Scheduled Intermittent Screening with Rapid Diagnostic Tests and Treatment with Dihydroartemisinin-Piperaquine versus Intermittent Preventive Therapy with Sulfadoxine-Pyrimethamine for Malaria in Pregnancy in Malawi: An Open-Label Randomized Controlled Trial.
BACKGROUND
In Africa, most plasmodium infections during pregnancy remain asymptomatic, yet are associated with maternal anemia and low birthweight. WHO recommends intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). However, sulfadoxine-pyrimethamine (SP) efficacy is threatened by high-level parasite resistance. We conducted a trial to evaluate the efficacy and safety of scheduled intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with dihydroartemisinin-piperaquine (DP) as an alternative strategy to IPTp-SP.


RESULTS
This was an open-label, two-arm individually randomized superiority trial among HIV-seronegative women at three sites in Malawi with high SP resistance. The intervention consisted of three or four scheduled visits in the second and third trimester, 4 to 6 wk apart. Women in the IPTp-SP arm received SP at each visit. Women in the intermittent screening and treatment in pregnancy with DP (ISTp-DP) arm were screened for malaria at every visit and treated with DP if RDT-positive. The primary outcomes were adverse live birth outcome (composite of small for gestational age, low birthweight [<2,500 g], or preterm birth [<37 wk]) in paucigravidae (first or second pregnancy) and maternal or placental plasmodium infection at delivery in multigravidae (third pregnancy or higher). Analysis was by intention to treat. Between 21 July 2011 and 18 March 2013, 1,873 women were recruited (1,155 paucigravidae and 718 multigravidae). The prevalence of adverse live birth outcome was similar in the ISTp-DP (29.9%) and IPTp-SP (28.8%) arms (risk difference = 1.08% [95% CI -3.25% to 5.41%]; all women: relative risk [RR] = 1.04 [95% CI 0.90-1.20], p = 0.625; paucigravidae: RR = 1.10 [95% CI 0.92-1.31], p = 0.282; multigravidae: RR = 0.92 [95% CI 0.71-1.20], p = 0.543). The prevalence of malaria at delivery was higher in the ISTp-DP arm (48.7% versus 40.8%; risk difference = 7.85%, [95% CI 3.07%-12.63%]; all women: RR = 1.19 [95% CI 1.07-1.33], p = 0.007; paucigravidae: RR = 1.16 [95% CI 1.04-1.31], p = 0.011; multigravidae: RR = 1.29 [95% CI 1.02-1.63], p = 0.037). Fetal loss was more common with ISTp-DP (2.6% versus 1.3%; RR = 2.06 [95% CI 1.01-4.21], p = 0.046) and highest among non-DP-recipients (3.1%) in the ISTp-DP arm. Limitations included the open-label design.


CONCLUSIONS
Scheduled screening for malaria parasites with the current generation of RDTs three to four times during pregnancy as part of focused antenatal care was not superior to IPTp-SP in this area with high malaria transmission and high SP resistance and was associated with higher fetal loss and more malaria at delivery.


BACKGROUND
Pan African Clinical Trials Registry PACTR201103000280319; ISRCTN Registry ISRCTN69800930.
College of Medicine, University of Malawi, Blantyre, Malawi.|Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Mwayiwawo
M
Madanitsa
College of Medicine, University of Malawi, Blantyre, Malawi.
Linda
L
Kalilani
College of Medicine, University of Malawi, Blantyre, Malawi.
Victor
V
Mwapasa
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Anna M
AM
van Eijk
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Carole
C
Khairallah
National Malaria Control Programme, Ministry of Health, Lilongwe, Malawi.
Doreen
D
Ali
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Cheryl
C
Pace
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
James
J
Smedley
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Kyaw-Lay
KL
Thwai
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America.
Brandt
B
Levitt
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Duolao
http://orcid.org/0000-0003-2788-2464
D
Wang
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Arthur
A
Kang'ombe
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Brian
B
Faragher
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America.|Duke Global Health Institute, Duke University, Durham, North Carolina, United States of America.
Steve M
SM
Taylor
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Steve
S
Meshnick
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Feiko O
FO
Ter Kuile
D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000009:adverse effects*; D037621:Artemisinins / Q000009:adverse effects*; D003955:Diagnostic Tests, Routine / Q000706:statistics & numerical data; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008288:Malaria / Q000517:prevention & control*; D008295:Malawi; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000517:prevention & control*; D011739:Pyrimethamine / Q000009:adverse effects*; D011804:Quinolines / Q000009:adverse effects*; D013413:Sulfadoxine / Q000009:adverse effects*; D055815:Young Adult; D010879:Piperazines
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D011739:Pyrimethamine; D011804:Quinolines; D013413:Sulfadoxine; C001205:fanasil, pyrimethamine drug combination; C039060:artenimol; C034759:piperaquine; D010879:Piperazines