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

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

doi:10.1186/s12936-020-03210-y

Abstract

BackgroundWhile 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.MethodsData 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).ResultsOverall, 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.ConclusionACT 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.

Highlights

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
Excluded from the analysis were records that lacked confirmation of anti-malarial exposure (271), birth weights collected past 7th day of life (221), those lost to follow-up (100), either miscarriages or stillbirths (139), either twins gestation or second pregnancy followup (90) and other reasons (194) (Fig. 1)
No evidence was found of an increased risk of low birth weight (LBW), small for gestational age (SGA) or prematurity among pregnancies with a confirmed exposure to ACT for malaria treatment during the first trimester of pregnancy is not associated with an increased risk of LBW, SGA and prematurity compared to newborns unexposed to anti-malarials

Summary

Introduction

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. Malaria infection during pregnancy is associated with maternal anaemia and intra-uterine growth restriction (IUGR), leading to poor pregnancy outcomes such as low birth weight (LBW) and small for gestational age (SGA) [1, 2]. LBW is defined as a birth weight of live-born infant of less than 2500 g regardless of gestational age [3]. Malaria accounts for 14 to 25% of LBW in sub-Saharan Africa [4,5,6]. LBW is a result of a short gestational period, IUGR or a combination of both processes, and contributes globally to high neonatal and infant mortality and morbidity [1, 3]. In sub-Saharan Africa (SSA), LBW neonates are nine times more likely to die in the 1st month of life than a normal-weight baby [7, 8]. Infants who are growth-restricted experience higher rates of fetal and infant death, birth asphyxia, hypothermia, hypoglycaemia, meconium aspiration, and long-term neurological impairment [9]

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Conclusion