Reproductive and cardio-metabolic health

Lead Research Organisation: University of Bristol

Abstract

We are trying to find out how to improve the success of in-vitro fertilisation (IVF) and make sure that women who have conceived by IVF or ‘naturally’ have a healthy pregnancy and birth.
IVF is common. In an average school class of 30 children 1 will have been born by IVF. New ways of using IVF might improve success rates but they need to be carefully evaluated.
Whether women conceive by IVF or naturally up to 40% will have one or more of pregnancy loss, high blood pressure or high blood sugar in pregnancy, a premature birth or an infant who is born unhealthily small or large. We do not know how to prevent these problems or predict which women will experience them.
We will use data from very large studies and new methods that help us to determine causes from ‘confounders’ (factors that fool us into thinking that something is a cause when it is not). This will allow us to work out how to improve IVF and prevent pregnancy problems. It will also improve our understanding of what risk factors in pregnancy affect children’s risk of being obese or having diabetes or heart problems later in their lives.

Technical Summary

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.

Publications

10 25 50

publication icon
Carlsen EØ (2020) Stumped by the Hump: The Curious Rise and Fall of Norwegian Birthweights, 1991-2007. in Epidemiology (Cambridge, Mass.)

 
Description A longitudinal population-based study of the development of cardiovascular risk in early childhood
Amount $1,217,906 (AUD)
Funding ID APP1164212 
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 10/2018 
End 09/2023
 
Description BHF Accelerator award
Amount £1,000,000 (GBP)
Funding ID AA/18/7/34219 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2019 
End 03/2023
 
Description Cardiometabolic health of women with and without adverse pregnancy outcomes: An electronic health records study
Amount £249,879 (GBP)
Funding ID PG/19/21/34190 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2020 
End 12/2023
 
Description Developing and Applying Statistical Genetics Methods to Elucidate the Developmental Origins of Health and Disease
Amount $327,387 (AUD)
Funding ID 1183074 
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 01/2020 
End 12/2022
 
Description Healthy Lives Malawi: Intergenerational Cohort of Chronic Conditions.
Amount £4,930,605 (GBP)
Funding ID 217013/Z/19/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2019 
End 09/2024
 
Description Identifying maternal and fetal genetic determinants of infant birthweight and their relationship to offspring cardiometabolic risk
Amount $367,992 (AUD)
Funding ID APP1157714 
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 11/2018 
End 10/2023
 
Description Innovating behaviour and health surveillance for cardiovascular disease prevention in Malaysia
Amount £281,479 (GBP)
Funding ID MR/T018984/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2019 
End 11/2021
 
Description The Avon Longitudinal Study of Parents and Children (ALSPAC): A multi-generation, longitudinal resource focusing on life course health and well-being.
Amount £8,327,295 (GBP)
Funding ID 217065/Z/19/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2019 
End 08/2024
 
Title Mendelian Randomization Dictionary 
Description An only easily searchable dictionary of Mendelian randomization methods, which we keep up to date and have a facility for users to inform us of updates or corrects they feel should be in the Dictionary We are currently working on making a web interface that supports greater interaction with it by users and an app 
Type Of Material Improvements to research infrastructure 
Year Produced 2019 
Provided To Others? Yes  
Impact Has been accessed over 4 million times; down loaded over 400 times & cited four times 
URL https://osf.io/6yzs7/
 
Description AR- Health 
Organisation National University of Singapore
Country Singapore 
Sector Academic/University 
PI Contribution We lead this collaboration which is establishing data sources and methods to determine the causal effects of different forms of medical Artificial Reproduction on Health (AR-Health). We have identified relevant studies, harmonised data across them and developed the appropriate methods for analysing these data.
Collaborator Contribution Partners are contributing data and expertise.
Impact The collaboration in multi-disciplinary, with expertise in epidemiology, biostatistics, data science, law, and clinicians from reproductive health, obstetrics and neonatology. This is a new collaboration and too new to have had impact or publication outputs yet.
Start Year 2020
 
