The influence of the gestational age at malaria detection and treatment during pregnancy on adverse outcomes in an area of low endemicity

Abstract

Background Each year, 125 million women are at risk of malaria in pregnancy (MiP). MiP is associated with several adverse pregnancy outcomes. The safety of artemisinins – the most effective antimalarials available – for the treatment of first-trimester falciparum MiP is a pressing question. Additionally, the influence of the gestational age (GA) when malaria is detected and treated on the effects of MiP is poorly elucidated, particularly in low endemicity areas. I sought to provide a temporal characterisation of the effects of falciparum and vivax MiP on adverse outcomes in a low endemicity area, starting with an assessment of the safety of first-trimester artemisinin treatment. This work will contribute to accurate quantification of the burden of MiP, and the evidence-base for safe treatment, and targeted, context-appropriate interventions for MiP.

Methods I analysed observational data collected from antenatal clinics between 1986 and 2015. The clinics were located in refugee camps and migrant communities on the Thai-Myanmar border, where malaria endemicity is low, and were operated by the Shoklo Malaria Research Unit (SMRU). SMRU antenatal care included weekly-to-fortnightly malaria screening. Data on all MiP episodes and pregnancy outcomes were available for analysis. I assessed the association between firsttrimester malaria and miscarriage, and the safety of first-trimester artemisinin treatment. I then assessed associations between MiP and other adverse outcomes [stillbirth, small-for-gestationalage (SGA), and preterm birth] with regards to the GA at malaria detection and treatment. I did a systematic review and meta-analysis to quantify the MiP-stillbirth association, and the influence of endemicity. Finally, I assessed associations between the GA at screening initiation and adverse outcomes in women with and without MiP, and associations between the length of screening absence prior to malaria detection and adverse outcomes in women with MiP.

Results Between 6 January 1986 and 31 December 2015, 68919 pregnant women presented to SMRU antenatal clinics. Of these women, 61836 met my minimum inclusion criteria (women living in the migrant communities or refugee camps, with a singleton pregnancy and an estimated GA), and 9350 (15%) women had MiP. First-trimester falciparum and vivax malaria increased miscarriage risk. However, I found no evidence that first-line artemisinin treatment of firsttrimester falciparum malaria, compared to quinine treatment, further increased the risk of miscarriage or of major congenital malformations. Falciparum malaria detected and treated in third trimester was associated with stillbirth, and both vivax and falciparum malaria detected and treated in any trimester was associated with fetal loss (miscarriage or stillbirth). Mediation analyses suggested that the MiP-stillbirth associations were mediated through maternal anaemia and SGA. In a systematic review and meta-analysis, the falciparum MiP-stillbirth association was two-fold greater in low-to-intermediate endemicity settings compared to high endemicity settings. Falciparum malaria detected and treated from 12 weeks’ gestation, and vivax malaria detected and treated from 20 weeks’ gestation, were associated with SGA and/or preterm birth, regardless of symptoms. Delayed initiation of antenatal malaria screening, and longer absences from malaria screening prior to initial malaria detection, were associated with poorer pregnancy outcomes.

Conclusion In this area of low malaria endemicity, falciparum and vivax MiP were associated with adverse outcomes, regardless of if and when during pregnancy it is detected and treated. The deleterious effects of MiP were present despite early detection and prompt treatment within the context of an intensive antenatal malaria screening program. MiP interventions should be started as early as possible during pregnancy. Control and elimination efforts in the general population and preconception interventions for women of reproductive age are needed to eliminate MiP and its adverse consequences.