Malaria in pregnancy alters l-arginine bioavailability and placental vascular development.

Chloe R Mcdonald,Mwayiwawo Madanitsa,Victor Mwapasa,Linda Kalilani-Phiri,Lindsay S Cahill,Robyn Elphinstone,Kevin C Kain,Lisa M Gazdzinski,John G Sled,Kathleen J Y Zhong,Feiko O Ter Kuile,Joel L Gamble,Andrea L Conroy,Adrienne C Philson

doi:10.1126/scitranslmed.aan6007

Abstract

Reducing adverse birth outcomes due to malaria in pregnancy (MIP) is a global health priority. However, there are few safe and effective interventions. L-arginine is an essential amino acid in pregnancy and an immediate precursor in the biosynthesis of nitric oxide (NO), but there are limited data on the impact of MIP on NO biogenesis. We hypothesized that hypoarginemia contributes to the pathophysiology of MIP and that L-arginine supplementation would improve birth outcomes. In a prospective study of pregnant Malawian women, we show that MIP was associated with lower concentrations of L- arginine and higher concentrations of endogenous inhibitors of NO biosynthesis, asymmetric and symmetric dimethylarginine, which were associated with adverse birth outcomes. In a model of experimental MIP, L-arginine supplementation in dams improved birth outcomes (decreased stillbirth and increased birth weight) compared with controls. The mechanism of action was via normalized angiogenic pathways and enhanced placental vascular development, as visualized by placental microcomputerized tomography imaging. These data define a role for dysregulation of NO biosynthetic pathways in the pathogenesis of MIP and support the evaluation of interventions to enhance L-arginine bioavailability as strategies to improve birth outcomes.

Highlights

An estimated 125 million women become pregnant in malaria-endemic regions every year, with more than 85 million at risk of Plasmodium falciparum malaria [1,2,3]
Placental malaria was associated with adverse birth outcomes, with 60.3% of infants born small-for-gestational age (SGA) positive for malaria by histology compared to 44.6% of appropriate-for-gestational age (AGA) infants (P = 0.01)
There was no difference in the proportion of women with histologically defined placental malaria according to treatment arm (P = 0.48), and treatment arm was not associated with adverse birth outcomes (LBW, preterm birth (PTB), SGA, P > 0.05 for all) or birth weight {mean (SD), intermittent-presumptive treatment in pregnancy [sulfadoxine pyrimethamine (IPTp-SP)], 2773 [461] g versus intermittent screening and treatment in pregnancy [dihydroartemisinin- piperaquine (ISTp-DP)], 2790 [388] g; P = 0.69}

Summary

Introduction

An estimated 125 million women become pregnant in malaria-endemic regions every year, with more than 85 million at risk of Plasmodium falciparum malaria [1,2,3]. First-time mothers, are more likely to be infected with falciparum malaria and to experience complications including maternal anemia, pregnancy loss, and low birth weight (LBW) resulting from small-for-gestational age (SGA) outcomes and/or preterm birth (PTB) [4,5,6,7]. Malaria in pregnancy (MIP) leads to the sequestration of malaria-infected red blood cells in the intervillous space of the placenta and the recruitment of mononuclear cells, generating a localized immune response at the maternal-fetal interface [8, 9]. MIP-induced immune responses in the placenta can disrupt normal angiogenic processes, resulting in placental insufficiency and the inability of the placenta to support rapid fetal growth in the third trimester, leading to SGA, PTB, and LBW [10].

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Conclusion