Prenatal Screening Tests (CFTS, Quadruple, NIPT/cfDNA) — Clinical Review

1. Executive Summary

1. NIPT (cfDNA / fetal DNA) is currently the prenatal screening test with the highest diagnostic performance for T21/T18/T13; In the Gil UOG 2017 meta-analysis, T21 DR was 99.7% (95% CI 99.1–99.9), FPR was 0.04% (95% CI 0.02–0.07).
2. Double screening (Combined First-Trimester Test, CFTS) is performed between 11+0 – 13+6 weeks with NT + PAPP-A + free/total β-hCG; T21 DR ~85%, FPR ~5%.
3. Quadruple Test between 15+0 – 22+6 weeks AFP + uE3 + hCG + DIA; T21 DR ~80%, FPR ~5%; Open NTD screening bonus via AFP.
4. Triple Test — AFP + hCG + uE3 — is no longer recommended in modern practice (DR ~69%, 10+ points lower than quadruple); ACOG PB 226, NICE NG201 and UpToDate 2026 have delisted it.
5. NIPT positive result ABSOLUTELY requires invasive confirmation. PPV is 46–81% for T21 in the general obstetric population; ~93% in the older age group. NIPT is not a diagnostic test; The decision to terminate a pregnancy is not made with NIPT alone.
6. NIPT no-call ~1–3% — retry ~60–80% successful. Nonreportable result per se is indicative of aneuploidy + increased risk for adverse pregnancy outcomes (Norton AJOG 2023, aOR 2.2 aneuploidy).
7. NIPT sex chromosome performance lower than T21: 45,X DR ~90–98%, FPR ~0.14–0.23%, PPV 14.5%; XXX/XXY/XYY DR ~93–100%, PPV 37–100%. Special pretest consultation is required.
8. NIPT microdeletion (22q11.2 et seq.) screening is not routinely recommended — ISPD 2023 and SMFM Consult #74 (2025): do not recommend microdeletion screening in unselected population (insufficient prospective data, low PPV).
9. CVS (10–13+6 wk) and amniocentesis (≥15 wk) procedure-related risk of gestational loss lower than former “1%” claim: Salomon UOG 2019 meta-analysis — amnio 0.30% (95% CI 0.11–0.49), CVS 0.20% (95% CI −0.13 – 0.52); In a similar risk profile subgroup, both are statistically indistinguishable from zero. RCOG Green-top 8 (2021): "additional risk of miscarriage <0.5% with experienced operator".
10. Practice in Türkiye: 11–14-week NT + first-trimester combined screening is the common baseline; followed by 16–18-week quadruple testing or increasingly NIPT (private lab / out-of-pocket). The triple test does not even appear as an alternative in modern guidelines. There is no universal SGK-funded NIPT in Türkiye.
11. Anomaly USG (18–22 weeks) and 1st trim auxiliary signs (nasal bone, ductus venosus, tricuspid regurgitation) additionally contribute to screening; Smoking, BMI, ART status, multiple pregnancy change screening interpretation.
12. ACMG (2023) "cfDNA universal preferred" vs NICE NG201 "contingent cfDNA only" source position is not a contradiction but a difference in systemic application (private payment in the US vs NHS funding in the UK). Presented side by side.

2. Question Type and Evidence Strategy

The question type for this review is diagnostic/screening performance (sensitivity/specificity, DR/FPR, PPV/NPV). Hierarchy of evidence: diagnostic-SR > QUADAS-eligible large cross-sectional > prospective cohort. RCT is not a peak for screening test (a performance-based question, not intervention-based).

Literature search method: UpToDate (Apr 2026 literature coverage) as primary synthesis source; society guidelines (ACOG PB 226, NICE NG201, RCOG Green-top 8, ISPD 2023, SMFM Consult #74, ACMG 2023, ISUOG, SOGC No. 262) verified against current versions; 14 key primary PubMed publications (Bianchi NEJM 2014, Norton NEJM 2015 NEXT, Gil UOG 2017 meta-analysis, Salomon UOG 2019, Akolekar UOG 2015, Norton AJOG 2023 nonreportable, Judah/Gil UOG 2021 twin, Della Valle UOG 2025 twin, Sucaldito 2025 NT alone, Prats Prenat Diagn 2014, Audibert JOGC 2017, Alldred Cochrane 2017).