Description AR- Health 
Organisation Norwegian Institute of Public Health
Country Norway 
Sector Public 
PI Contribution We lead this collaboration which is establishing data sources and methods to determine the causal effects of different forms of medical Artificial Reproduction on Health (AR-Health). We have identified relevant studies, harmonised data across them and developed the appropriate methods for analysing these data.
Collaborator Contribution Partners are contributing data and expertise.
Impact The collaboration in multi-disciplinary, with expertise in epidemiology, biostatistics, data science, law, and clinicians from reproductive health, obstetrics and neonatology. This is a new collaboration and too new to have had impact or publication outputs yet.
Start Year 2020
 
Description AR- Health 
Organisation University College Cork
Country Ireland 
Sector Academic/University 
PI Contribution We lead this collaboration which is establishing data sources and methods to determine the causal effects of different forms of medical Artificial Reproduction on Health (AR-Health). We have identified relevant studies, harmonised data across them and developed the appropriate methods for analysing these data.
Collaborator Contribution Partners are contributing data and expertise.
Impact The collaboration in multi-disciplinary, with expertise in epidemiology, biostatistics, data science, law, and clinicians from reproductive health, obstetrics and neonatology. This is a new collaboration and too new to have had impact or publication outputs yet.
Start Year 2020
 
Description AR- Health 
Organisation University of Amsterdam
Country Netherlands 
Sector Academic/University 
PI Contribution We lead this collaboration which is establishing data sources and methods to determine the causal effects of different forms of medical Artificial Reproduction on Health (AR-Health). We have identified relevant studies, harmonised data across them and developed the appropriate methods for analysing these data.
Collaborator Contribution Partners are contributing data and expertise.
Impact The collaboration in multi-disciplinary, with expertise in epidemiology, biostatistics, data science, law, and clinicians from reproductive health, obstetrics and neonatology. This is a new collaboration and too new to have had impact or publication outputs yet.
Start Year 2020
 
Description AR- Health 
Organisation University of Auckland
Country New Zealand 
Sector Academic/University 
PI Contribution We lead this collaboration which is establishing data sources and methods to determine the causal effects of different forms of medical Artificial Reproduction on Health (AR-Health). We have identified relevant studies, harmonised data across them and developed the appropriate methods for analysing these data.
Collaborator Contribution Partners are contributing data and expertise.
Impact The collaboration in multi-disciplinary, with expertise in epidemiology, biostatistics, data science, law, and clinicians from reproductive health, obstetrics and neonatology. This is a new collaboration and too new to have had impact or publication outputs yet.
Start Year 2020
 
Description AR- Health 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution We lead this collaboration which is establishing data sources and methods to determine the causal effects of different forms of medical Artificial Reproduction on Health (AR-Health). We have identified relevant studies, harmonised data across them and developed the appropriate methods for analysing these data.
Collaborator Contribution Partners are contributing data and expertise.
Impact The collaboration in multi-disciplinary, with expertise in epidemiology, biostatistics, data science, law, and clinicians from reproductive health, obstetrics and neonatology. This is a new collaboration and too new to have had impact or publication outputs yet.
Start Year 2020
 
Description AR- Health 
Organisation University of Paris
Country France 
Sector Academic/University 
PI Contribution We lead this collaboration which is establishing data sources and methods to determine the causal effects of different forms of medical Artificial Reproduction on Health (AR-Health). We have identified relevant studies, harmonised data across them and developed the appropriate methods for analysing these data.
Collaborator Contribution Partners are contributing data and expertise.
Impact The collaboration in multi-disciplinary, with expertise in epidemiology, biostatistics, data science, law, and clinicians from reproductive health, obstetrics and neonatology. This is a new collaboration and too new to have had impact or publication outputs yet.
Start Year 2020
 
Description AR- Health 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution We lead this collaboration which is establishing data sources and methods to determine the causal effects of different forms of medical Artificial Reproduction on Health (AR-Health). We have identified relevant studies, harmonised data across them and developed the appropriate methods for analysing these data.
Collaborator Contribution Partners are contributing data and expertise.
Impact The collaboration in multi-disciplinary, with expertise in epidemiology, biostatistics, data science, law, and clinicians from reproductive health, obstetrics and neonatology. This is a new collaboration and too new to have had impact or publication outputs yet.
Start Year 2020
 
