RECURRENCE RATE OF MALARIA AND ASSOCIATED RISK FACTORS IN INFANTS BORN TO WOMEN WHO RECEIVED IPTp-DP OR IPTp-SP: UTILITY OF CONDITIONAL FRAILTY, PWP-GAP TIME AND FRAILTY MODELS.

Abstract

Background: Malaria remains a leading cause of morbidity and mortality in children under five in Sub-Saharan Africa, with infants in high transmission regions experiencing high rates of recurrent malaria. Despite implementation of preventive strategies like Intermittent Preventive Treatment in Pregnancy, the burden of recurrent malaria episodes in infancy persists. Recurrent malaria not only increases the risk of severe anemia and developmental delays but also presents unique challenges for statistical modeling, as episodes are often correlated and influenced by individual-level heterogeneity. Studies have explored different dynamics of malaria in infants and how to address them but gaps still remain in contextualizing specific risk factors and how they influence malaria recurrence in this age group while making use of the most appropriate modeling techniques which account for event dependence and heterogeneity. Objective: This study aimed to investigate the recurrence rate of malaria and associated risk factors in infants born to mothers who received either IPTp-DP or IPTp-SP, and to evaluate utility of the conditional frailty, PWP-gap time, and shared frailty models in analyzing this kind of recurrent malaria data.Methods: Secondary data was used, obtained from the PROMOTE study, a prospective cohort double-blinded randomized controlled phase III trial which followed 640 infants born to women randomized to receive IPTp-DP or IPTp-SP in Busia district, Uganda. Analysis compared performance of the conditional frailty, PWP-gap time, and shared frailty models in accounting for event dependence and heterogeneity. Covariates included maternal education, age, gravidity, distance to health facility, and other socio-demographic factors. Model performance was assessed using AIC and BIC.Results: Infants whose mothers received IPTp-DP had a 6% lower hazard of recurrent malaria episodes compared to those whose mothers received IPTp-SP (HR=0.94, 95% CI: 0.82-1.07), but this difference was not statistically significant. Maternal education was protective as infants born to mothers with primary, secondary, and higher education had 21%, 42%, and 48% lower risks of malaria recurrence, respectively, compared to those whose mothers had no education. Advanced maternal age was also protective (HR=0.72, 95% CI: 0.53–0.97), while infants of multigravida mothers (≥3 pregnancies) had a 36% increased risk (HR=1.36, 95% CI: 1.02–1.80). Living 3–5 km from a health facility was associated with a 40% higher hazard of malaria recurrence (HR=1.40, 95% CI: 1.11–1.77). The conditional frailty model best fit the data with the lowest AIC=9486.1 and it accurately captured event dependence with minimal unmeasured heterogeneity.Conclusions: IPTp-DP did not significantly reduce malaria recurrence in infants compared to IPTp-SP. Socio-demographic factors like maternal education, age, and healthcare accessibility had stronger associations with malaria recurrence risk. The conditional frailty model proved most appropriate for analyzing recurrent malaria data, effectively accounting for event dependence and yielding robust estimates. These findings demonstrate the need for integrated strategies beyond malaria chemoprevention, emphasizing maternal empowerment and health system strengthening.