Impact of malaria in pregnancy and intermittent preventive treatment of malaria in pregnancy on the risk of malaria in infants

Abstract

Background: Placental malaria (PM) has been associated with an increased risk of malaria during infancy in observational studies suggesting that effective intermittent preventive treatment of malaria in pregnancy (IPTp) may reduce the risk of malaria in infants. However, there are no randomised controlled trials that have shown that improved IPTp leads to less malaria during infancy. To address this knowledge gap, this thesis aimed to: 1) compare the incidence of malaria in infants during the first year of life among infants born to mothers with PM detected by histology and infants born to mothers without PM; 2) compare the incidence of malaria during the first year of life among infants born to mothers randomised to receive monthly IPTp with sulfadoxine-pyrimethamine (SP) versus those born to mothers randomised to receive monthly IPTp with dihydroartemisinin-piperaquine (DP); and 3) evaluate the effect of PM and IPTp on cord blood levels of IgG antibodies to Plasmodium falciparum malaria antigens in infants born to mothers enrolled in the trial. Methods: Infants born to HIV-uninfected pregnant mothers who participated in a double-blind, randomised trial of monthly IPTp with SP or DP in Busia, Uganda were followed from birth to 12 months of age. The primary outcome was the incidence of malaria measured by passive surveillance during the first year of life. PM was categorised as: 1) no PM (no parasites or pigment), 2) active PM (presence of parasites), 3) mild-moderate past PM (>0-20% high powered fields [HPFs] with pigment), and 4) severe past PM (>20% HPFs with pigment). Cord blood IgG antibody levels to P. falciparum antigens: apical membrane antigen-1 (AMA1), erythrocyte binding antigen-140 (EBA140), EBA175, EBA181, glutamate-rich protein (GLURP), merozoite surface protein-1 (MSP1), reticulocyte-binding protein homologue-2 (Rh2), Rh4, and Rh5 were measured using a multiplex antibody bead assay. Results: Between December 9, 2016 and December 7, 2017, 678 infants were born into the cohort, including 339 to mothers receiving IPTp-DP and 339 to mothers receiving IPTp-SP. A total of 581 infants (85.7%) were followed to 12 months of age. There were 1131 malaria episodes diagnosed in infants during 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. When the analysis was stratified by infant sex, the incidence of malaria was higher in male infants born to mothers with severe past PM than in those born to mothers with no PM (aIRR 2.17, 95% CI 1.45-3.25, p<0.001), but not in female infants (aIRR 0.74, 95% CI 0.46-1.20, p=0.22). The association between IPTp and malaria incidence in infants was modified by infant sex. Compared to IPTp-SP, IPTp-DP was associated with a lower incidence of malaria among male infants (IRR 0·75, 95% CI 0·58-0·98, p=0·03), but not female infants (IRR 0.99, 95% CI 0.79-1.24, p=0.93). There was no significant difference in the cord blood levels of IgG antibodies to Plasmodium falciparum among infants born to mothers with active PM, mild-moderate past PM, or severe past PM compared to infants born to mothers with no PM, and among infants born to mothers who received IPTp-DP compared to those born to mothers who received IPTp-SP. Conclusion: Severe past PM was associated with a higher incidence of malaria among male infants. IPTp-DP was associated with a lower incidence of malaria among male infants compared to IPTp-SP. PM and IPTp did not affect cord blood P. falciparum IgG antibody levels. These findings suggest that severe past PM may negatively impact antimalarial immunity in male infants and that highly effective IPTp may be protective among male infants.