Effect mechanisms of different malaria chemoprevention regimens in pregnancy on infant growth outcomes: causal mediation analysis of a randomized controlled trial

IntroductionIntermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) has become less effective at preventing malaria due to rising parasite resistance. IPTp with dihydroartemisinin-piperaquine (DP) alone or in combination with SP (DP+SP) dramatically lowers the risk of malaria in pregnancy compared to SP but is associated with lower birthweight and early life wasting. We estimated the effect of IPTp-DP, DP+SP, and SP on infant growth outcomes and assessed possible treatment mechanisms through a causal mediation analysis. MethodsWe used infant follow-up data (N=761) from a trial (NCT04336189) that randomized pregnant women to receive monthly IPTp-DP, SP, or DP+SP. We compared weight-for-length (WLZ) and length-for-age (LAZ) z-scores between treatment arms. We assessed possible mediation through pregnancy, birth, and infancy factors using interventional indirect effect models. ResultsCompared to IPTp-SP, IPTp-DP+SP decreased mean WLZ by 0.18 [95% confidence interval (CI) -0.03, 0.39] between 1-3 months and 0.28 (95% CI 0.07, 0.49) between 4-6 months, with the largest differences among primigravidae. Lower risk of active placental malaria in IPTp-DP+SP helped reduce differences in mean WLZ vs IPTp-SP (+0.06, 95% CI 0.02, 0.10). The IPTp-DP+SP arm had up to 0.28 lower mean LAZ between 7-13 months compared to IPTp-DP, particularly among children who were wasted between 0-6 months; low birthweight had a persistent, mediating effect on linear growth. ConclusionAdverse birth outcomes contributed to early growth faltering among children born to mothers receiving IPTp-DP+SP vs IPTp-SP, but the prevention of placental malaria partially counteracted the negative effects of IPTp-DP+SP on ponderal growth. Key MessagesO_LIIntermittent preventive treatment of malaria in pregnancy (IPTp) with a combination of dihydroartemisinin-piperaquine (DP) and sulfadoxine-pyrimethamine (SP) leads to lower birth weight compared to SP alone, but it is unclear whether effects persist through infancy and what mechanisms drive these differences. C_LIO_LIDP+SP provided some improvements to ponderal growth over SP by preventing active placental malaria, but these benefits were not large enough to offset negative effects associated with other prenatal factors. C_LIO_LIInfants born to mothers who received IPTp with DP+SP were at higher risk of growth faltering in the first year of life compared to DP or SP alone; while differences in weight-for-length subsided over time, some children developed chronic forms of malnutrition that may be difficult to recover from. C_LI