The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis

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.

Conflict of interest statement

AS serves on the Medicines for Malaria Venture Access and Product Management Advisory Committee; he does not receive an honoraria for this service, only travel expenses for an annual meeting. RS is employed by PATH. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. PRISMA flow diagram for search results June 15, 2015.

Fig 2. Pooled odds ratio for miscarriage after 2nd trimester exposures to artemisinins stratified by comparison group.

*McGready 2001 reported multiple types of artemisinin exposures that were combined for this analysis (12). ART artemisinins, AL artemether-lumefantrine, AS-SP artesunate sulfadoxine pyrimethamine, SP sulfadoxine pyrimethamine, No exp. No exposure to antimalarials.

Fig 3. Pooled odds ratio for stillbirth after 2-3rd trimester exposures to artemisinins compared to other drugs.

*McGready 2001 reported multiple types of artemisinin exposures that were combined for this analysis and reported as ACT (12). ^McGready 1999 MQ or Q exposures include patients given MQ, Q, or both (33). ART: artesunate, AL: artemether-lumefantrine, AAP: artesunate atovaquone proguanil, AS-AQ: artesunate-amodiaquine, Q: quinine, Q+C: quinine+clindamycin, SP: sulfadoxine pyrimethamine, AQ: amodiaquine, SP+CQ: sulfadoxine pyrimethamine chloroquine, MQ: mefloquine, SP-AZM: sulfadoxine pyrimethamine azithromycin, CD: chlorproguanal-dapsone, IPT: intermittent preventative treatment, RCT: randomized controlled trial, ACT: artemisinin combination therapy, No exp. no exposure to antimalarials.

Fig 4. Pooled Odds ratio for fetal loss after 2-3rd trimester exposures to artemisinins stratified by comparison group.

*McGready 2001 reported multiple types of artemisinin exposures that were combined for this analysis and reported as ACTs (12). ^McGready 1999 MQ or Q exposures include patients given MQ, Q, or both (33). ART: artesunate, AS-MQ: artesunate mefloquine, AL: artemether-lumefantrine, DP: dihydroartemisinin-piperaquine, AAP: artesunate atovaquone proguanil, AS-SP: artesunate sulfadoxine pyrimethamine, AS-AQ: artesunate-amodiaquine, Q: quinine, Q+C: quinine+clindamycin, SP: sulfadoxine pyrimethamine, AQ: amodiaquine, SP+CQ: sulfadoxine pyrimethamine chloroquine, MQ: mefloquine, SP-AZM: sulfadoxine pyrimethamine azithromycin, CD: chlorproguanal-dapsone, IPT: intermittent preventative treatment, RCT: randomized controlled trial, ACT: artemisinin combination therapy, No exp. No exposure to antimalarials.

Fig 5. Pooled odds ratio for congenital anomalies after 2-3rd trimester exposures to artemisinins stratified by comparison group.

*McGready 2001 reported multiple types of artemisinin exposures that were combined for this analysis and reported as ACTs (12). ART: artesunate, AL: artemether-lumefantrine, AAP: artesunate- atovaquone proguanil, AS-AQ: artesunate-amodiaquine, Q: quinine, Q+C: quinine+clindamycin, SP: sulfadoxine pyrimethamine, AQ: amodiaquine, SP+AQ: sulfadoxine pyrimethamine amodiaquine, MQ: mefloquine, CD: chlorproguanal-dapsone, RCT: randomized controlled trial, ACT: artemisinin combination therapy, No exp. No exposure to antimalarials.