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

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Infectious and Tropical Diseases

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description Children's Investment Fund Foundation (CIFF) Consortium on Low Birthweight 
Organisation Children's Investment Fund Foundation
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution The ASPIRE Trial has been used to inform CIFF - world's largest philanthropy that focuses specifically on improving children's lives - on antenatal interventions that will reduce the incidence of low birthweight (LBW). This partnership has also led to involvement in a study in Kenya and Tanzania entitled, "Determining the impact of an enhanced support package for birth weight measurement on the estimate of LBW prevalence in Kenya and Tanzania: A historically controlled study." Because of this partnership, the ASPIRE Trial is using the most precise baby scales on the market (manufactured in the UK) that measure newborn weight in increments of 2 grams.
Collaborator Contribution Study questions: 1. What is the prevalence of LBW among children born in health facilities in selected health districts in Kenya and Tanzania? 2. Will the introduction of an enhanced support package (i.e. use of improved scales and standard operating procedures, and enhanced staff supervision and feedback) result in a different estimate of LBW prevalence than the current practice in the selected health facilities? Study design This is a historically controlled study with a Prospective Study Group and a Historical Control Group. The target population (for external validity) is all newborn babies born in health facilities in the selected districts in Kenya and Tanzania. The study sample is chosen from newborn babies born in the selected health facilities in the selected districts in Kenya and Tanzania, born either during the prospective data collection period (Prospective Study Group), or during the same calendar months in the preceding year (Historical Control Group). Prospective Study Group: includes provision of an enhanced support package for birth weight measurement to improve the quality of birth weight data. Historical Control Group: Birth weight data were collected using routine weight measuring practices and equipment as part of the normal practice at health facilities.
Impact Ongoing
Start Year 2019
 
Description Imperial College London - Faculty of Medicine, Department of Metabolism, Digestion and Reproduction 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution One of the swabs that we are collecting from pregnant women during antenatal consultations will be used to measure maternal cytokines. We hope to be able to show differing cytokine profiles among pregnant women that reflect their treatment allocation and infection profiles.
Collaborator Contribution TDRC is collecting these vaginal swabs and preserving them in -80 freezers for future DNA extraction and cytokine analysis at Imperial College.
Impact Ongoing
Start Year 2018
 
Description Sekisui Medical / Diagnostics - Rapid Point of Care Testing 
Organisation Sekisui Medical
Country Japan 
Sector Hospitals 
PI Contribution This is related to the collaboration with the WHO that involves evaluating the rapid point of care tests for trichomoniasis and bacterial vaginosis.
Collaborator Contribution This evaluation of these two POC tests lays the groundwork for broader antenatal use of in Zambia and other low- and middle-income countries where laboratory facilities and trained are unable to provide timely diagnoses for pregnant women
Impact Ongoing
Start Year 2018
 
Description Tropical Disease and Research Centre (TDRC) in Zambia 
Organisation Tropical Disease Research Centre
Country Zambia 
Sector Academic/University 
PI Contribution The Tropical Disease and Research Centre (TDRC) in Zambia is our in-country research partner and liaison with the National Health Research Authority (NHRA), the Zambia Medicines Regulatory Authority (ZAMRA), and the five participating health facilities in the Nchelenge District where the trial is being conducted. With TDRC, we have trained nearly 100 Zambian healthcare professionals in the principles of Good Clinical Practice (GCP), all of whom are now GCP certified. With TDRC, we have trained the same staff members in electronic data capture, using tablets to reduce data-entry error and improve our ability to monitor activities on a daily basis. The TDRC has positioned all necessary consumables for the microbiology components of the trial.
Collaborator Contribution The TDRC has facilitated our links with the Chief Medical Officers at the Provincial and District levels. Indeed, these efforts have led the District Medical Officer to secure and invest additional financial resources for facilities where the trial is being conducted. The District Medical Officer is fully engaged in the trial, has formally become a co-investigator and has expressed interest in pursuing post-graduate studies at the London School of Hygiene and Tropical Medicine.
Impact We have enrolled enrolled more than 350 women into the ASPIRE trial and trained nearly 100 health care providers in GCP as of 10 March 2020.
Start Year 2018
 