Retraction/erratum check: query PubMed retraction notice and Retraction Watch for 14 primary publications—no retractions or erratums. Trial registry check: NCT01663350 (Bianchi 2014) and NCT01511458 (Norton 2015 NEXT) verified, published; Publication bias is not evident.

3. General Concepts — Screening and Diagnostic Tests

Screening test determines the risk probabilistically; It does not provide a definitive diagnosis. Diagnostic testing (diagnostic — invasive sampling + karyotype/CMA) gives definitive results. All positive screening results (including NIPT) should be confirmed by invasive diagnosis before a pregnancy termination or management decision.

3.1 Main metric definitions

3.2 Effect of maternal age

T21 prevalence increases with age: 25 years ~1/1300, 35 years ~1/350, 40 years ~1/85. At the same DR/FPR, PPV increases with age (Bayes theorem). NIPT PPV T21 ~80% in general obstetric population; ~93% in older age.

3.3 Ultrasound soft markers — adjunctive, not screening

NT, nasal bone (NB) hypoplasia, ductus venosus (DV) flow anomaly, tricuspid regurgitation (TR), echogenic intracardiac focus, hyperechogenic bowel, short femur/humerus, pyelectasis. An isolated finding does not indicate high risk; USG anomaly + biochemistry/cfDNA composite increases the risk. Aagaard-Tillery 2009 and Lindquist 2018: If NT increase + biochemistry is positive, additional evaluation is required for atypical chromosome anomaly (microdeletion, segmental).

4. Combined First-Trimester Test — CFTS

4.1 Method

1. Nuchal translucency (NT) ultrasound measures the subcutaneous fluid collection behind the fetal neck when crown-rump length is 45–84 mm (approximately 11+0–13+6 weeks). Some protocols permit measurement from 10.5 weeks. FMF (Fetal Medicine Foundation)-certified measurement and quality control are critical.
2. PAPP-A (pregnancy-associated plasma protein-A): complex high molecular weight glycoprotein; Low in T21. The optimal window is 9+0 – 13+0 weeks.
3. Free or total β-hCG: Elevated (~double) at T21. Measurement between 11+0 – 13+6 weeks.
4. Maternal age + these three values ​​+ smoking, BMI, ethnicity, GA, IVF, twin status (MoM adjustments) are combined with the software algorithm; threshold typically 1/250 or 1/300 (laboratory variability).

4.2 Test performance

• T21 DR ~85%, FPR ~5% (combined result of multiple meta-analyses; UpToDate Apr 2026; SURUSS / FASTER trial references)
• T18: characteristic pattern — very low β-hCG + very low PAPP-A + large NT; FASTER trial DR 60%, FPR 0.1%
• T13: does not require separate scanning (captured with T18)

4.3 Advantages

• Early screening (1st trim) → CVS 11–13+6 weeks early diagnosis opportunity if necessary
• One visit, fast results
• Isolated T18 side gain

4.4 Disadvantages

• DR (~85%) significantly lower than NIPT
• FPR (5%) significantly higher than NIPT → more unnecessary invasive recommendations
• USG NT technical skill required; FMF certification recommended
• Open NTD requires additional 2nd trim AFP or USG 18–22 weeks
• Maternal weight, race, smoking, GA, IVF, multiple pregnancy require MoM adjustment

4.5 Comparison of authority positions — First-trimester combined screening

Point of conflict: UpToDate/ACOG considers cfDNA to be “superior” while NICE does not use universal cfDNA — this is not a contradiction but a difference in systemic suitability (cost, NHS funding).

