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

Abstract

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.

Methods and findings: 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.

Trial registration: Pan African Clinical Trials Registry PACTR201103000280319; ISRCTN Registry ISRCTN69800930.

Fig 1. Flow chart.

^aOne woman randomized to IPTp-SP was erroneously recorded as being in the ISTp-DP arm on her antenatal care card and as a result received ISTp-DP. She was included in the ITT population under the IPTp-SP arm. ^bScreening failures were not followed to delivery and were excluded from the modified ITT population. ^cWomen lost to follow-up prior to delivery and women who withdrew consent were included in the ITT population and contributed to the antenatal follow-up analyses (e.g., incidence of malaria). IPTp-SP, intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine; ISTp-DP, intermittent screening and treatment in pregnancy with dihydroartemisinin-piperaquine; ITT, intention to treat; SGA/LBW/PT, small for gestational age or low birthweight or preterm.

Fig 2. Efficacy of ISTp-DP versus IPTp-SP on the primary outcomes of adverse live birth outcome and maternal or placental plasmodium infection at delivery (any measure).

Adjusted RR values obtained from multivariate log binomial regression models with missing values imputed and adjusting for gravidity, study site, and seven other prespecified covariates: malaria status at enrollment (binary), season during pregnancy (terciles based on average ranked rainfall during the last 6 mo of pregnancy), maternal height (terciles), hemoglobin status at enrollment (terciles), maternal years of schooling (terciles), socioeconomic status (terciles of socioeconomic index calculated using principal component analysis), and gestational age at first antenatal visit (binary based on median). There were no differences in effect size for paucigravidae versus multigravidae (p-value for interaction term: p = 0.271 for adverse live birth outcome and p = 0.454 for plasmodium infection at delivery). IPTp-SP, intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine; ISTp-DP, intermittent screening and treatment in pregnancy with dihydroartemisinin-piperaquine; LBW, low birthweight; RR, relative risk; SGA, small for gestational age.

Fig 3. Secondary maternal outcomes: anemia and malaria.

The p-value for the interaction term depicts the p-value for differences in effect size between paucigravidae and multigravidae. *Data given as the number of women with an event, the number of events/person-years of follow-up, and, in parentheses, the incidence rate per 100 person-years. ^#Maternal plasmodium infection detected by PCR, microscopy, or RDT. RDT data considered only when women were symptomatic (febrile). To allow for comparison between study arms, the routine scheduled RDT data in the ISTp-DP arm were not included. Hb, hemoglobin; IPTp-SP, intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine; IRR, incidence rate ratio; ISTp-DP, intermittent screening and treatment in pregnancy with dihydroartemisinin-piperaquine; py, person-years; RR, relative risk.

Fig 4. Secondary newborn outcomes: birth outcomes and neonatal follow-up.

The P-value for the interaction term depicts the p-value for differences in effect size between paucigravidae and multigravidae. IPTp-SP, intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine; ISTp-DP, intermittent screening and treatment in pregnancy with dihydroartemisinin-piperaquine; RR, relative risk.