Mediation of the effect of malaria in pregnancy on stillbirth and neonatal death in an area of low transmission: observational data analysis

Abstract

Background: 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.

Methods: We 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.

Results: Of 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).

Conclusions: Prevention 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.

Keywords: Malaria in pregnancy; Mediation analysis; Neonatal death; Stillbirth.

Fig. 1

Directed acyclic graph for the mediated association between malaria in pregnancy and birth outcome. Malaria was either falciparum or vivax, and birth outcome was antepartum stillbirth or neonatal death, depending on the association being assessed for mediation. Preterm birth was only included in models where neonatal death was the outcome. Maternal anaemia was only included in models where stillbirth was the outcome because <1% of women in the neonatal death sub-set were anaemic

Fig. 2

Analysis profile. ‘Visitors’, who are not residents of the migrant communities or refugee camps where SMRU clinics are located, were excluded because they do not regularly attend SMRU clinics throughout their pregnancy

Fig. 3

The association between falciparum and vivax malaria in pregnancy and antepartum or intrapartum stillbirth. The reference group refers to women without falciparum malaria or vivax malaria in pregnancy. Models include women lost to follow-up (until gestation time last seen), but percentage calculations for stillbirth do not. Where the numbers of stillbirths in the asymptomatic and symptomatic malaria categories do not total the number of stillbirths in the malaria (all) category, missing values for the presence of symptoms should be assumed. First-, second-, and third-trimester malaria refers to both symptomatic and asymptomatic malaria; in women with multiple episodes during pregnancy the trimester categorisation is based on the last episode detected. Associations were similar when the analysis was restricted to women with only one episode of malaria in pregnancy (see Additional file 6). Models were adjusted for gravidity, clinic site, and yearly malaria incidence. See Additional file 7 for table versions of this figure, including univariable associations

Fig. 4

The association between falciparum and vivax malaria in pregnancy and fetal loss. The reference group refers to women without falciparum malaria or vivax malaria in pregnancy. Models include women lost to follow-up (until gestation time last seen), but percentage calculations for fetal loss do not. Where the numbers of fetal losses in the asymptomatic and symptomatic malaria categories do not total the number of stillbirths in the malaria (all) category, missing values for the presence of symptoms should be assumed. First-, second-, and third-trimester malaria refers to both symptomatic and asymptomatic malaria; in women with multiple episodes during pregnancy the trimester categorisation is based on the last episode detected. Models were adjusted for gravidity, clinic site, and yearly malaria incidence. See Additional file 8 for a table version of this figure, including univariable associations