5. Quadruple Test

5.1 Method

4 maternal serum markers, 15+0 – 22+6 weeks (ideal 15+0 – 18+6):

1. AFP (alpha-fetoprotein) — low at T21 (~25–30% decreased); for high AFP open NTD screening
2. uE3 (unconjugated estriol) — low at T21
3. hCG — elevated (~double) at T21
4. DIA (dimeric inhibin A) — high at T21

Maternal age + 4 values are integrated; T21 risk is calculated. The threshold is typically 1/250 or 1/270.

5.2 Test performance

• T21 DR ~80% (75–85), FPR ~5% (cut-off 1/250)
• T18 pattern: AFP, uE3, hCG all low → DR 90%, FPR 0.1% (1/100 cut-off; in serum-integrated combination)
• T13 cannot be detected by quadruple screening
• May indicate risk for Smith-Lemli-Opitz syndrome (uE3 low + other)

5.3 Why quadruple instead of triad?

• Triple test (AFP + uE3 + hCG) DR ~69% (FASTER/SURUSS data), ~10+ points lower than quadruple
• The extra marker of the quadruple, inhibin A, significantly increases sensitivity
• ACOG PB 226, NICE NG201 and UpToDate 2026 no longer list the triple test as an alternative

5.4 Advantages and disadvantages

Benefits: NTD screening bonus (via AFP); Suitable for patients who apply late to the 2nd trim; results ~1 week; cost significantly lower than NIPT (approximately 1/8–1/12 by 2026 in Türkiye). Disadvantages: DR significantly lower than NIPT; 2nd trim result → CVS option passed, amnio only; T13 underdetection.

5.5 Authority position comparison — Quadruple

6. NIPT (cfDNA — Cell-Free Fetal DNA)

6.1 Biology

• Fetal–placental cfDNA can be detected in maternal blood from week 5 and is almost always present at 9–10 weeks
• The main source is placental syncytiotrophoblast apoptosis (not fetal — this is a false-positive/negative source)
• Maternal cfDNA from hematopoietic cells; fetal cfDNA fragments ~142 bp, maternal ~166 bp
• Fetal fraction (FF) ~10–20% (1st/2nd trim); minimum 1–3.5% for successful NIPT; higher for microdeletion
• After birth, cfDNA is half eliminated in ~1 hour, completely cleared in 2 days → subsequent pregnancies are not affected

6.2 Test methodology (4 different methods)

1. Whole genome sequencing (massive parallel / shotgun) — most common; count over whole genome (chromosome 21 ratio normally 1.3% → high at T21)
2. Targeted genome sequencing — targeting 21, 18, 13 (and X/Y) only; requires less resources
3. SNP method — analyzes polymorphic SNPs; can detect triploidy, twin zygosity, and vanishing twin. NOT suitable in cases of egg donation, organ/bone marrow transplantation, or a gestational carrier — an alternative method is required.
4. Microarray + RCA (rolling circle amplification) — specifically targeted

According to Gil UOG 2017 meta-analysis, all methods show similar high sensitivity/specificity.

6.3 Test performance (singleton; UpToDate + Gil 2017 + Norton AJOG)

6.4 PPV — dependent on population prevalence

• Low risk (general obstetrics) — T21 PPV 80.9% (Norton NEXT); Wapner cohort 93%
• High risk (≥35 years) — T21 PPV ~93%
• T18 PPV: overall ~76%, older age ~85%
• T13 PPV: overall ~44%, older age ~55%
• SCA PPV 14.5% (45,X) – 100% (47,XYY)

NPV: ≥99.9% for all T21/T18/T13. Norton 100 000+ pregnancy cohort → only 2 false negatives T21.

