The online version of this article (doi:10.1186/1475-2875-11-141) contains supplementary material, which is available to authorized users.
CM, KK, HUO and EJ have no competing interests. UDA has received research funding from Sigma Tau and Sanofi-Aventis. He has also received travel grants from Sigma Tau and Novartis. KH is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
All authors met International Committee of Medical Journal Editors criteria for authorship. All authors contributed to the development of the outline, revised the manuscript critically, and read and approved the final manuscript.
Malaria during pregnancy, particularly Plasmodium falciparum malaria, has been linked to increased morbidity and mortality, which must be reduced by both preventive measures and effective case management. The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) to treat uncomplicated falciparum malaria during the second and third trimesters of pregnancy, and quinine plus clindamycin during the first trimester. However, the national policies of many African countries currently recommend quinine throughout pregnancy. Therefore, the aim of this article is to provide a summary of the available data on the safety and efficacy of artemether-lumefantrine (AL) in pregnancy. An English-language search identified 16 publications from 1989 to October 2011 with reports of artemether or AL exposure in pregnancy, including randomized clinical trials, observational studies and systematic reviews. Overall, there were 1,103 reports of AL use in pregnant women: 890 second/third trimester exposures; 212 first trimester exposures; and one case where the trimester of exposure was not reported. In the second and third trimesters, AL was not associated with increased adverse pregnancy outcomes as compared with quinine or sulphadoxine-pyrimethamine, showed improved tolerability relative to quinine, and its efficacy was non-inferior to quinine. There is evidence to suggest that the pharmacokinetics of anti-malarial drugs may change in pregnancy, although the impact on efficacy and safety needs to be studied further, especially since the majority of studies report high cure rates and adequate tolerability. As there are fewer reports of AL safety in the first trimester, additional data are required to assess the potential to use AL in the first trimester. Though the available safety and efficacy data support the use of AL in the second and third trimesters, there is still a need for further information. These findings reinforce the WHO recommendation to treat uncomplicated falciparum malaria with quinine plus clindamycin in early pregnancy and ACT in later pregnancy.
Additional file 1: Ovid search strategy. Ovid was used to search the EMBASE, MEDLINE, BIOSIS (included In-Process and Other Non-indexed Citations, Daily Update) and Cochrane (included Cochrane Database of Systematic Reviews, APC Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment, NHS Economic Evaluation Database) databases between 1948 and 2011. Six queries were performed using the search terms shown. *Search for the term shown with or without any number of additional letters; ?Search for the term shown with or without one additional letter. (DOC 40 KB)12936_2011_2112_MOESM1_ESM.doc
Additional file 2: Results of literature search: Number of references identified for each query and database. EMBASE, MEDLINE, BIOSIS and Cochrane were searched on 16 December, 2011. Malaria in Pregnancy consortium library, Clinicaltrials.gov and WHO ICTRP were searched on 8 December, 2011 and TrialTrove was searched on 14 December, 2011. ICTRP, International Clinical Trials Registry Platform. (DOC 37 KB)12936_2011_2112_MOESM2_ESM.doc
Additional file 3: 400 unique references recovered in the literature search. (DOC 386 KB)12936_2011_2112_MOESM3_ESM.doc
