Unexplained elevated or low maternal serum alpha-fetoprotein (MSAFP) is reported to indicate adverse perinatal outcome. We designed a prospective matched pair study to gain additional information about the type and frequency of adverse neonatal or maternal outcomes. Subjects were selected from 16,445 women who received second trimester MSAFP screening during the 4.5 year study period. For each unexplained elevated or low subject, a control patient in the second trimester of pregnancy was chosen by matching eight individual traits. After follow-up, 356 pairs were identified, for the unexplained low MSAFP group and 139 pairs for the unexplained elevated MSAFP group. Outcome information was obtained by way of a physician questionnaire. For the unexplained low MSAFP group, complications occurred no more often than for the paired controls and these pregnancies may not be considered at high risk for adverse outcome. Our study supports a strong association between unexplained elevated MSAFP and adverse neonatal outcomes of low birth weight, fetal death, preterm delivery, and fetal growth retardation. The highest frequency of adverse neonatal outcome occurred when the multiple of median value was > or = 4.0. Our study does not support an association between elevated MSAFP and maternal complications of hypertensive disorder, oligohydramnios, or placental abruption.