Volume 93, Issue 2
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Since there is no ideal candidate to replace sulfadoxine–pyrimethamine (SP) for intermittent preventive treatment (IPTp), alternatives need to be evaluated on basis of their benefit–risk ratio. We reanalyzed the first Beninese trial on mefloquine (MQ) versus SP for IPTp using a multiple outcome approach, which allowed the joint assessment of efficacy and tolerability. Overall superiority of MQ to SP was defined as superiority on at least one efficacy outcome (low birth weight [LBW], placental malaria, or maternal anemia), non-inferiority on all of them as well as on tolerability defined as cutaneous or neuropsychiatric adverse events (AEs) or low compliance with the treatment. The analysis included 1,601 women. MQ was found to be overall superior to SP ( = 0.004). Performing several sensitivity analyses to handle both missing data and stillbirths provided similar results. Using MQ for IPTp as an example, we show that a multiple outcome analysis is a pragmatic way to assess the benefits/disadvantages of one drug compared with another. In the current context of a lack of antimalarials that could be used for IPTp, such a statistical approach could be widely used by institutional policy makers for future recommendations regarding the prevention of malaria in pregnancy (MiP).


Article metrics loading...

Loading full text...

Full text loading...



  1. Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, Newman RD, , 2007. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 7: 93104.[Crossref]
  2. WHO, 2004. A Strategic Framework for Malaria Prevention and Control during Pregnancy in the Africa Region. AFR/MAL/04/01. Brazzaville, Republic of the Congo: WHO Regional Office for Africa.
  3. WHO, 2012. Updated WHO Policy Recommendation: Intermittent Preventive Treatment of Malaria in Pregnancy Using Sulfadoxine–Pyrimethamine (IPTp–SP). Available at: http://www.who.int/malaria/publications/atoz/who_iptp_sp_policy_recommendation/en/. Accessed November 30, 2014.
  4. Kayentao K, Garner P, van Eijk AM, Naidoo I, Roper C, Mulokozi A, MacArthur JR, Luntamo M, Ashorn P, Doumbo OK, ter Kuile FO, , 2013. Intermittent preventive therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine–pyrimethamine and risk of low birth weight in Africa: systematic review and meta-analysis. JAMA 309: 594604.[Crossref]
  5. Ward SA, Sevene EJ, Hastings IM, Nosten F, McGready R, , 2007. Antimalarial drugs and pregnancy: safety, pharmacokinetics, and pharmacovigilance. Lancet Infect Dis 7: 136144.[Crossref]
  6. Briand V, Bottero J, Noël H, Masse V, Cordel H, Guerra J, Kossou H, Fayomi B, Ayemonna P, Fievet N, Massougbodji A, Cot M, , 2009. Intermittent treatment for the prevention of malaria during pregnancy in Benin: a randomized, open-label equivalence trial comparing sulfadoxine–pyrimethamine with mefloquine. J Infect Dis 200: 9911001.[Crossref]
  7. González R, Mombo-Ngoma G, Ouédraogo S, Kakolwa MA, Abdulla S, Accrombessi M, Aponte JJ, Akerey-Diop D, Basra A, Briand V, Capan M, Cot M, Kabanywanyi AM, Kleine C, Kremsner PG, Macete E, Mackanga JR, Massougbodgi A, Mayor A, Nhacolo A, Pahlavan G, Ramharter M, Rupérez M, Sevene E, Vala A, Zoleko-Manego R, Menéndez C, , 2014. Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-negative women: a multicentre randomized controlled trial. PLoS Med 11: e1001733.[Crossref]