6.5 No-call (test failure)

• Overall 1–3% (varies by laboratory; fetal fraction enriching technologies <1%)
• Causes: early GA (<10 wk), maternal obesity (>110 kg 10.5% no-call; >181 kg 1st trim 18%, 2nd trim 6%), LMWH (<20 wk), IVF (no-call ~2–3 times), multiple pregnancy, some aneuploidies (T18, triploidy paradoxical low FF)
• No-call itself is a sign of abnormal results — Norton AJOG 2023: nonreportable aOR aneuploidy 2.2 (1.1–4.4); preterm birth aOR 1.5; composite adverse outcome aOR 1.5
• Second sample redraw ~60–80% success

6.6 NIPT — additional features

• Twin pregnancy: ACOG PB 226 + ISPD 2023 + SOGC No. 262 (Audibert 2017) confirms. Test failure 3.8%; DR T21 99% (Judah/Gil UOG 2021; Della Valle UOG 2025 QUADAS-2 SR: sense 98.8%, sp 100%); FPR ~0.02%. Can't say which twin was affected — aggregate result.
• Triplet: test failure up to 20%; similar performance if successful
• Microdeletions (22q11.2 DiGeorge and others): CONTROVERSIAL — ISPD 2023 and SMFM Consult #74 (2025) do not recommend routine screening. Low PPV (5–22%), high FPR, insufficient prospective data.
• Sex chromosome aneuploidy (SCA): requires special pretest counseling; isolated 45,X PPV 14.5%
• Rare autosomal trisomies (RAT): some whole-genome methods detect; clinical significance unclear
• Contingent / reflexive cfDNA: secondary screening after biochemistry-based positive (frequent in Europe, decreasing in the USA); DR 95%, FPR 0.02% (reflexive 22 000 patients)

6.7 ACOG 2020 universal offering decision

In a historic decision, ACOG PB 226 (Oct 2020) listed NIPT as an option that should be offered to all pregnant women, regardless of age/baseline risk. SMFM and ACMG 2023 parallel.

6.8 Authority position comparison — NIPT (side-by-side)

Point of conflict: ACMG (2023) says “cfDNA preferred” while NICE NG201 says “primary cfDNA not universal — post-high risk contingent”. This is not a contradiction but a difference in systemic practice — private insurance + solvency in the US, NHS funding constraint in the UK.

7. Short Tests Block (Rare or Not Recommended in Türkiye)

7.1 Triple Test — NO LONGER RECOMMENDED IN MODERN PRACTICE

• 15–22 weeks AFP + uE3 + hCG (no DIA)
• T21 DR ~69%, FPR ~5% (UpToDate 2026, FASTER reference) — ~10–12 points lower DR than quad
• ACOG PB 226, NICE NG201 and UpToDate 2026 delisted
• Still performed on request in some laboratories in Türkiye — contrary to current guidelines; it is recommended that the clinician choose quadruple or NIPT

7.2 Full Integrated Test

• 1st trim PAPP-A + NT + 2nd trim quadruple → 6 markers + age → single risk calculation
• T21 DR 85%, FPR 1% (FPR 2% at 90% DR) — lowest FPR
• Disadvantage: Result hidden until 2nd trim, patient anxiety
• Rare in Türkiye — operational difficulty of two separate visits/samples

7.3 Serum Integrated Test

• 1st trim PAPP-A + 2nd trim quad (NO NT)
• Alternative for regions without NT technical skills
• FPR ~4% at 85% DR (7% if quad) — superior to quad, inferior to fully integrated
• rare in Türkiye

7.4 Sequential — Stepwise / Contingent

• 1st trim result → very high risk (≥1/50) immediate CVS; low risk normal follow-up; intermediate risk 2nd trim quad
• FASTER trial: stepwise DR 95%, FPR 5% → close to integrated; early result advantage
• Rare in Türkiye — requires systematic infrastructure

8. Comparison Table (Summary)

9. Abnormal Result Management Algorithm

9.1 Risk thresholds and decision algorithm

Low risk (≤ subthreshold)

• Standard antenatal follow-up
• 18–22 weeks detailed anomaly USG (if not performed)
• Anomaly for NTD if low risk based on biochemistry Visual + AFP combination on USG

