A Non-Inferiority, Individually Randomized Trial of Intermittent Screening and Treatment versus Intermittent Preventive Treatment in the Control of Malaria in Pregnancy

Abstract

Background: The efficacy of intermittent preventive treatment for malaria with sulfadoxine-pyrimethamine (IPTp-SP) in pregnancy is threatened in parts of Africa by the emergence and spread of resistance to SP. Intermittent screening with a rapid diagnostic test (RDT) and treatment of positive women (ISTp) is an alternative approach.

Methods and findings: An open, individually randomized, non-inferiority trial of IPTp-SP versus ISTp was conducted in 5,354 primi- or secundigravidae in four West African countries with a low prevalence of resistance to SP (The Gambia, Mali, Burkina Faso and Ghana). Women in the IPTp-SP group received SP on two or three occasions whilst women in the ISTp group were screened two or three times with a RDT and treated if positive for malaria with artemether-lumefantrine (AL). ISTp-AL was non-inferior to IPTp-SP in preventing low birth weight (LBW), anemia and placental malaria, the primary trial endpoints. The prevalence of LBW was 15.1% and 15.6% in the IPTp-SP and ISTp-AL groups respectively (OR = 1.03 [95% CI: 0.88, 1.22]). The mean hemoglobin concentration at the last clinic attendance before delivery was 10.97g/dL and 10.94g/dL in the IPTp-SP and ISTp-AL groups respectively (mean difference: -0.03 g/dL [95% CI: -0.13, +0.06]). Active malaria infection of the placenta was found in 24.5% and in 24.2% of women in the IPTp-SP and ISTp-AL groups respectively (OR = 0.95 [95% CI 0.81, 1.12]). More women in the ISTp-AL than in the IPTp-SP group presented with malaria parasitemia between routine antenatal clinics (310 vs 182 episodes, rate difference: 49.4 per 1,000 pregnancies [95% CI 30.5, 68.3], but the number of hospital admissions for malaria was similar in the two groups.

Conclusions: Despite low levels of resistance to SP in the study areas, ISTp-AL performed as well as IPTp-SP. In the absence of an effective alternative medication to SP for IPTp, ISTp-AL is a potential alternative to IPTp in areas where SP resistance is high. It may also have a role in areas where malaria transmission is low and for the prevention of malaria in HIV positive women receiving cotrimoxazole prophylaxis in whom SP is contraindicated.

Trial registration: ClinicalTrials.gov NCT01084213 Pan African Clinical trials Registry PACT201202000272122.

Fig 1. CONSORT Flow Diagram.

Footnote: LTFU—Lost to follow-up. * two of these 3 deaths occurred on the day of delivery. ^$ missed subsequent visit but remained in follow up. ^# numbers shown at post-partum include 8 and 9 women in IPTp-SP and ISTp-AL groups respectively who were not seen at delivery but who remained in follow-up.

Fig 2. Non-inferiority plots for primary outcomes and mean birth weight.

The figures show two-sided 90%, 95% and 99% confidence intervals (largest to smallest vertical bars, respectively), equivalent to one-sided 95%, 97.5% and 99.5% confidence intervals. The dashed blue vertical line indicates the non-inferiority margin. ATP, according to protocol population (adjusted for site); adjusted, ATP population adjusted for site, gravidity, age group, gestational age, ITN use and socio-economic status; ITT, intention to treat, (adjusted for site). Numbers included in the analyses and numeric values of the estimates are provided in the supplement (S4 Table).

Fig 3. Distribution of birth weight (A) and hemoglobin concentration (B) at fourth ANC visit by intervention group.

Birth weight distributions were estimated using data from 2183 women in the IPTp-SP group and from 2208 women in the ISTp-AL group. Hemoglobin distributions utilise data from 1534 women in the IPTp-SP group and from 1600 women in the ISTp-AL group.