Intrauterine growth restriction (IUGR) and preeclampsia (PE) are associated with impaired placentation. Patients who are at risk of developing both these disorders can be identified by abnormal uterine artery Doppler at mid-trimester pregnancy. Nitric oxide (NO)-donors like pentaerithrityl-tetranitrate (PETN) reduce the impedance in the uteroplacental vessels and possess protecting effects on the endothelium. We tested the effectiveness of the NO-donor PETN for secondary prevention of IUGR, PE, and preterm birth in pregnancies at risk. Some 111 women who presented with abnormal placental perfusion at 19-24 weeks of gestation (w.o.g.) were included into a prospective, randomized, placebo-controlled, double-blinded study. The primary endpoint was IUGR and/or perinatal death. Secondary endpoints were preterm birth, PE, and placental abruption. Pentaerithrityl-tetranitrate significantly decreased the risk for IUGR and/or perinatal death [adjusted odds ratio (OR) 0.410; 95% confidence interval, CI, 0.184-0.914] and for IUGR (adjusted OR 0.436; 95% CI 0.196-0.970). Preterm birth before 32 w.o.g. (adjusted OR 0.204; 95% CI 0.052-0.801) was reduced, but not the risk for PE. No placental abruption occurred in the PETN, but five occurred in the placebo group [corrected]. These results suggest that secondary prophylaxis of adverse pregnancy outcome might be feasible in pregnancies exhibiting abnormal placentation using PETN.