Preterm Birth and Malaria Susceptibility in Offspring of Uninfected Multigravid Women.

Importance: Pregnancy malaria (PM) is associated with adverse pregnancy outcomes such as stillbirth, early neonatal death, preterm delivery (PTD), and low birthweight. PM also increases the risk of malaria infection in infants. However, it is unknown whether PTD modifies the risk of malaria infection during early childhood. Objective: To investigate the association of PM and PTD with child susceptibility to malaria infection and disease. Design, Setting, and Participants: Pregnant women were enrolled between November 23, 2010, and December 9, 2014, into an observational longitudinal cohort study of mother-child pairs in Ouélessébougou, Mali, an area of high seasonal malaria transmission. Follow-up was completed through pregnancy. Children were enrolled at birth and followed up from January 21, 2011, to July 31, 2016, for as long as 5 years with monthly clinical visits during the malaria transmission season and every 2 months during the dry season. Data were analyzed from November 4, 2024, to July 15, 2025. Exposure: PM and PTD. Main Outcomes and Measures: Study end points included Plasmodium falciparum infection, clinical malaria, and severe malaria infections. Malaria diagnosis and clinical data were collected during scheduled examinations and unscheduled sick visits. Cox proportional hazards models were used to analyze whether hazards of first malaria infection and first clinical malaria infection were associated with PM and PTD. Associations between the incidence rate of parasitemia and risk factors (eg, maternal infection history, PTD) were estimated using negative binomial models. Cox proportional hazards and negative binomial models with an interaction term among PTD, pregnancy malaria, and gravidity were used to evaluate associations within strata of the 3 covariates. Results: In 1679 children included in adjusted models (848 female [50.5%] and 831 male [49.5%]), 760 (45.3%) were born during the malaria transmission season and 96 (5.7%) were born preterm. Children were followed up for a mean (SD) of 25.8 (16.1) months. PM was associated with an increased hazard of first malaria infection and first clinical malaria infection in children of women of all gravidities, while PTD (vs full-term delivery) was associated with increased hazard of first malaria infection (hazard ratio, 1.76; 95% CI, 1.05-2.95; P = .03) in offspring of multigravid women only. Further, the hazard ratio of first parasitemia for preterm compared with full-term offspring was 2.17 (95% CI, 1.25-3.75; P = .006) and 3.63 (95% CI, 1.90-5.93; P < .001) in offspring of uninfected secundigravida and multigravida women, respectively. The parasitemia infection incidence rate ratio for PTD was 2.74 (95% CI, 1.80-4.18) in offspring of uninfected multigravida women. Conclusions and Relevance: In this cohort study of young children, the association between PTD and the hazard of malaria varied based on maternal gravidity and maternal infection history during pregnancy. This information could be used to evaluate the health effects of active monitoring of P falciparum infection or adherence to malaria chemoprevention in children born preterm.