INTRODUCTION: Low maternal serum levels of pregnancy-associated plasma protein A (PAPP-A) measured in the first trimester and high levels of alpha fetoprotein (AFP) measured in the second trimester have been associated with adverse pregnancy outcomes reflective of placental insufficiency, and there is a synergistic relationship between the two. We investigated the utility as a screening test of a simple ratio of maternal serum AFP to PAPP-A (AFP:PAPP-A) measured in the first trimester. METHODS: We studied 4057 nulliparous women with a singleton pregnancy from the Pregnancy Outcome Prediction (POP) study. We studied the predictive ability for adverse outcome of the AFP:PAPP-A ratio measured in the first trimester with and without correction for maternal weight and gestational age at measurement. We compared the AFP:PAPP-A ratio with corrected AFP and PAPP-A on their own and in combination. RESULTS: An AFP:PAPP-A ratio >10 was associated with placentally-related adverse outcomes, including fetal growth restriction (risk ratio (RR) 3.74, 95% confidence interval (CI) 2.30-6.09), severe preeclampsia (RR 2.12, 95% CI 1.39-3.25) and stillbirth (RR 5.05, 95% CI 1.48-17.18). The ratio performed favorably in predicting adverse pregnancy outcomes when compared with corrected measurements of either AFP or PAPP-A, and was equivalent to a model combining the two. Its predictive ability was not affected by correction for maternal weight or gestational age at measurement. DISCUSSION: An elevated maternal AFP:PAPP-A ratio in the first trimester is associated with placentally-related adverse outcomes in a cohort of unselected nulliparous women.