Dual-niche profiling identifies maternal gut microbiome differences associated with intermittent preventive treatment with sulfadoxine-pyrimethamine, with no detectable association in vaginal communities

Abstract Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) remains central to malaria control, yet its associations with the maternal microbiome are incompletely characterized. We conducted a cross-sectional study using 16 S rRNA gene sequencing to profile the gut and vaginal microbiota of term-pregnant Ghanaian women. IPTp-SP uptake was assessed using two contrasts: no versus any exposure and suboptimal (< 3 doses) versus optimal (≥ 3 doses) uptake. Vaginal communities were predominantly Lactobacillus -dominated, with no statistically significant differences in diversity or composition across uptake groups. In the gut, optimal uptake was associated with lower Shannon diversity and differences in unweighted UniFrac composition compared with suboptimal uptake. However, compositional associations were accompanied by unequal group dispersion, were attenuated when parity was represented as a three-level variable, and were not supported by a significant continuous dose-response relationship. Four Clostridia-class amplicon sequence variants differed between uptake groups in unadjusted analyses, but these associations were sensitive to parity adjustment and sensitivity analysis. In the stool subset, G6PD status and IPTp-SP uptake overlapped completely: all participants receiving fewer than three doses had partial or full G6PD deficiency, whereas all participants receiving three or more doses had normal G6PD status. This complete overlap limited the ability to distinguish associations with IPTp-SP uptake from those with G6PD status. These exploratory findings suggest niche-specific microbiome associations with IPTp-SP uptake and support longitudinal studies with larger samples and stronger control of confounding.