What prenatal screening and diagnostic tests are recommended for pregnant individuals at risk of fetal genetic disorders, using maternal bio markers?

Prenatal Screening and Diagnostic Tests for Fetal Genetic Disorders Using Maternal Biomarkers

All pregnant individuals at risk for fetal genetic disorders should be offered first trimester screening with combined nuchal translucency (NT) measurement, pregnancy-associated plasma protein A (PAPP-A), and human chorionic gonadotropin (hCG) before 14 weeks' gestation, followed by appropriate diagnostic testing based on risk assessment. 1, 2

First Trimester Screening Options

Combined First Trimester Screening (11-13+6 weeks)

• Nuchal Translucency (NT) measurement: Ultrasound measurement of fluid-filled space behind fetal neck
  • Detection rate for Down syndrome: ~70% with 5% false-positive rate 1
  • NT ≥3.5mm warrants detailed anatomic ultrasound and echocardiogram even with normal karyotype 1
• Maternal serum biomarkers:
  • PAPP-A (typically reduced in Down syndrome)
  • hCG (typically elevated in Down syndrome)
    • Free beta hCG is superior, though intact hCG is commonly used in the US 1
• Combined approach: NT + PAPP-A + hCG achieves 75-80% detection rate for trisomy cases with 5% false-positive rate 2

Additional First Trimester Markers

• Nasal bone assessment: Optional addition to screening protocol
  • Requires specialized training and ongoing quality assurance 1
  • Absence associated with Down syndrome 1

Diagnostic Testing Options

Chorionic Villus Sampling (CVS)

• Available from 10-13 weeks 2
• Risk of pregnancy loss: 0.5% (equivalent to amniocentesis) 3
• Provides definitive diagnosis of chromosomal abnormalities
• Caution: 1-2% incidence of confined placental mosaicism 3
• Should not be performed before 9 weeks due to potential risk of limb reduction defects 3

Amniocentesis

• Available after 15 weeks 2
• Risk of pregnancy loss: 0.5% 3
• Provides definitive diagnosis of chromosomal abnormalities
• Early amniocentesis (before 15 weeks) may increase risk of talipes equinovarus 3

Second Trimester Screening Options

• Multiple marker screening: For women presenting after 14 weeks 1
• Quadruple screening (15-20 weeks): Recommended option for second trimester aneuploidy screening 2
• Detailed anatomy scan: Standard at 18-20 weeks 2
  • For obese patients, consider scan at 20-22 weeks with follow-up in 2-4 weeks if incomplete 2

Integrated Screening Approaches

• Sequential or contingency screening: Combines first and second trimester results
  • Improved detection rates and lower false-positive rates compared to single-trimester screening 1
  • Sequential screening with disclosure of first trimester results may be preferable for some patients 1

Special Considerations

Carrier Testing

• Optimal timing: Before conception when possible 1
• During pregnancy: Screen expectant mother as early as possible 1
• Partner testing:
  • If woman is carrier of autosomal recessive disorder, biologic father should be offered testing 1
  • For advanced gestational age (after 14 weeks), concurrent rather than sequential testing of partners 1

Multiple Gestations

• First trimester screening can be used but has lower sensitivity than in singleton pregnancies 1
• Serum marker levels may be averaged between fetuses, reducing accuracy 1
• NT measurement alone is useful but has higher positive screening rate 1

Clinical Algorithm for Prenatal Genetic Testing

1. Pre-pregnancy or early pregnancy: Offer carrier screening based on family history, ethnicity, and risk factors
2. 11-13+6 weeks: Offer combined first trimester screening (NT, PAPP-A, hCG)
3. Risk assessment:
   • High risk: Offer diagnostic testing (CVS if <14 weeks, amniocentesis if >15 weeks)
   • Intermediate risk: Consider sequential screening with second trimester markers
   • Low risk: Routine prenatal care with standard anatomy scan at 18-20 weeks
4. 15-20 weeks: Offer quadruple screening if no first trimester screening was performed
5. After any screening: Provide adjusted risk assessment and allow patient to make informed decisions

Important Caveats

• Quality control is essential for both laboratory assays and NT measurements 1
• Sonographers must be appropriately trained in NT measurement technique with proper certification 1
• Women who have first trimester screening/CVS should be offered MSAFP screening and/or anatomic survey at 16-20 weeks for neural tube defect detection 1
• No single test can identify all genetic disorders; testing should focus on individual risk factors 4, 5
• Prenatal genetic testing has benefits including reassurance with normal results, optimizing neonatal outcomes, and allowing informed pregnancy management decisions 4, 5