Description AR- Health 
Organisation University of Turin
Country Italy 
Sector Academic/University 
PI Contribution We lead this collaboration which is establishing data sources and methods to determine the causal effects of different forms of medical Artificial Reproduction on Health (AR-Health). We have identified relevant studies, harmonised data across them and developed the appropriate methods for analysing these data.
Collaborator Contribution Partners are contributing data and expertise.
Impact The collaboration in multi-disciplinary, with expertise in epidemiology, biostatistics, data science, law, and clinicians from reproductive health, obstetrics and neonatology. This is a new collaboration and too new to have had impact or publication outputs yet.
Start Year 2020
 
Description LifeCycle - IVF cohort 
Organisation Barcelona Institute for Global Health
Country Spain 
Sector Multiple 
PI Contribution We are the central organisers of the collaboration. We draft analysis plans, share these with partners, undertake individual participant study analyses and meta-analyses of data across all studies. We will write the first draft of initial papers and redraft following in put from partners
Collaborator Contribution Partners: 1. Contribute to the development of analysis plans 2. Provide individual participant data or summary results 3. Contribute to drafting manuscripts
Impact Too early for outputs
Start Year 2018
 
Description LifeCycle - IVF cohort 
Organisation Bradford Teaching Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We are the central organisers of the collaboration. We draft analysis plans, share these with partners, undertake individual participant study analyses and meta-analyses of data across all studies. We will write the first draft of initial papers and redraft following in put from partners
Collaborator Contribution Partners: 1. Contribute to the development of analysis plans 2. Provide individual participant data or summary results 3. Contribute to drafting manuscripts
Impact Too early for outputs
Start Year 2018
 
Description LifeCycle - IVF cohort 
Organisation Erasmus University Rotterdam
Country Netherlands 
Sector Academic/University 
PI Contribution We are the central organisers of the collaboration. We draft analysis plans, share these with partners, undertake individual participant study analyses and meta-analyses of data across all studies. We will write the first draft of initial papers and redraft following in put from partners
Collaborator Contribution Partners: 1. Contribute to the development of analysis plans 2. Provide individual participant data or summary results 3. Contribute to drafting manuscripts
Impact Too early for outputs
Start Year 2018
 
Description LifeCycle - IVF cohort 
Organisation Norwegian Institute of Public Health
Country Norway 
Sector Public 
PI Contribution We are the central organisers of the collaboration. We draft analysis plans, share these with partners, undertake individual participant study analyses and meta-analyses of data across all studies. We will write the first draft of initial papers and redraft following in put from partners
Collaborator Contribution Partners: 1. Contribute to the development of analysis plans 2. Provide individual participant data or summary results 3. Contribute to drafting manuscripts
Impact Too early for outputs
Start Year 2018
 
Description LifeCycle - IVF cohort 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution We are the central organisers of the collaboration. We draft analysis plans, share these with partners, undertake individual participant study analyses and meta-analyses of data across all studies. We will write the first draft of initial papers and redraft following in put from partners
Collaborator Contribution Partners: 1. Contribute to the development of analysis plans 2. Provide individual participant data or summary results 3. Contribute to drafting manuscripts
Impact Too early for outputs
Start Year 2018
 
Description LifeCycle - IVF cohort 
Organisation University of Groningen
Country Netherlands 
Sector Academic/University 
PI Contribution We are the central organisers of the collaboration. We draft analysis plans, share these with partners, undertake individual participant study analyses and meta-analyses of data across all studies. We will write the first draft of initial papers and redraft following in put from partners
Collaborator Contribution Partners: 1. Contribute to the development of analysis plans 2. Provide individual participant data or summary results 3. Contribute to drafting manuscripts
Impact Too early for outputs
Start Year 2018
 
Description LifeCycle - IVF cohort 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution We are the central organisers of the collaboration. We draft analysis plans, share these with partners, undertake individual participant study analyses and meta-analyses of data across all studies. We will write the first draft of initial papers and redraft following in put from partners
Collaborator Contribution Partners: 1. Contribute to the development of analysis plans 2. Provide individual participant data or summary results 3. Contribute to drafting manuscripts
Impact Too early for outputs
Start Year 2018
 
