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

Introduction: Intermittent 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. Methods: We 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. Results: Compared 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. Conclusion: Adverse 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 Messages: Intermittent 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.DP+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.Infants 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.