  8. Denoeud-Ndam L, Zannou DM, Fourcade C, Taron-Brocard C, Porcher R, Atadokpede F, Komongui DG, Dossou-Gbete L, Afangnihoun A, Ndam NT, Girard PM, Cot M, , 2014. Cotrimoxazole prophylaxis versus mefloquine intermittent preventive treatment to prevent malaria in HIV-infected pregnant women: two randomized controlled trials. J Acquir Immune Defic Syndr 65: 198206.[Crossref]
  9. González R, Desai M, Macete E, Ouma P, Kakolwa MA, Abdulla S, Aponte JJ, Bulo H, Kabanywanyi AM, Katana A, Maculuve S, Mayor A, Nhacolo A, Otieno K, Pahlavan G, Rupérez M, Sevene E, Slutsker L, Vala A, Williamsom J, Menéndez C, , 2014. Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-infected women receiving cotrimoxazole prophylaxis: a multicenter randomized placebo-controlled trial. PLoS Med 11: e1001735.[Crossref]
  10. Malaria Policy Advisory Committee to the WHO, 2013. Conclusions and recommendations of September 2013 meeting. Malar J 12: 456.[Crossref]
  11. Bloch DA, Lai TL, Su Z, Tubert-Bitter P, , 2007. A combined superiority and non-inferiority approach to multiple endpoints in clinical trials. Stat Med 26: 11931207.[Crossref]
  12. Bloch DA, Lai TL, Tubert-Bitter P, , 2001. One-sided tests in clinical trials with multiple endpoints. Biometrics 57: 10391047.[Crossref]
  13. Bertin G, Briand V, Bonaventure D, Carrieu A, Massougbodji A, Cot M, Deloron P, , 2011. Molecular markers of resistance to sulphadoxine–pyrimethamine during intermittent preventive treatment of pregnant women in Benin. Malar J 10: 196.[Crossref]
  14. Moussiliou A, De Tove YS, Doritchamou J, Luty AJ, Massougbodji A, Alifrangis M, Deloron P, Ndam NT, , 2013. High rates of parasite recrudescence following intermittent preventive treatment with sulphadoxine–pyrimethamine during pregnancy in Benin. Malar J 12: 195.[Crossref]
  15. Aubouy A, Fievet N, Bertin G, Sagbo JC, Kossou H, Kinde Gazard D, Kiniffo R, Massougbodji A, Deloron P, , 2007. Dramatically decreased therapeutic efficacy of chloroquine and sulfadoxine–pyrimethamine, but not mefloquine, in southern Benin. Trop Med Int Health 12: 886894.[Crossref]
  16. Sowunmi A, Gbotosho GO, Happi C, Okuboyejo T, Folarin O, Balogun S, Michael O, , 2009. Therapeutic efficacy and effects of artesunate–mefloquine and mefloquine alone on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in southwest Nigeria. Am J Trop Med Hyg 81: 979986.[Crossref]
  17. Briand V, Denoeud L, Massougbodji A, Cot M, , 2008. Efficacy of intermittent preventive treatment versus chloroquine prophylaxis to prevent malaria during pregnancy in Benin. J Infect Dis 198: 594601.[Crossref]
  18. 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, , 2012. Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study. Lancet Infect Dis 12: 388396.[Crossref]
  19. Nosten F, Vincenti M, Simpson J, Yei P, Thwai KL, de Vries A, Chongsuphajaisiddhi T, White NJ, , 1999. The effects of mefloquine treatment in pregnancy. Clin Infect Dis 28: 808815.[Crossref]
  20. Steketee RW, Wirima JJ, Hightower AW, Slutsker L, Heymann DL, Breman JG, , 1996. The effect of malaria and malaria prevention in pregnancy on offspring birthweight, prematurity, and intrauterine growth retardation in rural Malawi. Am J Trop Med Hyg 55: 3341.
  21. Schlagenhauf P, Blumentals WA, Suter P, Regep L, Vital-Durand G, Schaerer MT, Boutros MS, Rhein HG, Adamcova M, , 2012. Pregnancy and fetal outcomes after exposure to mefloquine in the pre- and periconception period and during pregnancy. Clin Infect Dis 54: e124e131.[Crossref]

Data & Media loading...

  • Received : 05 Dec 2014
  • Accepted : 22 Apr 2015

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error