Abstract
BackgroundPlacental 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 randomised to IPTp with dihydroartemisinin–piperaquine (DP) or Sulfadoxine–pyrimethamine (SP) was analysed. 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 registration ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622
Highlights
Placental malaria (PM) has been associated with a higher risk of malaria during infancy
Each 1% increase in the proportion of high-power fields (HPF) with pigment deposition in fibrin was associated with a higher incidence of malaria in infants but the difference was not statistically significant
No significant difference in the incidence of malaria was observed in female infants
Summary
Placental malaria (PM) has been associated with a higher risk of malaria during infancy. Several observational studies have reported associations between PM and increased risks of malaria, non-malaria febrile illnesses, and anaemia in infancy, possibly due to immune tolerance induced by in utero exposure to malaria antigens [9,10,11,12,13]. Most of these studies defined PM as the detection of malaria parasites in placental blood by microscopy, which has limited sensitivity and does not account for past placental infections characterized by the presence of malaria pigment [14]. Whether the severity of malaria pigment deposition in the placenta is associated with the risk of malaria in infancy is unknown
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