Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort

Dominic Mosha, Festo Mazuguni, Sigilbert Mrema, Esperanca Sevene, Salim Abdulla, Blaise Genton, Dominic Mosha, Festo Mazuguni, Sigilbert Mrema, Esperanca Sevene, Salim Abdulla, Blaise Genton

Abstract

Background: There is limited data available regarding safety profile of artemisinins in early pregnancy. They are, therefore, not recommended by WHO as a first-line treatment for malaria in first trimester due to associated embryo-foetal toxicity in animal studies. The study assessed birth outcome among pregnant women inadvertently exposed to artemether-lumefantrine (AL) during first trimester in comparison to those of women exposed to other anti-malarial drugs or no drug at all during the same period of pregnancy.

Methods: Pregnant women with gestational age <20 weeks were recruited from Maternal Health clinics or from monthly house visits (demographic surveillance), and followed prospectively until delivery.

Results: 2167 pregnant women were recruited and 1783 (82.3%) completed the study until delivery. 319 (17.9%) used anti-malarials in first trimester, of whom 172 (53.9%) used (AL), 78 (24.4%) quinine, 66 (20.7%) sulphadoxine-pyrimethamine (SP) and 11 (3.4%) amodiaquine. Quinine exposure in first trimester was associated with an increased risk of miscarriage/stillbirth (OR 2.5; 1.3-5.1) and premature birth (OR 2.6; 1.3-5.3) as opposed to AL with (OR 1.4; 0.8-2.5) for miscarriage/stillbirth and (OR 0.9; 0.5-1.8) for preterm birth. Congenital anomalies were identified in 4 exposure groups namely AL only (1/164[0.6%]), quinine only (1/70[1.4%]), SP (2/66[3.0%]), and non-anti-malarial exposure group (19/1464[1.3%]).

Conclusion: Exposure to AL in first trimester was more common than to any other anti-malarial drugs. Quinine exposure was associated with adverse pregnancy outcomes which was not the case following other anti-malarial intake. Since AL and quinine were used according to their availability rather than to disease severity, it is likely that the effect observed was related to the drug and not to the disease itself. Even with this caveat, a change of policy from quinine to AL for the treatment of uncomplicated malaria during the whole pregnancy period could be already envisaged.

Figures

Figure 1
Figure 1
Flow chart of participants in the study. AL = Artemether-lumefantrine; Qn = Quinine; SP = Sulphadoxine-pyrimethamine; AQ = Amodiaquine; None = No anti-malarial.

References

    1. Dellicour S, Tatem AJ, Guerra CA, Snow RW, ter Kuile FO. Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study. PLoS Med. 2010;7:e1000221. doi: 10.1371/journal.pmed.1000221.
    1. Desai 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;7:93–104. doi: 10.1016/S1473-3099(07)70021-X.
    1. Steketee RW, Nahlen BL, Parise ME, Menendez C. The burden of malaria in pregnancy in malaria-endemic areas. Am J Trop Med Hyg. 2001;64:28–35.
    1. CfDER. Reviewer guidance evaluating the risks of drug exposure in human pregnancies. USA: Food and Drug Administration; 2005.
    1. WHO. Guidelines for the treatment of malaria: second edition. Geneva: World Health Organization; 2010.
    1. White TE, Clark RL. Sensitive periods for developmental toxicity of orally administered artesunate in the rat. Birth Defects Res B Dev Reprod Toxicol. 2008;83:407–417. doi: 10.1002/bdrb.20157.
    1. WHO. Assessment of the safety of artemisinin compounds in pregnancy: report of two informal consultations convened in 2006. Geneva: World Health Organization; 2007.
    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, 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. doi: 10.1186/1475-2875-9-249.
    1. Lefevre G, Marrast AC, Grueninger H. Novartis Malaria Initiative: best practice example of pharmaceutical industry’s engagement in the fight against malaria. Ann N Y Acad Sci. 2011;1222:19–29. doi: 10.1111/j.1749-6632.2011.05973.x.
    1. Ministry of Health of Tanzania. National guideline for malaria diagnosis and treatment 2005. Tanzania: National Malaria Control Programme; 2006.
    1. Mbwasi R, Mlaki W. Increasing access to medicines in Tanzania. Lancet. 2008;372:205–206.
    1. Rutta E, Kibassa B, McKinnon B, Liana J, Mbwasi R, Mlaki W, Embrey M, Gabra M, Shekalaghe E, Kimatta S, Sillo H. Increasing access to subsidized artemisinin-based combination therapy through accredited drug dispensing outlets in Tanzania. Health Res Policy Syst. 2011;9:22. doi: 10.1186/1478-4505-9-22.
    1. McCombie SC. Treatment seeking for malaria: a review of recent research. Soc Sci Med. 1996;43:933–945. doi: 10.1016/0277-9536(95)00446-7.
    1. Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ. Aquamat group. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;376:1647–1657. doi: 10.1016/S0140-6736(10)61924-1.
    1. 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. doi: 10.1016/S1473-3099(10)70202-4.
    1. Okombo J, Ohuma E, Picot S, Nzila A. Update on genetic markers of quinine resistance in Plasmodium falciparum. Mol Biochem Parasitol. 2011;177:77–82. doi: 10.1016/j.molbiopara.2011.01.012.
    1. Parker D, Lerdprom R, Srisatjarak W, Yan G, Sattabongkot J, Wood J, Sirichaisinthop J, Cui L. Longitudinal in vitro surveillance of Plasmodium falciparum sensitivity to common anti-malarials in Thailand between 1994 and 2010. Malar J. 2012;11:290. doi: 10.1186/1475-2875-11-290.
    1. Statistics TNBo. Preliminary results of the 2011–12 Tanzania HIV/Aida and malaria indicator survey (THMIS) NBS. 2012. pp. 24–27.
    1. Everett C. Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice. BMJ. 1997;315:32–34. doi: 10.1136/bmj.315.7099.32.
    1. Lufesi NN, Andrew M, Aursnes I. Deficient supplies of drugs for life threatening diseases in an African community. BMC Health Serv Res. 2007;7:86. doi: 10.1186/1472-6963-7-86.
    1. Twaweza. Stock out or in stock? Acess to medicines in Tanzania. Twaweza. 2013;5:1–4.
    1. Maxwell JP. The use of quinine during pregnancy, labour, and the puerperium. Trans R Soc Trop Med Hyg. 1908;1:229–235.
    1. WHO. Congenital anomalies. Geneva: World Health Organization; 2012.
    1. Cheng B, Dong Y, He L, Tang W, Yu H, Lu J, Xu L, Zheng B, Li K, Xiao C. Crossed polydactyly type I caused by a point mutation in the GLI3 gene in a large Chinese pedigree. J Clin Lab Anal. 2006;20:133–138. doi: 10.1002/jcla.20121.
    1. David O, David M. The prevalence, spontaneous resolution, and parent’s attitudes towards umbilical hernia coexisting in Nigerian children presenting with other surgical pathology. Ann Pediatr Surg. 2009;5:16–20.
    1. Meier DE, OlaOlorun DA, Omodele RA, Nkor SK, Tarpley JL. Incidence of umbilical hernia in African children: redefinition of “normal” and reevaluation of indications for repair. World J Surg. 2001;25:645–648. doi: 10.1007/s002680020072.

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