First-Trimester Placentation and the Risk of Antepartum Stillbirth

In approximately 85% of stillbirths, the fetus dies before labor begins. Whether the risk of stillbirth is determined in the first trimester—like several complications of pregnancy, including preterm birth and low birth weight—is not clear. This large-sale multicenter trial, a prospective cohort study, assessed the risk of antepartum stillbirth as related to maternal serum levels of 2 placental proteins, pregnancy-associated plasma protein A (PAPP-A) and the free beta subunit of human chorionic gonadotropin (hCG). Protein levels were determined within 10 weeks after conception in 7934 women living in Scotland in the years 1998–2000 who had singleton births at or after 24 weeks gestation. The median gestational age at the time of blood sampling was 11.9 weeks. Low PAPP-A levels could not be related to any maternal characteristics, but were more frequent with male than with female fetuses. Ten of the 25 antepartum stillbirths were ascribed to placental causes, 4 of them to abruption. The risk of stillbirth from any cause was increased 9.2-fold in women with a low PAPP-A level (the lowest fifth percentile) and 58-fold when stillbirth was a result of abruption. The risk was increased 40-fold in small-for-gestational-age unexplained stillbirths and 46% when stillbirth was the result of placental dysfunction. These associations remained just as strong after adjusting for maternal factors. No relationship was noted between the risk of stillbirth from any cause and maternal serum levels of the free beta subunit of hCG. An association between maternal PAPP-A levels and stillbirth is plausible because this protein is known to be a protease for insulin-like growth factor-binding proteins. Low levels might well result in reduced levels of free insulin-like growth factor, which appears to play an important role in trophoblast function. Identifying placental function in early pregnancy may help to anticipate serious complications of late pregnancy and guide prenatal care.