Abstract
Given the high morbidity for mother and fetus associated with malaria in pregnancy, safe and efficacious drugs are needed for treatment. Artemisinin derivatives are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when used in early pregnancy. However, several organ systems are still under development later in pregnancy. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinins monotherapy or as artemisinin-based combination therapy during the 2nd or 3rd trimesters relative to pregnant women who received non-artemisinin antimalarials or none at all. Pooled odds ratio (POR) were calculated using Mantel-Haenszel fixed effects model with a 0.5 continuity correction for zero events. Eligible studies were identified through Medline, Embase, and the Malaria in Pregnancy Consortium Library. Twenty studies (11 cohort studies and 9 randomized controlled trials) contributed to the analysis, with 3,707 women receiving an artemisinin, 1,951 a non-artemisinin antimalarial, and 13,714 no antimalarial. The PORs (95% confidence interval (CI)) for stillbirth, fetal loss, and congenital anomalies when comparing artemisinin versus quinine were 0.49 (95% CI 0.24–0.97, I2 = 0%, 3 studies); 0.58 (95% CI 0.31–1.16, I2 = 0%, 6 studies); and 1.00 (95% CI 0.27–3.75, I2 = 0%, 3 studies), respectively. The PORs comparing artemisinin users to pregnant women who received no antimalarial were 1.13 (95% CI 0.77–1.66, I2 = 86.7%, 3 studies); 1.10 (95% CI 0.79–1.54, I2 = 0%, 4 studies); and 0.79 (95% CI 0.37–1.67, I2 = 0%, 3 studies) for miscarriage, stillbirth and congenital anomalies respectively. Treatment with artemisinin in 2nd and 3rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine. This study updates the reviews conducted by the WHO in 2002 and 2006 and supports the current WHO malaria treatment guidelines malaria in pregnancy.
Highlights
Given the high morbidity and mortality associated with malaria in pregnancy, safe and effective drugs are needed for treatment and prevention [1]
There was no indication that the risk of late miscarriage was higher in artemisinin recipients compared to women who received no antimalarials in the 2nd trimester or to SP for treatment, the latter comparison included only a single study
There were fewer studies that compared the risk of late miscarriage, but in 3 studies that compared the risk against women who received no antimalarials in the 2nd trimester, and in 1 study against women who received SP for treatment, there was no evidence for an increased risk
Summary
Given the high morbidity and mortality associated with malaria in pregnancy, safe and effective drugs are needed for treatment and prevention [1]. The World Health Organization (WHO) currently recommends the use of artemisininbased combination therapy (ACT) for the treatment of uncomplicated malaria in adults, children and in pregnant women in the 2nd or 3rd trimester [4]. Seven days of quinine with clindamycin is recommended for uncomplicated malaria in the first trimester of pregnancy [5]. Rabbits, and primates have reported the artemisinin class of antimalarial drugs to be embryotoxic and teratogenic [2]. These animal studies suggest that the etiologically relevant time period for exposure in humans is within the first trimester. Animal data do not always mirror the effects observed in humans
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