Description LifeCycle - IVF cohort 
Organisation University of Turin
Country Italy 
Sector Academic/University 
PI Contribution We are the central organisers of the collaboration. We draft analysis plans, share these with partners, undertake individual participant study analyses and meta-analyses of data across all studies. We will write the first draft of initial papers and redraft following in put from partners
Collaborator Contribution Partners: 1. Contribute to the development of analysis plans 2. Provide individual participant data or summary results 3. Contribute to drafting manuscripts
Impact Too early for outputs
Start Year 2018
 
Description MR-PREG 
Organisation Bradford Teaching Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Our contributions are: 1. Draft analysis plans 2. Complete analyses 3. Draft papers 4. Support other partners to lead projects
Collaborator Contribution Partners contribute to: 1. Analysis plans. So far these have been initially written by my group but partners make important contributions to revising the first draft (before we begin analyses) and to any decisions about any revisions after analyses have started 2. Data provision and/or analyses. Participants provide individual participant data for analyses in Bristol and/or undertake analyses in their groups and provide summary results 3. Critical comments on drafted papers
Impact Analyses have been completed but no publications yet.
Start Year 2018
 
Description MR-PREG 
Organisation Harvard University
Country United States 
Sector Academic/University 
PI Contribution Our contributions are: 1. Draft analysis plans 2. Complete analyses 3. Draft papers 4. Support other partners to lead projects
Collaborator Contribution Partners contribute to: 1. Analysis plans. So far these have been initially written by my group but partners make important contributions to revising the first draft (before we begin analyses) and to any decisions about any revisions after analyses have started 2. Data provision and/or analyses. Participants provide individual participant data for analyses in Bristol and/or undertake analyses in their groups and provide summary results 3. Critical comments on drafted papers
Impact Analyses have been completed but no publications yet.
Start Year 2018
 
Description MR-PREG 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Our contributions are: 1. Draft analysis plans 2. Complete analyses 3. Draft papers 4. Support other partners to lead projects
Collaborator Contribution Partners contribute to: 1. Analysis plans. So far these have been initially written by my group but partners make important contributions to revising the first draft (before we begin analyses) and to any decisions about any revisions after analyses have started 2. Data provision and/or analyses. Participants provide individual participant data for analyses in Bristol and/or undertake analyses in their groups and provide summary results 3. Critical comments on drafted papers
Impact Analyses have been completed but no publications yet.
Start Year 2018
 
Description MR-PREG 
Organisation Norwegian Institute of Public Health
Country Norway 
Sector Public 
PI Contribution Our contributions are: 1. Draft analysis plans 2. Complete analyses 3. Draft papers 4. Support other partners to lead projects
Collaborator Contribution Partners contribute to: 1. Analysis plans. So far these have been initially written by my group but partners make important contributions to revising the first draft (before we begin analyses) and to any decisions about any revisions after analyses have started 2. Data provision and/or analyses. Participants provide individual participant data for analyses in Bristol and/or undertake analyses in their groups and provide summary results 3. Critical comments on drafted papers
Impact Analyses have been completed but no publications yet.
Start Year 2018
 
Description MR-PREG 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution Our contributions are: 1. Draft analysis plans 2. Complete analyses 3. Draft papers 4. Support other partners to lead projects
Collaborator Contribution Partners contribute to: 1. Analysis plans. So far these have been initially written by my group but partners make important contributions to revising the first draft (before we begin analyses) and to any decisions about any revisions after analyses have started 2. Data provision and/or analyses. Participants provide individual participant data for analyses in Bristol and/or undertake analyses in their groups and provide summary results 3. Critical comments on drafted papers
Impact Analyses have been completed but no publications yet.
Start Year 2018
 
Description MR-PREG 
Organisation University of Oulu
Country Finland 
Sector Academic/University 
PI Contribution Our contributions are: 1. Draft analysis plans 2. Complete analyses 3. Draft papers 4. Support other partners to lead projects
Collaborator Contribution Partners contribute to: 1. Analysis plans. So far these have been initially written by my group but partners make important contributions to revising the first draft (before we begin analyses) and to any decisions about any revisions after analyses have started 2. Data provision and/or analyses. Participants provide individual participant data for analyses in Bristol and/or undertake analyses in their groups and provide summary results 3. Critical comments on drafted papers
Impact Analyses have been completed but no publications yet.
Start Year 2018
 
