Pharmacovigilance of artemether-lumefantrine in pregnant women followed until delivery in Rwanda

Stephen Rulisa, Nadine Kaligirwa, Steven Agaba, Corine Karema, Petra F Mens, Peter J de Vries, Stephen Rulisa, Nadine Kaligirwa, Steven Agaba, Corine Karema, Petra F Mens, Peter J de Vries

Abstract

Background: The World Health Organization presently recommends Artemisinin-based combination therapy (ACT) as first-line therapy for uncomplicated P. falciparum malaria. Many malaria-endemic countries, including Rwanda, have adopted these treatment guidelines. The Artemisinin derivative Artemether, in combination with lumefantrine, is currently used in Rwanda for malaria during the second and third trimesters of pregnancy. Safety data on the use of ACT in pregnancy are still limited though and more data are needed.

Methods: In this pharmacovigilance study, the exposed group (pregnant women with malaria given artemether-lumefantrine), and a matched non-exposed group (pregnant women without malaria and no exposure to artemether-lumefantrine) were followed until delivery. Data were collected at public health centres all over Rwanda during acute malaria, routine antenatal visits, after hospital delivery or within 48 hours after home delivery. Information gathered from patients included routine antenatal and peri-partum data, pregnancy outcomes (abortions, stillbirths, at term delivery), congenital malformations and other adverse events through history taking and physical examination of both mothers and newborns.

Results: The outcomes for the total sample of 2,050 women were for the treatment (n=1,072) and control groups (n=978) respectively: abortions: 1.3% and 0.4%; peri-natal mortality 3.7% and 2.8%; stillbirth 2.9% and 2.4%; neonatal death [less than or equal to]7 days after birth 0.5% and 0.4%; premature delivery 0.7% and 0.3%; congenital malformations 0.3% and 0.3%. A total of 129 obstetric adverse events in 127 subjects were reported (7.3% in the treatment group, 5.0% in the control group). In a multivariate regression model, obstetric complications were more frequent in the treatment group (OR (95% CI): 1.38 (0.95, 2.01)), and in primigravidae (OR (95% CI) 2.65 (1.71, 4.12) and at higher age (OR per year: 1.05 (1.01-1.09).

Conclusions: There were no specific safety concerns related to artemether-lumefantrine treatment for uncomplicated falciparum malaria in pregnancy. However, more obstetric complications were observed in the treatment group. These increased occurrence of complications could, however, be caused by the malaria episode itself, but further assessment is required.

References

    1. Government of Rwanda (GOR) Rwanda National Health Sector Policy -2005. GOR; 2005. , Accessed 1 October 2011.
    1. WHO. WHO Guidelines for the Treatment of Malaria. Second. World Health Organization, Geneva; 2010.
    1. Ehrhardt S, Meyer CG. Artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria. Ther Clin Risk Manag. 2009;5:805–815.
    1. Makanga M, Krudsood S. The clinical efficacy of artemether/lumefantrine (Coartem) Malar J. 2009;8(Suppl 1):S5. doi: 10.1186/1475-2875-8-S1-S5.
    1. Falade C, Manyando C. Safety profile of Coartem: the evidence base. Malar J. 2009;8(Suppl 1):S6. doi: 10.1186/1475-2875-8-S1-S6.
    1. TDR. Assessment of the safety of Artemisinin compounds in pregnancy. TDR; 2006. , Accessed 10 March 2012.
    1. Dellicour S, Hall S, Chandramohan D, Greenwood B. The safety of artemisinins during pregnancy: a pressing question. Malar J. 2007;6:15. doi: 10.1186/1475-2875-6-15.
    1. FDA. Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. FDA; 2008. , Accessed 31 January 2012.
    1. UNAIDS/WHO. Ethical considerations in biomedical HIV prevention trials: UNAIDS/WHO guidance document. 2007. , Accessed 15 May 2012.
    1. EMEA. Guideline on the exposure to medicinal products during pregnancy: need for post-authorisation data. EMEA; 2005. , Accessed 3 June 2012.
    1. Clark RL, White TE, Clode A, Gaunt I, Winstanley P, Ward SA. Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit. Birth Defects Res B Dev Reprod Toxicol. 2004;71:380–394. doi: 10.1002/bdrb.20027.
    1. Longo M, Zanoncelli S, Manera D, Brughera M, Colombo P, Lansen J, Mazue G, Gomes M, Taylor WR, Olliaro P. Effects of the antimalarial drug dihydroartemisinin (DHA) on rat embryos in vitro. Reprod Toxicol. 2006;21:83–93. doi: 10.1016/j.reprotox.2005.05.005.
    1. Nosten F, White NJ. Artemisinin-based combination treatment of falciparum malaria. AmJTrop Med Hyg. 2007;77:181–192.
    1. Dellicour S, ter Kuile FO, Stergachis A. Pregnancy exposure registries for assessing antimalarial drug safety in pregnancy in malaria-endemic countries. PLoS Med. 2008;5:e187. doi: 10.1371/journal.pmed.0050187.
    1. WHO Multicentre Growth Reference Study Group. WHO Motor Development Study. Windows of achievement for six gross motor development milestones. Acta Paediatrica Supplement. 2006;450:86–95.
    1. Steketee RW, Nahlen BL, Parise ME, Menendez C. The burden of malaria in pregnancy in malaria-endemic areas. AmJTrop Med Hyg. 2001;64:28–35.
    1. Whitty CJ, Edmonds S, Mutabingwa TK. Malaria in pregnancy. BJOG. 2005;112:1189–1195. doi: 10.1111/j.1471-0528.2005.00714.x.
    1. McGready R, Tan SO, Ashley EA, Pimanpanarak M, Viladpai-Nguen J, Phaiphun L, Wustefeld K, Barends M, Laochan N, Keereecharoen L. A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated Plasmodium falciparum treatment in pregnancy. PLoS Med. 2008;5:e253. doi: 10.1371/journal.pmed.0050253.
    1. Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N, Nyehangane D, Snounou G, Ashley EA, McGready R, Nosten F. 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. doi: 10.1016/S1473-3099(10)70202-4.
    1. Adam I, Elhassan EM, Omer EM, Abdulla MA, Mahgoub HM, Adam GK. Safety of artemisinins during early pregnancy, assessed in 62 Sudanese women. Ann Trop Med Parasitol. 2009;103:205–210. doi: 10.1179/136485909X398285.
    1. Manyando C, Mkandawire R, Puma L, Sinkala M, Mpabalwani E, Njunju E, Gomes M, Ribeiro I, Walter V, Virtanen M. et al.Safety of artemether-lumefantrine in pregnant women with malaria: results of a prospective cohort study in Zambia. Malar J. 2010;9:249. doi: 10.1186/1475-2875-9-249.
    1. National Malaria Control Programme (NMCP) -Rwanda. Integrated Approach to Reducing Malaria Related Morbidity and Mortality in Rwanda. NMCP; 2008. , Accessed 12 December 2011.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe