Malaria in pregnancy: a call for a safe, efficient, and patient-centred approach to first-trimester treatment
Authors: V Bhargavi Rao, Tomas O Jensen, B Carolina Jimenez, Jo Robays, Estrella Lasry, Esther Sterk, Martin de Smet
Journal: The Lancet Global Health (2018)

World Malaria Day 2018 is themed "Ready to beat malaria", but circulated key talking points ignore an important group: pregnant women. Unpublished reports from Médecins Sans Frontières (MSF) programmes, in contexts where up to 50% of women attending antenatal care routinely test positive for malaria, suggest that current WHO recommendations on malaria in pregnancy1WHOGuidelines for the treatment of malaria.3rd edn. World Health Organization, Geneva2015Google Scholar cause confusion and may risk poor outcomes in this highly vulnerable population. Malaria during pregnancy can lead to maternal anaemia, miscarriage, stillbirth, and low birthweight, and pregnant women are at a high risk of infection, with the highest burden in the first and second trimesters.2Desai M ter Kuile FO Nosten F et al.Epidemiology and burden of malaria in pregnancy.Lancet Infect Dis. 2007; 7: 93-104Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar, 3Rogerson SJ Desai M Mayor A Sicuri E Taylor SM van Eijk AM Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem.Lancet Infect Dis. 2018; 18: e107-e118Summary Full Text Full Text PDF PubMed Scopus (134) Google Scholar Quality treatment and prevention is essential to protect both mother and child. Current WHO guidance on treatment of uncomplicated Plasmodium falciparum malaria1WHOGuidelines for the treatment of malaria.3rd edn. World Health Organization, Geneva2015Google Scholar recommends artemisinin-based combination therapies (ACTs) in the second and third trimesters, but quinine in the first, owing to concerns over embryo toxicity with early exposure to artemisinins. Observational studies show that ACTs are safe in the first trimester (ethical concerns having precluded first-trimester randomised trials). In their meta-analysis of prospective observational studies of first trimester ACTs or quinine, Dellicour and colleagues4Dellicour 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; 14: e1002290Crossref PubMed Scopus (47) Google Scholar found no difference in the risk of miscarriage, stillbirth, or major congenital anomalies. In a secondary analysis, quinine in early pregnancy was associated with increased risk of miscarriage compared with pregnancies in which malaria treatment was not required, but there was no such significant association for women treated with ACTs. However, the authors suggest that the increased risk of miscarriage associated with quinine might be confounded by malaria itself being a miscarriage risk and thus reflect inadequately treated malaria due to the long treatment course, poor tolerability, and associated poor patient compliance.4Dellicour 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; 14: e1002290Crossref PubMed Scopus (47) Google Scholar In a meta-analysis by Burger and colleagues,5Burger RJ van Eijk AM Bussink M Hill J Ter Kuile FO Artemisinin-based combination therapy versus quinine or other combinations for treatment of uncomplicated Plasmodium falciparum malaria in the second and third trimester of pregnancy: a systematic review and meta-analysis.Open Forum Infect Dis. 2016; 3: ofv170Crossref PubMed Scopus (21) Google Scholar the use in pregnancy of ACTs administered once or twice daily for 3 days compared with a 7-day course of 8-hourly quinine was associated with lower prevalence of side-effects, including vomiting (pooled relative risk 0·33, 95% CI 0·15–0·73)—a side-effect that would be particularly distressing in first trimester. ACTs may be more effective than quinine in pregnancy. They are associated with a longer time to recurrence than quinine in pregnant women6Laochan N Zaloumis SG Imwong M et al.Intervals to Plasmodium falciparum recurrence after anti-malarial treatment in pregnancy: a longitudinal prospective cohort.Malaria J. 2015; 14: 221Crossref PubMed Scopus (11) Google Scholar and are known to exert a post-treatment protective effect,7The PREGACT Study GroupFour artemisinin-based treatments in African pregnant women with malaria.N Engl J Med. 2016; 374: 913-927Crossref PubMed Scopus (8) Google Scholar which may be important in a group where other preventative measures have poor uptake and coverage. For instance, fewer than 39% of women slept under a bednet in 2014,8Desai M Hill J Fernandes S et al.Prevention of malaria in pregnancy.Lancet Infect Dis. 2018; 18: e119-e132Summary Full Text Full Text PDF PubMed Scopus (76) Google Scholar and only 19% of eligible pregnant women received three or more doses of intermittent preventative therapy in 2016.9WHOWorld malaria report 2017. World Health Organization, Geneva2017Google Scholar In a recent unpublished survey of MSF projects with malaria in pregnancy activities (Chiara Morrison, MSF London, personal communication), a third of sites reported using ACTs in first trimester pregnancies, citing side-effects and confusion with protocols for other trimesters as the main reasons for not administering quinine. Worryingly, although intravenous artesunate is the first-line treatment for all pregnant women with severe malaria in all trimesters,1WHOGuidelines for the treatment of malaria.3rd edn. World Health Organization, Geneva2015Google Scholar 50% of projects surveyed gave intravenous quinine to patients with severe malaria in the first trimester. All projects cited confusion around guidelines and differences with Ministry of Health protocols as the main barriers to use of intravenous artesunate. Our inference from this work is that the recommendation of different drugs in different trimesters for uncomplicated malaria leads to confusion in the management of severe malaria, with potentially severe consequences. As a result of these issues, the new MSF malaria strategy advocates the use of ACTs for P falciparum malaria in all trimesters of pregnancy. We have taken this decision based on current evidence as well as being guided by a patient-centred and access approach: ACTs are at least as effective and more efficient than quinine, and possibly safer given worries around tolerability and compliance with quinine. Compliance begins with the prescriber, and here we promote a shorter and more tolerable treatment course with less frequent dosing to enable compliance by the patient, thereby reducing the risk of adverse outcomes from partially treated malaria. This is especially relevant for chaotic contexts such as displacement, conflict, or outreach to communities with poor access where malaria thrives.9WHOWorld malaria report 2017. World Health Organization, Geneva2017Google Scholar Importantly, using ACTs in all trimesters may also have secondary safety implications if a simpler guideline means that women with severe malaria are not treated with inferior regimens of intravenous quinine. WHO's Malaria Policy Advisory Committee has recommended that guidelines for treatment of malaria in the first trimester of pregnancy be revised.10WHOMalaria Policy Advisory Committee to the WHO: conclusions and recommendations of September 2013 meeting.Malaria J. 2013; 12: 456Crossref PubMed Scopus (29) Google Scholar We strongly support this recommendation, and urge WHO to follow our position and thus reduce barriers to access to the best quality care for pregnant women. We declare no competing interests.