NIHRDataInsights/HRCSData huggingface dataset:
Title: A randomised controlled trial to compare two different doses of maternal B12 supplementation in improving infant B12 deficiency and neurodevelopment
Funder: Department for International Development

Abstract: Supplementation with Iron and folate have been part of a worldwide strategy targeting anaemia and neural tube defects for many years. However, vitamin B12 deficiency has received much less attention. High prevalence of B12 deficiency in mothers in the antenatal period and in their infants has been documented. Multiple case series document the neurological consequences of severe deficiency and their reversal with B12. Trials on the subject are limited and those available have either used an ineffective dose or for a short duration. We propose this randomised controlled trial to compare the efficacy of two different doses of maternal Vitamin B12 supplementation in preventing infant B12 deficiency and adverse neurodevelopment. We propose to undertake a multi-centric trial in India and Nepal at a pay-for-service hospital catering to middle income populace from India and a public hospital catering to lower income groups from Nepal. We will recruit 720 vegetarian, pregnant women from the antenatal clinics of the Indian and Nepalese centres at their first antenatal visit. In Stage 1, recruited mothers will be randomized into 2 equal groups (Intervention and Control). Intervention group will be given daily 250 microgram vitamin B12 supplementation. Control group would receive a daily dose of 50 micrograms vitamin B12 supplementation from 1st trimester and continued up to 6 months post-partum. In Stage 2, the birth and post-delivery course of the new-born will be monitored and documented for any morbidity. At 9 months, the neurodevelopmental, complementary feeding and home environment will be assessed and infant B12 status will be determined. The 2 groups will be compared for the primary (neurodevelopment) and secondary outcomes (biochemical parameters in mother and infant). The results of this study will be used to generate scientific evidence on whether B12 should be supplemented in pregnant women to prevent it's deficiency and adverse neurodevelopment consequences


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Application of PLCzeta-mediated oocyte activation at fertilization to improve the efficacy of Assisted Reproductive Technology (ART)
Funder: Health and Care Research Wales (Welsh Government)

Abstract: The fundamental event during creation of a new life occurs when a fertilizing sperm initiates embryo development by activating the female oocyte. In mammals, activation of the oocyte is mediated by a series of characteristic transients in cytoplasmic calcium (calcium oscillations), which are initiated by a sperm-specific protein factor termed PLCzeta. Calcium oscillations directly influence the efficacy of subsequent embryo development, and may therefore underlie the surprisingly low success rates of current fertility treatments. Considering that infertility affects 1 in 7 (~70 million) couples, while ‘sub-fertility’ affects 1 in 15 men worldwide, it is worrying that fertility treatment success rates remain as low as 22%. Thus, considering the major expense of available fertility treatments, and the fact that multiple ‘cycles’ of treatment are required before a successful pregnancy is established, it is imperative we improve the efficacy of such treatments to provide patients with a transformational improvement in conception rates, and to reduce the financial strain put upon NHS resources. Thus, the proposed project anticipates that utilisation of PLCzeta as a diagnostic test and clinical intervention would benefit couples seeking fertility treatment, significantly enhancing IVF success rates. This project will screen levels of PLCzeta in sperm from a range of fertile and infertile males to examine if PLCzeta is underlying levels of low fertility. Furthermore, the project will examine whether applying a range of PLCzeta improves the efficacy of embryogenesis in a mouse model, to resolve whether this can be utilised as a therapeutic drug within the fertility clinic. Finally, considering the essential role of PLCzeta in male fertility, this project will also investigate the prospects for screening a potentially reversible, non-hormonal male contraceptive, and also for developing a revolutionary assay involving human sperm injection into mouse eggs producing a highly informative functional test for male infertility.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Impact of maternal diet on the epigenome and potentially modifiable effects on offspring health
Funder: Medical Research Council

