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

Rukhsana Ahmed, Jeanne R. Poespoprodjo, Din Syafruddin, Carole Khairallah, Cheryl Pace, Theda Lukito, Sylvia S. Maratina, Puji B.S. Asih, Maria A. Santana-Morales, Emily R. Adams, Vera T. Unwin, Christopher T. Williams, Tao Chen, James Smedley, Duolao Wang, Brian Faragher, Richard N. Price, Feiko O. ter Kuile

    Research output: Contribution to journalArticleResearchpeer-review

    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.

    Original languageEnglish
    Pages (from-to)973-987
    Number of pages15
    JournalThe Lancet Infectious Diseases
    Volume19
    Issue number9
    DOIs
    Publication statusPublished - 1 Sep 2019

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    Indonesia
    Malaria
    Safety
    Pregnancy
    Therapeutics
    dihydroartemisinin
    Mothers
    Routine Diagnostic Tests
    Fever

    Cite this

    Ahmed, Rukhsana ; Poespoprodjo, Jeanne R. ; Syafruddin, Din ; Khairallah, Carole ; Pace, Cheryl ; Lukito, Theda ; Maratina, Sylvia S. ; Asih, Puji B.S. ; Santana-Morales, Maria A. ; Adams, Emily R. ; Unwin, Vera T. ; Williams, Christopher T. ; Chen, Tao ; Smedley, James ; Wang, Duolao ; Faragher, Brian ; Price, Richard N. ; ter Kuile, Feiko O. / 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. In: The Lancet Infectious Diseases. 2019 ; Vol. 19, No. 9. pp. 973-987.
    @article{8edc1c1240404927976a18a5e0aafeaa,
    title = "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.",
    author = "Rukhsana Ahmed and Poespoprodjo, {Jeanne R.} and Din Syafruddin and Carole Khairallah and Cheryl Pace and Theda Lukito and Maratina, {Sylvia S.} and Asih, {Puji B.S.} and Santana-Morales, {Maria A.} and Adams, {Emily R.} and Unwin, {Vera T.} and Williams, {Christopher T.} and Tao Chen and James Smedley and Duolao Wang and Brian Faragher and Price, {Richard N.} and {ter Kuile}, {Feiko O.}",
    year = "2019",
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    doi = "10.1016/S1473-3099(19)30156-2",
    language = "English",
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    pages = "973--987",
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    Ahmed, R, Poespoprodjo, JR, Syafruddin, D, Khairallah, C, Pace, C, Lukito, T, Maratina, SS, Asih, PBS, Santana-Morales, MA, Adams, ER, Unwin, VT, Williams, CT, Chen, T, Smedley, J, Wang, D, Faragher, B, Price, RN & ter Kuile, FO 2019, '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', The Lancet Infectious Diseases, vol. 19, no. 9, pp. 973-987. https://doi.org/10.1016/S1473-3099(19)30156-2

    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. / Ahmed, Rukhsana; Poespoprodjo, Jeanne R.; Syafruddin, Din; Khairallah, Carole; Pace, Cheryl; Lukito, Theda; Maratina, Sylvia S.; Asih, Puji B.S.; Santana-Morales, Maria A.; Adams, Emily R.; Unwin, Vera T.; Williams, Christopher T.; Chen, Tao; Smedley, James; Wang, Duolao; Faragher, Brian; Price, Richard N.; ter Kuile, Feiko O.

    In: The Lancet Infectious Diseases, Vol. 19, No. 9, 01.09.2019, p. 973-987.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - 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

    T2 - a cluster-randomised, open-label, superiority trial

    AU - Ahmed, Rukhsana

    AU - Poespoprodjo, Jeanne R.

    AU - Syafruddin, Din

    AU - Khairallah, Carole

    AU - Pace, Cheryl

    AU - Lukito, Theda

    AU - Maratina, Sylvia S.

    AU - Asih, Puji B.S.

    AU - Santana-Morales, Maria A.

    AU - Adams, Emily R.

    AU - Unwin, Vera T.

    AU - Williams, Christopher T.

    AU - Chen, Tao

    AU - Smedley, James

    AU - Wang, Duolao

    AU - Faragher, Brian

    AU - Price, Richard N.

    AU - ter Kuile, Feiko O.

    PY - 2019/9/1

    Y1 - 2019/9/1

    N2 - 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.

    AB - 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.

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