Devising a strategy for prevention of malaria in pregnant women in the Asia Pacific
Authors: R Matthew Chico, Jorge Cano
Journal: The Lancet Infectious Diseases (2019)

Malaria in pregnancy is a leading cause of adverse pregnancy outcomes in low-income and middle-income countries.1Rogerson SJ Desai M Mayor A Sicuri E Taylor SM van Eijk AM Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem.Lancet Infect Dis. 2018; 18: e107-e118Summary Full Text Full Text PDF PubMed Scopus (119) Google Scholar WHO recommends intermittent preventive treatment (IPT) with sulphadoxine–pyrimethamine in areas of Africa where there is moderate to high transmission of Plasmodium falciparum, the most prevalent malaria species in the region. However, parasite sensitivity to sulphadoxine–pyrimethamine is compromised, particularly in parts of east Africa, prompting trials of IPT with dihydroartemisinin–piperaquine.2Kakuru A Jagannathan P Muhindo MK et al.Dihydroartemisinin–piperaquine for the prevention of malaria in pregnancy.N Engl J Med. 2016; 374: 928-939Crossref PubMed Scopus (134) Google Scholar, 3Kajubi R Ochieng T Kakuru A et al.Monthly sulfadoxine–pyrimethamine versus dihydroartemisinin–piperaquine for intermittent preventive treatment of malaria in pregnancy: a randomised controlled trial.Lancet. 2019; 393: 1428-1439Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 4Desai M Gutman J L'lanziva A et al.Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin–piperaquine versus intermittent preventive treatment with sulfadoxine–pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial.Lancet. 2016; 386: 2507-2519Google Scholar WHO does not have an equivalent prevention strategy for the Asia-Pacific region where we estimate (unpublished) that more than 90 million pregnant women are at risk of malaria. The epidemiological context of the region poses unique challenges. Plasmodium vivax infection is characterised by unpredictable relapses when hypnozoites emerge from dormancy in the liver, and primaquine—the only effective treatment against liver-stage infection—is contraindicated in pregnancy. P falciparum resistance to sulphadoxine–pyrimethamine emerged 40 years ago along the Thai–Cambodia border and quickly saturated the region,5Verdrager J Epidemiology of the emergence and spread of drug-resistant falciparum malaria in South-East Asia and Australasia.J Trop Med Hyg. 1986; 89: 277-289PubMed Google Scholar two decades before WHO recommended its use for IPT in Africa. Malaria transmission intensity is diverse, and most mosquito vectors in the Asia-Pacific region are exophagic, exophilic, and active in early evening, all behaviours that undermine the effectiveness of insecticide-treated bednets and indoor residual spraying.6Rijken MJ McGready R Boel ME et al.Malaria in pregnancy in the Asia-Pacific region.Lancet Infect Dis. 2012; 12: 75-88Summary Full Text Full Text PDF PubMed Scopus (111) Google Scholar In 2012, Indonesia was the first country in the region to implement a strategy of screening and treating malaria at the first antenatal visit, with passive case management provided thereafter.7Hill J Landuwulang CU Hoyt J et al.Evaluation of the national policy of single screening and treatment for the prevention of malaria in pregnancy in two districts in Eastern Indonesia: health provider perceptions.Malaria J. 2018; 17: 309Crossref PubMed Scopus (11) Google Scholar In The Lancet Infectious Diseases, Rukhsana Ahmed and colleagues8Ahmed R Poespoprodjo JR Syafruddin D et al.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.Lancet Infect Dis. 2019; (published online July 25.)http://dx.doi.org/10.1016/S1473-3099(19)30156-2Google Scholar report the results of the first IPT study in the WHO South-East Asia region, a three-arm, open-label, cluster-randomised controlled trial in HIV-negative women from Sumba island (site of low malaria transmission) and southern Papua (site of moderate, year-round, malaria transmission), eastern Indonesia. Participants (of any gravidae between 16 and 30 weeks' gestation) received either single screening with a rapid diagnostic test and treatment with dihydroartemisinin–piperaquine if parasitaemic or passive case detection to delivery, intermittent screening with a rapid diagnostic test at each antenatal visit and treatment with dihydroartemisinin–piperaquine if parasitaemic, or IPT with dihydroartemisinin–piperaquine at monthly visits without screening. The primary endpoint was malaria infection in the mother at delivery. Malaria prevalence was much lower than expected in Sumba, where only one woman of the first 696 tested positive by rapid diagnostic test