Elevated maternal serum midtrimester alpha-fetoprotein levels are associated with fetoplacental ischemia

Elevation of maternal serum alpha-fetoprotein in the second trimester is associated with poor pregnancy outcome, including fetal death, preterm delivery, and fetal growth restriction. We hypothesized that placental ischemia may be the common underlying pathogenesis of these outcomes. Thus we tested angiogenin, a potent inducer of neovascularization, in midtrimester amniotic fluid of patients with elevated maternal serum alpha-fetoprotein values to determine whether alpha-fetoprotein elevation is due to ischemia with subsequent stimulation of angiogenesis.

In this case-control study, patients with elevated maternal serum alpha-fetoprotein levels (> or = 2.0 multiples of the median, n = 9) at triple screen were matched with two controls (n = 18) on the basis of year of amniocentesis and maternal age, race, and parity. The median elevation of maternal serum alpha-fetoprotein in the study population was 4.01 multiples of the median (range 2.65 to 7.24 multiples of the median). Inclusion criteria were (1) singleton gestation, (2) no evidence of fetal structural or chromosomal anomalies, and (3) genetic amniocentesis. Amniotic fluid was immunoassayed for angiogenin (Quantikine, R&D Systems; sensitivity 0.026 ng/ml, interassay and intraassay coefficients of variation 4.6% and 2.9%, respectively). Statistical analysis included one-way analysis of variance and regression with p < 0.05 significant. Angiogenin and maternal serum alpha-fetoprotein values were normalized with use of natural log transformation for statistical analysis.

Angiogenin values were significantly elevated in patients with high maternal serum alpha-fetoprotein levels (median 31.1 [range 9.2 to 54.6] vs 17.1 [range 9.0 to 29.2] ng/ml, p = 0.02). Mean gestational age at sampling, maternal age, and year of amniocentesis were not significantly different between the study and control groups (each p > 0.05). As anticipated, there was a significant increase in preterm deliveries and small-for-gestational-age neonates in the patients with elevated maternal serum alpha-fetoprotein levels (each p < 0.01).

Midtrimester amniotic fluid angiogenin levels are significantly elevated in patients with elevated midtrimester maternal serum alpha-fetoprotein levels. Because angiogenin is a known marker of tissue ischemia, resulting in neovascularization, we hypothesize that elevation of maternal serum alpha-fetoprotein levels at triple screen is due to placental ischemia.