L-arginine during pregnancy-a preclinical meta-analysis on fetal growth and maternal blood pressure

INTRODUCTION: L-Arginine supplementation during pregnancy has been studied as a prenatal therapeutic and preventive approach for fetal growth restriction (FGR) or preeclampsia (PE). While beneficial effects on fetal growth and maternal blood pressure have been reported in human studies, limitations in study design (small number of patients per study, low risk group) hinders us to draw a clear conclusion. We conducted a meta-analysis on the effect of L-arginine on fetal growth and maternal blood pressure in preclinical and clinical studies. This combined animal/human meta-analysis enables us to identify modifiable factors-such as dose and administration strategy-to improve human RCT. METHODS: Pubmed, Embase, and the Cochrane Library were search for studies reporting on the effect of prenatal supplementation with L-Arginine on fetal growth or maternal blood pressure. Ratio of mean birth weight and mean differences in blood pressure were calculated. We conducted a meta-analysis with subgroup analysis (species, administration timing, route, and scheme, prevention vs. treatment, model) to identify potential factors that influence the efficacy of L-arginine the most. Dose-response curves expressed in metabolic weight (mg/kg0.75/24h) were fitted using splines. RESULTS: 30 animal (mouse, rat, pig, sheep, cow, horse) and 12 human studies were included. This meta-analysis shows that L-arginine increases fetal growth in FGR/PE compared to risk groups or healthy pregnancies (1.13 [1.09;1.7] vs. 1.04 [0.99;1.10] vs.1.02 [0.99;1.04]; p=1e-9). The effect was comparable between species, administration route and scheme, but administration in middle or late pregnancy appeared to be more effective than early or full gestation (p=9e-10). L-Arginine significantly lowers maternal blood pressure in FGR/PE only (-22 [-32.4;-12.8] mmHg; p=6e-6) with the decrease depending on the baseline blood pressure. The effect was similar in administration timing and route, but stronger in rats compared to humans and in continuous administration. There was no dose-response effect in fetal growth or in blood pressure. CONCLUSION: this meta-analysis supports that prenatal supplementation with L-Arginine improves fetal growth and maternal blood pressure in pregnancies complicated by FGR/PE. This combined meta-analysis shows differences in blood pressure in continuous versus interval administration; whether this is influenced by effect in species remains to be elucidated. The use of L-arginine seems to be especially optimal for treatment rather than prevention of placental insufficiency. Current doses used in studies suffice to gain optimal effect for both fetal growth and blood pressure.