NIHRDataInsights/HRCSData huggingface dataset:
Title: Methods for addressing complex causal questions relating to health research in low- and middle-income countries
Funder: Medical Research Council

Abstract: This proposal focuses on three situations in low- and middle-income countries in which epidemiologic data are used to address complex causal questions. The questions identified are complex as they face the problem of causal feedback. That is, interest lies in estimating the causal effect of a variable A on a variable B, but future values of A are also potentially affected by past values of B. For example, it is believed that high fertility leads to high child mortality and also that high child mortality can influence mothers‘ decisions to have more children. If the likely impact of family planning programmes on child mortality is to be estimated, then these two causal pathways - acting in opposing directions - must be teased apart. Three methods (g-computation formula, inverse-probability-weighted-estimation of marginal structural models, g-estimation of structural nested models) have been developed to estimate causal effects in the presence of causal feedback, using longitudinal data. However, these methods suffer from some limitations. The broad aim is to extend the three methods to address some of these limitations, to apply the extended methods in settings where, hitherto, they have not been applied, and in doing so, to make them more accessible to applied researchers. Specifically, inverse-probability-weighted-estimation of MSMs will be extended to deal with repeated time-to-event outcomes, and g-estimation of SNMs will be extended to fit a logistic model for binary outcomes. Attrition can be dealt with in all three methods under the missing at random assumption, but extensions are required to deal with intermittent patterns of missingness. Sensitivity analyses, assessing the robustness of conclusions to violations of structural assumptions (such as missing at random and no unmeasured confounders), will be extended to longitudinal settings. Finally, existing software routines will be extended and new ones written in Stata and R. These objectives are motivated by the need to address important complex causal questions in three settings, and the work will be illustrated using high-quality datasets from these settings. The first concerns the causal effect of episodes of diarrhoea during early childhood on stunting at 24 months. Causal feedback is present since malnourishment (manifested in stunting) also leads to increased risk of diarrhoea. The second concerns the effect of antiretroviral therapy on hospitalisation in HIV-positive individuals. Here, there is feedback between ART use and the important confounder, CD4 count. The final setting is the one mentioned above, concerning the causal effect of fertility on child mortality.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: Intermittent screening and treatment or intermittent preventive therapy for control of malaria in pregnancy in Indonesia
Funder: Medical Research Council

Abstract: BACKGROUND: Malaria in Pregnancy (MiP) can have devastating consequences to mother and newborn, yet the harmful effects are entirely preventable. Annually, 70% of 125.2 million pregnancies in malaria endemic regions occur in the Asia-Pacific region, and cost-effective prevention strategies are urgently needed in this region which has predominantly low-intensity falciparum and vivax transmission. Indonesia is the first country in Asia to introduce systematic screening at first antenatal visit (Single Screening and Treatment: SSTp). SSTp may not detect subsequent infections. A proposed extension is intermittent screening and treatment (ISTp) consisting of repeated screening with rapid diagnostic tests (RDTs) as part of focused antenatal care and treating the RDT positive women with long-acting drugs that also provides several weeks of post-treatment prophylaxis. Screening strategies however may miss low density PCR-positive infections, not detectable by RDT or microscopy. Recently completed surveys in Asia have shown an unexpectedly high prevalence of these infections in asymptomatic pregnant women. Under these circumstances, intermittent preventive therapy (IPTp) is another approach, not yet evaluated in Asia though widely used in sub-Saharan Africa. OBJECTIVES AND METHODS: Open-label three-arm parallel-group multicentre cluster-randomised controlled superiority trial conducted in two rural sites in Eastern Indonesia comparing the efficacy, safety and cost-effectiveness of IPTp and ISTp with the current SSTp strategy. Dihydroartemisinin-piperaquine will be used in all three arms The study is designed to detect 50% reduction in malaria infection at birth from 10% to 5%; Unit of randomization: antenatal clinics. Sample size: 23 clusters of 41 women per arm (N=3198) (Power 90%, alpha 0.025, ICC 0.002, allowing for 20% loss-to-follow-up and 13% efficiency loss due to varying cluster sizes). Secondary endpoints include clinical malaria, maternal anaemia, preterm birth, low birthweight and safety endpoints. Enrolled women of all parities in the 2nd trimester make 3 or 4 scheduled ANC visits 6-8 weeks apart. Infant follow-up is 42 days. Sub-studies of the cost-effectiveness, acceptability/feasibility studies will be conducted alongside the main clinical trial. PARTNERS AND PRODUCT: The project builds on an existing MiP research collaborations between the Liverpool School of Tropical Medicine (trial sponsor), the Eijkman Institute in Jakarta (coordinating Institute) and between the Timika Research Facility in Indonesia, and the Menzies School of Health Research, Australia and is designed to inform national, regional and global policy. It is designed in close collaboration with the policy makers and main implementers in Indonesia, notably the MoH, WHO and UNICEF-Indonesia. The project will take 3.5 years.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: Raising a Child Without the Village? Social Support and Maternal Wellbeing in the Time of COVID-19
Funder: The British Academy

