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

BackgroundIn 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 FindingsThis 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.ConclusionsScheduled 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 RegistrationPan African Clinical Trials Registry PACTR201103000280319; ISRCTN Registry ISRCTN69800930

Provider and user acceptability of intermittent screening and treatment for the control of malaria in pregnancy in Malawi

“…This is important given the results of the current trial which found that RDTs only detected around 45% of PCR-positive infections in paucigravidae and 30% in multigravidae; as women were treated according to RDT result, this may explain the higher prevalence of malaria infections at delivery in the ISTp-DP arm [22]. However, it is important to note that the biological impact of such low-level parasitaemia during pregnancy is unclear [37, 38] and the incidence of clinical malaria was not significantly different between the trial arms [22]. Compliance with RDT result was not an issue in the trial setting but it is unclear whether or not non-compliance would be observed in a screening strategy involving asymptomatic pregnant women under routine conditions.…”

“…Both health workers and pregnant women also perceived that DP had fewer side effects than SP for women enrolled in the trial. This is interesting, given that the trial found no significant differences in clinical malaria or adverse events between the two arms [22]. Sentiments regarding the effectiveness of either drug by both health workers and pregnant women influenced their opinions of the concept of prevention versus cure.…”

“…Methods of the main trial have been described elsewhere [22]. Briefly, HIV sero-negative women of all gravidae, between 16 and 28 weeks of gestation presenting for their first antenatal visit were enrolled and randomized to either the ISTp-SP or ISTp-DP arm.…”

“…The aim is to clear existing infections and provide additional post-treatment prophylaxis for 3–6 weeks. ISTp should be delivered at least three times during the second and third trimesters of pregnancy as part of focused ANC (fANC) [21] and ensures only those women who are parasitaemic are exposed to anti-malarial medication [22]. …”

“…However, its effectiveness under operational conditions depends in part on its acceptability to health workers and pregnant women, and opportunities for scale-up. The aim of this study was to assess the perceptions, experiences and attitudes of health workers and pregnant women towards IPTp-SP and ISTp using dihydroartemisinin–piperaquine (DP) within the context of a randomized controlled superiority trial (RCT) conducted in Southern Malawi [22]. …”