Abstract: We have discovered that methylation at a key region affecting an imprinted gene expressing a non-coding RNA (VTRNA2-1 also termed nc886) is strongly affected by the season at which a baby is conceived. The evidence points to variations in maternal diet (and hence a mother’s methyl donor metabolome) as being responsible; when methyl donor supply is poor, resulting in a displacement of the intermediary pathways driving methylation (especially the SAM/SAH ratio), there is a higher frequency of offspring showing loss of imprinting. This project has 3 key aims: Aim 1: Extend our analysis of VTRNA2-1 methylation to include 700+ additional mother/infant pairs to better characterise the periods of critical exposure. This will help to refine our insights into the maternal nutritional exposures responsible for loss of imprinting. We will extend our analysis of the maternal methyl donor metabolome to an additional 350 mothers and an extended panel of nutrients and intermediary markers. We will then work with in silico modellers to establish which are the critical drivers of methylation variation; Aim 2: Examine the implications of imprinting or loss of imprinting at VTRNA2-1 on gene expression and cellular function using a recall-by-epigenotype methodology; Aim 3: To design a nutriceutical intervention to prevent disrupted DNA methylation. This aim will be based on insights gained from Aim 1 and will perform small scale preliminary interventions in small groups of non-pregnant women in preparation for anticipated large scale trials.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: HeartLight: Heart Rate Monitoring for Neonatal Resuscitation
Funder: Medical Research Council

Abstract: Approximately 10% of newborns require some form of resuscitation at birth, for example because the baby doesn’t begin breathing after delivery. If babies are not resuscitated effectively they can suffer a range of poor outcomes, for example cerebral palsy due to low oxygen levels. Effective resuscitation is guided by changes in heart rate (HR). Current methods of assessing HR (via a stethoscope) are prone to error, interrupt resuscitation or only give HR after too long (1-2 mins). “HeartLight” is a platform technology for monitoring HR whose effectiveness has already been studied on 210 babies. The objectives, for this joint clinical, design and engineering team, are to integrate the HeartLight optical sensor into a single use newborn hat and undertake clinical studies on newborn babies. The hat will enable clinicians to resuscitate ‘hands-free’, reduce delays and errors, and so improve resuscitation outcomes, giving newborn babies the best start to life.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Integrative epidemiology for exploring how women’s reproductive health influences cardiometabolic health.
Funder: Medical Research Council

Abstract: Our aim is to provide the evidence base that will improve treatment success with IVF and enable stratified and effective antenatal care in IVF and spontaneous conceptions (SC). This is important because up to 40% or pregnancies are affected by one or more of miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, preterm birth or delivery or a small or large for gestational aged infant, but we do not know the best way of preventing these. IVF is now the commonest treatment for infertility with >250K IVF cycles completed per year in the UK and on average 1 in 30 primary school children were born as a result of in vitro fertilisation (IVF). Success rates vary by couple and treatment characteristics but are between 20-30%. There are suggestions that IVF per se, and pregnancy complications in IVF and SC have important adverse effects on future offspring cardio-metabolic health, but whether these associations are causal and if so their magnitude is unclear. Our objectives are to accurately predict and identify causal paths for: (i) response to IVF; (ii) healthy pregnancy and perinatal outcomes in IVF and SC; and (iii) offspring cardio-metabolic health. Methods Our focus will primarily be on maternal smoking, physical activity, sleep patterns, adiposity, pregnancy metabolic profiles and fetal (cord-blood) DNA methylation as potential predictors or risk factors. We will use data from detailed clinical and general pregnancy/birth cohorts. We will work with relevant consortia, including the EuroCHILD pan-European birth cohort that we are involved in establishing from 26 existing cohorts, early growth genetics (EGG) consortia, in which we co-lead maternal-offspring genetic analyses, the Genetics of Diabetes In Pregnancy (GENdip) consortia that we have recently developed, and the pregnancy/birth cohorts working group aligned to the Consortia Of METabolomics Studies (COMETS), which we lead, as well as the Pregnancy And Child Epigenetics (PACE) consortia, which we work closely with alongside Relton’s MRC Integrative Epidemiology Unit programme. We will triangulate results across the following analytical methods applied to these data sources: multivariable regression (MV), Mendelian randomization (MR), non-genetic instrumental variable (IV) analyses, within sibship and negative control studies. Translation Building on our successful impact on clinical guidelines in the first five-years of this programme, we will continue to work with relevant clinicians, patient groups and NICE guideline developers. For new methodological developments we will provide and share datasets and code and widely disseminate these.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Developmental Clinical Studies - Reversing endometrial glucocorticoid deficiency in heavy menstrual bleeding
Funder: Medical Research Council