Medium risk (e.g. 1/250–1/1000)

• Recommend NIPT — ACOG PB 226 (2020) universal cfDNA recommendation → age/baseline risk-neutral screening option
• If the patient does not want NIPT: secondary cfDNA + amnio or direct amnio evaluation

High risk (>1/50, >1/100 or soft marker + NT >3.0 mm)

• Recommend diagnostic testing (CVS or amnio)
• Patient may opt for NIPT; If positive, CVS/amnio confirmation
• Genetic counseling (before + after)

9.2 After NIPT positive — invasive confirmation (Emphasis by Cem Bey)

1. CVS (10+0 – 13+6 weeks) — direct preparation 2 days, culture 7–10 days
   • Advantage: early result (1st trim termination option)
   • Risk: CPM may occur (1–2%) — especially T13/45,X; amniocentesis may be required to distinguish placental mosaicism from true fetal involvement
2. Amniocentesis (≥15+0 weeks) — rapid result (FISH/QF-PCR) 2 days; full karyotype 8–14 days
   • More reliable than CVS (actual fetal genotype)
   • Lower risk of pregnancy loss (Salomon UOG 2019: 0.30% vs CVS 0.20%; both do not leave statistical zero in similar-risk profile sub-analysis)
3. Karyotype + CMA (Chromosomal Microarray Analysis) — CMA detects additional microdeletions/duplications
4. Pre-test and post-test genetic counseling

9.3 Risk of gestational loss — current data

Conclusion: All intervals either include zero or are very low. RCOG Green-top 8 (July 2021): “additional risk of miscarriage <0.5% with experienced operator” is appropriate. The single categorical “1% risk” message is outdated; Current data should be given to the patient.

9.4 NIPT no-call management

1. Second sample redraw → ~60–80% success
2. No-call → invasive diagnosis still recommended (Norton AJOG 2023: nonreportable aOR aneuploidy 2.2)
3. Or conventional biochemistry + USG (alternative)
4. Patient-specific decision (anxiety, insurance, patient preference)

9.5 USG auxiliary signs (1st trim)

• Absence of nasal bone (NB) — OR for T21 ~146 (composite); is not isolated
• Ductus venosus (DV) reversed a-wave — T21 OR ~21
• Tricuspid regurgitation (TR) — T21 OR ~10

These flags can be added to the binary scan calculation; FMF risk calculator included.

9.6 18–22 weeks anomaly ultrasound

• T21 soft markers: short femur/humerus, heart defect (AVSD), duodenal atresia, cystic hygroma, echogenic intracardiac focus, hyperechogenic bowel, thick nuchal fold (>5 mm 18–24 weeks)
• T18: multiple organ anomaly (~93% detected on USG 20+ weeks)
• T13: early soft markers + major anomalies
• Structural anomaly + NIPT negative → CMA recommended (microdeletion detected by CMA)

9.7 Genetic counseling

• Before: testing options, performance, limits, possible outcomes, next steps
• Post-test (positive): natural history of the condition, prognosis, pregnancy options, social support resources
• It is recommended to consult the National Society of Genetic Counselors (NSGC) contact guides

10. GRADE Certainty Summary

11. Evidence Summary and Source Count

Transparent reporting of the evidence base underlying this review. Total sources searched: 28 (6 UpToDate topics + 14 PubMed publications + 8 guides).

Is there conflicting data? There is no apparent contradiction. The only discrepancy: NICE NHS does not apply universal cfDNA (contingent), ACMG recommends universal cfDNA – not a contradiction but a difference in systemic practice, presented side by side (Section 6.8).

Retraction/trial registry check: PubMed retraction notice and Retraction Watch for 14 primary publications—no retractions/erratums. Validated ClinicalTrials.gov NCT01663350 (Bianchi 2014) + NCT01511458 (Norton NEXT 2015); Publication bias is not evident.

Risk-of-bias assessment tool: QUADAS-2 was used for diagnostic systematic review and cross-sectional studies. In the deep analysis subset, RoB was evaluated for each study (high RoB → weight dropped even if high-IF).

