Introduction

An estimated 125 million pregnancies are exposed to malaria each year (1). Pregnant women are more susceptible to malaria compared with non-pregnant women placing both mother and fetus at risk of the adverse consequences (2). In areas of low transmission, women acquire limited antimalarial immunity and are susceptible to symptomatic and sometimes severe malaria, and fetal and maternal death (3). In areas of stable malaria transmission, such as in most of sub-Saharan Africa, infection with Plasmodium falciparum in pregnancy is frequently classified as ‘asymptomatic’ (afebrile) and therefore remain undetected (4). If left untreated these infections cause maternal anaemia (5) are a major cause of preventable low birth weight (LBW) (6), a significant risk factor for neonatal and infant death (7). The prevalence of malaria in pregnancy is highest in first time pregnancies and in women aged 15–19 years and decreases with each subsequent pregnancy (2). Malaria is also much more prevalent in HIV-infected women regardless of the number of previous pregnancies (8).

The World Health Organization (WHO) recommends universal coverage with long lasting insecticide-treated nets (LLINs) for the prevention of malaria in pregnancy (8) and, in malaria-endemic areas in Africa, intermittent preventive treatment in pregnancy (IPTp) with at least three doses of sulphadoxine-pyrimethamine (SP) beginning in the second trimester (9).

Methodology summary

In this commentary, we provide an overview of a systematic review of the efficacy of insecticide-treated nets (ITNs) in reducing anaemia, fetal loss and low birth weight in pregnant women from clinical trials (10, 11), and in reducing neonatal mortality from national surveys (12). We review the coverage of ITNs among pregnant women (13), and the barriers to ITN access and use (14).

In the meta-analysis of clinical trials by Gamble et al. (10, 11), the effect of ITNs on the prevention of malaria in pregnancy was compared to no nets or untreated nets. Inclusion criteria were individual or cluster randomized controlled trials of ITNs in pregnant women. Five trials enrolling a total of 6418 pregnant women were included. Three trials (all in Africa) were cluster-randomized providing ITNs to entire village populations and reported the results among pregnant women as a sub-group (n=5455) (15-17). Two trials randomized individual pregnant women - one from western Kenya (n=963) (18) and one from Thailand (n=223) (19). Three studies recruited women of any parity (15, 17, 19), one trial recruited women having their first or second baby (18), and one trial recruited women having their first baby (16). Four trials used permethrin, and one used cyfluthrin as the insecticide on the nets (18). Nets were distributed before pregnancy (2 studies), before the start of the study (1 study), or at the time of recruitment of the pregnant women (2 studies). In one of the five trials, women in both arms also received intermittent preventive therapy.

Primary outcomes were maternal anaemia during pregnancy and infant birth weight. Secondary outcomes included: clinical malaria, peripheral and placental parasitaemia, parasite density, preterm delivery, abortion or still birth, neonatal, infant or maternal death. Two comparisons were made: ITNs compared to no net usage, and ITNs compared to untreated nets.

In a meta-analysis of birth cohorts from 32 national cross-sectional surveys in 25 African countries from 2000-2010, Eisele et al. (12) assessed the effectiveness of malaria prevention in pregnancy (ITNs or IPTp) at preventing low birth weight and neonatal mortality under routine programme conditions in malaria endemic countries. Publicly available datasets from multiple indicator cluster surveys, demographic and health surveys, malaria indicator surveys, and AIDS indicator surveys from 2011 were used. Confounding bias was limited through exact matching on potential confounding factors associated with exposure to malaria prevention (ITNs or IPTp with SP) in pregnancy and birth outcomes, including local malaria transmission, neonatal tetanus vaccination, maternal age and education, and household wealth. Logistic regression modelling was used to test for associations between malaria prevention in pregnancy and low birth weight, and a Poisson regression model for the outcome of neonatal mortality. Both models incorporated the matched strata as a random effect, while accounting for additional potential confounding factors with fixed effect covariates.

Van Eijk et al. (13) used data from nationally representative household surveys from 2009-11 to estimate coverage of intermittent preventive treatment, use of ITNs, and attendance at antenatal clinics by pregnant women in sub-Saharan Africa. Demographic data for births and published data for malaria exposure was used to estimate the number of malaria-exposed births (livebirths and stillbirths combined) for 2010 by country. Factors associated with coverage of intermittent preventive treatment and use of ITNs were explored by meta-regression.

