Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), an antifolate drug with antimalarial and antibiotic activity, reproducibly improves birthweight across sub-Saharan Africa and the Western Pacific. This clinical protection is independent of SP’s original malaria indication: it is not diminished by widespread antimalarial resistance or reduced transmission, and SP outperforms more potent non-antibiotic antimalarials (e.g., dihydroartemisinin-piperaquine, DP) for fetal growth. The biological mechanism is unexplained. We previously showed that gestational weight gain (GWG) is a significant component of this mechanism and mediates two-thirds of SP’s overall birthweight benefit (NCT03009526). In the first longitudinal characterization of antifolate antibiotic effects on the pregnant gut microbiome, we show that ∼45% of SP’s GWG advantage over DP is explained by gut microbial changes consistent with its pharmacology. Microbiome-mediated GWG coincided with 126g higher birthweight in SP but not DP recipients (95%CI 22.6-229.3g; p=0.019). Relative to DP, SP suppressed gastrointestinal pathobionts and enriched anaerobic commensals with recognized roles in mucosal immunity and host metabolism, a microbiome-sparing pattern distinct from conventional antibiotic-associated dysbiosis.

The authors have declared no competing interest.

NCT03009526

https://clinicaltrials.gov/study/NCT03009526

Funding: The research leading to these results (data collection, analysis and interpretation) has received support from the National Institute of Allergy and Infectious Diseases (5R21AI125800-02). The parent comparing IPTp-SP to IPTp-DP, with activities relevant to the current study (patient recruitment and clinical data collection) was funded by the US President's Malaria Initiative through CDC Cooperative agreement U01GH001206 to the Malaria Alert Centre. During the manuscript preparation stage, AW was supported by the National Center for Advancing Translational Sciences through Grant K12TR004416 and JJJ received support through the National Institute of Allergy and Infectious Diseases (K24AI134990).

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This study was reviewed and approved by the Institutional Review Boards at the University of North Carolina at Chapel Hill (#16-1260), the Centers for Disease Control and Prevention (#6836), and the College of Medicine Research and Ethics Committee (COMREC), University of Malawi (#P.02/16/1872). All participants provided written informed consent. The trial is registered at ClinicalTrials.gov (NCT03009526)

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Raw 16S rRNA gene amplicon sequencing reads have been deposited in the NCBI Sequence Read Archive under BioProject accession PRJNA1416942 and are currently under embargo pending publication. A de-identified minimal dataset sufficient to reproduce the reported downstream analyses is available to editors and reviewers during peer review via a private link and will be deposited publicly upon publication in the Carolina Digital Repository. This dataset includes the processed sequence variant count table, relative abundance tables, and the de-identified sample metadata used in the manuscript analyses. Source data underlying the main figures are available to editors and reviewers during peer review and will be provided in full with the Article upon publication. Additional individual-level metadata are not publicly available because of participant privacy and consent restrictions but may be made available through an appropriate controlled-access mechanism where permitted.