Abstract
BackgroundAnnually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring.Methods and findingsBetween April 2014 and April 2015, we followed 421 Malawian mother–baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur–Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], −7.53 [−13.04, −2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], −8.57 [−13.09, −4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies.ConclusionsThis mother–baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children.
Highlights
Developmental delays are prevalent in low- and middle-income countries (LMICs), where an estimated 1 in 3 preschool-age children do not reach cognitive and socio-emotional milestones [1]
Malaria in pregnancy is associated with severe health consequences for mother and child, including maternal anemia, pregnancy loss, and low birth weight (LBW) due to preterm birth (PTB) and/or fetal growth restriction [6]
The pathophysiology of Plasmodium falciparum malaria infection in pregnancy is driven by the accumulation of parasitized erythrocytes binding to chondroitin sulfate A in the placental intervillous space, where they lead to the recruitment, retention, and activation of mononuclear cells [6]
Summary
Developmental delays are prevalent in low- and middle-income countries (LMICs), where an estimated 1 in 3 preschool-age children do not reach cognitive and socio-emotional milestones [1]. This proportion approaches 1 in 2 in sub-Saharan Africa (44%) [1], and these early developmental delays are proven predictors of worse long-term educational attainment, economic productivity, and psychiatric disease in adulthood [1,2]. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring
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