Description UCLEB 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Country United Kingdom 
Sector Academic/University 
PI Contribution One of the key partners Collaboration is concerned with the use of genetics in risk prediction and aetiology (Mendelian randomization) of cardiometabolic disease. Includes the use of metabolomics
Collaborator Contribution As above
Impact Large number of publications - See CV
Start Year 2007
 
Description UCLEB 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution One of the key partners Collaboration is concerned with the use of genetics in risk prediction and aetiology (Mendelian randomization) of cardiometabolic disease. Includes the use of metabolomics
Collaborator Contribution As above
Impact Large number of publications - See CV
Start Year 2007
 
Description UPBEAT RCT 
Organisation King's College London
Department Women's Health Academic Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-applicant on a recently obtained MRC grant related to adding metabolomics data to this RCT I will lead analyses of this RCT and the LIMIT RCT (see other entry) in relation to long term mother and offspring outcomes in particular adiposity and metabolomics outcomes.
Collaborator Contribution See entry for LIMIT RCT collaboration
Impact Successful grant Poston L, Lawlor DA, Nelson SM, Sattar N. The UPBEAT RCT mother-child study. Stratifying and treating obese pregnant women to prevent adverse pregnancy, perinatal and longer term outcomes. MRC £825, 398: February 2014 for 48 months Published book chapter: Fraser A, Lawlor DA. Long-term consequences of maternal obesity and gestational weight gain for offspring obesity and cardiovascular risk - intrauterine or shared familial mechanisms? In: Poston L, Gillman M (eds). Obesity and Pregnancy. Cambridge Press. 2012
Start Year 2012
 
Description Pilot study with 'We the Curious' and public scientific museum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact We the curious is a science museum in Bristol. We are doing a pilot project with them that will enable us to determine the youngest age (in children) at which it is feasible to capture data on capillary glycocalix through an imaging technology. The data assessment requires a probe to be placed under the child's tongue for 7-10 minutes to capture sufficient image data. We worked with We the Curious to agree the recruitment and data collection protocol. Older children / young adults (14-19 year old) will collect data and with our support do analyses. The results will provide the answer we need and all data will be destroyed once analyses are completed.
We will use the results to decide the age groups in ALSPAC G2 and in other cohorts (e.g. in Bradford) in which we will collect these data.
We the curious are keen to work on other projects with us and to build stronger links with the University for mutual benefit with respect to public engagement and involvement. This current project is the first project with them. Hopefully, it will lead to many further projects.
Year(s) Of Engagement Activity 2020
 
Description Published a paper on environmental data collection in ALSPAC birth cohort with two ALSPAC participants as co-authors 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a unique experience of real participant/public involvement - working with two of the study participants to document all of the environmental and social data in ALSPAC, priorities for new data and methods for collecting these. The participant co-authors contributed to all aspects of the paper, including describing the methods for collecting data (including burden on them) for existing data, advising on what they would consider key priorities for future data collection and the best methods for collecting those data.
Publication is
Boyd A, Thomas R, Hansell AL, Gulliver J, Hicks LM, Griggs R, Hey JV, Taylor CM, Morris T, Golding J, Doerner R, Fecht D, Henderson J, Lawlor DA, Timpson NJ, Macleod J, Data Resource Profile: The ALSPAC birth cohort as a platform to study the relationship of environment and health and social factors International Journal of Epidemiology 2019; doi: 10.1093/ije/dyz063
This experience forms a blueprint for further co-production research with other cohort participants
Year(s) Of Engagement Activity 2019
URL https://academic.oup.com/ije/article/48/4/1038/5475780
 
Description You-tube video describing the Avon Longitudinal Study of Parents and Children - Generation 2 cohort and its contribution to research 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I produced a you-tube video with ALSPAC study participants and staff who collect data in ALSPAC, to inform a wide range of people about the value of the multi-generational ALSPAC study and the research it has contributed to. We also promoted the importance of population health studies such as ALSPAC in general.
The video can be found here
https://www.youtube.com/watch?v=sQtnmCNgmXI
Year(s) Of Engagement Activity 2019
URL https://www.youtube.com/watch?v=sQtnmCNgmXI