Evidence for treating malaria with artemisinin-based combination therapy in the first trimester of pregnancy
Authors: Julie R Gutman, R Matthew Chico
Journal: The Lancet Infectious Diseases (2020)

Treatment of malaria during pregnancy requires balancing the need for radical cure while avoiding teratogenic exposure. In The Lancet Infectious Diseases, Makoto Saito and colleagues report the results of a systematic review and meta-analysis that used individual patient data on antimalarial efficacy and tolerability in pregnancy.1Saito M Mansoor R Kennnon K et al.Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis.Lancet Infect Dis. 2020; (published online April 29.)https://doi.org/10.1016/S1473-3099(20)30064-5Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar This impressive undertaking comprises nearly all published evidence and clearly highlights the superiority of artemisinin-based combination therapy (ACT) over quinine monotherapy, building on previous studies that focused on ACT safety in the second and third trimesters.2Kovacs SD van Eijk AM Sevene E et al.The safety of artemisinin derivatives for the treatment of malaria in the 2nd or 3rd trimester of pregnancy: a systematic review and meta-analysis.PLoS One. 2016; 11e0164963Crossref PubMed Scopus (20) Google Scholar Quinine has been the only treatment for malaria in much of the world over the past four centuries, with the first reported use for a microscopically confirmed diagnosis of malaria during pregnancy in 1908.3Maxwell JP The use of quinine during pregnancy, labour and the puerperium.J Trop Med Hyg. 1908; 11: 191-194Google Scholar WHO recommends quinine for the treatment of malaria in the first trimester, ideally in combination with clindamycin. First-trimester use of ACTs is only advised when quinine is not available.4WHOGuidelines for the treatment of malaria.3rd edn. World Health Organization, Geneva2015Google Scholar However, because clindamycin is rarely available at the point of care in malaria-endemic countries, the vast majority of pregnant women diagnosed with first-trimester malaria are given quinine monotherapy, or an ACT if pregnancy is not recognised.5Hill J D'Mello-Guyett L Hoyt J van Eijk AM ter Kuile FO Webster J Women's access and provider practices for the case management of malaria during pregnancy: a systematic review and meta-analysis.PLoS Med. 2014; 11e1001688Crossref PubMed Scopus (29) Google Scholar, 6Riley C Dellicour S Ouma P et al.Knowledge and adherence to the national guidelines for malaria case management in pregnancy among healthcare providers and drug outlet dispensers in rural, western Kenya.PLoS One. 2016; 11e0145616Crossref PubMed Scopus (18) Google Scholar Saito and colleagues found that quinine plus clindamycin had a similar PCR-corrected efficacy on day 28 compared to artemether-lumefantrine (AL; 99·9% vs 96·9%, respectively; adjusted hazard ratio 0·48 [95% CI 0·04–5·24]), whereas quinine monotherapy had an efficacy of only 87·7% (6·11, 2·57–14·57) compared to AL. The substantially lower efficacy of quinine monotherapy versus AL is further evidence to support the change to WHO's treatment guidelines recommended by the Malaria Policy Action Committee in 2016.7WHO malaria policy advisory committee and secretariatMalaria policy advisory committee to the WHO: conclusions and recommendations of eighth biannual meeting (September 2015).Malar J. 2016; 15: 117Crossref PubMed Scopus (48) Google Scholar Although only 33 of 4968 total episodes in the meta-analysis were in their first trimester, there is no evidence to suggest that the relative efficacy of antimalarials in the first trimester would differ from treatment later in pregnancy. Moreover, the higher efficacy of artemisinin over quinine is more apparent in severe disease for which parenteral artemisinin is already the preferred option.4WHOGuidelines for the treatment of malaria.3rd edn. World Health Organization, Geneva2015Google Scholar It is difficult to draw conclusions regarding safety given the very small number of first-trimester pregnancies in this study. However, the safety of ACT in pregnancy is supported by data for 30 618 pregnancies (947 exposed to quinine and 717 exposed to ACTs in the first trimester) that showed that the risk of miscarriage and stillbirth are similar between ACTs and quinine. Compared with quinine, the risk of ACTs on miscarriage were 0·73 (95% CI 0·44–1·21) and the risk of ACT on stillbirth were 0·29 (0·08–1·02).8Dellicour S Sevene E McGready R et al.First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: a meta-analysis of observational studies.PLoS Med. 2017; 14e1002290Crossref PubMed Scopus (42) Google Scholar Neither ACTs nor quinine were associated with an increased risk of stillbirth compared with no antimalarial treatment in the first trimester. Quinine administered in the first trimester was associated with increased risk of miscarriage compared with no antimalarial treatment, although ACTs were not. The risks of congenital malformations from quinine and ACTs were similar. These numbers are only sufficient to exclude a greater than approximately two-fold increase in the risk of miscarriage and stillbirth, underscoring the need for more data.8Dellicour S Sevene E McGready R et al.First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: a meta-analysis of observational studies.PLoS Med. 2017; 14e1002290Crossref PubMed Scopus (42) Google Scholar However, it has taken two decades to collect the evidence to date, and it is unlikely that more data will be available soon. There is also the issue of poor tolerability associated with quinine, whereby a very high proportion of patients reported symptoms of cinchonism, including tinnitus, by day 7 of therapy.9White NJ Looareesuwan S Warrell DA Warrell MJ Bunnag D Harinasuta T Quinine pharmacokinetics and toxicity in cerebral and uncomplicated Falciparum malaria.Am J Med. 1982; 73: 564-572Summary Full Text PDF PubMed Scopus (194) Google Scholar These adverse effects might be so bothersome that therapy is discontinued prematurely, further reducing its efficacy. Effective treatment clearly reduces the risk of stillbirth caused by malaria infection.10Moore KA Simpson JA Scoullar MJL McGready R Fowkes FJI Quantification of the association between malaria in pregnancy and stillbirth: a systematic review and meta-analysis.Lancet Glob Health. 2017; 5: e1101-e1112Summary Full Text Full Text PDF PubMed Scopus (58) Google Scholar Therefore, even if it was ensured that all first-trimester women with parasitaemia receive quinine plus clindamycin for 7 days, these patients might not be optimally served. Today, there are insufficient safety data for the use of ACTs in first trimester to argue for their use in first trimester for scenarios in which malaria testing is not done before dosing (eg, mass drug administration) or for scenarios in which the drug is provided prophylactically (eg, intermittent preventive treatment in pregnancy). However, considering the evidence base of efficacy, adherence, and tolerability, the risk-benefit analysis for treatment favours the use of ACTs for confirmed malaria in the first trimester of pregnancy.7WHO malaria policy advisory committee and secretariatMalaria policy advisory committee to the WHO: conclusions and recommendations of eighth biannual meeting (September 2015).Malar J. 2016; 15: 117Crossref PubMed Scopus (48) Google Scholar This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on May 5, 2020 This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on May 5, 2020 We declare no competing interests. Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysisEfficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation. Full-Text PDF Open AccessCorrection to Lancet Infectious Diseases 2020; published online April 29. https://doi.org/10.1016/ S1473-3099(20)30064-5Gutman JR, Chico RM. Evidence for treating malaria with artemisinin-based combination therapy in the first trimester of pregnancy. Lancet Infectious Diseases 2020; published online April 29. https://doi.org/10.1016/ S1473-3099(20)30064-5—In this Comment, one of the author's name has been corrected to read R Matthew Chico. This correction has been made to the online version as of May 5, 2020, and will be made to the printed version. 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