Abstract: Treatment of menstrual bleeding complaints has a major impact on health care costs. The proposed studies will provide proof of concept of efficacy of the glucocorticoid Dex, together with pharmacodynamic data concerning optimal endometrial Dex concentrations required for efficacy in treatment of women with heavy menstrual bleeding (HMB). The data generated will justify further investment in a phase III trial and new intrauterine delivery systems. A sequence of two studies is proposed with outcome in each being reduction in objectively measured menstrual blood loss (MBL). Study A is an initial open uncontrolled dose-ranging study to assess the effect of Dex on MBL and will explore a range of therapeutic doses. Study B is a follow-on phase II double blind crossover RCT, comparing Dex (at two doses, selected using findings of Study A) to placebo treatment. Assessments to be used are: Patient Clinical History; Recruitment Questionnaire of HMB problem; MBL estimated from daily menstrual bleeding pictogram diaries and objective measurement of MBL measured in 'no treatment' baseline cycles and 2nd of a pair of cycles for each treatment/dose; Menstrual diary (allowing recording of medication consumption, adverse events); Questionnaire report of treatment effect. Endometrial response to luteal phase administration of Dex will be evaluated (including vascular morphology and differentiation) and endometrial Dex concentration assayed by (LCMS/MS). Ovarian function will be monitored by measurement of urinary sex steroid metabolites. Endometrial function will be assessed with DCE-MRI (dynamic contrast-enhanced MR imaging): images will be analysed using pharmacokinetic modelling techniques that monitor changes in uterine permeability kinetics and plasma volume fraction. MR Fluorine Spectroscopy will be used to measure dexamethasone concentrations in endometrium and this will be used simultaneously with MR blood flow measurements.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The Life Cycle And Legacy of Human Oocytes In Health, Age and Infertility
Funder: Medical Research Council

Abstract: Infertility is a major problem which affects 1 in 6 couples. While assisted reproductive technologies (ARTs) have revolutionised the treatment of infertility, treatments remain costly and inefficient and the problems worsen with age. One of the main reasons for the low success rates of ART is poor oocyte quality, as we know little about the mechanisms that confer oocyte developmental competence. We hypothesise that a detailed understanding of the fundamental biology of human oogenesis is vital if we are to define oocyte quality and characterise the impact of age and infertile pathologies on female reproduction. The proposed program of work aims to address these important issues by integrating targeted studies of human oocytes with mechanistic in vivo and in vitro models of oocyte development in sheep. Our multidisciplinary approach will quantify energy and amino acid metabolism, mitochondrial activity, chromosome health and gene expression in the same oocyte. Next generation sequencing will be conducted on staged human oocytes and cumulus cells. This strategy will generate the first high-resolution map of the metabolome, transcriptome and epigenome characterising the milestones of human oogenesis and defining the legacy of human oocytes in the peri-conceptual window. The function of 2 known candidate genes relevant to oocyte development will be tested using siRNAi and we will identify novel biomarkers of oocyte quality. We will quantify the impact of both the sustained endocrine disturbance associated with reproductive ageing and common infertile pathologies and ARTs on key functional and molecular indices of oocyte quality. Data on the transcriptome and metabolome of human oocytes will be used to create a mathematical model of human oocyte quality in health and age. This program of research will significantly advance our understanding of human oocyte biology and will help improve the success of assisted conception and the management of female reproductive health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Fetal Growth Restriction: A Failure of Placental Adaptation In Response To Fetal Nutrient Demand?
Funder: Medical Research Council

Abstract: Fetal growth restriction (FGR), the inability of a fetus to achieve its genetic growth potential, is a major clinical problem. FGR significantly increases the risk of stillbirth and childhood morbidity, whilst being born `small' increases the risk of diseases such as hypertension in adulthood. Whilst placental dysfunction is known to be a major causative factor in FGR, there are multiple aetiologies, many of which are still poorly understood. In normal pregnancy, there is evidence that placentas of differing size alter their nutrient supply capacity, to maintain normal fetal growth. In FGR, this adaptation appears to fail. I hypothesise that in pregnancies leading to appropriate growth of the fetus, there are fetal signals that adapt placental nutrient transfer capacity in order for the fetus to achieve its genetic growth potential. I also hypothesise that in FGR, fetuses either no longer produce these signals or the placenta is unable to respond to fetal signals. This study aims to test these hypotheses and determine the identity of some of the fetal signals that adapt nutrient transfer in normal pregnancies and whether these signals are lacking in FGR pregnancies. In order to meet the aims, metabolomic analysis will be carried out on blood collected from umbilical arteries together with proteomic analysis of placental tissue. This will enable the identification of candidate fetal signals that drive alterations in placental nutrient transport. In addition, candidate fetal signals will be administered specifically on the fetal side of the normal or FGR placenta in an ex-vivo perfused placenta model and their effect on maternofetal nutrient (calcium, amino acid) transport measured. Human studies will be complemented with work on mouse genetic models of abnormal fetal growth.This study will provide the first comprehensive profile of candidate fetal signals that drive placental adaptation and whether these are altered in FGR.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Communication between mother and fetus : Imprinting and endocrine adaptations to pregnancy
Funder: Medical Research Council