Additional file 4: Publications reporting on the safety, efficacy and pharmacokinetics of artemether and artemether-lumefantrine in pregnancy, including the number of exposures during pregnancy. Sixteen articles were identified by the literature search, all reporting on pregnancies exposed to artemether or artemether-lumefantrine. The number of pregnancies exposed to artemether or artemether-lumefantrine are reported, and it is noted where exposures have been previously reported. AL, artemether-lumefantrine; AE, adverse events; SAE, serious adverse events; SP, sulphadoxine-pyrimethamine; ACT, artemisinin-based combination therapies; †National treatment policy is quinine throughout pregnancy [ 55– 57]; †National treatment policy is quinine in the first trimester and ACT in the second and third trimesters of pregnancy [ 55, 58, 59]; §National treatment policy is quinine in the first trimester and SP in the second and third trimesters of pregnancy; Benin, † Burkina Faso, † Cameroon, † DRC, † Gabon, † Mozambique, † Mali, † Thailand, † Ghana, ‡ Kenya, ‡ Malawi, ‡ Nigeria, ‡ Sudan, ‡ Tanzania, ‡ Uganda, ‡ Zambia, §[ 26, 55, 57– 59]; #McGready et al., 2001 [ 17] includes all of the artemether exposures reported across three publications. To avoid duplication of pregnancy exposures the other two reports have not been included [ 18, 19]; ¶Included women with a pregnancy in the last 12 months that lasted until at least the third trimester. Current pregnancies were excluded; ††Mali, † Mozambique, † Thailand, † Kenya, ‡ Nigeria, ‡ Sudan, ‡ Tanzania, ‡ Zambia §[ 26, 55, 57, 59]; ‡‡National treatment policy is quinine/AL [ 60]. Wang, 1989 [ 20], Sowunmi et al., 1998 [ 15], McGready et al., 2001 [ 17], Adam et al., 2004 [ 16], McGready et al., 2006 [ 21], Dellicour et al., 2007 [ 14], McGready et al., 2008 [ 22], Kaye et al., 2008 [ 23], Orton et al., 2008 [ 61], Adam et al., 2009 [ 24], Tarning et al., 2009 [ 37], Piola et al., 2010 [ 25], Manyando et al., 2010 [ 26], McGready et al., 2011 [ 29], Sangaré et al., 2011 [ 27], Wilby and Ensom, 2011 [ 30]. (DOC 58 KB)
Authors’ original file for figure 112936_2011_2112_MOESM5_ESM.pdf
van 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: 35-40. PubMed
Menendez C, Romagosa C, Ismail MR, Carrilho C, Saute F, Osman N, Machungo F, Bardaji A, Quinto L, Mayor A, Naniche D, Dobaño C, Alonso PL, Ordi J: An autopsy study of maternal mortality in Mozambique: the contribution of infectious diseases. PLoS Med. 2008, 5: e44-10.1371/journal.pmed.0050044. PubMedCentralCrossRefPubMed
ter Kuile FO, Parise ME, Verhoeff FH, Udhayakumar V, Newman RD, van Eijk AM, Rogerson SJ, Steketee RW: The burden of co-infection with human immunodeficiency virus type 1 and malaria in pregnant women in sub-saharan Africa. Am J Trop Med Hyg. 2004, 71: 41-54. PubMed
WHO: Assessment of the safety of artemisinin compounds in pregnancy. http://www.who.int/malaria/publications/atoz/9789241596114/en/index.html,
WHO: World Malaria Report 2010. http://www.who.int/malaria/world_malaria_report_2010/en/index.html,
Sinclair D, Zani B, Donegan S, Olliaro P, Garner P: Artemisinin-based combination therapy for treating uncomplicated malaria. Cochrane Database Syst Rev. 2009, CD007483-
WHO: Guidelines for the Treatment of Malaria: Second Edition (2010). http://www.who.int/malaria/publications/atoz/9789241547925/en/index.html,
Clark RL, Lerman SA, Cox EM, Gristwood WE, White TE: Developmental toxicity of artesunate in the rat: comparison to other artemisinins, comparison of embryotoxicity and kinetics by oral and intravenous routes, and relationship to maternal reticulocyte count. Birth Defects Res B Dev Reprod Toxicol. 2008, 83: 397-406. 10.1002/bdrb.20165. CrossRefPubMed
