Impact of Severe Malaria in Pregnancy on Adverse Birth Outcomes, Neurodevelopment and Cognition

The in utero environment can have a profound impact on pre-and post-natal development. Low birth weight, due to preterm delivery, intrauterine growth restriction or a combination of the two, greatly increases the risk of neonatal morbidity and mortality. Despite the rising rates and public health impact of adverse birth outcomes, there are few early diagnostic tools or intervention strategies. We measured levels of inflammatory and angiogenic proteins in relation to preterm and small-for-gestational age outcomes in a cohort of Tanzanian women and observed distinct biomarker profiles with respect to birth outcome. The high rates of low birth weight outcomes in many low resource settings are due in part to malaria infection in pregnancy. Pregnant women are more likely to be infected with malaria and to experience severe clinical outcomes. To examine the impact of malaria on the placental environment we measured expression of endogenous drug transporters in maternal and fetal tissue. We observed altered levels of transporters in maternal and fetal tissues of malaria-infected dams, which impact drug metabolism, transport across the placenta and fetal exposure to xenobiotics. Despite the high rates of adverse birth outcomes associated with malaria in pregnancy there are few intervention strategies to improve fetal outcomes. Moreover, to date no research has examined the impact of exposure to maternal malaria infection on in utero neurodevelopment. We observed changes in learning and memory as well as anxiety-like behavior in malaria-exposed offspring that were rescued by genetic and pharmacological blockade of C5a-C5aR signaling. The behavioral phenotype was associated with altered levels of major biogenic amines in cortical and subcortical regions of the brain. This preclinical work suggests that therapeutic interventions targeting this pathway could improve adverse birth outcomes in children exposed to maternal malaria infection. However, antibodies for C5a are prohibitively expensive and therefore are not a viable option for low resource settings. Therefore we examined the use of L-Arginine, an essential amino acid in pregnancy, to target similar pathways through a more feasible strategy. We found that L-Arginine supplementation improved fetal weight and viability in malaria-exposed litters and altered inflammatory and angiogenic markers in the placenta.Ph.D.2017-06-16 00:00:0