Oral Citrulline supplementation in pregnancies with preeclampsia: a multicentre, randomized, double blind clinical trial

Cite : Norbert Winer, Emilie Misbert, Damien Masson, Aude Girault, Marie-Cecile Alexandre -Gouabau, Guillaume Ducarme, Vincent Dochez, Thibault Thubert, Marion Boivin, Véronique Ferchaud-Roucher, Morgane Péré, Dominique Darmaun,
Oral Citrulline supplementation in pregnancies with preeclampsia: a multicentre, randomized, double blind clinical trial,
The American Journal of Clinical Nutrition, 2024, ISSN 0002-9165, https://doi.org/10.1016/j.ajcnut.2024.12.001

Abstract

Background
Preeclampsia contributes to maternal and fetal mortality and morbidity. Supplementation with L-arginine, precursor of Nitric Oxide (NO), has not proven effective, possibly due to extensive arginine catabolism in splanchnic bed. Citrulline is converted by the kidney to L-arginine. Citrulline therefore, could be a more effective NO donor in the treatment of preeclampsia.

Objective
The aim of the study was to determine whether oral L-citrulline supplementation would prolong the delay between diagnosis and delivery in preeclamptic women.

Patients and Methods
A total of 115 women with mono-fetal preeclamptic pregnancy were enrolled before 36 weeks of gestation in a multicenter randomized double-blind, trial: 58 received oral L-citrulline supplementation, and 57 received placebo. Duration of pregnancy, neonatal and maternal outcome, and, soluble fms-like tyrosine kinase 1/placental growth factor (sFlt1/PLGF 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 (HR 0.90, 95% CI [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 placebo group ( 65.1 vs 33.2 UI and 70.4 vs 33.7 UI for ALAT and ASAT, respectively, (estimate 5.92, 95%CI [1.09 ; 10.74]) . Systolic blood pressure was higher at delivery in citrulline group versus control group (p = 0.015) whereas the diastolic blood pressure showed no difference. We did not find any difference on neonatal outcomes nor sFlt-1/ PlGF ratio.

Conclusion
The current trial found no benefit of oral L-citrulline supplementation to women with preeclampsia regarding either the duration of pregnancy, fetal growth, or maternal and neonatal outcome. Systolic blood pressure and liver enzymes at delivery were increased in the treated group. L-citrulline oral supplementation does not seem to be a promising candidate as a therapeutic intervention in pregnancies with preeclampsia.

Clinical Trial Registration (Registration. CITRUPE)

ClinicalTrials.gov ID
NCT02801695


Abbreviations

ALAT alanine aminotransferase
ASAT aspartate aminotransferase
ß-HCG human chorionic gonadotropic hormone
CTG cardiotocography
HELL Phemolysis, elevated liver enzymes and low platelets
IUGR intrauterine growth restriction
NO nitric oxide
PAAP Pregnancy associated plasma protein A
PE preeclampsia
PlGF Placental growth factor
sFlt-1 soluble fms-like tyrosine kinase 1
SGA small for gestational age
sEng soluble endoglin
TGF-β1 transforming growth factor-beta1
WG weeks of gestation