Description University College London Institute of Child Health 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Sample collection is ongoing with the aim of characterising the effect of treatment across trial arms on the vaginal and intestinal microbiota communities, vaginal and intestinal bacterial loads.
Collaborator Contribution We have worked closely with TDRC to ensure that samples of the vaginal and intestinal microbiota are collected and preserved in -80 conditions for future batch analyses in partnership with the University College London.
Impact Ongoing
Start Year 2019
 
Description University of Bern 
Organisation University of Bern
Department Institute of Social and Preventive Medicine
Country Switzerland 
Sector Academic/University 
PI Contribution This partnership with the University of Bern in Switzerland has resulted in leveraging an additional CHF 20,300 for our Zambian partner, TDRC, to conduct qualitative research in the context of the ASPIRE trial. The grant is through the Swiss Network for International Research and is entitled, "Political prioritisation of the prevention and control of sexually transmitted infections: a global challenge."
Collaborator Contribution Research question What drives the position of STIs on the global health policy agenda? How do issues such as actor power, issue framing and contestation of disease burden contribute? What role does civil society play? Methodology We will use interdisciplinary methods, including policy analysis, epidemiology, anthropology, media and gender analysis to address three specific, but linked objectives. Objective 1: Determine factors influencing the political prioritisation of STIs as a global health issue We will use a theoretical framework to analyse the political prioritisation of STIs using process-tracing, document analysis and stakeholder interviews. Objective 2: Estimate the total burden of disease due to STI Using the 2017 Global Burden of Disease study and 2016 WHO estimates, we will generate new consensus estimates of the total burden of STI, including previously unattributed conditions such as STI in pregnancy. Objective 3: Examine community and key informant beliefs We will conduct comparative qualitative research nested in ongoing trials in Papua New Guinea and Zambia to explore the views of pregnant women and key informants about STIs and their prevention. Expected results and their relevance We will produce an analysis of STIs on the global agenda, understanding the roles that empirical evidence, community perceptions and stakeholder views play in agenda-setting. The findings will help to leverage opportunities to move STIs higher up global policy agendas.
Impact Ongoing
Start Year 2019
 
Description University of Exeter Medical School 
Organisation University of Exeter
Department Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We have worked closely with the co-investigator at the University of Exeter Medical School to tailor data collection for cost-effectiveness analyses on electronic tablets during the second antenatal visit. This is ongoing. We also facilitated a best-worst preference ranking to identify a flavour of candy to be given to pregnant women at the time of dosing to mask metallic taste of the treatment. This has been a novel experiment in the antenatal setting.
Collaborator Contribution Cost-effectiveness data collection is ongoing, but we completed the best-worst preference ranking in November 2019 and are in the process of preparing a report on the methods and results.
Impact Ongoing
Start Year 2019
 
Description WHO - Department of Reproductive Health Research (RHR), in HRP (the UNDP/UNFPA/UNICEF/WHO/World Bank Special programme of research, development and research training in human reproduction). 
Organisation World Health Organization (WHO)
Department Department of Reproductive Health and Research
Country Global 
Sector Academic/University 
PI Contribution Within the ASPIRE trial, we will evaluate two rapid Point of Care (POC) tests that have been prioritised by the WHO specifically manufactured by Sekisui Diagnostics: OSOM ® BVBLUE ® and OSOM ® Trichomonas Rapid Test. We will evaluate the positive predictive value and negative predictive value of two rapid tests. We will validate our POC test results versus gold standard results (PCR for trichomonas and Nugent scoring for bacterial vaginosis) by having the WHO reference laboratory in Sweden carry out Quality Assurance testing.
Collaborator Contribution WHO has provided the Co-Chief Investigator the POC testing protocol and will facilitate links with the WHO reference laboratory.
Impact Ongoing
Start Year 2018
 
Description STI & HIV 2019 World Congress in Vancouver, Candata, July 14 - 17, 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Co-Chief Investigator, R Matthew Chico, was invited to present results from a pregnancy cohort study conducted in Zambia and overview of the ASPIRE trial during the Pre-Congress Symposium entitled "The global challenges and opportunities of STIs in pregnancy" at the STI & HIV 2019 World Congress in Vancouver, Canada, July 14 - 17, 2019. In addition to reaching Congress attendees, we have prepared a scoping review of literature and manuscript entitled, "Sexually transmitted infections in pregnancy: global challenges and opportunities," that has been submitted to the Journal of STDs and is currently under peer review.
Year(s) Of Engagement Activity 2019
URL https://stihiv2019vancouver.com/event/pre-congress-symposium-3-the-global-challenges-and-opportuniti...