Abstract
SummaryBackgroundPlasmodium falciparum and Plasmodium vivax infections are important causes of adverse pregnancy outcomes in the Asia-Pacific region. We hypothesised that monthly intermittent preventive treatment (IPT) or intermittent screening and treatment (IST) with dihydroartemisinin–piperaquine is more effective in reducing malaria in pregnancy than the existing single screening and treatment (SST) strategy, which is used to screen women for malaria infections at the first antenatal visit followed by passive case detection, with management of febrile cases.MethodsWe did an open-label, three-arm, cluster-randomised, superiority trial in Sumba (low malaria transmission site) and Papua (moderate malaria transmission site), Indonesia. Eligible participants were 16–30 weeks pregnant. Clusters (antenatal clinics with at least ten new pregnancies per year matched by location, size, and malaria risk) were randomly assigned (1:1:1) via computer-generated lists to IPT, IST, or SST clusters. In IPT clusters, participants received the fixed-dose combination of dihydroartemisinin-piperaquine (4 and 18 mg/kg per day). In IST clusters, participants were screened with malaria rapid diagnostic tests once a month, whereas, in SST clusters, they were screened at enrolment only. In all groups, participants with fever were tested for malaria. Any participant who tested positive received dihydroartemisinin–piperaquine regardless of symptoms. The primary outcome was malaria infection in the mother at delivery. Laboratory staff were unaware of group allocation. Analyses included all randomly assigned participants contributing outcome data and were adjusted for clustering at the clinic level. This trial is complete and is registered with ISRCTN, number 34010937.FindingsBetween May 16, 2013, and April 21, 2016, 78 clusters (57 in Sumba and 21 in Papua) were randomly assigned to SST, IPT, or IST clusters (26 clusters each). Of 3553 women screened for eligibility, 2279 were enrolled (744 in SST clusters, 681 in IPT clusters, and 854 in IST clusters). At enrolment, malaria prevalence was lower in IST (5·7%) than in SST (12·6%) and IPT (10·6%) clusters. At delivery, malaria prevalence was 20·2% (128 of 633) in SST clusters, compared with 11·6% (61 of 528) in IPT clusters (relative risk [RR] 0·59, 95% CI 0·42–0·83, p=0·0022) and 11·8% (84 of 713) in IST clusters (0·56, 0·40–0·77, p=0·0005). Conditions related to the pregnancy, the puerperium, and the perinatal period were the most common serious adverse events for the mothers, and infections and infestations for the infants. There were no differences between groups in serious adverse events in the mothers or in their infants.InterpretationIST was associated with a lower prevalence of malaria than SST at delivery, but the prevalence of malaria in this group was also lower at enrolment, making interpretation of the effect of IST challenging. Further studies with highly sensitive malaria rapid diagnostic tests should be considered. Monthly IPT with dihydroartemisinin–piperaquine is a promising alternative to SST in areas in the Asia-Pacific region with moderate or high transmission of malaria.FundingJoint Global Health Trials Scheme of the Medical Research Council, Department for International-Development, and the Wellcome Trust.
Highlights
Loop mediated isothermal amplification (LAMP) LAMP assays were conducted at the Eijkman institute in Jakarta using to the Eiken LoopampTM MALARIA Pan Detection kit procedures (Eiken Chemical Company, Japan). 15 μL of DNA plus μL of water was added to the malaria Pan reaction tube with one negative and one positive control included in each reactions; primers, buffers and enzymes were reconstituted by inverting the samples in the lid of the reaction tubes, tubes were briefly spun and incubated at 65 °C for 40 minutes before polymerase inactivation at 80 °C for 5 minutes
Conclusion cardiac monitoring DP was associated with a mean prolongation of 20ms of the QTcF interval and 15ms of the QTcB, in pregnant women receiving DP for Intermittent preventive treatment (IPT) in Papua Indonesia
There was one woman with successive asymptomatic increases in QTc interval with subsequent courses, but overall there was no evidence that the QTc prolongation increases with successive number of monthly courses of DP with either Fridericia’s or Bazett’s method
Summary
The initial study design (protocol v2.0) required 26 clusters of 41 women per cluster/arm for an overall sample size of 3198 women. The revised sample size requires a total of 2279 women from 26 clusters per arm; 989 women in Sumba (57 clusters) and 1290 in Timika (21 clusters). It is open label because it will not be possible to blind the participants to their allocation, laboratory staff undertaking trial related diagnostic tests will be blinded. Whether objectives pertain to the the cluster level, the individual participant level or both
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