Safety of daily co-trimoxazole in pregnancy in an area of changing malaria epidemiology: a phase 3b randomized controlled clinical trial

Christine Manyando, Eric M Njunju, David Mwakazanga, Gershom Chongwe, Rhoda Mkandawire, Davies Champo, Modest Mulenga, Maaike De Crop, Yves Claeys, Raffaella M Ravinetto, Chantal van Overmeir, Umberto D' Alessandro, Jean-Pierre Van Geertruyden, Christine Manyando, Eric M Njunju, David Mwakazanga, Gershom Chongwe, Rhoda Mkandawire, Davies Champo, Modest Mulenga, Maaike De Crop, Yves Claeys, Raffaella M Ravinetto, Chantal van Overmeir, Umberto D' Alessandro, Jean-Pierre Van Geertruyden

Abstract

Introduction: Antibiotic therapy during pregnancy may be beneficial and impacts positively on the reduction of adverse pregnancy outcomes. No studies have been done so far on the effects of daily Co-trimoxazole (CTX) prophylaxis on birth outcomes. A phase 3b randomized trial was conducted to establish that daily CTX in pregnancy is not inferior to SP intermittent preventive treatment (IPT) in reducing placental malaria; preventing peripheral parasitaemia; preventing perinatal mortality and also improving birth weight. To establish its safety on the offspring by measuring the gestational age and birth weight at delivery, and compare the safety and efficacy profile of CTX to that of SP.

Methods: Pregnant women (HIV infected and uninfected) attending antenatal clinic were randomized to receive either daily CTX or sulfadoxine-pyrimethamine as per routine IPT. Safety was assessed using standard and pregnancy specific measurements. Women were followed up monthly until delivery and then with their offspring up to six weeks after delivery.

Results: Data from 346 pregnant women (CTX = 190; SP = 156) and 311 newborns (CTX = 166 and SP = 145) showed that preterm deliveries (CTX 3.6%; SP 3.0%); still births (CTX 3.0%; SP 2.1%), neonatal deaths (CTX 0%; SP 1.4%), and spontaneous abortions (CTX 0.6%; SP 0%) were similar between study arms. The low birth weight rates were 9% for CTX and 13% for SP. There were no birth defects reported. Both drug exposure groups had full term deliveries with similar birth weights (mean of 3.1 Kg). The incidence and severity of AEs in the two groups were comparable.

Conclusion: Exposure to daily CTX in pregnancy may not be associated with particular safety risks in terms of birth outcomes such as preterm deliveries, still births, neonatal deaths and spontaneous abortions compared to SP. However, more data are required on CTX use in pregnant women both among HIV infected and un-infected individuals.

Trial registration: Clinicaltrials.gov NCT00711906.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Study Design.
Figure 1. Study Design.
Figure 2. Trial Profile.
Figure 2. Trial Profile.

