First trimester use of artemisinin-based combination therapy and the risk of low birth weight and small for gestational age

Orvalho Augusto, Andy Stergachis, Stephanie Dellicour, Halidou Tinto, Anifa Valá, Maria Ruperez, Eusébio Macete, Seydou Nakanabo-Diallo, Adama Kazienga, Innocent Valéa, Umberto d'Alessandro, Feiko O Ter Kuile, Gregory S Calip, Peter Ouma, Meghna Desai, Esperança Sevene, Orvalho Augusto, Andy Stergachis, Stephanie Dellicour, Halidou Tinto, Anifa Valá, Maria Ruperez, Eusébio Macete, Seydou Nakanabo-Diallo, Adama Kazienga, Innocent Valéa, Umberto d'Alessandro, Feiko O Ter Kuile, Gregory S Calip, Peter Ouma, Meghna Desai, Esperança Sevene

Abstract

Background: While there is increasing evidence on the safety of artemisinin-based combination therapy (ACT) for the case management of malaria in early pregnancy, little is known about the association between exposure to ACT during the first trimester and the effect on fetal growth.

Methods: Data were analysed from prospective studies of pregnant women enrolled in Mozambique, Burkina Faso and Kenya designed to determine the association between anti-malarial drug exposure in the first trimester and pregnancy outcomes, including low birth weight (LBW) and small for gestational age (SGA). Exposure to anti-malarial drugs was ascertained retrospectively by record linkage using a combination of data collected from antenatal and adult outpatient clinic registries, prescription records and self-reported medication usage by the women. Site-level data synthesis (fixed effects and random effects) was conducted as well as individual-level analysis (fixed effects by site).

Results: Overall, 1915 newborns were included with 92 and 26 exposed to ACT (artemether-lumefantrine) and quinine, respectively. In Burkina Faso, Mozambique and Kenya at recruitment, the mean age (standard deviation) was 27.1 (6.6), 24.2 (6.2) and 25.7 (6.5) years, and the mean gestational age was 24.0 (6.2), 21.2 (5.7) and 17.9 (10.2) weeks, respectively. The LBW prevalence among newborns born to women exposed to ACT and quinine (QNN) during the first trimester was 10/92 (10.9%) and 7/26 (26.9%), respectively, compared to 9.5% (171/1797) among women unexposed to any anti-malarials during pregnancy. Compared to those unexposed to anti-malarials, ACT and QNN exposed women had the pooled LBW prevalence ratio (PR) of 1.13 (95% confidence interval (CI) 0.62-2.05, p-value 0.700) and 2.03 (95% CI 1.09-3.78, p-value 0.027), respectively. Compared to those unexposed to anti-malarials ACT and QNN-exposed women had the pooled SGA PR of 0.85 (95% CI 0.50-1.44, p-value 0.543) and 1.41 (95% CI 0.71-2.77, p-value 0.322), respectively. Whereas compared to ACT-exposed, the QNN-exposed had a PR of 2.14 (95% CI 0.78-5.89, p-value 0.142) for LBW and 8.60 (95% CI 1.29-57.6, p-value 0.027) for SGA. The level of between sites heterogeneity was moderate to high.

Conclusion: ACT exposure during the first trimester was not associated with an increased occurrence of LBW or SGA. However, the data suggest a higher prevalence of LBW and SGA for children born to QNN-exposed pregnancies. The findings support the use of ACT (artemether-lumefantrine) for the treatment of uncomplicated malaria during the first trimester of pregnancy.

Keywords: Artemisinins; Low birth weight; Pharmacovigilance; Prospective cohort; Small for gestational age; Sub-Saharan Africa.

Conflict of interest statement

The findings and conclusions presented in this manuscript are those of the authors and do not necessarily reflect the official position of the US Centers for Disease Control and Prevention. The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart of the recruited participants in ASAP cohort included in this analysis, 2015
Fig. 2
Fig. 2
Weight at birth mean difference in grams for different sites and random-effects pooled association, ASAP study
Fig. 3
Fig. 3
ASAP site specific and pooled low birth weight prevalence ratios
Fig. 4
Fig. 4
ASAP site specific and pooled small for gestation age prevalence ratios
Fig. 5
Fig. 5
ASAP site specific and pooled prematurity prevalence ratios

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