What is the significance of abnormal Alphafetoprotein (AFP) levels in pregnancy?

Significance of Abnormal Alphafetoprotein (AFP) Levels in Pregnancy

Abnormal AFP levels in pregnancy are critical screening markers that identify fetuses at risk for open neural tube defects, chromosomal abnormalities, and adverse pregnancy outcomes, requiring systematic follow-up with ultrasound, genetic counseling, and potentially amniocentesis to prevent significant fetal morbidity and mortality. 1, 2

Primary Clinical Significance

Elevated Maternal Serum AFP (MSAFP)

Elevated MSAFP is primarily used to detect open neural tube defects (ONTDs), achieving detection rates of 95% or greater for anencephaly and 75-90% for open spina bifida when using a 2.0 MoM (multiples of the median) cutoff level. 2

• The optimal screening window is 15-20 weeks gestation, with 16-18 weeks being ideal for maximizing detection while minimizing false positives 1, 2
• Screening cutoff levels typically range between 2.0 and 2.5 MoM, with screen-positive results defined as AFP MoM greater than or equal to the cutoff 1
• MSAFP screening is not diagnostic but a screening test that identifies pregnancies requiring further evaluation 1

Low MSAFP Values

• Low AFP values may indicate chromosomal abnormalities including Down syndrome, representing an emerging application of AFP screening 1, 2
• The risk threshold for low values should approximate the Down syndrome risk of a 35-year-old woman (1/270 in second trimester) 1

Other Adverse Outcomes Associated with Abnormal AFP

Beyond neural tube defects, abnormal MSAFP levels predict: 1, 3

• Imminent miscarriages
• Fetal demise
• Eventual prematurity
• Placental abnormalities with increased fetal-maternal transfer

Critical Modifying Factors That Affect Interpretation

AFP results must be adjusted for multiple patient-specific factors to avoid misinterpretation: 1, 2

• Gestational age: AFP concentrations decrease 13-15% per week from 15-22 weeks 1
• Maternal weight: Heavier women have diluted AFP levels requiring adjustment 1
• Race: Black/African American pregnancies have approximately half the ONTD risk, potentially warranting modified cutoffs (2.5 MoM vs 2.0 MoM) 1
• Insulin-dependent diabetes mellitus (IDDM): AFP levels are lower on average and ONTD risk is increased several-fold 1, 2
• Multiple gestation: Twin pregnancies have AFP levels approximately two times singleton levels, with cutoffs typically 4.0-5.0 MoM 1
• Method of gestational age assignment: Ultrasound dating "tightens" AFP distributions and reduces false-positive rates compared to last menstrual period dating 1

Systematic Follow-Up Algorithm for Elevated MSAFP

When MSAFP is elevated, follow this structured approach: 1, 2

1. Confirm gestational age with ultrasound to exclude dating errors as the cause of apparent elevation 1, 2
2. Perform level I ultrasound to identify multiple gestation or fetal demise 1
3. Consider repeat MSAFP testing when initial elevation is minimal and gestational age allows time for follow-up 1
4. Proceed to level II ultrasound by experienced operators capable of detecting neural tube defects 1, 2
5. Offer amniocentesis with amniotic fluid AFP and acetylcholinesterase (AChE) testing when indicated 2
6. Provide genetic counseling throughout the entire process 2

Amniotic Fluid AFP Interpretation

When amniocentesis is performed, amniotic fluid AFP provides diagnostic information: 1

• Abnormal amniotic fluid AFP is defined as ≥2.0 MoM 1
• Optimal diagnostic window is 13-22 weeks gestation, with results interpretable from 11-25 weeks 1
• AChE testing should accompany AFP to distinguish ONTDs from open ventral wall defects and to confirm true positives 1, 4
• Testing before 13 weeks has poorly defined diagnostic performance and requires cautionary interpretation 1

Critical Pitfalls to Avoid

Blood contamination can cause false-positive elevations in both maternal serum (from fetomaternal transfusion, especially after amniocentesis through anterior placenta) and amniotic fluid 1, 5

• Submit unspun amniotic fluid samples to allow direct detection of fetal blood 1
• Perform reflex fetal hemoglobin testing on samples with AFP elevations and/or positive AChE results 1

Fetal calf serum contamination from cytogenetics laboratory culture medium can cause false-positive AChE results, confirmed by testing for bovine serum albumin 1

Interpreting AFP in isolation without considering gestational age, maternal weight, race, and IDDM status leads to incorrect conclusions 2

Using commercial package insert medians rather than laboratory-specific population medians compromises accuracy 1

Inadequate patient education and directive counseling violates the principle that AFP screening should be voluntary with informed consent and nondirective counseling 1, 2

Essential Program Requirements

MSAFP screening should only be undertaken within a comprehensive program that provides: 1, 2

• Prompt result reporting
• Appropriate nondirective counseling before and after testing
• Access to confirmatory procedures including expert ultrasonography and amniocentesis
• Genetic counseling services
• Laboratory quality control with external proficiency testing 1

The vast majority of elevated MSAFP cases have normal amniotic fluid AFP, indicating that placental abnormalities allowing increased fetal-maternal transfer are more common than amniotic fluid leakage mechanisms 3. This explains the association between unexplained MSAFP elevations and adverse pregnancy outcomes even without structural defects 3.