Poor Birth Outcomes in Malaria in Pregnancy: Recent Insights Into Mechanisms and Prevention Approaches

Abstract

Pregnant women in malaria-endemic regions are susceptible to malaria in pregnancy, which has adverse consequences on birth outcomes, including having small for gestational age and preterm babies. These babies are likely to have low birthweights, which predisposes to infant mortality and lifelong morbidities. During malaria in pregnancy, Plasmodium falciparum-infected erythrocytes express a unique variant surface antigen, VAR2CSA, that mediates sequestration in the placenta. This process may initiate a range of host responses that contribute to placental inflammation and dysregulated placental development, which affects placental vasculogenesis, angiogenesis and nutrient transport. Collectively, these result in the impairment of placental functions, affecting fetal development. In this review, we provide an overview of malaria in pregnancy and the different pathological pathways leading to malaria in pregnancy-associated low birthweight. We also discuss current prevention and management strategies for malaria in pregnancy, and some potential therapeutic interventions that may improve birth outcomes. Lastly, we outline some priorities for future research that could bring us one step closer to reducing this health burden.

Keywords: VAR2CSA; low birthweight; malaria; pregnancy; preterm birth; small for gestational age.

Figure 1

Pathways leading to malaria in pregnancy-associated low birthweight. Infected erythrocytes express unique variant surface antigens that mediate binding to placental receptors. Sequestration leads to recruitment and activation of different immune cells that can result in a cascade of downstream inflammatory events. These inflammatory events include secretion of cytokines and chemokines that have been associated with poor pregnancy outcomes. The increased pro-inflammatory environment has been associated with – (1) dysregulated expression of growth hormones, vascular factors and angiopoietin-1 and -2; (2) abnormal placental development; and (3) reduced placental nutrient transport, overall contributing to placental insufficiency. Together, these factors contribute to malaria in pregnancy associated low birthweight which is the biggest predictor of infant morbidity and mortality globally and annually., ↑, increase; ↓, decrease; E, Erythrocytes; IE, Infected erythrocytes; SCT, Syncytiotrophoblast; IVS, Intervillous space; sFlt1, soluble fms-like tyrosine kinase-1; PIGF, Phosphatidylinositol-glycan biosynthesis class F protein; VEGF, Vascular endothelial growth factor; IGF, Insulin-like growth factor.

Figure 2

Timeline of pregnancy events with WHO recommendations and possible interventions. Malaria in pregnancy (MiP) is preventable and the current WHO recommendations for Africa include three or more doses of intermittent preventive treatment during pregnancy (IPT) with sulfadoxine-pyrimethamine (SP) taken one month apart starting from fetus quickening. In addition, sleeping under insecticide treated nets (ITNs) has been shown to reduce parasite burden during pregnancy. Strong evidence indicates that MiP starts during the first trimester with irreversible damage and it is during this period of time that pregnant mothers are at the highest risk of parasitemia. Furthermore, recent evidence suggests that women often harbor parasites before conception, and these parasites may switch to a placental-binding phenotype, that is likely to contribute to placental inflammation, especially in women pregnant for the first time. We propose several potential interventions which may help to alleviate the harmful impact of MiP. (1) ITNs should be used from early pregnancy, or before conception, to reduce the risk of acquiring new infections. (2) Indoor residual spraying should be evaluated for its effectiveness against MiP. (3) Pre-pregnancy intermittent screening for malaria, with treatment by safe and effective drugs, should be considered. (4) Pregnant women need access to an effective vaccine that can induce protection against MiP. Currently, there are two vaccines that are in clinical trials. (5) The nutritional status of the mother should be optimized during pregnancy with appropriate micro- or macronutrient supplements to ensure optimal placental development and thus better birth outcomes.