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


BACKGROUND
ClinicalTrials.gov NCT00146731.
Mutabingwa
Theonest K
TK
Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom. tk.bingwa@yahoo.com
Muze
Kandi
K
Ord
Rosalynn
R
Briceño
Marnie
M
Greenwood
Brian M
BM
Drakeley
Chris
C
Whitty
Christopher J M
CJ
D000328:Adult; D000655:Amodiaquine / Q000008:administration & dosage / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use*; D000077332:Artesunate; D003622:Dapsone / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008288:Malaria / Q000150:complications / Q000188:drug therapy*; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000188:drug therapy*; D002727:Proguanil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011739:Pyrimethamine / Q000008:administration & dosage / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000008:administration & dosage / Q000627:therapeutic use*; D013636:Tanzania; D055815:Young Adult
D037621:Artemisinins; D004338:Drug Combinations; C519882:chloroguanil, dapsone drug combination; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D000077332:Artesunate; D013413:Sulfadoxine; D003622:Dapsone; D002727:Proguanil; D011739:Pyrimethamine