Randomized trial of artesunate+amodiaquine, sulfadoxine-pyrimethamine+amodiaquine, chlorproguanal-dapsone and SP for malaria in pregnancy in Tanzania

Theonest K Mutabingwa, Kandi Muze, Rosalynn Ord, Marnie Briceño, Brian M Greenwood, Chris Drakeley, Christopher J M Whitty, Theonest K Mutabingwa, Kandi Muze, Rosalynn Ord, Marnie Briceño, Brian M Greenwood, Chris Drakeley, Christopher J M Whitty

Abstract

Background: Malaria in pregnancy is serious, and drug resistance in Africa is spreading. Drugs have greater risks in pregnancy and determining the safety and efficacy of drugs in pregnancy is therefore a priority. This study set out to determine the efficacy and safety of several antimalarial drugs and combinations in pregnant women with uncomplicated malaria.

Methods: Pregnant women with non-severe, slide proven, falciparum malaria were randomised to one of 4 regimes: sulfadoxine-pyrimethamine [SP]; chlorproguanil-dapsone [CD]; SP+amodiaquine [SP+AQ] or amodiaquine+artesunate [AQ+AS]. Randomisation was on a 1ratio2ratio2ratio2 ratio. Women were admitted for treatment, and followed at days 7, 14, 21, 28 after the start of treatment, at delivery and 6 weeks after delivery to determine adverse events, clinical and parasitological outcomes. Primary outcome was parasitological failure by day 28.

Results: 1433 pregnant women were screened, of whom 272 met entry criteria and were randomised; 28 to SP, 81 to CD, 80 to SP+AQ and 83 to AQ+AS. Follow-up to day 28 post treatment was 251/272 (92%), and to 6 weeks following delivery 91%. By day 28 parasitological failure rates were 4/26 (15%, 95%CI 4-35) in the SP, 18/77 (23%, 95%CI 14-34) in the CD, 1/73 (1% 95%CI 7-0.001) in the SP+AQ and 7/75 (9% 95%CI 4-18) in the AQ+AS arms respectively. After correction by molecular markers for reinfection the parasitological failure rates at day 28 were 18% for CD, 1% for SP+AQ and 4.5% for AQ+AS. There were two maternal deaths during the trial. There was no apparent excess of stillbirths or adverse birth outcomes in any arm. Parasitological responses were strikingly better in pregnant women than in children treated with the same drugs at this site.

Conclusions: Failure rates with monotherapy were unacceptably high. The two combinations tested were efficacious and appeared safe. It should not be assumed that efficacy in pregnancy is the same as in children.

Trial registration: ClinicalTrials.gov NCT00146731.

Conflict of interest statement

Competing Interests: No authors have personal conflicts of interest. CW has received funds for investigator-initiated resarch from Pfizer and GSK.

Figures

Figure 1. Flow through the trial.
Figure 1. Flow through the trial.
Data not adjusted for PCR correction. *Other includes living out of study area, multiple pregnancy, masking disease. Returned: returned to study area; no intercurrent treatment (d0–d28). SP = sulfadoxine-pyrimethamine AQ = amodiaquine CD = chlorproguanil-dapsone AS = artesunate. d14 = day 14 post-randomisation d28 = day 28 days post-randomisation; 6w post-del = 6 weeks post delivery.
Figure 2. Day 28 parasitological failure rate…
Figure 2. Day 28 parasitological failure rate (%), in pregnant women compared with children from the same site.*
Data on children from Mutabingwa TK et al. Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet. 2005;365:1474–80. Unadjusted for PCR correction, study in children >5 years 2003–4.
Figure 3. Prevalence of gametocytes, by study…
Figure 3. Prevalence of gametocytes, by study drug and day after treatment.
SP- sulfadoxine-pyrimethamine. SP+AQ- sulfadoxine-pyrimethamine+amodiaquine. AQ+AS amodiaquine+artesunate. CD- chlorproguanil-dapsone.

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