Elevated Alpha-Fetoprotein (AFP) in Prenatal Testing
An elevated AFP level in prenatal testing primarily indicates open neural tube defects (ONTDs), open ventral wall defects, or other serious fetal structural abnormalities that require immediate follow-up with targeted ultrasound and potentially amniocentesis.
Primary Indications of Elevated AFP
Open Neural Tube Defects (Most Important)
- Elevated maternal serum AFP (MSAFP) detects 75-90% of open spina bifida cases and 95% of anencephaly cases 1
- When amniotic fluid AFP is elevated (≥2.0 MoM) and combined with acetylcholinesterase (AChE) testing, the detection rate for open spina bifida reaches 97% with only a 0.1% false-positive rate 2
- Neural tube defects represent the most critical diagnosis to identify, as they significantly impact fetal morbidity and mortality 1, 3
Open Ventral Wall Defects
- Gastroschisis is associated with very elevated AFP levels, with AChE positive in over 95% of cases 2, 1
- Omphalocele can show normal to elevated AFP levels, with AChE negative in over 95% of cases 2, 1
- These defects are surgically correctable but require specialized perinatal planning 4
Other Fetal Conditions Associated with Elevated AFP
Serious structural abnormalities:
- Congenital nephrosis causes very elevated AFP with negative AChE 2
- Cystic hygroma results in very elevated AFP when hygroma fluid is inadvertently aspirated 2, 1
- Fetal demise elevates AFP levels 2, 5
Important technical considerations:
- Fetal blood contamination is a major cause of false-positive results, as fetal blood AFP levels are more than 100 times higher than amniotic fluid levels 2
- Maternal blood contamination can occasionally produce false-positive results 2
Critical Management Algorithm
When MSAFP is Elevated (>2.0-2.5 MoM):
- Verify gestational age immediately - Errors of 2 or more weeks require complete reinterpretation 1
- Perform genetic counseling 1, 3
- Obtain targeted level II ultrasound examination to identify structural abnormalities 1, 4
- Consider amniocentesis for amniotic fluid AFP and AChE testing if ultrasound is inconclusive or confirms abnormality 1, 3
When Amniotic Fluid AFP is Elevated (≥2.0 MoM):
- Reflexive AChE testing should be performed on all specimens with AFP ≥2.0 MoM that are free of fetal blood contamination 2
- Test for fetal hemoglobin if visible blood contamination is present, as this causes false-positive AChE results in about 2% of bloodstained samples 2
- Positive results must be transmitted to the referring provider within one working day by phone and/or fax 2
Optimal Screening Parameters
- Screening is optimally performed between 16-18 weeks gestation 1
- Cut-off levels for ONTD screening are typically 2.0-2.5 MoM in singleton pregnancies 1
- Twin pregnancies require higher cut-offs of 4.0-5.0 MoM 1
Critical Pitfalls to Avoid
Gestational age errors are the most common pitfall - Always confirm dating with ultrasound before interpreting AFP results, as AFP levels vary dramatically with gestational age 1
Sample timing matters - Samples drawn before 15 weeks gestation may give inaccurate results and should not be used for screening 1
Maternal factors affect interpretation:
- Lower maternal weight is associated with higher AFP levels and requires weight adjustment 1
- AFP levels are typically higher in Black/African American women compared to Caucasian women 1
- Insulin-dependent diabetes affects AFP distribution and interpretation 1
Blood contamination is frequently overlooked - Even minimal fetal blood contamination can cause significant AFP elevation and false-positive AChE results 2. Always test for fetal hemoglobin when blood contamination is suspected.
Not all elevated AFP indicates neural tube defects - The differential diagnosis is broad and includes both lethal conditions and surgically correctable anomalies 4. Detailed ultrasound examination is essential to distinguish between these conditions and can salvage many pregnancies that might otherwise be terminated 4.