Assessing the association between receipt of antimalarial drugs and adverse pregnancy outcomes using pooled data

Malaria is a major cause of maternal morbidity and mortality and neonatal death in areas of malaria transmission. Worldwide, it is responsible for up to 100,000 neonatal deaths and 10,000 maternal deaths annually. There is a need for better information on the safety of antimalarial drugs for women and their fetuses. Artemisinin-based combination therapies (ACT) are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when administered in early pregnancy. The limited observational studies in humans reported to-date have been reassuring. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinin monotherapy or artemisinin-based combination therapy during the 2nd or 3rd trimester relative to pregnant women who received non-artemisinin antimalarials or no antimalarial treatments in pregnancy. Pooled odds ratios (POR) were calculated using Mantel-Haenszel fixed effects models with a 0.5 continuity correction for zero events. To assess the risk of congenital malformations after receipt of an ACT during pregnancy, we pooled data from five recently completed randomized-controlled trials (RCT) and one multi-site, observational cohort study from the Malaria in Pregnancy Consortium (MIPc). We calculated prevalence risk ratios (PRR) comparing ACT exposed infants to ACT unexposed infants. From the meta-analysis, the pooled odds ratios (POR) (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. From the pooled analysis, there was no increased risk of congenital anomalies associated with receipt of an ACT during pregnancy compared to no such use (PRR 0.91, 95%CI 0.52-1.58). The PRR for congenital anomalies among the infants of women who received an ACT in the 1st, 2nd, and 3rd trimester compared to infants with no exposure to an ACT were 1.54 (95% CI 0.55-4.34), 0.79 (95%CI 0.47-1.34) and 1.08 (95%CI 0.57-2.07), respectively. Evidence from these studies supports the current WHO guidelines that call for the use of ACTs in 2nd and 3rd trimester to treat malaria. The findings from the analysis of the first trimester exposures and the risk of congenital anomalies are inconclusive due to the small number of malformations observed. Additional pharmacovigilance is recommended to obtain more reassurance of safety.