What is the double‑marker prenatal screening test in obstetrics‑gynecology?

Double Marker Prenatal Screening Test in Obstetrics

The double marker test is a first-trimester prenatal screening that combines maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (free β-hCG) with maternal age to assess the risk of fetal Down syndrome (trisomy 21) and other chromosomal abnormalities, typically performed between 11-13 weeks of gestation. 1

Test Components and Timing

The double marker screening consists of two biochemical markers measured in maternal blood:

• PAPP-A (Pregnancy-Associated Plasma Protein-A): Typically reduced in Down syndrome pregnancies 1
• Free β-hCG (Free Beta-Human Chorionic Gonadotropin): Elevated in Down syndrome pregnancies 1

Optimal timing is 11-13 weeks gestation, with free β-hCG performing better than intact hCG at 11-12 weeks (2-3% higher detection rate), while intact hCG may perform slightly better at 13 weeks (1-2% higher detection rate). 2

Performance Characteristics

The double marker test combined with maternal age detects approximately 70% of Down syndrome pregnancies at a 5% false-positive rate. 3 This represents a significant improvement over single markers alone. 3

When combined with nuchal translucency (NT) ultrasound measurement (forming the "combined first-trimester screening"), detection rates improve to 83-86% for Down syndrome at a 5% false-positive rate. 4 For women 35 years and older, detection rates exceed 80%. 4

Clinical Implementation Algorithm

When to Offer Double Marker Screening:

1. All pregnant women should be offered screening for chromosomal abnormalities early in pregnancy, regardless of maternal age or baseline risk. 1

2. Perform between 11-13 weeks gestation (with 12 weeks being ideal when combined with NT measurement). 1

3. Accurate gestational age dating is essential - use ultrasound crown-rump length measurement for dating, not hCG levels. 2

Risk Calculation Adjustments Required:

The laboratory must adjust risk calculations for:

• Maternal weight 4
• Race 4
• Insulin-dependent diabetes 4
• Number of fetuses 4
• Family history of neural tube defects 4

Interpreting Results:

Screen-positive threshold: Typically 1:250 or 1:300 risk cutoff for trisomy 21 1

• Positive screen: Offer genetic counseling and diagnostic testing (chorionic villus sampling or amniocentesis) 1
• Negative screen: Provides reassurance but does not eliminate all risk 1

Comparison to Other Screening Methods

Advantages of Double Marker Test:

• Earlier results than second-trimester screening (quad screen at 15-20 weeks), allowing earlier decision-making and the option of first-trimester CVS if diagnostic testing is desired 4
• Fewer diagnostic procedures needed: The positive predictive value (PPV) for traditional first-trimester combined screening is 3.6%, meaning 28 amniocenteses are needed to confirm one case of trisomy 21, compared to 28-45 procedures for second-trimester screening 1

Limitations:

• Lower detection rate than cell-free DNA (cfDNA/NIPS): NIPS has a PPV of 50-95% for trisomy 21, requiring only 1.1-2 diagnostic procedures to confirm one affected pregnancy 1
• Poor performance for structural abnormalities: First-trimester screening detects only 15% of cardiac defects and misses most other structural abnormalities 5
• Does not replace second-trimester anatomy ultrasound for detection of structural defects 5

Critical Pitfalls to Avoid

Technical Errors:

1. Never use hCG levels alone for gestational age dating - always use ultrasound crown-rump length measurement 2
2. Do not use singleton cutoffs for twin pregnancies - screening in multiples has lower sensitivity and requires specialized algorithms 1
3. Ensure proper timing - free β-hCG performs differently at 11 weeks versus 13 weeks 2

Clinical Management Errors:

1. Do not skip counseling about limitations - screening is not diagnostic and cannot predict severity of Down syndrome 3
2. Always offer diagnostic testing to women 35 and older in addition to screening options 4
3. Do not defer second-trimester anatomy ultrasound - first-trimester screening has poor sensitivity for structural abnormalities 5

Integration with Other Screening Modalities

The double marker test is most effective when combined with nuchal translucency (NT) ultrasound measurement, forming the "combined first-trimester screening" or "triple test" (PAPP-A + free β-hCG + NT + maternal age). 1 This combination increases detection rates by approximately 20-25% compared to NT alone. 4

Cell-free DNA (NIPS) is now an acceptable alternative with appropriate counseling about limitations, offering superior detection rates but at higher cost. 1 However, traditional screening methods like the double marker test remain widely used and cost-effective. 1

Special Populations

For twin pregnancies: NT measurement alone is more useful than serum markers, as serum levels from both pregnancies are averaged, reducing accuracy. 1 The positive screening rate is higher in multiples. 1

For women with risk factors: Maternal obesity, autoimmune disorders, and certain anticoagulants can affect test performance and should be factored into counseling. 1