What causes an elevated maternal serum alpha-fetoprotein (AFP) level?

Causes of Elevated Maternal Serum Alpha-Fetoprotein (MSAFP)

Elevated maternal serum alpha-fetoprotein (MSAFP) levels are primarily associated with open neural tube defects (ONTDs), ventral wall defects, and several other fetal and maternal conditions that require prompt evaluation and follow-up.

Fetal Structural Abnormalities

• Open Neural Tube Defects (ONTDs): 75-90% of ONTDs and 95% of anencephaly cases can be detected by elevated MSAFP levels 1
• Ventral Wall Defects: MSAFP screening may detect 85% of ventral wall defects including:
  • Gastroschisis: Associated with very elevated MSAFP levels 1
  • Omphalocele: Can have normal to elevated MSAFP levels 1
• Cystic Hygroma: Elevated MSAFP can be seen with cystic hygromas 1

Other Fetal Conditions

• Congenital Nephrosis: This rare condition is associated with very elevated MSAFP levels 1
• Fetal Demise: Fetal death can cause elevated MSAFP 1
• Multiple Gestation: Multiple pregnancies typically have higher MSAFP levels 2
• Fetal Liver Disease: Pathological overproduction of AFP in liver diseases can lead to elevated MSAFP 2
• Fetal Anemia: Increased transfer through edematous placenta in fetal anemia can cause elevated MSAFP 2

Placental and Membrane Abnormalities

• Placental Abnormalities: Various placental pathologies can lead to elevated MSAFP 3
• Fetomaternal Hemorrhage: Blood transfer from fetus to mother can cause elevated MSAFP 4
• Fetal Blood Contamination: During amniocentesis or other procedures 1

Maternal Factors

• Underestimated Gestational Age: When the pregnancy is more advanced than estimated, MSAFP may appear elevated 3
• Maternal Weight: Lower maternal weight is associated with higher MSAFP levels (values should be adjusted for maternal weight) 1
• Race: MSAFP levels are typically higher in Black/African American women compared to Caucasian women 1
• Insulin-Dependent Diabetes: This condition affects MSAFP distribution and interpretation 1

Clinical Significance and Management

• MSAFP screening is optimally performed between 16-18 weeks gestation, but can be done between 15-20.9 weeks 1
• Cut-off levels for ONTD screening are typically 2.0-2.5 MoM (multiples of the median) in singleton pregnancies and 4.0-5.0 MoM in twin pregnancies 1
• Extremely high MSAFP levels (≥8 MoM) have a stronger association with major fetal anomalies and adverse pregnancy outcomes 3
• When MSAFP is elevated, follow-up should include genetic counseling, targeted ultrasound examination, and possibly amniocentesis 1

Common Pitfalls in Interpretation

• Gestational Age Errors: If there is a discrepancy in gestational age of 2 or more weeks after ultrasound examination, the MSAFP result must be reinterpreted 1
• Sample Timing: Samples drawn at less than 15 weeks gestation may give inaccurate results and should be repeated with accurate gestational dating 1
• False Positives: Can occur due to maternal blood contamination or fetomaternal transfusion during amniocentesis, especially through an anterior placenta 4
• Inadequate Clinical Information: Proper interpretation requires accurate information about maternal weight, race, diabetes status, and gestational age 1

Understanding the various causes of elevated MSAFP is crucial for appropriate follow-up and management of affected pregnancies to optimize maternal and fetal outcomes.