12. References

1. Palomaki GE, Halliday JV, Russo ML. Prenatal screening for common fetal aneuploidies: Cell-free DNA test. UpToDate, Topic 458 Version 125.0, last updated September 15, 2025; literature coverage April 2026.
2. Down syndrome: Overview of prenatal screening. UpToDate, Apr 2026.
3. First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18. UpToDate, Apr 2026.
4. Chorionic villus sampling. UpToDate, Apr 2026.
5. Diagnostic amniocentesis. UpToDate, Apr 2026.
6. ACOG Practice Bulletin No. 226. Screening for Fetal Chromosomal Abnormalities. Obstet Gynecol 2020;136(4):e48–e69. DOI (PMID 32804883)
7. ACOG Practice Bulletin No. 226 Summary. Obstet Gynecol 2020;136(4):859–867. DOI (PMID 32976375)
8. NICE NG201: Antenatal care. Published: 19 Aug 2021, last reviewed: 27 Dec 2024. nice.org.uk/guidance/ng201
9. RCOG Green-top Guideline No. 8: Amniocentesis and Chorionic Villus Sampling. BJOG, July 2021 (5th ed.). rcog.org.uk/gtg8
10. Hui L, Bianchi DW, et al. Position statement from the International Society for Prenatal Diagnosis on the use of non-invasive prenatal testing for the detection of fetal chromosomal conditions in singleton pregnancies. Prenat Diagn 2023. DOI
11. SMFM Consult Series #74: Cell-free DNA screening for aneuploidies: Updated guidance. Society for Maternal-Fetal Medicine, 2025. (replaces #36, 2015)
12. Audibert F, Gagnon A. No. 262 — Prenatal Screening for and Diagnosis of Aneuploidy in Twin Pregnancies. J Obstet Gynaecol Can 2017;39(9):e347–e361. DOI (PMID 28859779)
13. ACMG Practice Guideline 2023 — Noninvasive prenatal screening for fetal chromosomal aneuploidies in all pregnant individuals.
14. Bianchi DW, Parker RL, Wentworth J, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014;370(9):799–808. DOI (PMID 24571752). NEJM IF ~158, Q1/D1.
15. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy (NEXT study). N Engl J Med 2015;372(17):1589–97. DOI (PMID 25830321)
16. Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 2017;50(3):302–14. DOI (PMID 28397325). UOG IF ~7.3, Q1.
17. Salomon LJ, Sotiriadis A, Wulff CB, Odibo A, Akolekar R. Risk of miscarriage following amniocentesis or chorionic villus sampling: systematic review of literature and updated meta-analysis. Ultrasound Obstet Gynecol 2019;54(4):442–51. DOI (PMID 31124209)
18. 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(1):16–26. DOI (PMID 25042845)
19. Norton ME, MacPherson C, Demko Z, et al. Obstetrical, perinatal, and genetic outcomes associated with nonreportable prenatal cell-free DNA screening results. Am J Obstet Gynecol 2023;229(3):300.e1–300.e9. DOI (PMID 36965866). AJOG IF ~9.5, Q1.
20. Norton ME. Cell-free DNA Screening for Aneuploidy. Clin Obstet Gynecol 2023;66(3):557–67. DOI (PMID 37650668)
21. Judah H, Gil MM, Syngelaki A, et al. Cell-free DNA testing of maternal blood in screening for trisomies in twin pregnancy: updated cohort study at 10-14 weeks and meta-analysis. Ultrasound Obstet Gynecol 2021;58(2):178–89. DOI (PMID 33838069)
22. Gil MM, Galeva S, Jani J, et al. Screening for trisomies by cfDNA testing of maternal blood in twin pregnancy: update of The Fetal Medicine Foundation results and meta-analysis. Ultrasound Obstet Gynecol 2019;53(6):734–42. DOI (PMID 31165549)
23. Della Valle L, Piergianni M, Khalil A, et al. Diagnostic accuracy of cell-free fetal DNA in maternal blood in detecting chromosomal anomalies in twin pregnancy: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2025;65(2):147–53. DOI (PMID 38775911)
24. Sucaldito MSFP, Besa JJV, Palileo-Villanueva LM. The Diagnostic Performance of Nuchal Translucency Alone as a Screening Test for Down Syndrome: A Systematic Review and Meta-analysis. Acta Med Philipp 2025;59(15):7–23. DOI (PMID 41281425; PMC12631045 — open access, full-text read)
25. Prats P, Rodríguez I, Comas C, Puerto B. Systematic review of screening for trisomy 21 in twin pregnancies in first trimester combining nuchal translucency and biochemical markers: a meta-analysis. Prenat Diagn 2014;34(11):1077–83. DOI (PMID 24916689)
26. 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. DOI (PMID 28295159)
27. Aagaard-Tillery KM, Malone FD, Nyberg DA, et al. Role of second-trimester genetic sonography after Down syndrome screening. Obstet Gynecol 2009;114(6):1189–96. DOI (PMID 19935018)
28. Lindquist A, Poulton A, Halliday J, Hui L. Prenatal diagnostic testing and atypical chromosome abnormalities following combined first-trimester screening: implications for contingent models of non-invasive prenatal testing. Ultrasound Obstet Gynecol 2018;51(4):487–92. DOI (PMID 29226487)

