The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis.
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.
Department of Epidemiology, University of Washington, Seattle, WA, United States of America.
Stephanie D
http://orcid.org/0000-0002-2171-821X
SD
Kovacs
Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Anna Maria
AM
van Eijk
Manhiça Health Research Centre, Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique.
Esperanca
E
Sevene
Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Stephanie
S
Dellicour
Department of Epidemiology, University of Washington, Seattle, WA, United States of America.
Noel S
NS
Weiss
Department of Biostatistics, University of Washington, Seattle, WA, United States of America.
Scott
S
Emerson
PATH, Seattle, WA, United States of America.
Richard
R
Steketee
Liverpool School of Tropical Medicine, Liverpool, United Kingdom.|Kenya Medical Research Institute (KEMRI) Centre for Global Health, Kisumu, Kenya.
Feiko O
FO
Ter Kuile
Department of Global Health, University of Washington, Seattle, WA, United States of America.|Department of Pharmacy, University of Washington, Seattle, WA, United States of America.
Andy
A
Stergachis
D000022:Abortion, Spontaneous; D000962:Antimalarials / Q000009:adverse effects* / Q000627:therapeutic use*; D037621:Artemisinins / Q000009:adverse effects* / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000188:drug therapy*; D011256:Pregnancy Outcome; D011262:Pregnancy Trimester, Second; D011263:Pregnancy Trimester, Third; D011803:Quinine / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic
D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin; D011803:Quinine