Effects of metronidazole plus intermittent preventive treatment of malaria in pregnancy on birth outcomes: a randomised controlled trial in Zambia

In areas of East and Southern Africa, malaria infection during pregnancy and curable sexually transmitted and reproductive tract infections (STIs/RTIs) are very common. About one-third of women in the sub-region are infected with malaria parasites during pregnancy, one-half of them have bacterial vaginosis (BV) and one-quarter are infected with trichomonas vaginalis (TV). All of these cause adverse birth outcomes.

Malaria parasites sequester in the placenta and, therefore, taking conventional blood test may not detect the infection. Thus, the World Health Organization recommends that women who live in malaria-endemic areas receive intermittent preventive treatment (IPTp) using sulphadoxine-pyrimethamine (SP) during their second and third trimesters of pregnancy. However, malaria parasites have developed resistance against SP. An alternative to SP, dihydroartemisinin-piperaquine (DP), has been shown to clear malaria parasites from pregnant women better than SP. However, SP appears also to confer some protection against non-malaria causes of adverse birth outcomes including curable STIs/RTIs. So a switch from SP to DP might not be best. It is possible that SP or DP - if combined with treatment against BV and TV metronidazole (MTZ), a medicine that is also safe to administer in the second and third trimesters of pregnancy - may be better than providing SP, the current standard of care. To examine this, we are proposing a three-arm trial, partially placebo-controlled, that will compare SP plus MTZ placebo versus SP plus MTZ versus DP plus MTZ in a geographic area of north-east Zambia where malaria transmission is high, malaria parasite-resistance to SP is high, and the prevalence of BV and TV in pregnant women is also high.

As part of the main trial, we will also conduct a full economic evaluation of trial interventions establish costs, the incremental cost-effectiveness, and acceptability of the three study treatments using discrete choice experiments. We will ask prospective participants if they will provide vaginal swabs and stool samples which we will use to characterise the effect of treatment across trial arms on the vaginal and intestinal microbiota communities, vaginal and intestinal bacterial loads and identify potential triggers of preterm birth that are related to inflammation. Finally, we will also measure the drug sensitivity of several pathogens implicated with vaginal discharge, lower abdominal pain, or genital ulcers.

Current interventions in sub-Saharan Africa to reduce the burden of malaria infection and curable sexually transmitted and reproductive tract infections (STIs/RTIs) in pregnancy are inadequate. To protect against adverse pregnancy outcomes in malaria-endemic areas, the World Health Organization (WHO) recommends the provision of intermittent preventive treatment of malaria (IPTp) in pregnancy using sulphadoxine-pyrimethamine (SP). However, the loss of parasite sensitivity to SP has compromised this intervention. The WHO recommends the syndromic management of curable STIs/RTIs in low- and middle-income countries. Bacterial vaginosis (BV) and Trichomonas vaginalis (TV) are included in these guidelines. However, syndromic management fails to detect the majority of infections in women. Metronidazole (MTZ), safe during the second and third trimester of pregnancy, is curative of TV and inhibits recurrence of BV.

IPTp using dihydroartemisinin-piperaquine (DP) is the leading candidate to replace IPTp-SP. A trial in Kenya showed that IPTp-DP was superior to IPTp-SP in preventing malaria-related endpoints. However, IPTp-SP was superior to IPTp-DP in reducing the incidence of low birth weight, small-for-gestational age, and preterm birth. A potential explanation is that IPTp-SP also protects against non-malarial causes of adverse pregnancy outcomes.

Thus, we propose a three-arm trial that will compare SP plus MTZ placebo versus SP plus MTZ versus DP plus MTZ in a geographic area of north-east Zambia where malaria transmission is high, malaria parasite-resistance to SP is high, and the prevalence of BV and TV in pregnant women is also high. We will conduct cost-effectiveness analyses and discrete choice experiments, as well as two sub-studies that are key to interpreting results from the main trial and understanding microbiological mechanics of chemoprevention against adverse birth outcomes and antimicrobial resistance.

This trial addresses pressing questions on how to treat malaria infection and sexually transmitted and reproductive tract infections (STIs/RTIS) during pregnancy. Current antenatal care (ANC) interventions recommended by the WHO - specifically IPTp-SP for malaria and the syndromic management of curable STIs/RTIs - are inadequate given the high prevalence of these infection in pregnancy in low- and middle-income countries and their adverse impact on birth outcomes.
Pregnant women in these settings are commonly co-infected with malaria and bacterial vaginosis (BV) or Trichomonas vaginalis (TV), and there is an urgent need for evidence on how to combine preventive treatment of in the context of drug resistance. Widespread malaria parasite resistance to SP has prompted the replacement using DP, and two trials, funded by EDCTP and the MRC, are designed to address the dual-burden of malaria and curable STIs/RTIs with three treatment arms: IPTp-SP versus IPTp-DP versus IPTp-DP plus azithromycin. Azithromycin has a widely established curative effect against Chlamydia trachomatis and Neisseria gonorrhoeae, important curable STIs. However, Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are far less prevalent compared to BV and TV. Moreover, there is substantial concern about azithromycin resistant NG; azithromycin use in IPTp may contribute unnecessarily to the spread of untreatable gonococcus with global health implications. The anticipated impact of our trial will show if there is a safe and cost-effective combination treatment against malarial, BV and TV that can be given to pregnant women to improve birth outcomes without using azithromycin.

Findings from this trial will inform programme and policymakers working on the agenda of global importance: reducing the incidence of preterm birth in low- and middle-income countries where infection is disproportionate driver of adverse birth outcomes. The WHO's Global Malaria Programme and the WHO's Reproductive Health Department are keen to integrate antenatal treatment that will reduce the dual-burden of malaria and curable STIs/RTIs. In addition, we anticipate that results of this trial will allow for direct comparisons across all three trials (the two funded by EDCTP and MRC, and this JGHT application), potentially producing important evidence for new WHO policy recommendations that are aimed at reducing the dual-burden of malaria and curable STIs/RTIs in pregnancy.

Findings from this study will inform researchers from the public and private sectors to aid in the development of new treatment strategies to reduce malaria, BV and TV prevalence in pregnancy, and ultimately, interventions to reduce poor birth outcomes. The population most likely to benefit immediately from our research are pregnant women at living in malaria-endemic regions where there is high malaria, BV and TV prevalence. The burden is considerable in sub-Saharan Africa. A systematic review and meta-analysis published in JAMA5 suggests that, in East and Southern Africa, 32.0% (25.9, 38.0) of pregnant women at ANC facilities had peripheral malaria, 25.8% (19.7, 31.9) had placental malaria; 50.1% (95% CI: 43.3, 58.4%) were diagnosed with BV, and 29.1% (95% CI: 20.9, 37.2) had TV. In West and Central Africa, 38.2% (32.3, 44.1) of women had peripheral malaria and 39.9% (34.2, 45.7) had placental malaria; 37.6% (18.0, 57.2) were diagnosed with BV, and 17.8% (12.4, 23.1) had TV infections. In sub-Saharan Africa, an efficacious intervention against these infections, even one that is partially efficacious, may have profound impact on reducing adverse birth outcomes.