What is the difference between the dual marker test and the enhanced quadruple marker test (including alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), inhibin A, and unconjugated estriol) for prenatal screening?

Dual Marker vs. Enhanced Quadruple Marker Screening

The enhanced quadruple marker test (quad screen) is superior to the dual marker test, detecting approximately 75-80% of Down syndrome cases compared to the dual marker's lower detection rate, and should be the preferred second-trimester screening approach. 1, 2

Key Differences Between Tests

Dual Marker Test Components

• Alpha-fetoprotein (AFP) - primarily screens for neural tube defects 1, 3
• Human chorionic gonadotropin (hCG) - elevated in Down syndrome, low in trisomy 18 3, 4

Enhanced Quadruple Marker Test Components

• AFP - screens for neural tube defects and modifies Down syndrome risk 1
• hCG - elevated in Down syndrome 3, 4
• Unconjugated estriol (uE3) - typically lower in Down syndrome 4, 5
• Inhibin A (INH-A) - typically higher in Down syndrome 1, 4

Detection Rate Comparison

Down Syndrome Detection

• Dual marker alone: Using AFP alone would detect only 21% of Down syndrome cases in women under 35 6
• Triple marker (AFP, hCG, uE3): Detects approximately 65% of Down syndrome cases 4, 6
• Quadruple marker (adds Inhibin A): Detects approximately 75% in women under 35 and over 80% in women 35 and older 1, 4
• Prospective data confirms superiority: The quad screen with inhibin A detected 85% of Down syndrome cases at a 19% false-positive rate, compared to 69% with triple marker alone 2

Other Conditions

• Neural tube defects: Both tests detect 75-90% of open neural tube defects and 95% of anencephaly through AFP elevation above 2.0-2.5 MoM 1, 3
• Trisomy 18: The quad screen identifies at-risk pregnancies through characteristic pattern of low AFP, low hCG, and low uE3 1
• Other aneuploidies: The quad screen detected 60% of other aneuploidies beyond Down syndrome 2

Clinical Implementation Guidelines

Timing and Gestational Age

• Optimal testing window: 16-18 weeks gestation for both tests 1, 3
• Acceptable range: 15-20 weeks, but requires accurate gestational age documentation 1
• Reinterpretation required: If gestational age changes by ≥2 weeks after ultrasound, results must be recalculated 1, 3

Risk Calculation Adjustments

Both tests require adjustment for:

• Maternal weight - AFP inversely related to weight 1, 3
• Race - Caucasian vs. Black/African American 1, 3
• Insulin-dependent diabetes 1, 3
• Number of fetuses - different cutoffs for twins (4.0-5.0 MoM vs. 2.0-2.5 MoM for singletons) 1, 3
• Family history of neural tube defects 1, 3

Guideline Recommendations

American College of Medical Genetics Position

• Multiple marker screening (AFP, hCG, uE3 with or without INH-A) should be offered to all women unless amniocentesis is already indicated or first trimester screening was performed 1
• MSAFP screening should be offered even to women who had first trimester screening or CVS, optimally at 16-18 weeks 1
• Women 35 and older should still be offered CVS and amniocentesis for definitive diagnosis 1

Integrated Screening Approach

• The SURUSS trial demonstrated that integrated screening (first trimester NT + PAPP-A combined with second trimester quad screen) is the most sensitive and cost-effective approach 1

Common Pitfalls to Avoid

Technical Errors

• Failing to use ultrasound dating: Ultrasound dating reduces false-positive rates and increases detection 1, 3
• Not reinterpreting with revised dates: Critical when gestational age changes ≥2 weeks 1, 3
• Using singleton cutoffs for twins: Twin pregnancies require 4.0-5.0 MoM cutoff vs. 2.0-2.5 MoM 1, 3

Clinical Management Errors

• Inadequate counseling: Patients must understand these are screening tests, not diagnostic 1
• Not offering follow-up: Screen-positive patients should be offered genetic counseling, targeted ultrasound, and amniocentesis 1
• Ignoring maternal factors: Not adjusting for weight, race, and diabetes reduces accuracy 1, 3

Additional Clinical Value

Beyond Aneuploidy Screening

• Adverse perinatal outcomes: The quad screen shows value in predicting risk of other adverse pregnancy outcomes in high-risk populations, with approximately 2-3 fold increased risk when markers are abnormal 7
• Pregnancy complications: Abnormal markers may indicate increased risk for preeclampsia and preterm labor 3

Cost-Effectiveness

• The quad screen detected 1 abnormal karyotype for every 22 amniocenteses performed, demonstrating reasonable positive predictive value 6
• At a 5.7% screen-positive rate after ultrasound evaluation, the quad screen provides efficient risk stratification 6