Maternal serum alpha-fetoprotein (MSAFP) screening is widely used for the detection of open neural tube defects (NTDs) and a variety of other anomalies and complications. We examined the outcomes of 44 pregnancies with MSAFP elevations of 8 or more multiples of the median (MoM) from among 40,676 screened pregnancies. At the initial evaluation by ultrasound, 82% of the patients had at least one finding that may have accounted for the elevation. Approximately 45% of the fetuses had a major fetal anomaly, 25% died, 16% had an identifiable placental abnormality, and 5% had an underestimation of gestational age; 18% of the elevations remained unexplained after ultrasound. In follow-up of the pregnancies, all of those with an unexplained elevation after initial ultrasound had at least one obstetric complication or placental abnormality. The overall positive predictive value of an MSAFP value of 8 or more MoM for NTDs was 22.7%. The proportion of infants born alive in the overall group was low, with only 16 live births among 46 fetuses. The majority of the nonviable outcomes were associated with a fetus with a major anomaly that was terminated or died before 20 weeks. Of the live-born infants, 31% had a major anomaly, 19% had intrauterine growth retardation (IUGR) and an anomaly, 12.5% had IUGR without an anomaly, and 25% were preterm. Eighty-eight percent of those pregnancies with a live-born infant had at least one obstetric complication. Among pregnancies with MSAFP of 8 or more MoM, the majority are associated with large structural fetal anomalies or fetal death before 20 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)