Prenatal Screening for Fetal Anomaly

Overview & Principles

1. First-Trimester Screening (11–13+6 Weeks)

A. Combined First-Trimester Screening

• Down syndrome (Trisomy 21) detection: ~88% (95% CI 84–89.4%)
• Trisomy 18: >90% detection with combined biochemistry + NT
• In women >35 years: 90–92% detection, but 16–22% false-positive rate

"In practice, screening is performed between 11 and 13 weeks of gestation." — Creasy & Resnik's Maternal-Fetal Medicine

B. Additional Ultrasound Markers (First Trimester)

• Absent nasal bone: Associated with trisomy 21 in ~73% of affected fetuses (vs 0.5% of euploid). Adding nasal bone to NT + maternal age improves detection to ~93% at 5% FPR.
• Other soft markers: tricuspid regurgitation, ductus venosus waveform abnormality.

2. Cell-Free DNA Screening (cfDNA / NIPS)

Mechanism

Performance (vs conventional screening)

• cfDNA is the most sensitive and specific screening test for common aneuploidies — superior to all serum/ultrasound screening methods
• Not diagnostic — positive results require invasive confirmation (CVS or amniocentesis)
• ACOG now recommends offering cfDNA to ALL pregnant women, not just high-risk
• Only one screening modality should be used per pregnancy
• "No-call" results (insufficient fetal fraction) carry higher aneuploidy risk (2.7% vs 0.4% background) and warrant genetic counseling + detailed ultrasound

Platforms

1. Massively parallel shotgun sequencing (MPSS) — most resource-intensive, broadest coverage
2. SNP allelic ratio — uses single nucleotide polymorphisms to model ploidy scenarios
3. Non-SNP allelic ratio — targeted enrichment + counting statistics

Limitations

• False negatives occur; not 100% sensitive
• Reduced performance for sex chromosome abnormalities
• Microdeletion syndromes (22q11.2, 5p, 1p36): SMFM does not currently recommend routine screening due to insufficient clinical validation and unknown PPV/NPV
• Causes of inaccurate results: confined placental mosaicism, fetal mosaicism, maternal sex chromosome abnormalities, organ transplant, co-twin demise, maternal malignancy
• Unusual/multiple aneuploidies on cfDNA may signal maternal malignancy → oncology referral warranted

cfDNA in Twin Pregnancies

• Performance for trisomy 21 is similar to singletons (detection rate ~99%, FPR <0.1%)
• Higher "no-call" rate due to lower fetal fraction per twin
• Cannot determine which twin is affected → invasive testing required to distinguish
• Data for trisomies 18 and 13 in twins are limited

3. Second-Trimester Screening

A. Maternal Serum AFP (MSAFP) — Neural Tube Defects

• Performed at 16–18 weeks (optimally; acceptable 15–20 weeks)
• AFP is synthesized by fetal yolk sac → GI tract → liver; leaks into amniotic fluid and maternal serum via open neural tube defects
• Cutoff 2.0–2.5 MoM: Detection rate ~100% for anencephaly, 85–92% for open spina bifida; FPR 2–5%

1. Ultrasound to confirm gestational age
2. Rule out multiple gestation
3. Identify other causes (fetal demise, etc.)
4. If unexplained, targeted ultrasound + consider amniocentesis for amniotic fluid AFP

B. Quadruple ("Quad") Screen

4. Structural Anomaly Scan — Second-Trimester Ultrasound (18–22 Weeks)

5. Invasive Diagnostic Tests (Following Screen-Positive Results)

6. Preimplantation Genetic Testing (PGT) — Pre-Conception

• PGT-A: Screens embryos for aneuploidies (blastocyst biopsy at day 5–6 + NGS/array CGH)
• PGT-M: Tests for monogenic conditions
• PGT-SR: Detects structural chromosome rearrangements

Summary: Screening Pathway

All patients → Offer counseling re: screening options
        ↓
First trimester (11–13 wks)
  ├── cfDNA (preferred, most sensitive) → if positive → CVS
  └── Combined screen (NT + PAPP-A + free β-hCG) → if positive → CVS
        ↓
Second trimester (15–22 wks)
  ├── MSAFP (16–18 wks) → NTD screening
  ├── Anomaly ultrasound (18–22 wks) → ALL patients
  └── Quad screen (if first-trimester screening not done)
        ↓
Screen-positive → Genetic counseling + amniocentesis

Key Clinical Points

• cfDNA replaced combined screening as first-line — SMFM Consult Series #74 (endorsed ACOG November 2025) confirms cfDNA as the most sensitive test for trisomies 21, 18, 13
• The 18–22 week anatomy scan is mandatory regardless of genetic screening choices
• False positives are lower with cfDNA but PPV drops markedly in low-risk populations — pre-test counseling is essential
• A positive screen is never diagnostic — always confirm with invasive testing before pregnancy management decisions
• No-call cfDNA results should prompt genetic counseling and detailed ultrasound

Creasy & Resnik's Maternal-Fetal Medicine, 9th ed. | Thompson & Thompson Genetics & Genomics in Medicine, 9th ed.