First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies

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 ...

Animal Embryotoxicity Studies of Key Non‐Artemisinin Antimalarials and Use in Women in the First Trimester

“…In a meta-analysis of five studies including data from Moore et al, 2016, the risk of miscarriage was higher with first trimester quinine (incidence 5 96/945 5 10.2%) compared with all artemisinins and ACTs combined (incidence 5 37/671 5 5.5%), but the hazard ratio for the two treatments (ratio of instantaneous risk calculated using the Cox proportional hazards model) was not statistically significant (Dellicour et al, 2017). The incidences of stillbirth for the two treatments were similar (11/615 5 1.8% for quinine versus 10/654 5 1.5% for artemisinins).…”

“…A meta-analysis of data from six articles was conducted recently to evaluate the effects of artesunate or ACTs administered during the first trimester (Dellicour et al, 2017). There were no detectable differences between the group treated with artemisinin or ACT (n 5 717 for evaluation of the miscarriage rate and n 5 551 for major congenital anomalies) compared with the group treated with quinine (n 5 947 and 741, respectively).…”

“…In recent years, there has been an increasing number of reports on the use of artesunate and ACTs in the first trimester which have not revealed an effect on pregnancy (e.g., Adam et al, 2009;Manyando et al, 2010Manyando et al, , 2015Rulisa et al, 2012;Mosha et al, 2014;Dellicour et al, 2015, Dellicour et al, 2017Tinto et al, 2015;Moore et al, 2016) leading the World Health Organization (WHO) to consider recommending ACTs for use in the first trimester. To aid in the evaluation of the safety of ACTs in the first trimester, this article will review the results of the pregnant animal studies of the nonartemisinin partner drugs in the ACTs mentioned above and then compare these animal results to what is known about the use of these drugs in women in the first trimester.…”

Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States

“…No randomized trials evaluating AL use during the first trimester of pregnancy were found (Table 3). However, a meta-analysis of observational and other studies from six sub-Saharan African countries and the Thai-Burmese border included data from a total of 717 women taking ACTs during the first trimester of pregnancy ( 22 ). Comparisons of pregnancy outcomes between women taking ACTs and those receiving a quinine-based regimen anytime during the first trimester and treatment with ACTs versus quinine-based regimen during 6–12 weeks’ gestational age demonstrated no differences in miscarriage, stillbirth, or pregnancy loss (miscarriage and still birth combined) for women treated with ACTs versus quinine-based regimens during either period.…”

“…Comparisons of pregnancy outcomes between women taking ACTs and those receiving a quinine-based regimen anytime during the first trimester and treatment with ACTs versus quinine-based regimen during 6–12 weeks’ gestational age demonstrated no differences in miscarriage, stillbirth, or pregnancy loss (miscarriage and still birth combined) for women treated with ACTs versus quinine-based regimens during either period. Although limited by sample size, the pooled prevalences of congenital anomalies in infants born to mothers taking ACTs versus quinine-based regimens in the first trimester were similar (1.5%, 95% CI = 0.6–3.5 versus 1.2%, 95% CI = 0.6–2.4, respectively) ( 22 ). …”