Abstract: Received wisdom holds it takes a village to raise a child. Across Western countries, the social distancing measures deployed in response to COVID-19 have significantly disrupted what remained of traditional support systems. Social support is increasingly recognised as a key determinant of postnatal health, predicting postnatal depression, mother-infant bonding, and breastfeeding outcomes. However, public health research typically focuses on partners and professional ‘medicalised’ support, neglecting the role of wider support and the diverse forms it takes. There is an urgent need to understand how maternal social support networks are being impacted during the COVID-19 pandemic. How social distancing is shifting access to different forms of social support will be elucidated with a UK-wide longitudinal study of mothers with young infants, and the impacts of this on postnatal depression, bonding, and breastfeeding assessed. By identifying the most beneficial network typologies we will evidence optimal targets for support interventions going forward.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: The impact of COVID-19 on service provision and maternal and neonatal outcomes, through the lens of inequalities
Funder: The Health Foundation

Abstract: There are significant inequalities in maternity care and outcomes in England. Black women are five times and Asian women are three times more likely to die than white women during pregnancy, birth and the postpartum period. During the COVID-19 pandemic, there have been substantial shifts in the way that maternity care is delivered. Care provision has had to be modified and maternity units have faced staffing shortages. The effects of these changes on maternity outcomes have not yet been measured, and it is unclear whether these changes have widened or narrowed existing inequalities. This research project will use data that is routinely collected during the course of maternity care to identify changes to outcomes for women and babies during the pandemic, and whether these were related to particular changes in maternity services offered. The study will then identify any maternity units where changes in practice during the pandemic narrowed existing gaps in outcomes between women from different ethnic groups, or units where the impact on existing inequalities was as small as possible. The results of the project will be used to identify priorities for restoration of services, with the aim that inequalities in maternity care that existed prior to the pandemic may be mitigated as part of the evolution towards a ‘new normal’. Recommendations will be provided on how the quality and safety of maternity care can be improved, and how it can ensure that all women, irrespective of their background or place of residence, have access to safe maternity care.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: Development of a low-cost, easy to use diagnostic device suitable for large scale screening of human cytomegalovirus in newborn babies
Funder: Division for Social Care and Health Research (Wales)

Abstract: Stage 1 Electrochemical impedance spectroscopy (EIS) has proven to be a powerful technique for direct and label-free detection of specific molecular binding at the biosensor surface [2-9]. Furthermore, the inclusion of nanomaterials at the surface of the working electrode is known to offer excellent sensitivity having a reported detection limit of 0.1pg/ml when using polycarbonate based nanostructured biosensor to detect dust mite antigen [2]. The proposed impedimetric electrochemical ZnO nanowire biosensor will be fabricated using a novel printing-assisted fabrication technique recently developed and patented at Swansea University [10,11]. The biosensor, consisting of working, counter and reference electrodes will be printed using carbon and Ag/AgCl ink respectively. After printing the electrodes, a solvent ZnO seed layer is then printed onto the working electrode. This seed layer will promote ZnO nanowires to grow selectivity at the working electrode during the hydrothermal growth process [12]. In this process, these ZnO nanowires are grown under ambient pressure and at mild aqueous temperature ( Stage 2 At this stage, the sensitivity of the biosensor will be optimised through varying the length of nanowires at the working electrode, separation of the electrodes and the size of the electrodes. A large number of biosensors (i.e. at least 100 devices) fabricated using an optimised design and fabrication processes will then undergo reproducibility testing at given HCMV concentrations. Furthermore, a portable meter for the EIS measurement will also be constructed. The key deliverables and milestone at this phase is reproducibility testing of the biosensors. Stage 3 The final stage of the project will involve a comparative clinical study to assess validity, sensitivity, and specificity of the biosensor for the detection of HCMV in urine samples. This includes comparisons of detectable concentration levels against PCR techniques used in the Wales Specialist Virology Centre. Tests will be performed using HCMV positive urine samples. Reliability testing, as part of quality assurance testing, will be carried out on a large number of the prototype biosensors to ensure the technology is fit and effective in the detection of HCMV. Finally, the research team will work with industry partner to exploit the route to market on the new diagnostic device. The deliverables of this final phase will consist of filing of Intellectual Property and dissemination of the clinical study results through peer-reviewed journal papers and conference presentations.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: Using linked HIV observational patient level databases to examine risk for and outcome of maternal HIV infection
Funder: Medical Research Council

