Perspective: L-arginine and L-citrulline Supplementation in Pregnancy: A Potential Strategy to Improve Birth Outcomes in Low-Resource Settings

The available data support the hypothesis that L-arginine or L-citrulline supplementation would be suitable for implementation in resource-constrained settings and will enhance placental vascular development and improve birth outcomes. In resource-constrained settings, the rates of adverse birth outcomes, including fetal growth restriction, preterm birth, and low birth weight, are disproportionately high. Complications resulting from preterm birth are now the leading cause of mortality in children <5 y of age worldwide. Despite the global health burden of adverse birth outcomes, few effective interventions are currently available and new strategies are urgently needed, especially for low-resource settings. L-arginine is a nutritionally essential amino acid in pregnancy and an immediate precursor of nitric oxide. During pregnancy, placental and embryonic growth increases the demand for L-arginine, which can exceed endogenous synthesis of L-arginine from L-citrulline, necessitating increased dietary intake. In many low-resource settings, dietary intake of L-arginine in pregnancy is inadequate owing to widespread protein malnutrition and depletion of endogenous L-arginine due to maternal infections, in particular malaria. Here we examine the role of the L-arginine-nitric oxide biosynthetic pathway in pregnancy including placental vascular development and fetal growth. We review the evidence for the relations between altered L-arginine bioavailability and pregnancy outcomes, and strategies for arginine supplementation in pregnancy. Existing studies of L-arginine supplementation in pregnancy in high-resource settings have shown improved maternal and fetal hemodynamics, prevention of preeclampsia, and improved birth outcomes including higher birth weight and longer gestation. Arginine supplementation studies now need to be extended to pregnant women in low-resource settings, especially those at risk of malaria.