Pathways through which intermittent preventive treatment for malaria in pregnancy influences child growth faltering: a mediation analysis
Authors: Tong Yanwei , Ratnasiri Kalani , Hanif Suhi , Nguyen Anna T. , Roh Michelle E. , Dorsey Grant , Kakuru Abel , Jagannathan Prasanna , Benjamin-Chung Jade 
Published: June 2024

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

Research in context

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.