Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis
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Date
2022
Journal Title
Journal ISSN
Volume Title
Publisher
The Lancet
Abstract
Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisininbased
combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum
malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns
about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisininbased
treatment (ABT) versus non-ABTs in the first trimester of pregnancy.
Methods For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase,
and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021,
containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this
search were added to those of a previous systematic review that included publications published up until
November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded
pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if
the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy
outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD
meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO,
number CRD42015032371.
Findings We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including
34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester
exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies
compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio
[aHR] 0·71, 95% CI 0·49–1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74,
0·47–1·17), stillbirth (aHR=0·71, 0·32–1·57), and major congenital anomalies (aHR=0·60, 0·13–2·87). The risk of
adverse pregnancy outcomes was lower with artemether–lumefantrine than with oral quinine in the first trimester of
pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36–0·92).
Interpretation We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or
major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with
artemether–lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the
known superior tolerability and antimalarial effectiveness of ACTs, artemether–lumefantrine should be considered
the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether–lumefantrine is
unavailable, other ACTs (except artesunate–sulfadoxine–pyrimethamine) should be preferred to quinine. Continued
active pharmacovigilance is warranted.
Description
Keywords
Pregnancy outcomes, First-trimester treatment, Artemisinin derivatives, Antimalarials
Citation
Saito, M., McGready, R., Tinto, H., Rouamba, T., Mosha, D., Rulisa, S., ... & Dellicour, S. (2022). Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis. The Lancet. https://doi.org/10.1016/ S0140-6736(22)01881-5