Sowunmi A, Oduola AM, Ogundahunsi OA, Fehintola FA, Ilesanmi OA, Akinyinka OO, Arowojolu AO: Randomised trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sufadoxine-pyrimethamine-resistant falciparum malaria during pregnancy. J Obstet Gynaecol. 1998, 18: 322-327. 10.1080/01443619867038. CrossRefPubMed
Wang TY: Follow-up observation on the therapeutic effects and remote reactions of artemisinin (Qinghaosu) and artemether in treating malaria in pregnant woman. J Tradit Chin Med. 1989, 9: 28-30. PubMed
McGready R, Tan SO, Ashley EA, Pimanpanarak M, Viladpai-Nguen J, Phaiphun L, Wustefeld K, Barends M, Laochan N, Keereecharoen L, Lindegardh N, Singhasivanon P, White NJ, Nosten F: A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated Plasmodium falciparum treatment in pregnancy. PLoS Med. 2008, 5: e253-10.1371/journal.pmed.0050253. PubMedCentralCrossRefPubMed
Kaye DK, Nshemerirwe R, Mutyaba TS, Ndeezi G: A randomized clinical trial comparing safety, clinical and parasitological response to artemether-lumefantrine and chlorproguanil-dapsone in treatment of uncomplicated malaria in pregnancy in Mulago hospital, Uganda. J Infect Dev Ctries. 2008, 2: 135-139. 10.3855/T2.2.135. CrossRefPubMed
Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N, Nyehangane D, Snounou G, Ashley EA, McGready R, Nosten F, Guerin PJ: Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. Lancet Infect Dis. 2010, 10: 762-769. 10.1016/S1473-3099(10)70202-4. CrossRefPubMed
Manyando C, Mkandawire R, Puma L, Sinkala M, Mpabalwani E, Njunju E, Gomes M, Ribeiro I, Walter V, Virtanen M, Schlienger R, Cousin M, Chipimo M, Sullivan FM: Safety of artemether-lumefantrine in pregnant women with malaria: results of a prospective cohort study in Zambia. Malar J. 2010, 9: 249-10.1186/1475-2875-9-249. PubMedCentralCrossRefPubMed
WHO: Antimalarial chlorproguanil-dapsone (LapDap™) withdrawn following demonstration of post-treatment haemolytic anaemia in G6PD deficient patients in a phase III trial of chlorproguanil-dapsone-artesunate (Dacart™) versus artemether-lumefantrine (Coartem®) and confirmation of findings in a comparative trial of LapDap™ versus Dacart™. http://www.who.int/medicines/publications/drugalerts/Alert_117_LapDap.pdf,
Ashley EA, Stepniewska K, Lindegardh N, McGready R, Annerberg A, Hutagalung R, Singtoroj T, Hla G, Brockman A, Proux S, Wilahphaingern J, Singhasivanon P, White NJ, Nosten F: Pharmacokinetic study of artemether-lumefantrine given once daily for the treatment of uncomplicated multidrug-resistant falciparum malaria. Trop Med Int Health. 2007, 12: 201-208. 10.1111/j.1365-3156.2006.01785.x. CrossRefPubMed
Piola P, Fogg C, Bajunirwe F, Biraro S, Grandesso F, Ruzagira E, Babigumira J, Kigozi I, Kiguli J, Kyomuhendo J, Ferradini L, Taylor W, Checchi F, Guthmann JP: Supervised versus unsupervised intake of six-dose artemether-lumefantrine for treatment of acute, uncomplicated Plasmodium falciparum malaria in Mbarara, Uganda: a randomised trial. Lancet. 2005, 365: 1467-1473. 10.1016/S0140-6736(05)66416-1. CrossRefPubMed
Lefèvre G, Looareesuwan S, Treeprasertsuk S, Krudsood S, Silachamroon U, Gathmann I, Mull R, Bakshi R: A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg. 2001, 64: 247-256. PubMed
Tarning J, McGready R, Lindegardh N, Ashley EA, Pimanpanarak M, Kamanikom B, Annerberg A, Day NP, Stepniewska K, Singhasivanon P, White NJ, Nosten F: Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria. Antimicrob Agents Chemother. 2009, 53: 3837-3846. 10.1128/AAC.00195-09. PubMedCentralCrossRefPubMed
WHO: Global report on antimalarial drug efficacy and drug resistance: 2000-2010. http://www.who.int/malaria/publications/atoz/9789241500470/en/index.html,
McGready R, Lee SJ, Wiladphaingern J, Ashley EA, Rijken MJ, Boel M, Simpson JA, Paw MK, Pimanpanarak M, Mu O, Singhasivanon P, White NJ, Nosten FH: Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study. Lancet Infect Dis. 2011, 10.1016/S1473-3099(11)70339-5.