at enrolment in the single screening and treatment (SST) and intermittent screening and treatment (IST) groups. On the basis of these data, the ethics committee in Indonesia suspended recruitment in Sumba but allowed researchers to re-calculate the sample size for Papua to ensure enough statistical power. Overall, the intention-to-treat analysis showed that malaria prevalence in mothers at delivery was 20·2% (128 of 633) in the SST clusters versus 11·8% (84 of 713) in the IST clusters (relative risk 0·56, 0·40–0·77; p=0·0005) and 11·6% (61 of 528) in the IPT clusters (0·59, 0·42–0·83; p=0·0022). Adjusted analysis found IPT to be significantly more effective at preventing malaria infections than IST (0·69, 0·48–1·00; p=0·050, padjusted=0·0044). These findings suggest that monthly dosing with dihydroartemisinin–piperaquine might be required to clear new P falciparum and P vivax infections and keep relapses of P vivax infection in check. A larger trial of IPT is needed to establish whether monthly IPT with dihydroartemisinin–piperaquine will translate into better birth outcomes relative to SST. Results from Sumba indicate there is a threshold of malaria transmission intensity below which IST and IPT with dihydroartemisinin–piperaquine is no more protective than SST against malaria and, potentially, adverse pregnancy outcomes. By contrast, IPT with sulphadoxine–pyrimethamine in Africa remains protective against low birthweight even in areas where malaria prevalence is extremely low.9Stoner MC Vwalika B Smid M et al.Dosage of sulfadoxine–pyrimethamine and risk of low birth weight in a cohort of Zambian pregnant women in a low malaria prevalence region.Am J Trop Med Hyg. 2017; 96: 170-177Crossref PubMed Scopus (12) Google Scholar A meta-regression analysis of IPT studies in Africa was not able to detect a cutoff of malaria transmission below which sulphadoxine–pyrimethamine no longer protects against low birthweight.10Chico RM Cano J Ariti C et al.Influence of malaria transmission intensity and the 581G mutation on the efficacy of intermittent preventive treatment in pregnancy: systematic review and meta-analysis.Trop Med Int Health. 2015; 20: 1621-1633Crossref PubMed Scopus (41) Google Scholar This finding might be explained, in part, by evidence that IPT with sulphadoxine–pyrimethamine, despite concerning amounts of parasite resistance, confers protection against adverse pregnancy outcomes among women with malaria, as well as among those with curable sexually transmitted infections and reproductive tract infections.11Chico RM Chaponda EB Ariti C Chandramohan D Sulfadoxine–pyrimethamine exhibits dose-response protection against adverse birth outcomes related to malaria and sexually transmitted and reproductive tract infections.Clin Infect Dis. 2017; 64: 1043-1051Crossref PubMed Scopus (36) Google Scholar Dihydroartemisinin–piperaquine alone—as SST, IST, or IPT—is unlikely to provide similar dual-protection, although this might be inconsequential in Indonesia if co-infection is less common than in Africa.12Chaponda EB Chico RM Bruce J et al.Malarial infection and curable sexually transmitted and reproductive tract infections among pregnant women in a rural district of Zambia.Am J Trop Med Hyg. 2016; 95: 1069-1076Crossref PubMed Scopus (13) Google Scholar However, pregnant women in Papua New Guinea probably shoulder a dual-burden of infection,13Mueller I Rogerson S Mola GD Reeder JC A review of the current state of malaria among pregnant women in Papua New Guinea.P N G Med J. 2008; 51: 12PubMed Google Scholar, 14Vallely LM Toliman P Ryan C et al.Prevalence and risk factors of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and other sexually transmissible infections among women attending antenatal clinics in three provinces in Papua New Guinea: a cross-sectional survey.Sex Health. 2016; 13: 420-427Crossref PubMed Scopus (23) Google Scholar similar to their African counterparts.15Chico RM Mayaud P Ariti C Mabey D Ronsmans C Chandramohan D Prevalence of malaria and sexually transmitted and reproductive tract infections in pregnancy in sub-Saharan Africa: a systematic review.JAMA. 2012; 307: 2079-2086Crossref PubMed Scopus (126) Google Scholar Nonetheless, the evidence presented by Ahmed and colleagues is important and shows that IPT with dihydroartemisinin–piperaquine might help to shape a WHO strategy that protects pregnant women in the Asia-Pacific region against P falciparum and P vivax infections. We declare no competing interests. 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 trialIST 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. Full-Text PDF Open Access