In a systematic review and meta-analysis of 98 studies, Hill et al. (14) explored the factors affecting delivery, access, and use of IPTp and ITNs among healthcare providers and women. Data on barriers and facilitators, and the effect of interventions, were explored using content analysis and narrative synthesis. A meta-analysis of determinants of ITN and IPTp uptake using random effects models, and subgroup analysis to evaluate consistency across interventions and study populations, countries, and enrolment sites, was also performed. Key categories of barriers to uptake of ITNs and IPTp were aligned with findings from the intervention studies to determine the extent to which the interventions addressed known barriers

Evidence summary

Insecticide-treated nets compared to no nets (10)
Severe anaemia during pregnancy
Pooled analysis of data from two cluster-randomized trials showed lower odds of severe anaemia (haemoglobin <70 or 80 g/L) during the third trimester among women receiving ITNs, but the 95% CI did not exclude the possibility of no effect (OR 0.77, 95% CI [0.56 to 1.08], p=0.13). Similarly, estimates of treatment effect for any anaemia (haemoglobin <100 or 110 g/L) were not statistically significant overall. However, in subgroup analysis of women pregnant with up to their fourth child, a statistically significant reduction in any anaemia at birth was observed (HR 0.79, 95% CI [0.65 to 0.96], 1 cluster-randomized trial, p=0.02) (15). In this same trial, mean haemoglobin levels were significantly higher. There was no evidence for an impact on haemoglobin levels in grand multigravidae (fifth pregnancy or above) (15).

Low birth weight (<2.5 kg)
The average birth weight was 55 g (95% CI 21-88), p=0.001, 4 trials) higher in the ITN group in women of low gravidity (first, first two, or first four pregnancies depending on the study report), but no difference was detected in women of higher gravidity groups (-20g, 95% CI -74-33, p=0.45), 2 trials). ITNs were also associated with a 23% reduction in the risk of delivering a low birth weight baby among women of low gravidity in pooled analysis (RR 0.77, 95% CI [0.61 to 0.98], p=0.03; 2 trials), and not in later pregnancies.

Additional outcomes
In pooled analysis of two trials, the risk of peripheral parasitaemia at delivery was reduced with assignment to ITNs (RR 0.76, 95% CI [0.67 to 0.86], p<0.001) as well as the risk of placental parasitaemia (RR 0.79, 95% CI [0.63 to 0.98], p=0.034; 3 trials). The risk of fetal loss was also 33% lower in the ITN arms among women of low gravidity (RR 0.67, 95% CI [0.47 to 0.97], p=0.03; 3 trials), but not among high gravidity women. Preterm delivery, neonatal death and maternal death were not different between groups.

Non-African settings, ITNs against untreated or no nets
The prevalence of anaemia was significantly lower at delivery in the ITN group than the no-net group (RR=0.50, 95% CI 0.29-0.90, p=0.03) or the non-impregnated bed net group (RR=0.63, 95% CI 0.42-0.93, p=0.03). In one study site, but not the other 2, ITNs reduced parasite densities (p=0.049) and the incidence of malaria infection compared to women not using an impregnated net (no nets or untreated nets pooled) (RR=0.50, 95% CI 0.21-1.07, p=0.0563). Relative to women not using an impregnated net, ITNs were not associated with reductions in fetal loss (RR=0.33, 95% CI 0.07-1.43, p=0.1511) or low birth weight (RR=1.01, 95% CI 0.57-1.78, p=1.00).

Neonatal mortality (12)
Results from 32 countries in sub-Saharan Africa, show that LLIN or IPTp use among women in their first or second pregnancies under routine programme conditions was significantly associated with a decreased risk of neonatal mortality (incidence rate ratio 0·82, 95% confidence interval (CrI), 0·698–0·96, p=0.006) and reduced odds of low birth weight (adjusted odds ratio 0·79, 95% CI 0·73–0·86, p<0·0001), compared with newborn babies of mothers with no protection. ITNs in addition to IPTp with SP did not provide additional protection against neonatal mortality, nor did IPTp in addition to ITNs. No interaction between ITNs and IPTp on neonatal mortality was detected. In women with any IPTp, ITN ownership provided significant additional protection against low birth weight among all parities (adjusted OR 0·895; 0·803–0·997, p<0·05); the effect was similar but not significant among women in their first two pregnancies. These results in routine programme conditions are, for the most part, consistent with the efficacy results from controlled trials.

