Mounting evidence for use of artemisinin derivatives for malaria in early pregnancy
Authors: Modest Mulenga, Christine Manyando
Journal: The Lancet Infectious Diseases (2016)

Malaria in pregnancy can be a clinically devastating condition, and exacts substantial morbidity and mortality in vulnerable populations particularly in the developing world.1Desai M ter Kuile FO Nosten F McGready R Asamoa K Brabin B Newman RD Epidemiology and burden of malaria in pregnancy.Lancet Infect Dis. 2007; 7: 93-104Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar Its complications are conspicuous in pregnant women who are prone to severe anaemia, and their offspring face possibilities of still births, miscarriages, or low birthweight.2Van geertruyden JP Thomas F Erhart A D'Alessandro U The contribution of malaria in pregnancy to perinatal mortality.Am J Trop Med Hyg. 2004; 71: 35-40Crossref PubMed Google Scholar To prevent malaria in pregnancy and its complications, various measures to reduce human–malaria vector contact such as the use of insecticide-treated nets and insecticide residual spraying are applied extensively. Chemoprevention with sulfadoxine–pyrimethamine is used to mitigate adverse pregnancy outcomes, but is also largely compromised by resistance.3ter Kuile FO van Eijk AM Filler SJ Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: a systematic review.JAMA. 2007; 297: 2603-2616Crossref PubMed Scopus (238) Google Scholar Furthermore, these measures are not foolproof in that acquisition of malaria still occurs. Therefore, chemotherapy is imperative to eliminate the infection and prevent complications. Many endemic countries now recommend artemisinin-based combinations as first-line treatment of malaria in the general population.4WHOGuidelines for the treatment of malaria. second edition. World Health Organization, Geneva2014http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdfGoogle Scholar Therefore, their widespread use makes inadvertent exposure in early pregnancy inevitable.5Manyando C, Kayentao K, D'Alessandro U, Okafor HU, Juma E, Hamed K. A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated plasmodium malaria during pregnancy. Malar J 201; 11 141.Google Scholar Although substantial information has accumulated to support the safe use of certain artemisinin derivatives as the most appropriate drugs for treatment of malaria in the second and third trimesters of pregnancy, more evidence is needed to support their safe use in the first trimester. Concerns about embrotoxicity and possible teratogenicity have led to extreme caution about the use of artemisinin derivatives in early pregnancy.6Clark R Embryotoxicity of artemisinin antimalarials and potential consequences for use in women in the first trimester.Reprod Toxicol. 2009; 28: 285-296Crossref PubMed Scopus (94) Google Scholar The general recommendation is to use artemisinins only when the benefits outweigh the consequences of the infection. To that effect, clinical trials of artemisinin derivatives in early pregnancy have been slow in coming, because extreme caution is required to avoid untoward outcomes or missing out subtle damages that might be caused by the drugs.7Greenwood B Alonso P O ter Kuile F Hill F Steketee RW Malaria in pregnancy: priorities for research.Lancet Infect Dis. 2007; 7: 169-174Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar Systematic information about the safety of artemisinin derivatives in the early pregnancy comes from observational studies including pregnancy registries, particularly in situations where the drugs are taken inadvertently.5Manyando C, Kayentao K, D'Alessandro U, Okafor HU, Juma E, Hamed K. A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated plasmodium malaria during pregnancy. Malar J 201; 11 141.Google Scholar Such studies have many limitations including absence of rigor to estimate the period and duration of exposure and inability to account for confounding factors or to detect subtle and long-term adverse outcomes in the offspring.7Greenwood B Alonso P O ter Kuile F Hill F Steketee RW Malaria in pregnancy: priorities for research.Lancet Infect Dis. 2007; 7: 169-174Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar In The Lancet Infectious Disease, Kerryn A Moore and colleagues8Moore KA Simpson JA Paw MK et al.Safety of artemisinins in first trimester in prospectively followed pregnancies: an observational study.Lancet Infect Dis. 2016; (published online Feb 8.)http://dx.doi.org/10.1016/S1473-3099(15)00547-2Summary Full Text Full Text PDF Scopus (55) Google Scholar report a large study describing a prospective observation of 2558 women with first-trimester malaria and analyses of 183 with initial exposure to various artemisinin derivatives. The study gives more precise details than previous studies about exposure to quinine and the available artemisinin derivatives, their doses, and the duration of exposure. The study affirms the association between infection with either vivax or falciparum malaria and miscarriages, and underscores the importance of treatment with efficacious drugs such as artemisinins in the first trimester to avoid adverse outcomes.9McGready R Lee SJ Wiladphaingern J et al.Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study.Lancet Infect Dis. 2012; 12: 388-396Summary Full Text Full Text PDF PubMed Scopus (160) Google Scholar The investigators uniquely estimate the gestation period of exposure (including the embryo-sensitive period) to the artemisinin derivatives, and by use of so-called left truncation they have accounted for confounding from other causes of miscarriages.10Howards PP Hertz-Picciotto I Poole C Conditions for bias from differential left trunation.Am J Epidemiol. 2006; 165: 444-452Crossref PubMed Scopus (73) Google Scholar This study, in our view, presents a unique and innovative approach to the generation of rigorous evidence for safety of artemisinin derivatives when used in early pregnancy. Although recent studies have shown encouraging results from some artemisinin derivatives, more data are still needed to ascertain the safety of many other artemisinin derivatives in pregnancy. For example, there is mounting evidence about the use of artemether–lumefantrine, but more safety information is needed on such drugs as dihydroartemisinin–piperaquine, which is highly efficacious, has a simple treatment regimen, and has a relatively long protective period following intake—an attribute that should be of important, especially in areas of high transmission.11The Four Artemisinin-Based Combinations (4ABC) Study GroupA head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial.PLoS Med. 2011; 8: e1001119Crossref PubMed Scopus (121) Google Scholar Similar to other drugs under observation, artemisinin-based combinations need to be subjected to intense pharmacovigilance to ensure that subtle anomalies or genetically related effects, some of which might manifest in the long term, are identified and documented.7Greenwood B Alonso P O ter Kuile F Hill F Steketee RW Malaria in pregnancy: priorities for research.Lancet Infect Dis. 2007; 7: 169-174Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar Genetic differences in the metabolism of various components of the derivatives are still a concern, so studies in diverse populations are needed to generate information across different ethnic groups. With this strong evidence from this study, large randomised trials are justified to be undertaken at this stage to investigate other effects that might not have been shown in study designs reported previously. The study further shows that artemisinins are as safe as quinine, and can be used safely in the first trimester. It has made a strong case to support the acceleration of the processes for recommending the use of artemisinin derivatives for treating malaria during the whole period of pregnancy. We declare no competing interests. Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational studyFirst-trimester falciparum and vivax malaria both increase the risk of miscarriage. We noted no evidence of an increased risk of miscarriage or of major congenital malformations associated with first-line treatment with an artemisinin derivative compared with quinine. In view of the low efficacy of quinine and wide availability of highly effective artemisinin-based combination therapies, it is time to reconsider first-trimester antimalarial treatment recommendations. Full-Text PDF Open Access