Last updated: September 11, 2026 · Content Lead: Cem Akaltun, MD, Specialist in Obstetrics and Gynecology. This review is for educational and informational purposes only; clinical decision-making should be based on patient-specific assessment and applicable institutional protocols.

📖 Comprehensible version for expectant mothers: For a colloquial explanation of the same subject, you can check out our blog post "Prenatal Screening Tests: Guide for Expectant Mothers".

🔄 Current Developments (2026)

The most critical change in this issue is in the source hierarchy: ACOG Practice Bulletin No. 226 (2020) is now repealed. ACOG approved SMFM Consult Series #74 in November 2025 and made clear that this document replaced PB 226 with the Practice Advisory titled “Screening for Fetal Chromosomal Abnormalities” published in January 2026 (ACOG Practice Advisory, January 2026). Therefore, ACOG's current primary document is SMFM #74 (2025) + ACOG Advisory, not PB 226.

SMFM Consult Series #74 (Pregnancy 2025;1:e70139; DOI 10.1002/pmf2.70139) introduced eight GRADE-rated recommendations and replaced SMFM #36 (2015). Two nuances are new compared with previous guidance. First, screening for sex chromosome aneuploidies (SCA) is now formalized as an "opt-in" choice following appropriate pre-test counseling (SMFM #74 Recommendation 3, GRADE 1C)—replacing the earlier "specific pre-test counseling" phrasing with an explicit model. Second, the stance on microdeletions has been sharpened: routine general-population screening is not recommended for any microdeletion; for pregnant patients seeking fetal copy number variant (CNV) information, direct diagnostic testing (CVS/amniocentesis with chromosomal microarray) is recommended rather than a cfDNA microdeletion panel (SMFM #74 Recommendation 4, GRADE 1C). In twin pregnancies, cfDNA is first-line screening for trisomy 21 and is also recommended for trisomies 18 and 13 (GRADE 1B); SCA screening in twins and cfDNA screening in triplet or higher-order pregnancies are not recommended (GRADE 1C).

On the Canadian side SOGC Guideline No. 456 (Audibert F et al., J Obstet Gynaecol Can 2024;46(11):102694; PMID 39419445) published, updating the 2017 version of SOGC; It positions NIPT as the most accurate screening method for major aneuploidies.

In the UK, the approach remains unchanged: as of its latest review on 27 December 2024, NICE NG201 continues to retain the combined test (11+0–13+6) as the first option and NIPT within the NHS as a contingent test following a high-risk result (NICE NG201).