Abstract: Management of HIV disease is particularly complex in pregnancy, as maternal health needs, the pregnancy itself and the developing fetus all need consideration. Combination antiretroviral therapy (ART), highly effective for preventing HIV disease progression and mother-to-child transmission (MTCT), is widely used in pregnancy despite a lack of robust and long-term safety data. Research is needed to address how best to use cART safely, effectively and appropriately in pregnancy, particularly among emerging groups (including women with complex treatment histories, coinfections, vertically-acquired infection). The aim of this project is to address such contemporary questions central to clinical practice and to public health, and to improve the scientific basis for HIV prevention, diagnosis and optimal management of pregnant women and their infants. This will be achieved through analysis of data collected through the National Study of HIV in Pregnancy and Childhood (NSHPC), a comprehensive dataset of all pregnancies in the UK and Ireland in women with diagnosed HIV infection with ~1600 pregnancies reported annually, and through record linkage within the UK Platform for Integrated Clinical & Research Data in HIV (known as DHICE) and with the NHS Information Centre and ONS. The objectives are: 1) to characterize the contemporary population of HIV-positive pregnant women; 2) to quantify rates of MTCT, explore risk factors for transmission, including drug resistance and coinfections, and examine the use of therapeutic and obstetric interventions to prevent MTCT in newly diagnosed HIV-infected pregnant women and in women with established diagnosis; 3) to investigate adverse pregnancy outcomes among HIV-positive pregnant women and their associations with ART and 4) to evaluate the long-term safety of fetal and neonatal exposure to HIV and ART in uninfected individuals through "flagging" and data linkage.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: Screening for chlamydia related bacteria to prevent miscarriage. Proof of principle study
Funder: Medical Research Council

Abstract: Background: Chlamydiales species in the genitourinary tract may be associated with miscarriage, but no prospective studies have been done and we do not know how common these organisms are in healthy pregnant women.We have 915 stored urine samples from a carefully characterised cohort of pregnant women (mean 7 weeks gestation) recruited in 1998-2000 to a prospective study to investigate the association of bacterial vaginosis or chlamydial infection with miscarriage before 16 weeks. Follow up was 99.8% with a miscarriage rate of 10%. Unfunded preparatory work in 2011-12 confirmed bacterial DNA integrity in stored urines and showed Chlamydiales species including Waddlia chondrophila were detectable. Objectives: To find the prevalence of Chlamydiales species in first void urine samples before 10 weeks gestation, and to see if infection is associated with miscarriage before 16 weeks. Design: Community-based cohort study Setting: 37 general practices and five family planning clinics in south London Participants: 915 pregnant women, mean age 31 years (range 16 to 46), presenting in the community at less than 10 weeks gestation. 22% were from ethnic minorities; and 15% had bacterial vaginosis, 2% C.trachomatis and 1% M.genitalium at baseline. Of these women, 92 miscarried before 16 weeks: 41 at <10 weeks, 40 at 10-12 weeks, and 11 at 13-15 weeks. Thirty nine women (4%) had a preterm birth before 37 weeks gestation. Methods: In 2013-14, samples stored at Statens Serum Institut, Denmark, will be tested using validated Chlamydiales and W.chondrophila specific real-time PCRs. Main outcome measures: Prevalence and predictors of Chlamydiales in 915 women Relative risk of miscarriage before 16 weeks in 894 women with and without Chlamydiales infection at <10 weeks gestation.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: The National Survey of Sexual Attitudes and Lifestyles 2010 (Natsal 2010).
Funder: Wellcome Trust

Abstract: As requested, to ensure that both the Wellcome Trust and the MRC have the same information, the summaries submitted to the MRC have been uploaded (Document 4).


