| Summary: | <h4>Background</h4> <p>Artemisinins, the most effective antimalarials available, are not recommended for falciparum malaria during the first trimester due to safety concerns. Therefore, quinine is used despite poor efficacy. Assessing artemisinin safety requires weighing the risks of malaria and its treatment.</p> <h4>Methods</h4> <p>We assessed the effect of first-trimester malaria and artemisinin treatment on miscarriage and major congenital malformations. The effects of falciparum and vivax malaria were studied in antenatal clinics on the Thai-Myanmar border between January 1994 and December 2013. The relationship between artemisinin treatments (artesunate, dihydroartemisinin, or artemether) on miscarriage and malformation was assessed using Cox regression with left-truncation and time-varying exposures.</p> <h4>Findings</h4> <p>Of 25485 women, 2558 (10%) had first-trimester malaria, The hazard of miscarriage increased 1·61-fold after an initial first-trimester falciparum episode (95% CI: 1·32, 1·97), 3·24-fold following falciparum recurrence (95% CI: 2·24, 4·68), and 2·44-fold (95% CI: 1·01, 5·88) following recurrent symptomatic vivax. No difference was observed in miscarriage in first-line falciparum treatments with artemisinin (N=183) vs. quinine (N=842) (HR: 0·78; 95% CI: 0·45, 1·34), or risk of major congenital malformations (1·83% [2/109; 95% CI: 0·22, 6·47] and 1·25% [8/641; 95% CI: 0·54, 2·44], respectively).</p> <h4>Interpretation</h4> <p>First-trimester falciparum and vivax malaria increases the risk of miscarriage. This observational study of prospectively followed pregnancies found no evidence of an increased risk of miscarriage or major congenital malformations associated with first-line treatment with an artemisinin derivative compared to quinine. Given the low efficacy of quinine and wide availability of highly effective artemisinin combination treatments, it is time to reconsider first-trimester treatment recommendations.</p>
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