Efficacy and safety of intermittent preventive treatment and intermittent screening and treatment versus single screening and treatment with dihydroartemisinin-piperaquine for the control of malaria in pregnancy in Indonesia: a cluster-randomised, open-label, superiority trial

Abstract

Background: Plasmodium 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.

Methods: We 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.

Findings: Between 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.

Interpretation: IST 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.

Funding: Joint Global Health Trials Scheme of the Medical Research Council, Department for International-Development, and the Wellcome Trust.

Figure 1

Trial profile IPT=intermittent preventive treatment. IST=intermittent screening and treatment. SST=single screening and treatment. *The number of recruited participants per cluster was restricted to a maximum of five per day to keep the number needed to follow-up manageable in subsequent visits. On some days, more than five participants were eligible, in which case they were chosen at random by drawing lots among all eligible participants who presented that morning.

Figure 2

IPT versus SST for the primary outcome and key secondary outcomes, overall and by site (modified ITT population) ITT=intention to treat. LAMP=loop-mediated isothermal amplification. IPT=intermittent preventive treatment. SST=single screening and treatment. RR=relative risk. *Adjusted for site (in the overall models only) and six additional, prespecified, participant-level covariates. †Detected by LAMP, PCR, microscopy, or malaria rapid diagnostic test. ‡Detected by LAMP, PCR, microscopy, malaria rapid diagnostic test, or histology (active and past infection). §Defined as fetal loss, low birthweight, small for gestational age, or preterm birth.

Figure 3

IST versus SST in the primary outcome and key secondary outcomes, overall and by site (modified ITT population) ITT=intention to treat. LAMP=loop-mediated isothermal amplification. IST=intermittent screening and treatment. SST=single screening and treatment. RR=relative risk. *Adjusted for site (in the overall models only) and six additional, prespecified, participant-level covariates. †Detected by LAMP, PCR, microscopy, or malaria rapid diagnostic test. ‡Detected by LAMP, PCR, microscopy, malaria rapid diagnostic test, or histology (active and past infection). §Defined as fetal loss, low birthweight, small for gestational age, or preterm birth.

Figure 4

IPT versus IST in the primary outcome and key secondary outcomes, overall and by site (modified ITT population) LAMP=loop-mediated isothermal amplification. IPT=intermittent preventive treatment. IST=intermittent screening and treatment. RR=relative risk.*Adjusted for site (in the overall models only) and six additional, prespecified, participant-level covariates. †Detected by LAMP, PCR, microscopy, or malaria rapid diagnostic test. ‡Detected by LAMP, PCR, microscopy, malaria rapid diagnostic test, or histology (active and past infection). §Defined as fetal loss, low birthweight, small for gestational age, or preterm birth