What is the significance and management of abnormal alpha fetoprotein (AFP) levels during pregnancy?

Alpha-Fetoprotein in Pregnancy

Maternal serum alpha-fetoprotein (MSAFP) screening should be offered as a voluntary screening test between 16-18 weeks gestation to detect open neural tube defects, ventral wall defects, and other fetal anomalies, with abnormal results requiring a systematic workup including ultrasound confirmation of gestational age, genetic counseling, level II ultrasound, and potentially amniocentesis. 1

Understanding AFP as a Screening Test

MSAFP is a screening test, not a diagnostic test, and this distinction is critical for proper patient counseling. 1 The test has both false-positive and false-negative results, making it imperfect but valuable when used within a comprehensive program. 1

What AFP Detects

Elevated MSAFP levels are associated with:

• Open neural tube defects - detected in 75-90% of open spina bifida cases and 95% of anencephaly cases 2, 3, 4
• Ventral wall defects including gastroschisis (very elevated levels) and omphalocele (normal to elevated) 2, 3, 5
• Fetal demise 3, 5
• Congenital nephrosis (very elevated levels) 3
• Cystic hygroma 3

Low MSAFP levels may indicate:

• Chromosomal abnormalities including Down syndrome 1, 6, 5
• Other structural anomalies such as congenital diaphragmatic hernia and duodenal atresia 5

Optimal Timing and Testing Protocol

The optimal screening window is 16-18 weeks gestation. 1, 3 Testing before 15 weeks may yield inaccurate results. 3

Standard Screening Protocol

When MSAFP screening is performed, the following sequence should be followed: 1

• First serum specimen evaluation
• Second serum specimen evaluation if the first is minimally elevated and time permits 1
• Genetic counseling at each step 1
• Level I ultrasound to confirm gestational age and exclude multiple gestation 1, 2
• Level II targeted ultrasound if abnormalities persist 1, 2
• Amniocentesis with amniotic fluid AFP and acetylcholinesterase testing when indicated 1, 6

Critical Interpretation Factors

Several patient-specific factors must be considered when interpreting MSAFP results:

• Gestational age errors of 2 or more weeks require complete reinterpretation of results 2, 3
• Maternal weight affects AFP levels, with lower weight associated with higher values requiring adjustment 1, 3
• Race influences baseline levels, with Black/African American women typically having higher AFP levels 2, 3
• Insulin-dependent diabetes mellitus lowers average AFP levels and requires separate normative values 1, 3
• Multiple gestation increases AFP levels (cutoff 4.0-5.0 MoM for twins vs 2.0-2.5 MoM for singletons) 3

Management Algorithm for Abnormal Results

For Elevated MSAFP

When MSAFP is elevated, proceed systematically: 2, 6

1. Confirm gestational age with ultrasound - errors are the most common cause of apparent elevation 2, 3
2. Exclude multiple gestation and fetal demise with level I ultrasound 1
3. If extremely elevated (>10,000 ng/mL), assess for adnexal masses to evaluate for germ cell tumor 2
4. Perform level II targeted ultrasound to evaluate for neural tube defects, ventral wall defects, and other structural anomalies 1, 2
5. Offer amniocentesis with amniotic fluid AFP and acetylcholinesterase testing if ultrasound is inconclusive or confirms abnormality 1, 6
6. Provide genetic counseling throughout the evaluation process 6, 3

For Low MSAFP

Low values warrant evaluation for chromosomal abnormalities, particularly Down syndrome, with consideration of amniocentesis for karyotyping. 1, 6

Essential Program Requirements

MSAFP screening should only be undertaken when the following infrastructure exists: 1

• Access to a qualified laboratory with appropriate quality control 1
• Prompt reporting of results to obstetrical care providers 1
• Availability of genetic counseling 1
• Access to level I and level II ultrasound performed by experienced sonographers 1
• Capability to perform amniocentesis with AFP and acetylcholinesterase assays 1

Patient Counseling and Consent

Screening must be voluntary with informed consent documented in writing. 1 Counseling should be nondirective and begin early in pregnancy to allow unhurried decision-making. 1 Patients must understand that:

• The test is a screening tool, not diagnostic 1
• Both false-positive and false-negative results occur 1
• Abnormal results require additional testing 1
• Some couples may prefer not to undergo screening for religious or ethical reasons 1

Critical Pitfalls to Avoid

Common errors that compromise AFP screening accuracy include:

• Interpreting results without confirming gestational age - the single most important factor 2, 3
• Failing to adjust for maternal weight, race, and diabetes status 1, 3
• Relying on AFP alone without confirmatory ultrasound and amniocentesis when results are abnormal 6
• Providing directive rather than nondirective counseling 1
• Misinterpreting blood-contaminated amniotic fluid samples - fetal blood contamination falsely elevates amniotic fluid AFP 7
• Testing outside the optimal 16-18 week window, particularly before 15 weeks 1, 3