Prenatal diagnosis of neural tube defects. II. Analysis of false positive and false negative alpha-fetoprotein results

Abstract

Certain problems and pitfalls attend the use of the alpha-fetoprotein (AFP) assay for the prenatal diagnosis of neural tube defects (NTDs). Analysis of 2495 consecutive cases revealed 57 (2.3%) with amniotic fluid AFP levels greater than 3 SD above the mean. Fetal deaths (9), various fetal abnormalities, (7) and spontaneous abortions (4) occurred among this group. In addition, there were 30 cases with AFP levels greater than + 3 SD above the mean in which a normal child was delivered--a true false positive rate of 1.2%. To determine if the false positive rate could be diminished, 40 amniotic fluid samples with AFP greater than + 2 SD were subjected to further detailed analysis for fetal hemoglobin, total protein, and IgM concentrations. Even with this battery of tests, we estimate that between 1 and 2% of normal amniotic fluids have elevated AFP levels and either fall as expected outside the + 3 SD range, or have elevated AFP levels due to unknown causes.

PIP: Although the assay of alpha fetoprotein (AFP) levels from midtrimester amniotic fluid has been valuable in the diagnosis of neural tube defects (NTDs), this test is not specific for these defects, does not detect closed NTDs (about 10% of all NTDs), and false positive and false negative results have made interpretation of results difficult. The analysis of 2495 amniotic fluid samples led to a findings of 122 cases of false positive results (AFP elevated +2SD) not associated with NTD; 85 pregnancies were normal (with 8 more pending). Of 57 samples with AFP +3SD, 9 pregnancies resulted in fetal death, 7 in miscellaneous fetal abnormalities, 4 in spontaneous abortion, 30 in normal infants (with 7 pending). A true false positive rate of 1.2% therefore exists even using +3SD as the cut-off for normal. Further tests on 40 randomly selected false positive samples (fetal hemoglobin, IgM, and total protein) failed to reduce this false positive rate. All 49 cases of open NTD had AFP elevation of 3SD.