References

    1. WHO (2012) World Malaria Report.
    1. WHO (2006) Roll Back Malaria Partnership.
    1. Shulman CE, Dorman EK (2003) Reducing childhood mortality in poor countries - importance and prevention of malaria in pregnancy. Trans R Soc Trop Med Hyg 97: 30–35.
    1. Whitty CJ, Edmonds S, Mutabingwa TK (2005) Malaria in pregnancy. BJOG 112: 1189–1195.
    1. WHO: Assessment of the safety of artemisinin compounds in pregnancy [].Accessed 2014 April 15.
    1. Nosten F, McGready R, Simpson JA, Thwai KL, Balkan S, et al. (1999) Effects of Plasmodium vivax malaria in pregnancy. Lancet 354: 546–549.
    1. Steketee R, Wirima JJ HA, Slustker L, Heymann DL, Brenman 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: 33–41.
    1. van Geertruyden JP, Thomas F, Erhart A, D’Alessandro U (2004) The contribution of malaria in pregnancy to perinatal mortality. Am J Trop Med Hyg 71: 35–40. 71/2_suppl/35 [pii].
    1. Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, et al.. (2007) Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 7: 93–104. S1473–3099(07)70021-X [pii]; 10.1016/S1473–3099(07)70021-X [doi].
    1. Steketee R, Wirima JJ, Bloland PB, Chilima B, Mermin JH, et al. (1996) Impairment of a pregnant woman’s acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type-1. Am J Trop Med Hyg 55: 42–49.
    1. Allen S, Van de perre P, Serufilira A, Lepage P, Carael M, et al. (1991) Human Immunodeficiency virus and malaria in a representative sample of childbearing women in Kigali, Rwanda. J infect Dis 164: 67–71.
    1. ter Kuile FO, Parise ME, Verhoeff FH, Udhayakumar V, Newman RD, et al.. (2004) 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 71: 41–54. 71/2_suppl/41 [pii].
    1. Verhoeff FH, Brabin BJ, Hart CA, Chimsuku L, Kazembe P, et al. (1999) Increased prevalence of malaria in HIV-infected pregnant women and its implications for malaria control. Trop Med Int Health 4: 5–12.
    1. van Eijk AM, Ayisi JG, ter Kuile FO, Misore AO, Otieno JA, et al. (2002) Risk factors for malaria in pregnancy in an urban and peri-urban population in western Kenya. Trans R Soc Trop Med Hyg 96: 586–592.
    1. Ayisi JG, van Eijk AM, ter Kuile FO, Kolczak MS, Otieno JA, et al. (2003) The effect of dual infection with HIV and malaria on pregnancy outcome in western Kenya. AIDS 17: 585–594 10.1097/01.aids.0000042977.95433.37 [doi].
    1. Ticconi C, Mapfumo M, Dorrucci M, Naha N, Tarira E, et al. (2003) Effect of maternal HIV and malaria infection on pregnancy and perinatal outcome in Zimbabwe. J Acquir Immune Defic Syndr 34: 289–294.
    1. Bloland PB, Wirima JJ, Steketee RW, Chilima B, Hightower A, et al. (1995) Maternal HIV infection and infant mortality in Malawi: Evidence for increased mortality due to placental malaria infection. AIDS 9: 721–726.
    1. Anglaret X, Chene G, Attia A, Toure S, Lafont S, et al.. (1999) Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Cote d’Ivoire: a randomised trial. Cotrimo-CI Study Group. Lancet 353: 1463–1468. S0140673698073991 [pii].
    1. Brentlinger PE, Behrens CB, Micek MA (2006) Challenges in the concurrent management of malarria and HIV in pregnancy in subsaharan Africa. Lancet Infect Dis 6: 100–111.
    1. WHO (2010) World Malaria Report. []. Accessed 2014 April 15.
    1. WHO (2007) Assessment of the safety of artemisinin compounds in pregnancy. []. Accessed 2014 April 15.
    1. WHO (2010) World Malaria report: Summary. []. Accessed 2014 April 15.
    1. Garner P GA (2003) Drugs for preventing malaria-related illness in pregnant women and death in the newborn. 1: CD000169.
    1. Cot M, Deloron P (2003) Malaria prevention strategies. Br Med Bull 67: 137–148.
    1. Peters PJ, Thigpen MC, Parise ME, Newman RD (2007) Safety and toxicity of sulfadoxine/pyrimethamine: implications for malaria prevention in pregnancy using intermittent preventive treatment. Drug Saf 30: 481–501. 3063 [pii].
    1. WHO (2012) Intermittent Preventive Treatment of malaria in pregnancy using Sulfadoxine-Pyrimethamine (IPTp-SP). []. Accessed 2014 April 15.
