Neurocognitive outcomes in Malawian children exposed to malaria during pregnancy: An observational birth cohort study

Background Annually 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 findings Between 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. Conclusions This 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.
Andrea Weckman and co-workers study associations between children’s neurodevelopmental outcomes and malaria in pregnancy.
Author summary Why was this study done? Large human cohorts have linked maternal infection during pregnancy (without congenital infection) to an increased risk for neurocognitive deficits and neuropsychiatric disease in exposed children. Excessive maternal immune activation, irrespective of pathogen, is thought to mediate this effect. Millions of pregnant women are at risk for malaria infection each year. To our knowledge, the impact of malaria during pregnancy on child neurodevelopment has not been systematically studied in a clinical setting. What did the researchers do and find? We conducted an observational cohort follow-up study nested within a larger randomized controlled trial with detailed records of malaria in pregnancy to examine the impact of malaria in pregnancy on neurocognitive development in exposed children. To our knowledge, our data provide the first indication in a clinical cohort that malaria in pregnancy may be a previously unrecognized risk factor for neurodevelopmental delay. Furthermore, the association of systemic inflammation with reduced neurocognitive scores highlights a potential mechanistic pathway through which malaria in pregnancy could be affecting fetal neurodevelopment. What do these findings mean? There are millions of children in malaria-endemic regions who are not currently meeting their developmental potential. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental delay in children exposed in utero. Our findings suggest that scaling up efforts to prevent malaria infection could be an effective strategy to protect mother–baby dyads from poor developmental outcomes. Larger trials powered to address potential residual confounding, with a longer follow-up period and more diverse neurocognitive and neuropsychiatric tests, are required to confirm and extend these findings.