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: Are non-malarial fevers in pregnancy significant causes of under recognised maternal mortality and morbidity and low birth weight in Laos?
Funder: Wellcome Trust

Abstract: Laos had one of the highest maternal mortality rates in Asia at 405/100,000 live births with slow progress in reducing maternal mortality rate. Although obstetric problems are clearly important, the abundance and diversity of infectious diseases in Laos suggests that these may also contribute to maternal mortality and morbidity and poor birth outcomes. That this may be so is suggested by a research project on the aetiology and impact of fever during pregnancy in Vientiane, Laos, for which Dr Vilada Chansamouth is the PI. This has suggested that dengue fever, scrub typhus and murine typhus are key causes of febrile illness during pregnancy and have adverse pregnancy outcomes. However, Vientiane, being the main urban centre in Laos, is atypical of the country and we propose to determine the incidence of fever in pregnant women in a poor rural southern province (Salavan) in a cohort study of 1,800 pregnant women and to determine the causes and impact of non-malarial fevers amongst these women and their newborns. These are the key goals.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: The effectiveness of Mooncups to reduce school absenteeism, and sexual and reproductive harms in Kenyan schoolgirls
Funder: Wellcome Trust

Abstract: Disproportionate mortality and morbidity in adolescent girls in sub-Saharan Africa reflects high HIV and STI prevalence, and poor teen maternal outcomes. Over a quarter of girls report first sexual encounter was forced, and early sexual debut is a risk factor for STIs. These neglected harms prevent attainment of millennium development goals. Sanitation studies identify poor menstrual management and fear of pregnancy as top stressors. Girls use unsanitary products which leak and irritate, impact on school engagement, and exacerbate sexual exposure as males consider them sexually mature, and girls seek money for pads from sex. An FDA approved silicon-bell vaginal receptacle (menstrual cup; Mcup), which collects menstrual blood without leakage, is a potential cost-effective solution to enhance school engagement, reduce sexual exposure and harms, and improve girls' quality of life. This 3-year, open 2-armed cluster-randomised controlled prevention trial will be conducted in western Kenya, an area with high rates of HIV, STI, forced sex, and school drop-out among girls, with a well-established health and demographic surveillance system. It is designed to detect a 33% reduction in absenteeism in girls from 21% to 14%; unit of randomisation: schools. Sample size: 76 paired clusters of 40 girls per cluster; power 90%, alpha 0.05, ICC 0.1; enrolling 7600 girls allowing 20% loss-to-follow-up. Secondary outcomes include Mcup tolerability, HIV incidence, sexual and reproductive tract infections, frequency of partners, forced sex, and age at debut. Data will be generated from unannounced school attendance surveys, pre- and post-HIV testing, 6-weekly nurse screening on Mcup use and infections (with laboratory confirmation), sexual behaviour and quality of life surveys, daily menstrual diaries and social studies over 24 months intervention. Economic sub-studies will examine return on investment for free, subsidised or full cost Mcups. Analysis will be by intention to treat and per-protocol using Poisson regression or negative binomial regression, taking the cluster design into account. The study will have one interim analysis at 12 months. The trial strengthens existing collaborations between Liverpool and Bangor Universities, the KEMRI/CDC Research and Public Health Collaboration, the African Population Health and Research Centre, the Ministries of Public Health and Sanitation, Medical Services, and Education. Advisory support from DFID-sponsored SWASH (school water and sanitation), PATH, the German development agency (GIZ), and WHO Collaborating Centre on Violence, provides further partnership development. Findings will inform policy on prevention and care of adolescent girls, through menstrual solutions, at local, national, and international level, and the cost implications.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION
Title: Group-B streptococci: developing a correlate of protection for future vaccine trials with the help of pregnant Gambian women and their infants.
Funder: Wellcome Trust

Abstract: Group-B Streptococcal (GBS) disease is a major cause of infant mortality and morbidity, but could be prevented by vaccination of pregnant women. Early and late-onset disease may be caused by transmission from a colonised mother to her newborn. Protection from neonatal invasive disease is associated with maternal antibody to certain serotypes of GBS. Therefore, maternal immunization to elicit an antibody response to protect newborns represents an attractive disease prevention strategy for both ea rly- and late-onset disease. Early phases of multivalent GBS-vaccine trials are complete. Efficacy trials are hindered by the need for very large number of individuals to assess if maternal antibody response to the vaccine is effective in preventing neonatal disease. Thus an alternative laboratory test to predict serotype-specific vaccines effectiveness is needed. The global effectiveness of GBS vaccines is also uncertain due to variations in serotype by geographical region and only few datasets exist from these settings. This project aims to understand the association of newborn bacterial carriage with serotype-specific antibody transferred from their mothers. It will then use a laboratory marker to test effectiveness of these antibodies to kill GBS in vitro in order to inform future vaccine development and testing to prevent this disease.


Research activity codes: 3.4 VACCINES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;INFECTION