Abstract: Late gestation in mammals is accompanied by multiple adaptations of maternal energy homeostasis, to divert maternal resources towards the supply of glucose for the rapidly-growing fetus. These adaptations include a reduction in hepatic lipogenesis and adipose deposition. During pregnancy there is considerable remodelling of the anterior pituitary which causes an increase in somatolactotrophic cells. In addition, the placenta secretes placental lactogen and a pregnancy-specific version of growth hormone (GH). Since GH and its family members cause insulin resistance and inhibit hepatic lipogenesis, increased activity of the pituitary-placental axis is thought to modulate maternal adaptations in late pregnancy. The product of the imprinted Delta-like homologue 1, DLK1, is a signalling molecule that reaches a high concentration in maternal serum from mid to late pregnancy in rodents and humans. We recently discovered that that the conceptus is the source, and that DLK1 may therefore be a novel endocrine signal from fetus to mother. Our studies with genetically-modified mice show that endocrine DLK1 acts to inhibit hepatic lipogenesis and increase beta oxidation in skeletal muscle. Moreover, elevated DLK1 causes an increase in pituitary GH secretion. Using genetic models of altered Dlk1 gene dosage, we will test the hypothesis that DLK1 produced by the conceptus alters the activity of the pituitary-placental axis, modulating important metabolic changes in maternal resource allocation. Moreover, Dlk1 is a member of an imprinted gene network that we propose acts in the maternal pituitary gland during pregnancy. We wish to understand the regulation of this network. Understanding the function of DLK1 and other imprinted genes in pregnancy has potential clinical value since failures of growth and timely development occur when maternal resource allocation is disrupted. Moreover, maternal serum DLK1 could be used as a non-invasive biomarker of poor pregnancy outcome.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The UPBEAT RCT mother-child study. Stratifying and treating obese pregnant women to prevent adverse pregnancy, perinatal and longer term outcomes.
Funder: Medical Research Council

Abstract: The challenge of maternal pregnancy obesity and its associated complications of gestational diabetes (GDM), pre-eclampsia and fetal macrosomia dominates clinical obstetrics worldwide. Insulin resistance, dyslipidaemia, adipocyte and inflammatory mediated processes and vascular endothelial dysfunction are all implicated but in the absence of definitive causal pathways, development of targeted and validated interventions which improve clinical outcomes has yet to be achieved. Emerging evidence also suggests that fetal development is compromised, leading to persistently positive energy balance and childhood obesity.This study attempts to characterise the metabolic pathways leading to GDM, pre-eclampsia, small for gestational age and large for gestational age deliveries in obese pregnant women. We shall also interrogate associations between the metabolic environment in fetal life and childhood obesity. Our strategy includes measuring a portfolio of metabolic markers, previously implicated, as well as NMR metabolic profiling, a validated fast throughput technology (and suitable for NHS labs in due course) with state of the art computational bioinformatics facilitating reliable identification and quantification of molecular species.Once identified, metabolic markers associated with specific outcomes will be combined with clinical risk factors in early pregnancy to model predictive tools for these adverse outcomes which will be validated in an Australian cohort. Associations between maternal metabolic markers and offspring BMI and fat mass at 6 months and 3 years will also be evaluated. This study is facilitated by samples and the database from UPBEAT study, a RCT of a complex intervention in 1546 obese pregnant women which combines dietary and physical activity advice to reduce GDM and fetal macrosomia. Follow up of the children at 3yrs is being undertaken in UPBEAT TEMPO, an EU funded study. These existing studies provide important added value to this project.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH