In this secondary analysis of data from a birth cohort of infants born to women randomised to receive monthly IPTp with SP vs DP, infants born to mothers with active PM and severe past PM had a non-significant higher incidence of malaria and complicated malaria during the first year of life compared to infants born to mothers without PM. However, the association between severe past PM and infant malaria was sex-specific. In male, but not female, infants, severe past PM was associated with a significantly higher incidence of malaria, a higher rate of first malaria episode, a higher incidence of complicated malaria, and a higher prevalence of parasitaemia during routine visits, compared to no PM. No sex-specific differences were observed between active PM and the incidence of malaria in infancy. Importantly, male infants born to mothers given IPTp-DP had significantly less malaria in infancy than males born to mothers given IPTp-SP, and 89.7% of this effect was mediated through prevention of PM.
Several prior studies have reported associations between active PM defined as detection of parasites in placental blood or tissue and an increased risk of malaria during infancy [9-11, 23-25]. Active PM detected by microscopy was associated with a higher risk of malaria infection in Ugandan infants , an increased rate of first parasitaemia in Beninese infants , and a higher risk of first episode of malaria in Gabonese infants . In Mozambique, active PM detected by histology was also associated with higher odds of malaria compared to no PM . The results from the current study, although not statistically significant, are consistent with these prior studies. The exact mechanisms through which PM might impact on the incidence of malaria in infancy are not well understood, but may be due to the effects of PM on the fetal immune system, including modulation of innate and adaptive cellular immune responses, as well as altered maternal-fetal transfer of antibodies to P. falciparum . Alternatively, these associations may represent confounding secondary to shared levels of exposure to malaria parasites between mothers and their infants. To limit the effect of confounding by malaria exposure in the current study, IPTp arm and markers of exposure, including housing structure and maternal parasitaemia at enrolment were adjusted for, but the possibility of residual confounding persists.
Importantly, in this study, there was an association between the severity of past PM, defined as the proportion of HPF with malaria pigment deposition, with malaria risk, but only in male infants. Severity of malaria pigment deposition in the placenta has been previously reported as a strong predictor of adverse birth outcomes . To our knowledge, this is the first report to suggest that severity of past PM is also associated with increased risk of malaria in infancy, and that infant sex may modify these associations.
Although the precise mechanism by which infant sex modifies the relationship between PM and infant malaria risk remains uncertain, there is a growing body of evidence of sex-based differences in susceptibility to infectious diseases in infants [27, 28]. While one study in southern Sudan suggested that pregnant women who bore female infants were more likely to have PM than those who bore male infants , several adverse pregnancy outcomes, including stillbirths, have been shown to be more common in males than in females . This suggests that in utero fetal exposures may have more severe consequences for male infants than female infants . Furthermore, male infants exposed to malaria in utero have been shown to have higher frequencies of regulatory T cells in cord blood compared to female infants with similar exposure , suggesting that in utero malaria exposure may differentially induce tolerance to malaria antigens in male, but not female, infants. Alternatively, other sex-based differences, including malaria-induced responses to toll-like receptor ligands [27, 32], expression of x-chromosome encoded genes , and/or glucocorticoid receptor expression  may be responsible for these findings. Future studies are needed to better understand how PM may result in different sex-specific outcomes in infants.
IPTp with highly effective drugs such as DP can reduce the severity of PM, and in this study, IPTp-DP was associated with a statistically significant lower incidence of malaria among male infants, and a non-significant lower incidence of malaria among all infants, compared with IPTp-SP. In the mediation analysis, 89.7% of the effect of IPTp-DP vs SP on the incidence of malaria among male infants was mediated through prevention of PM. Although this result was not statistically significant, possibly due to limited sample size to conduct this stratified mediation analysis, these results suggest that in addition to preventing adverse birth outcomes in all infants, effective interventions in pregnancy that reduce severe PM may also result in a lower risk of malaria in male infants.
In this study, there was no significant association between PM and the incidence of non-malaria febrile illnesses in infancy, contrary to other reports that suggest that in utero exposure may also influence immune responses to non-malarial infections [7, 35]. Furthermore, effective prevention of PM with IPTp-DP was not associated with a lower incidence of non-malarial febrile illnesses in infancy compared with IPTp-SP . These data suggest that PM may specifically impact infant malaria risk, although the possibility that it may impact other non-malaria infections cannot be excluded.
This study had some limitations. This secondary analysis was exploratory in nature and did not use categories of PM based on malaria pigment deposition in fibrin used by previous studies [15, 20]. However, prior studies assessed associations between the severity of placental pigment and adverse birth outcomes. This is the first study to assess associations between the severity of placental pigment deposition and infant malaria risk. It would be desirable to come up with a standardized classification system relating the severity of placental pigment deposition to infant malaria risk using data from multiple independent studies from different epidemiological settings. There were relatively small number of infants in the severe past and active PM categories, and these findings should, therefore, be interpreted with caution. The study was conducted in a very high malaria transmission setting and therefore its findings cannot be generalized to other malaria transmission settings. Finally, exclusion of infants with missing placental histology results (3.2%) and losses to follow-up may have reduced the power of the study and introduced bias if the infants excluded and those lost to follow-up were different from those who completed follow-up. However, there were no significant differences between infants excluded from the analysis, those lost to follow-up, and the infants who completed the study.