Infant Sex Modifies Associations Between Placental Malaria and Risk of Malaria in Infancy

Abstract

Background Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM.MethodsData from a birth cohort of 656 infants born to HIV-uninfected mothers randomized to IPTp with dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP) was analyzed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (>0-20% high powered fields [HPFs] with pigment), or severe past PM (>20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. ResultsThere were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p=0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p=0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p<0.001), but not female infants (aIRR 0.74, 95% CI 0.46-1.20, p=0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM.ConclusionPM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk.Trial registrationTrial registration: ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622

Pregnancy and malaria: the perfect storm

“…Infant sex appears to modify this risk. In Uganda, malaria incidence in infancy was higher in male, but not female, infants of women with severe placental malaria [adjusted incidence rate ratio (IRR) 2.17, 95% CI 1.45, 3.25] [5].…”

“…These cells express the parasite protein VAR2CSA on their surface, which binds to chondroitin sulfate A (CSA) on placental cells. The consequences of placental malaria can include severe maternal anemia, miscarriage, stillbirth and perinatal mortality [2 ▪ ,3 ▪ ], premature delivery, small for gestational age (SGA) and low birth weight (LBW; birth weight <2500 g) [4], and altered risk of malaria in infancy [5]. Each year, ∼900 000 babies are born with LBW attributable to malaria in pregnancy, and ∼100 000 infants die.…”

Gender difference in the incidence of malaria diagnosed at public health facilities in Uganda

“…Although information on gender is routinely collected from patients presenting to public health facilities, stratification of malaria surveillance data by gender is rarely done. Studies have suggested differences may exist between females and males in the risk of infection and disease, but few studies have evaluated gender differences in the context of routine malaria surveillance data from public health facilities [3,4]. An appreciation of gender difference in malaria burden would be important for improving the understanding of factors that may influence susceptibility to malaria, case management practices, and targeting control interventions.…”

“…Most data available on associations between gender and malaria come from cohort and cross-sectional studies [3,4,13,14], which may not be representative of patients who seek care at public health facilities and contribute to routine malaria surveillance data through HMIS. In Uganda, an enhanced health facility-based malaria surveillance system has been established at sentinel public health centres to provide high quality data around the country.…”