Chi BH, Vwalika B, Killam WP, Wamalume C, Giganti MJ, Mbewe R, Stringer EM, Chintu NT, Putta NB, Liu KC, Chibwesha CJ, Rouse DJ, Stringer JS: Implementation of the Zambia electronic perinatal record system for comprehensive prenatal and delivery care. Int J Gynaecol Obstet. 2011, 113: 131-136. 10.1016/j.ijgo.2010.11.013. PubMedCentralCrossRefPubMed
Onyamboko MA, Meshnick SR, Fleckenstein L, Koch MA, Atibu J, Lokomba V, Douoguih M, Hemingway-Foday J, Wesche D, Ryder RW, Bose C, Wright LL, Tshefu AK, Capparelli EV: Pharmacokinetics and pharmacodynamics of artesunate and dihydroartemisinin following oral treatment in pregnant women with asymptomatic Plasmodium falciparum infections in Kinshasa DRC. Malar J. 2011, 10: 49-10.1186/1475-2875-10-49. PubMedCentralCrossRefPubMed
Morris CA, Onyamboko MA, Capparelli E, Koch MA, Atibu J, Lokomba V, Douoguih M, Hemingway-Foday J, Wesche D, Ryder RW, Morris CA, Onyamboko MA, Capparelli E, Koch MA, Atibu J: Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria. Malar J. 2011, 10: 114-10.1186/1475-2875-10-114. PubMedCentralCrossRefPubMed
Malaria in pregnancy consortium: Pharmacokinetic Studies. http://www.mip-consortium.org/projects/pharmacokinetics.htm,
Birku Y, Mekonnen E, Bjorkman A, Wolday D: Delayed clearance of Plasmodium falciparum in patients with human immunodeficiency virus co-infection treated with artemisinin. Ethiop Med J. 2002, 40 (Suppl 1): 17-26. PubMed
German P, Parikh S, Lawrence J, Dorsey G, Rosenthal PJ, Havlir D, Charlebois E, Hanpithakpong W, Lindegardh N, Aweeka FT: Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV-uninfected healthy volunteers. J Acquir Immune Defic Syndr. 2009, 51: 424-429. 10.1097/QAI.0b013e3181acb4ff. CrossRefPubMed
South Africa National Department of Health: Guidelines for the treatment of malaria in South Africa. http://www.kznhealth.gov.za/medicine/2009malariaguideline.pdf,
President's Malaria Initiative: Malaria Operational Plan (MOP) - FY2011 Ethiopia. http://www.fightingmalaria.gov/countries/mops/fy11/ethiopia_mop-fy11.pdf
Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Sugiarto P, Tjitra E, Anstey NM, Price RN: Highly effective therapy for malaria in pregnancy improves maternal and neonatal health outcome [abstract]. Am J Trop Med Hyg. 2011, 85 (Suppl 6): Abstract number 455-
WHO: Country antimalarial drug policies: by region. WHO African Region, http://www.who.int/malaria/am_drug_policies_by_region_afro/en/index.html,
Roll Back Malaria Partnership: 2005 China Country Profile. http://www.rollbackmalaria.org/wmr2005/profiles/china.pdf,
Roll Back Malaria Partnership: 2005 Thailand Country Profile. http://www.rollbackmalaria.org/wmr2005/profiles/thailand.pdf,
Ugandan Malaria Control Programme: Ugandan National Policy on Malaria. 2005, http://www.health.go.ug/mcp/NationalPolicyonMalariaTreatment(07_03_06).pdf,
Azairwe R, Achan J: Malaria in South Sudan 4: treatment of uncomplicated P. falciparum malaria. Southern Sudan Medical Journal. 2011, 4: 30-32.
WHO: Country antimalarial drug policies by region. WHO Western Pacific Region, http://www.who.int/malaria/am_drug_policies_by_region_wpro/en/index.html,
Orton LC, Omari AA: Drugs for treating uncomplicated malaria in pregnant women. Cochrane Database Syst Rev. 2008, CD004912.
- A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy
Henrietta U Okafor
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