The positive effect of malaria IPTp-SP on birthweight is mediated by gestational weight gain but modifiable by maternal carriage of enteric pathogens

BACKGROUND: Poor pregnancy and birth outcomes are common in sub-Saharan Africa and have complex aetiologies. Sulfadoxine-pyrimethamine (SP), given for intermittent preventive therapy of malaria in pregnancy (IPTp), is one of few existing interventions that improves outcomes of both mother and baby despite widespread SP-resistant malaria. Compelling evidence exists that malaria-independent pathways contribute to this protective effect, but the exact sources of non anti-malarial protection remained unknown. We hypothesized that the beneficial effect of SP on birthweight is mediated by SP activity on maternal factors, including increased gestational weight gain and antibiotic activity on pathogens in the maternal gut. METHODS: Expectant mothers from a larger randomized control trial comparing the efficacy of IPTp-SP to IPTp with dihydroartemisinin-piperaquine (DP) were also enrolled in this sub-study study at their first antenatal care visit before commencement of IPTp (n = 105). Participants were followed monthly until delivery. Weights and mid-to-upper-arm circumferences (MUAC) were recorded. Monthly stool samples were collected and screened for five Escherichia coli pathotypes, Shigella spp., Vibrio cholerae, Salmonella, Campylobacter coli/jejuni, and three protozoa (Giardia spp., Entameba histolytica, and Cryptosporidium spp.) using previously validated molecular assays. FINDINGS: IPTp-SP vs. IPTP-DP was associated with higher maternal gestational weight gain (GWG) and nutritional indicators (MUAC and body-mass index, BMI). GWG was found to be a mediator of the birthweight and IPTp-SP relationship, as the birthweight of SP infants, but not DP infants, varied according to maternal GWG. The burden of maternal enteric infections was high. The three most commonly observed pathogens were enteroaggregative E. coli (EAEC), atypical enteropathogenic E.coli/enterohaemorrhagic E. coli (aEPEC/EHEC), and typical enteropathogenic E.coli (tEPEC). We found that SP reduced the prevalence of EAEC in a dose-dependent manner. After 3 or more doses, SP-recipients were 90% less likely to be infected with EAEC compared to DP-recipients (OR(adj) = 0.07, CI95 = 0.12, 0.39, p = 0.002). Compared to DP, this coincided with higher maternal gestational weight gain (GWG) and nutritional indicators (MUAC and body-mass index, BMI). The beneficial effect of SP on maternal GWG, MUAC and BMI, was lower if SP mothers had detectable EAEC, aEPEC/EHEC, tEPEC, and LT-ETEC at baseline. Maternal EAEC and tEPEC at baseline associated with lower birthweight for babies of both SP mothers and DP mothers. When comparing IPTp regimens, the positive effect of SP on birthweight compared to DP was only observed for infants of women who did not test positive for EAEC at baseline (adjusted mean birthweight difference SP vs. DP = 156.0 g, CI95 = -18.0 g, 336.9 g, p = 0.087), though confidence intervals crossed the null. INTERPRETATION: Our findings indicate that in pregnant Malawian women, IPTp-SP vs. IPTp-DP is consistently associated with higher MUAC, BMI, and GWG following the WHO-recommended regimen of at least 3 doses, but carriage of maternal gut pathogens before initiation of IPTp lessens this effect. Because GWG was a mediator of the association between birthweight and SP, we show that SP's previously proven positive effect on birthweight is by promoting maternal weight gain. Overall, our results present one plausible pathway SP exerts malaria-independent protection against poor birth outcomes in the context of its waning antimalarial activity and warrants further investigation. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.