Coverage with ITNs (13)
Of 26.9 million malaria-exposed births across 37 countries, an estimated 10.5 million (38.8%, 95% CI 34.6-43.0) were born to mothers who used an ITN during pregnancy. Antenatal care was attended at least once by 16.3 of 20.8 million women (78.3%, 75.2-81.4; n=26 countries) and at least twice by 14.7 of 19.6 million women (75.1%, 72.9-77.3; n=22 countries). For the countries with previous estimates for 2007, use of ITNs increased from 17.9% (15.1-20.7) to 41.6% (37.2-46.0; n=24 countries) in 2010. A fall in coverage by more than 10% was seen in 3 of 30 countries (Equatorial Guinea, the Gambia and Malawi). High disbursement of funds for malaria control and high total fertility rate were associated with the greatest use of ITNs, whereas a high per-head gross domestic product (GDP) was associated with less use of nets than was a lower GDP. Overall, countries achieved reasonable equity based on socio-economic status, education and location of residence, however high heterogeneity between countries limits relevance. Primigravid women who are most at risk of adverse outcomes were less likely to use ITNs than multigravida women.

Barriers to access and use (14)
Key barriers to pregnant women receiving and using ITNs were women’s low knowledge of ITNs, household or cultural constraints such as low social position or economic dependency, high cost and lack of availability of ITNs. These barriers correlated with the key determinants of ITN use among pregnant women assessed from 27 studies: age, marital status, education, employment status, knowledge about malaria/ITNs, and receipt of IPTp. Younger (under 19 years of age) single women were the least likely to use an ITN as were women with lower education or lower knowledge of malaria or ITNs. Intervention studies which targeted these barriers included social marketing campaigns to increase awareness, and delivery of free or heavily subsidised ITNs through campaigns, antenatal care (ANC) or community-based approaches which aimed to increase access.

Among healthcare providers, key barriers to delivering ITNs to pregnant women were provider knowledge, provider attitudes, health facility organisation, fees for services, and stock-outs of ITNs. No relevant studies that evaluated interventions that directly addressed these provider barriers were identified.

Discussion

Applicability of the results

ITN use in pregnancy under trial conditions is associated with substantial benefits for women and their babies. While the results from these trials are applicable to areas of moderate to high transmission in Africa, only a single trial has been conducted outside of Africa. The promising impact of ITN use on birth weight from clinical trials was mirrored in the meta-analysis of national survey data by Eisele et al. despite concerns that the potential impact in real life settings could be lower than in the trials due to lower coverage and lack of a community or mass effect. The benefits of ITNs were greatest among the most vulnerable women; i.e. those in the first few pregnancies and among women not protected by IPTp. In the advent of universal coverage (8), population-wide coverage can achieve equitable community-wide benefits equivalent to or greater than personal protection, such as that provided by protecting pregnant women or children alone (20).

The evidence for efficacy in areas outside of Africa, which have more complex vector populations, is much more limited. The primary vectors outside of Africa are often less inclined to bite indoors at night, and less dependent upon human blood, so both the personal protection and mass effects may be less dramatic (21, 22).

Implementation in settings with limited resources

The use of ITNs in pregnancy is now recommended by all national malaria control programmes in sub-Saharan Africa, but use among pregnant women remains well below the international target for 2010 of 80% coverage, and even further from the 2015 target of universal coverage. The median use of an ITN the previous night among pregnant women across 37 countries for 2009–2011 was 35.3% (range, 5.2%–75.5%) (13), with only 5 countries exceeding 60% by 2015 (Benin, Madagascar, Mali, Rwanda and Tanzania) (World Malaria Report, 2015). ITN use was higher in areas with both a high disbursement of funds for malaria control and a lower per-head GDP. There have been reports of ITNs being reallocated from routine delivery in ANC clinics to campaign delivery (23) and policy makers have to make difficult decisions to balance costs with the benefits and impact of investments in LLINs. WHO's Malaria Policy Advisory Committee has recommended that routine LLIN distribution (through ANC and EPI) continue “before, during, and after” campaigns, and that this recommendation needs to be adopted by Ministries of Health and donors alike. Future research should focus on improved methods to increase the coverage and use of ITNs among pregnant women.

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Disclaimer

The named authors alone are responsible for the views expressed in this document.

Declarations of interests

Conflict of interest statements were collected from all named authors and no conflicts were identified.