Date Published: May 2, 2017
Publisher: Public Library of Science
Author(s): Stephanie Dellicour, Esperança Sevene, Rose McGready, Halidou Tinto, Dominic Mosha, Christine Manyando, Stephen Rulisa, Meghna Desai, Peter Ouma, Martina Oneko, Anifa Vala, Maria Rupérez, Eusébio Macete, Clara Menéndez, Seydou Nakanabo-Diallo, Adama Kazienga, Innocent Valéa, Gregory Calip, Orvalho Augusto, Blaise Genton, Eric M. Njunju, Kerryn A. Moore, Umberto d’Alessandro, Francois Nosten, Feiko ter Kuile, Andy Stergachis, Sanjeev Krishna
Abstract: BackgroundAnimal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment.Methods and findingsElectronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model.There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08–1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36–1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6–12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54–2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26–2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52–2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%–3.5%]) and quinine exposures (1.2% [95% CI 0.6%–2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns.ConclusionsCompared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens.Review registrationPROSPERO CRD42015032371
Partial Text: Artemisinin combination therapies (ACTs), the most efficacious antimalarials available, are the recommended first-line treatment for Plasmodium falciparum malaria except in the first trimester of pregnancy . Preclinical studies have demonstrated that artemisinin derivatives are embryotoxic and can induce fetal death and congenital anomalies at doses close to the therapeutic range in multiple animal species [2–10]. In rodents, artemisinins cause embryolethality as well as cardiovascular (ventricular septal and vessel defects) and skeletal defects (shortened or bent long bones and scapulae, misshapen ribs, cleft sternebrae, and incompletely ossified pelvic bones) . In monkeys, embryolethality was observed following prolonged treatment (12 to 20 d), but there were no malformations [2,4]. The artemisinin embryotoxic effect occurs through depletion of embryonic erythroblasts . It is unknown how findings from animal studies would translate in humans because the mechanism of teratogenicity and the drug sensitive period may differ significantly in humans [3,12]. The last review by the World Health Organization (WHO) dates from 2006, when evidence on 170 human first-trimester artemisinin treatments was reassuring but insufficient to inform policy change . Consequently, quinine remains the recommended treatment for uncomplicated P. falciparum malaria in the first trimester. Presently, artemisinins are recommended in the first trimester only if quinine cannot be used or in cases of severe malaria where the benefit outweighs the potential risk.
Twenty-seven studies were identified, of which seven were eligible and five were included in the analysis: four from sub-Saharan Africa and one from the SMRU in Thailand  (Figs 1 and S1). The four African studies included a study conducted in three sites under a single multicenter study protocol (ASAP study)  and three additional stand-alone studies [36–38].
To our knowledge, this meta-analysis provides the most comprehensive and up-to-date analysis of the potential effects of inadvertent or intentional treatment with artemisinin derivatives in the first trimester of pregnancy and includes results from 1,664 well-documented pregnancies followed prospectively after artemisinin (717) or quinine (947) treatment in the first trimester.