Risks of miscarriage and inadvertent exposure to artemisinin derivatives in the first trimester of pregnancy: a prospective cohort study in western Kenya

Stephanie Dellicour, Meghna Desai, George Aol, Martina Oneko, Peter Ouma, Godfrey Bigogo, Deron C Burton, Robert F Breiman, Mary J Hamel, Laurence Slutsker, Daniel Feikin, Simon Kariuki, Frank Odhiambo, Jayesh Pandit, Kayla F Laserson, Greg Calip, Andy Stergachis, Feiko O ter Kuile, Stephanie Dellicour, Meghna Desai, George Aol, Martina Oneko, Peter Ouma, Godfrey Bigogo, Deron C Burton, Robert F Breiman, Mary J Hamel, Laurence Slutsker, Daniel Feikin, Simon Kariuki, Frank Odhiambo, Jayesh Pandit, Kayla F Laserson, Greg Calip, Andy Stergachis, Feiko O ter Kuile

Abstract

Background: The artemisinin anti-malarials are widely deployed as artemisinin-based combination therapy (ACT). However, they are not recommended for uncomplicated malaria during the first trimester because safety data from humans are scarce.

Methods: This was a prospective cohort study of women of child-bearing age carried out in 2011-2013, evaluating the relationship between inadvertent ACT exposure during first trimester and miscarriage. Community-based surveillance was used to identify 1134 early pregnancies. Cox proportional hazard models with left truncation were used.

Results: The risk of miscarriage among pregnancies exposed to ACT (confirmed + unconfirmed) in the first trimester, or during the embryo-sensitive period (≥6 to <13 weeks gestation) was higher than among pregnancies unexposed to anti-malarials in the first trimester: hazard ratio (HR) = 1.70, 95 % CI (1.08-2.68) and HR = 1.61 (0.96-2.70). For confirmed ACT-exposures (primary analysis) the corresponding values were: HR = 1.24 (0.56-2.74) and HR = 0.73 (0.19-2.82) relative to unexposed women, and HR = 0.99 (0.12-8.33) and HR = 0.32 (0.03-3.61) relative to quinine exposure, but the numbers of quinine exposures were very small.

Conclusion: ACT exposure in early pregnancy was more common than quinine exposure. Confirmed inadvertent artemisinin exposure during the potential embryo-sensitive period was not associated with increased risk of miscarriage. Confirmatory studies are needed to rule out a smaller than three-fold increase in risk.

Figures

Fig. 1
Fig. 1
Study participant flow diagram from screening to inclusion in data analysis
Fig. 2
Fig. 2
Miscarriage rate, unadjusted and adjusted hazard rates for the association between different anti-malarial exposure categories and miscarriage

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