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Prevention of malaria in pregnancy

https://doi.org/10.1016/S1473-3099(18)30064-1Get rights and content

Summary

Malaria remains one of the most preventable causes of adverse birth outcomes. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine–pyrimethamine is used to prevent malaria, but resistance to this drug combination has decreased its efficacy and new alternatives are needed. In Africa, a meta-analysis showed three-course or monthly IPTp with sulfadoxine–pyrimethamine to be safe and more effective than the original two-course sulfadoxine–pyrimethamine strategy, prompting WHO to update its policy in 2012. Although resistance to sulfadoxine–pyrimethamine reduces the parasitological efficacy of IPTp, this drug combination remains associated with reduced incidence of low birthweight in areas where prevalence of parasites with quintuple Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthetase (Pfdhps) mutations is greater than 90%. Nevertheless, its effectiveness is compromised in women infected with sextuple mutant parasites. Six trials of IPTp showed that neither amodiaquine, mefloquine, nor chloroquine–azithromycin are suitable replacements for sulfadoxine–pyrimethamine because of poor tolerability. Furthermore, four trials showed that intermittent screening and treatment with the current generation of malaria rapid diagnostic tests was not a suitable alternative strategy to IPTp with sulfadoxine–pyrimethamine, even in areas with high prevalence of quintuple mutations. Two trials showed that IPTp with dihydroartemisinin–piperaquine was well tolerated, effective, and acceptable for IPTp, with monthly regimens being the most effective. Coverage of IPTp and insecticide-treated nets continues to lag behind targets. The key barriers to uptake are well documented, and many are open to intervention. Outside of Africa, a single trial suggests a potential role for integrated approaches that combine sulfadoxine–pyrimethamine with azithromycin for IPTp in areas of Papua New Guinea where malaria transmission is high. Modelling analysis suggests the importance of the prevention of malaria early in pregnancy and the need to protect pregnant women declines more slowly than the rate at which transmission declines. Improved funding has led to an increase in the number of prevention trials in the past decade, showing the value of more sustained protection with monthly IPTp regimens. There is a need for confirmatory trials of the safety, efficacy, and feasibility of IPTp with dihydroartemisinin–piperaquine, for studies of intermittent screening and treatment with more sensitive rapid diagnostic tests, for studies of integrated strategies for malaria and other co-infections, and for studies of prevention strategies for malaria in pregnant women who are HIV-positive and living outside of Africa. Additional research is required on how to improve uptake of WHO's updated policy on IPTp with sulfadoxine–pyrimethamine and insecticide-treated nets.

Introduction

Plasmodium infections are notable causes of adverse birth outcomes, including fetal loss, intrauterine growth retardation, and preterm delivery.1, 2 In areas in Africa where malaria is endemic, WHO recommends a combination of insecticide-treated nets (ITNs) and either intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine–pyrimethamine for women who are HIV-negative,3, 4 or daily co-trimoxazole prophylaxis for HIV-positive women.5 In areas in Asia and Latin America with low transmission, control of malaria in pregnancy mostly relies on early detection by screening asymptomatic women for malaria at the first antenatal visit, passive case detection of symptomatic cases, and ITNs given as part of antenatal care.

In sub-Saharan Africa, effectiveness of IPTp with sulfadoxine–pyrimethamine is threatened by parasite resistance. In the past decade, several trials have aimed to find alternative drugs for IPTp or alternative strategies that can replace IPTp with screen-and-treat approaches. Herein, we review the effect of resistance to sulfadoxine–pyrimethamine on the effectiveness of IPTp, and summarise trials to prevent malaria in pregnancy, with a focus on the cost-effectiveness, acceptability, operational feasibility, and modelled effect of existing and newer strategies. In addition, we reviewed the status of prevention trials done in endemic areas outside of sub-Saharan Africa.

Section snippets

Efficacy, effectiveness, and cost-effectiveness

For the efficacy component, we found 865 articles, of which 65 (44 reviews and 21 studies) were included. For the cost-effectiveness component, we found 106 articles; 15 of these articles met the inclusion criteria for qualitative synthesis, while none met the criteria for quantitative synthesis (figure 1). The characteristics of the included articles and important results related to efficacy and cost-effectiveness are included in the appendix.

Acceptability, feasibility, and public health impact of malaria prevention in pregnancy

For the acceptability, operational feasibility, and public health impact component, we found 1043 articles, of which 52 were included (36 quantitative, 15 qualitative, and one mixed methods; figure 1). The characteristics of the included articles and important results related to acceptability, operational feasibility, and public health impact are included in the appendix.

Modelling malaria in pregnancy and the effect of interventions

Our search found 62 articles, five of which were included (figure 1). Only three models of the link between malaria transmission and the risk or burden of malaria in pregnancy have been reported (appendix).111, 112, 113 The first relates to the burden of neonatal mortality to malaria in pregnancy and prevalence of malaria transmission by use of a simple empirical hazard-based model.111 The second model covers the relationship between maternal mortality and malaria, including a measure of

Discussion

The past decade has generated substantial evidence to address the research gaps in the prevention of malaria in pregnancy highlighted in 2007.116 Several observational studies15, 16 have shown that sulfadoxine–pyrimethamine has a beneficial effect on birthweight that is surprisingly resilient, even in areas where about 50% of paucigravidae had recurrent infections within 42 days of their first course of IPTp with sulfadoxine–pyrimethamine,15 and this finding is supported by mathematical

Search strategy and selection criteria

We did four separate systematic reviews, one for each of the major topic areas: efficacy and effectiveness, cost-effectiveness, acceptability and feasibility, and modelling impact. The respective search strategies are outlined in the appendix. Our general approach followed PRISMA guidelines; we searched multiple databases for studies and reviews of the prevention of malaria in pregnancy. For each of the four topic areas, we used a two-step strategy whereby we identified and summarised data from

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