    1. Parise ME, Ayisi JG, Nahlen BL, Schultz LJ, Roberts JM, et al. (1998) Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. Am J Trop Med Hyg 59: 813–822.
    1. Verhoeff FH, Brabin BJ, Chimsuku L, Kazembe P, Russell WB, et al. (1998) An evaluation of the effects of intermittent sulfadoxine-pyrimethamine treatment in pregnancy on parasite clearance and risk of low birthweight in rural Malawi. Ann Trop Med Parasitol 92: 141–150.
    1. Omar SA, Bakari A, Owiti A, Adagu IS, Warhurst DC (2001) Co-trimoxazole compared with sulfadoxine-pyrimethamine in the treatment of uncomplicated malaria in Kenyan children. Trans R Soc Trop Med Hyg 95: 657–660.
    1. Mermin J, Lule J, Ekwaru JP, Malamba S, Downing R, et al.. (2004) Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda. Lancet 364: 1428–1434. S0140673604172255 [pii]; 10.1016/S0140–6736(04)17225–5 [doi].
    1. Hauth JC, Goldenberg RL, Andrew WN, Dubard MB, Copper RL (1995) Reduced incidence of preterm delivery with metronidazole and erytromycin in women with bacterial vaginosis. N Engl J Med 333: 1732–1736.
    1. Walter J, Mwiya M, Scott N, Kasonde P, Sinkala M, et al.. (2006) Reduction in preterm delivery and neonatal mortality after the introduction of antenatal cotrimoxazole prophylaxis among HIV-infected women with low CD4 cell counts. J Infect Dis 194: 1510–1518. JID36726 [pii]; 10.1086/508996 [doi].
    1. Manyando C, Njunju EM, D’Alessandro U, van Geertruyden JP (2013) Safety and Efficacy of Co-Trimoxazole for Treatment and Prevention of Plasmodium falciparum Malaria: A systematic Review. PLos one 8: e56916.
    1. Chizema-Kawesha E, Miller JM, Steketee RW, Mukonka V, Mukuka C, et al. (2010) Scaling up malaria control in Zambia: progress and impact 2005–2008. Am J Trop Med Hyg 83: 480–488.
    1. Masaninga F, Sekeseke-Chinyama M, Malambo T, Moonga H, Babaniyi O, et al.. (2012) Finding parasites and finding challenges: improved diagnostic access and trends in reported malaria and anti-malarial drug use in Livingstone district, Zambia. Malar J 11.
    1. Dubowitz LMS, Dubowitz V, Goldberg C (1970) Clinical assessment of gestational age in the new born infant. J Pediatr 77: 1–10.
    1. WHO (2006) Guidelines on Cotrimoxazole prophylaxis for HIV-related infections among children, adolescents and adults: Recommendations for a public health approach. []. Accessed 2014 Apr 15.
    1. Thera MA, Sehdev PS, Coulibaly D, Traore K, Garba MN, et al.. (2005) Impact of trimethoprim-sulfamethoxazole prophylaxis on falciparum malaria infection and disease. J Infect Dis 192: 1823–1829. JID35552 [pii]; 10.1086/498249 [doi].
    1. Meshnick SR, Mwapasa V, Rogerson S (2006) Protecting pregnant women from malaria in areas of high HIv infection prevalence. J infect Dis 194: 273–275.
    1. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J (2001) The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol 15: 637–646. S0890623801001782 [pii].
    1. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA (2000) Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 343: 1608–1614 10.1056/NEJM200011303432204 [doi].
    1. Siega-Riz AM, Savitz DA, Zeisel SH, Thorp JM, Herring A (2004) Second trimester folate status and preterm birth. Am J Obstet Gynecol 191: 1851–1857. S0002937804008609 [pii]; 10.1016/j.ajog.2004.07.076 [doi].
    1. Marti-Carvajal V, Pena-Marti, Comunian-Carraso G (2004) Prematurity and maternal folate deficiency: anaemia during pregnancy study group results in Valencia, Venezuela. Arch LatinoamNutri 54: 45–49.
    1. Juarez-Vazquez J, Bonizzoni E SA (2002) Iron plus folate is more effective than iron alone in the treatment of iron deficiency anaemia in pregnanct: a randomised, bouble blind clinical trial. BJOG 109: 1009–1014.
    1. Manyando C, Mkandawire R, Puma L, Sinkala M, Mpabalwani E, et al. (2010) Safety of artemether-lumefantrine in pregnant women with malaria: results of a prospective cohort study in Zambia. Malaria J 9: 249.
    1. Altman DG, Bland JM (1995) Absence of evidence is not evidence of absence BMJ, 311. (7003): 485.

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