Oral citrulline supplementation in pregnancies with preeclampsia: a multicenter, randomized, double-blind clinical trial

Background: Preeclampsia (PE) contributes to maternal and fetal mortality and morbidity. Supplementation with L-arginine, the precursor of nitric oxide, has not proven effective, possibly due to extensive arginine catabolism in the splanchnic bed. Citrulline is converted by the kidney to L-arginine. Citrulline, therefore, could be a more effective nitric oxide donor in the treatment of PE. Objectives: The study aimed to determine whether oral L-citrulline supplementation would prolong the delay between diagnosis and delivery in preeclamptic females. Methods: A total of 115 females with monofetal preeclamptic pregnancy were enrolled before 36 weeks of gestation in a multicenter randomized, doubleblind trial: 58 received oral L-citrulline supplementation, and 57 received placebo. The duration of pregnancy, neonatal and maternal outcomes, and soluble fms-like tyrosine kinase 1/placental growth factor ratio, an index of placental dysfunction, were monitored. Results: Gestational age at inclusion was similar in both groups. The duration of pregnancy between inclusion and delivery was unaltered (hazard ratio: 0.90; 95% confidence interval: 0.62, 1.31). Neither neonatal weight nor pregnancy outcome differed between groups. Liver enzymes were higher on the day of delivery in the treated, compared to the placebo group (65.1 compared with 33.2 UI and 70.4 compared with 33.7 UI for alanine aminotransferase and aspartate aminotransferase, respectively, (estimate: 5.92; 95% confidence interval: 1.09, 10.74). Systolic blood pressure (BP) was higher at delivery in the citrulline group compared with the control group (P 1/4 0.015), whereas the diastolic BP showed no difference. We did not find any difference in neonatal outcomes nor soluble fms-like tyrosine kinase 1/placental growth factor ratio. Conclusions: The current trial found no benefit of oral L-citrulline supplementation to females with PE regarding either the duration of pregnancy, fetal growth, or maternal and neonatal outcomes. Systolic BP and liver enzymes levels were found to increase at delivery in the treated group. L-citrulline oral supplementation does not seem to be a promising candidate as a therapeutic intervention in pregnancies with PE. This trial was registered at CITRUPE as NCT02801695.