RJ, Gosden CM, Berry C, Campbell S. Ultrasonographically detectable markers of fetal chromosomal abnormalities. Lancet 1992; 340 (8821) 704-707
    CrossrefPubMedSearch in Google Scholar
  • 38 Bethune M. Time to reconsider our approach to echogenic intracardiac focus and choroid plexus cysts. Aust N Z J Obstet Gynaecol 2008; 48 (02) 137-141
    CrossrefPubMedSearch in Google Scholar
  • 39 Doubilet PM, Copel JA, Benson CB, Bahado-Singh RO, Platt LD. Choroid plexus cyst and echogenic intracardiac focus in women at low risk for chromosomal anomalies: the obligation to inform the mother. J Ultrasound Med 2004; 23 (07) 883-885
    CrossrefPubMedSearch in Google Scholar
  • 40 Hayat Roshanai A, Ingvoldstad C, Lindgren P. Fetal ultrasound examination and assessment of genetic soft markers in Sweden: are ethical principles respected?. Acta Obstet Gynecol Scand 2015; 94 (02) 141-147
    CrossrefPubMedSearch in Google Scholar
  • 41 Viaux-Savelon S, Dommergues M, Rosenblum O. et al. Prenatal ultrasound screening: false positive soft markers may alter maternal representations and mother-infant interaction. PLoS One 2012; 7 (01) e30935
    CrossrefPubMedSearch in Google Scholar
  • 42 Nevay DL, Hippman C, Inglis A, Albert A, Austin J. Impact of increased risk for fetal aneuploidy on maternal mood: a prospective longitudinal study. Acta Obstet Gynecol Scand 2016; 95 (10) 1120-1128
    CrossrefPubMedSearch in Google Scholar
  • 43 Lo YM, Lau TK, Zhang J. et al. Increased fetal DNA concentrations in the plasma of pregnant women carrying fetuses with trisomy 21. Clin Chem 1999; 45 (10) 1747-1751
    CrossrefPubMedSearch in Google Scholar
  • 44 Farina A, LeShane ES, Lambert-Messerlian GM. et al. Evaluation of cell-free fetal DNA as a second-trimester maternal serum marker of Down syndrome pregnancy. Clin Chem 2003; 49 (02) 239-242
    CrossrefPubMedSearch in Google Scholar
  • 45 Lo YM, Tein MS, Lau TK. et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet 1998; 62 (04) 768-775
    CrossrefPubMedSearch in Google Scholar
  • 46 Bianchi DW, Rava RP, Sehnert AJ. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014; 371 (06) 578
    PubMedSearch in Google Scholar
  • 47 Bianchi DW, Parker RL, Wentworth J. et al; CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014; 370 (09) 799-808
    CrossrefPubMedSearch in Google Scholar
  • 48 Walker BS, Jackson BR, LaGrave D, Ashwood ER, Schmidt RL. A cost-effectiveness analysis of cell free DNA as a replacement for serum screening for Down syndrome. Prenat Diagn 2015; 35 (05) 440-446
    CrossrefPubMedSearch in Google Scholar
  • 49 Sharma G, McCullough LB, Chervenak FA. Ethical considerations of early (first vs. second trimester) risk assessment disclosure for trisomy 21 and patient choice in screening versus diagnostic testing. Am J Med Genet C Semin Med Genet 2007; 145C (01) 99-104
    CrossrefPubMedSearch in Google Scholar
  • 50 Wapner RJ, Martin CL, Levy B. et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012; 367 (23) 2175-2184
    CrossrefPubMedSearch in Google Scholar
  • 51 Dugoff L, Norton ME, Kuller JA. Society for Maternal-Fetal Medicine (SMFM). Electronic address: pubs@smfm.org. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol 2016; 215 (04) B2-B9
    CrossrefPubMedSearch in Google Scholar
  • 52 Daum H, Stern S, Shkedi-Rafid S. Is it time for prenatal chromosomal-microarray analysis to all women? A review of the diagnostic yield in structurally normal fetuses. Curr Opin Obstet Gynecol 2021; 33 (02) 143-147
    CrossrefPubMedSearch in Google Scholar
  • 53 Maya I, Salzer Sheelo L, Brabbing-Goldstein D. et al. Residual risk for clinically significant copy number variants in low-risk pregnancies, following exclusion of noninvasive prenatal screening-detectable findings. Am J Obstet Gynecol 2022; 226 (04) 562.e1-562.e8
    CrossrefPubMedSearch in Google Scholar
  • 54 Petrovski S, Aggarwal V, Giordano JL. et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet 2019; 393 (10173): 758-767
    CrossrefPubMedSearch in Google Scholar
  • 55 Hui L, Johnson JA, Norton ME. ISPD 2022 debate-when offering a first trimester ultrasound at 11 + 0 to 13 + 6 weeks, a detailed review of fetal anatomy should be included. Prenat Diagn 2023; 43 (04) 421-427
    CrossrefPubMedSearch in Google Scholar
  • 56 Esteves KM, Tugarinov N, Lechmann G. et al. The value of detailed first-trimester ultrasound in the era of noninvasive prenatal testing. Am J Obstet Gynecol 2023; 229 (03) 326.e1-326.e6
    CrossrefPubMedSearch in Google Scholar
  • 57 Salomon LJ, Alfirevic Z, Bilardo CM. et al. ISUOG practice guidelines: performance of first-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 2013; 41 (01) 102-113
    CrossrefPubMedSearch in Google Scholar
  • 58 AIUM practice parameter for the performance of detailed diagnostic obstetric ultrasound examinations between 12 weeks 0 days and 13 weeks 6 days. J Ultrasound Med 2021; 40 (05) E1-E16
    PubMedSearch in Google Scholar
  • 59 Haberman S, Futterman ID, Minkoff H. The case for making the first-trimester anatomical survey a standard of care post Dobbs. Am J Obstet Gynecol 2024; 230 (01) 66-68
    CrossrefPubMedSearch in Google Scholar
  • 60 Chasen ST, Kalish RB. Can early ultrasound reduce the gestational age at abortion for fetal anomalies?. Contraception 2013; 87 (01) 63-66
    CrossrefPubMedSearch in Google Scholar
  • 61 Lugthart MA, Verbaarschot E, van Nisselrooij AEL. et al. Early detection of isolated severe congenital heart defects is associated with a lower threshold to terminate the pregnancy. Fetal Diagn Ther 2023; 50 (04) 248-258
    CrossrefPubMedSearch in Google Scholar
  • 62 Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA 2016; 316 (07) 734-742
    CrossrefPubMedSearch in Google Scholar
  • 63 Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol 2017; 129 (03) e35-e40
    CrossrefPubMedSearch in Google Scholar
  • 64 Gregg AR, Aarabi M, Klugman S. et al; ACMG Professional Practice and Guidelines Committee. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2021; 23 (10) 1793-1806
    CrossrefPubMedSearch in Google Scholar
  • 65 Pyle A, Adams SY, Cortezzo DE. et al. Navigating the post-Dobbs landscape: ethical considerations from a perinatal perspective. J Perinatol 2024; (e-pub ahead of print)
    CrossrefPubMedSearch in Google Scholar