Background Intermittent preventive treatment for malaria in pregnancy (IPTp) can improve birth outcomes, but whether it confers benefits to postnatal growth is unclear. We investigated the effect of IPTp on infant growth in Uganda and its pathways of effects using causal mediation analyses.

Methods We analyzed data from 633 infants born to mothers enrolled in a randomized trial of monthly IPTp with dihydroartemisinin-piperaquine (DP) vs sulfadoxine-pyrimethamine (SP) (NCT 02793622). Weight and length were measured from 0-12 months of age. Using generalized linear models, we estimated effects of DP vs. SP on gravidity-stratified mean length-for-age (LAZ) and weight-for-length Z-scores (WLZ). We investigated mediation by placental malaria, gestational weight change, maternal anemia, maternal inflammation-related proteins, preterm birth, birth length, and birth weight. Mediation models adjusted for infant sex, gravidity, gestational age at enrollment, maternal age, maternal parasitemia at enrollment, education, and wealth.

Findings SP increased LAZ by 0.18-0.28 Z from birth through age 4 months compared to DP, while DP increased WLZ by 0.11-0.28 Z from 2-8 months compared to SP among infants of multigravidae. We did not observe these differences among primigravida. Mediators of SP included increased birth weight and length and maternal stem cell factor at delivery. Mediators of DP included placental malaria and birth length, maternal IL-18, CDCP1, and CD6 at delivery.

Interpretation In high malaria transmission settings, different IPTp regimens influenced infant growth among multigravidae through distinct pathways in the period of exclusive breastfeeding, when few other interventions are available.

Funding Stanford Center for Innovation and Global Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation

Evidence before this study Intermittent Preventive Treatment in Pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by the WHO for regions with moderate-to-high malaria transmission. While SP is effective in reducing neonatal mortality and low birth weight, its efficacy has diminished in some areas of sub-Saharan Africa due to widespread parasite resistance to SP. Although IPTp with dihydroartemisinin-piperaquine (IPTp-DP) has demonstrated superior efficacy in reducing malaria in pregnancy, its impact on birth outcomes has not significantly surpassed that of SP. The ultimate goal of IPTp extends beyond enhancing birth outcomes to include benefits during infancy and later stages. Yet, the effects of SP vs. DP in relation to infant growth post-birth and the underlying mechanisms remain unknown. Prior studies also found that different IPTp regimens worked through different pathways, with DP influencing birth outcomes by reducing placental malaria and SP influencing them through non-malarial pathways such as maternal weight gain. Here, we re-analyzed data from of a randomized trial in Uganda to explore the impacts of these two IPTp regimens on infant growth and to understand potential mechanisms underlying its impacts on infant growth.

Added value of this study This study quantified how IPTp with SP compared to DP influenced infants’ growth trajectories, both ponderal and linear, during the first year of life. We found that SP improved linear growth of infants up to age 4 months compared to DP, and DP improved ponderal growth of infants from 2-8 months compared to SP among babies who were born to multigravidae. In addition, we identified birth size, placental malaria, and certain markers of maternal inflammation measured at delivery using the Olink Target 96 inflammation panel as pathways through which IPTp influenced infant growth. Our approach provides new insights into effects of IPTp beyond birth and the mechanisms by which IPTp impacts infant growth.

Implications of all the available evidence Our study provides evidence that different IPTp regimens can influence infant postnatal growth through distinct pathways. Our findings highlight the potential of combined SP and DP IPTp regimens and bolster the evidence base for continued delivery of IPTp to improve maternal and child health outcomes, particularly in malaria-endemic regions.

The authors have declared no competing interest.

This study was supported by the Stanford Center for Innovation in Global Health (270519). The original trial was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01 HD059454) and the Bill & Melinda Gates Foundation. Research reported in this publication was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Numbers K01AI141616 (PI: Benjamin-Chung), U01 AI155325 (PI: Jagannathan), and the National Heart, Lung, And Blood Institute of the National Institutes of Health under award number T32HL151323 (Nguyen). MER is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Pathway to Independence Award (K99HD111572). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Jade Benjamin-Chung is a Chan Zuckerberg Biohub Investigator.

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This study was approved by the Institutional Review Board at Stanford University (#40857); the original trial was approved by ethics committees of Makerere University School of Biomedical Sciences (Kampala, Uganda, approval number SBS-342), the Uganda National Council for Science and Technology (Kampala, Uganda; HS 2052).

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