The risk of adverse perinatal outcome among 8839 women recruited to a multicenter, prospective cohort study was related to maternal circulating concentrations of trophoblast-derived proteins at 8–14 wk gestation. Women with a pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile at 8–14 wk gestation had an increased risk of intrauterine growth restriction [adjusted odds ratio, 2.9; 95% confidence interval (CI), 2.0–4.1], extremely premature delivery (adjusted odds ratio, 2.9; 95% CI, 1.6–5.5), moderately premature delivery (adjusted odds ratio, 2.4; 95% CI, 1.7–3.5), preeclampsia (adjusted odds ratio, 2.3; 95% CI, 1.6–3.3), and stillbirth (adjusted odds ratio, 3.6; 95% CI, 1.2–11.0). The strengths of the associations were similar when the test was performed before 13 wk gestation or between 13 and 14 wk gestation. In contrast, levels of free β-human CG, another circulating protein synthesized by the syncytiotrophoblast, were not predictive of later outcome in multivariate analysis. PAPP-A has been identified as a protease specific for IGF binding proteins. We conclude that control of the IGF system in the first and early second trimester trophoblast may have a key role in determining subsequent pregnancy outcome.