Abstract
BackgroundMalaria in pregnancy is preventable and contributes significantly to the estimated 5.5 million stillbirths and neonatal deaths that occur annually. The contribution of malaria in pregnancy in areas of low transmission has not been quantified, and the roles of maternal anaemia, small-for-gestational-age status, and preterm birth in mediating the effect of malaria in pregnancy on stillbirth and neonatal death are poorly elucidated.MethodsWe analysed observational data routinely collected at antenatal clinics on the Thai-Myanmar border (1986–2015). We used Cox regression and sequential mediation analysis to determine the effect of falciparum and vivax malaria in pregnancy on antepartum (death in utero) and intrapartum (death during labour) stillbirth and neonatal mortality as well as mediation through maternal anaemia, preterm birth, and small-for-gestational-age status.ResultsOf 61,836 women, 9350 (15%) had malaria in pregnancy, and 526 (0.8%) had stillbirths. In a sub-set of 9090 live born singletons followed from birth there were 153 (1.7%) neonatal deaths. The hazard of antepartum stillbirth increased 2.24-fold [95% confidence interval: 1.47, 3.41] following falciparum malaria (42% mediated through small-for-gestational-age status and anaemia), driven by symptomatic falciparum malaria (hazard ratio, HR: 2.99 [1.83, 4.89]) rather than asymptomatic falciparum malaria (HR: 1.35 [0.61, 2.96]). The hazard of antepartum stillbirth increased 2.21-fold [1.12, 4.33] following symptomatic vivax malaria (24% mediated through small-for-gestational-age status and anaemia) but not asymptomatic vivax malaria (HR: 0.54 [0.20, 1.45]). There was no association between falciparum or vivax malaria in pregnancy and intrapartum stillbirth (falciparum HR: 1.03 [0.58, 1.83]; vivax HR: 1.18 [0.66, 2.11]). Falciparum and vivax malaria in pregnancy increased the hazard of neonatal death 2.55-fold [1.54, 4.22] and 1.98-fold [1.10, 3.57], respectively (40% and 50%, respectively, mediated through small-for-gestational-age status and preterm birth).ConclusionsPrevention of malaria in pregnancy, new and existing interventions to prevent small-for-gestational-age status and maternal anaemia, and improved capacity for managing preterm and small-for-gestational-age newborns will reduce the number of malaria-associated stillbirths and neonatal deaths in malaria-endemic areas.
Highlights
Malaria in pregnancy is preventable and contributes significantly to the estimated 5.5 million stillbirths and neonatal deaths that occur annually
Most stillbirths occur in regions outside of Africa where malaria transmission is low [24], and the effect of malaria on stillbirth is likely to be greater in areas of low transmission where there is little or no maternal immunity [10, 14]. In this area of low transmission, but in the context of early detection and treatment, we found that falciparum malaria detected during pregnancy more than doubled the risk of antepartum stillbirth, and 4.5% of all stillbirths in our population were attributed to falciparum malaria
The proportion of the effect of malaria on neonatal death mediated through SGA and preterm was greater for vivax malaria than falciparum malaria, despite falciparum malaria more commonly being associated with these mediating variables; this may be a true effect, or it may be related to unmeasured confounding variables mentioned previously. The results of this analysis suggest that many malariaassociated stillbirths and neonatal deaths are the extreme consequences of more common adverse pregnancy outcomes caused by malaria in pregnancy
Summary
Malaria in pregnancy is preventable and contributes significantly to the estimated 5.5 million stillbirths and neonatal deaths that occur annually. The contribution of malaria in pregnancy in areas of low transmission has not been quantified, and the roles of maternal anaemia, small-for-gestational-age status, and preterm birth in mediating the effect of malaria in pregnancy on stillbirth and neonatal death are poorly elucidated. Malaria in pregnancy is associated with maternal anaemia and small-for-gestational-age (SGA) babies, which are risk factors for stillbirth and preterm birth. The contribution of mediating factors between malaria in pregnancy and stillbirth and neonatal death, including maternal anaemia, SGA status, and preterm birth have not been fully elucidated, preventing identification of potential pathways that can be targeted by existing or new interventions
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