Effect of sulfadoxine-pyrimethamine resistance on birthweight and parasite persistence among women receiving intermittent preventive treatment for malaria in pregnancy in Northern Uganda: a directed acyclic graph-guided analysis.

OBJECTIVES: In 2023, malaria infected 12 million pregnant women in Africa. Preventive treatment with sulfadoxine-pyrimethamine (SP-IPTp) is recommended, but its efficacy is threatened by parasite resistance, driven by mutations in the P. falciparum dhfr (N51I, C59R, S108N, I164L) and dhps (A437G, K540E, A581G) genes. We assessed the effect of resistant infections on birthweight and examined the effectiveness of SP-IPTp dose timing on parasite persistence. METHODS: Between July 2022 and October 2023, we conducted a facility-based prospective cohort study among pregnant women attending antenatal care (ANC) in three health facilities in Northern Uganda. Eligible participants were those with confirmed pregnancy, informed consent, and delivery planned at the study site. At each ANC visit, malaria screening by microscopy was performed, and blood samples from positive cases were analyzed for dhfr/dhps resistance markers through PCR and Sanger sequencing. Confirmed infections were treated with standard antimalarial therapy, distinct from SP-IPTp. Only parasitemic women were included in the analysis, and outcomes were birthweight and parasite persistence. Multivariable modelling was guided by directed acyclic graphs (DAGs), and inverse probability weighting (IPW) was applied to correct for sequencing-related selection bias. RESULTS: Of 462 parasitemic women, 278 (60.1%) infections were successfully genotyped, of which 82% were quintuple and 14% sextuple mutants. Adjusted analysis found no significant association between resistance haplotypes and birthweight (-77gr, p=0.330) nor parasite persistence (aOR 3.81, p=0.166). Infants of primigravidae weighted 238gr less (95%CI -38 to -96gr, p=0.001) than those of multigravidae, despite near-universal SP-IPTp coverage and standard case management. In contrast, each additional SP-IPTp dose administered after a detected infection was associated with higher odds of persistent parasitemia at follow-up ANC visits (aOR 1.90, 95% CI 1.28-2.82; p=0.002). CONCLUSIONS: Resistant haplotypes affected neither birthweight nor persistence. However, birthweight was significantly inferior among primigravidae despite SP-IPTp, and post-infection dosing was associated with increased risk of persistence.