Prenatal alcohol exposure, childhood development and teenage drinking: a study of trans-generational effects

Lead Research Organisation: University of Bristol
Department Name: Social Medicine

Abstract

Binge-drinking among teenagers in the UK is higher than in any other Western European country. The aim of this study is to identify what determines how early teenagers start consuming alcohol and how much they drink. We will look at whether alcohol was consumed by teenagers‘ mothers during pregnancy, at the family environment in which they grew up, at how much alcohol was drunk in the household and how often, and at inherited genetic factors, as possible causes of problem teenage drinking. We will try to isolate the influence of each factor from the others, and especially of alcohol consumed by mothers during pregnancy. We will further try to understand exactly how this might affect the foetus, by studying the consequences it might have on child‘s development, behaviour and school results, and by measuring whether alcohol has induced temporary or permanent changes in some genes. If drinking mothers can predispose their unborn babies to drinking more and at a younger age, this will create a spiral of problem drinking, which gets worse with every generation. Therefore, this work could open new windows of opportunity for the prevention of problem teenage drinking, for example by advising pregnant women to avoid alcohol.

Technical Summary

Aim
To understand the mechanisms linking parental alcohol consumption with offspring alcohol consumption in order to develop appropriate preventive measures for problem adolescent drinking.

Objectives
1. To determine whether maternal alcohol consumption in pregnancy has a biological effect on adolescent drinking behaviours and the onset of problem drinking, independent of family history of problem drinking, parental drinking during the offspring‘s childhood and adolescence and other components of shared environment such as socio-economic position and neighbourhood circumstances.
2. To use maternal genetic variants that are known to be robustly associated with alcohol consumption as instrumental variables for the causal effect of maternal alcohol consumption on offspring consumption, with control for the same variants in offspring.
3. To determine whether risk-factors for adolescent drinking such as school performance and peer group choice, which are often linked to more important outcomes in the domains of cognition and development, are mediators of the effect of prenatal alcohol exposure on adolescent drinking behaviours.
4. To determine whether prenatal alcohol exposure causes differences in methylation status of candidate genes associated with adolescent drinking and cognitive/developmental outcomes (epigenetic effect).
5. To determine whether paternal alcohol consumption pre-conception contributes to the adolescent alcohol phenotype and cognition/development, independently of intrauterine alcohol exposure and later drinking.
6. To study the association of prenatal alcohol exposure with cognitive and developmental outcomes using an instrumental variable approach and within-siblings comparisons, and to compare the results to those from a different population to strengthen their interpretation (UK Vs Norway).

Methodology
The Avon Longitudinal Study of Parents And Children -N=15000- and the Norwegian Mother and Child Cohort -N=100000- will prode data on parents (socio-demographic and lifestyle) and offspring (developmental and cognitive outcomes, adolescent drinking behaviour), collected prospectively since the index pregnancy. DNA banks exist for both studies. These will allow genotyping alcohol-related genetic variants, to be linked to offspring cognitive/behavioural/alcohol outcomes in instrumental variable analyses, and analysing offspring DNA methylation signatures. Relevant statistical methods - multivariable analysis, structural equation modelling, instrumental variables analysis - will be used as appropriate.

Medical opportunities
Understanding to what extent the association of maternal pregnancy alcohol intake with offspring initiation and amount of alcohol consumption is due to potentially irreversible intrauterine biological pathways, rather than shared familial lifestyles or shared genes, is important in order to determine strategies for the prevention of problem drinking in adolescents. This may be particularly important for female offspring, as their behaviour in pregnancy might affect their own offspring -an irreversible intrauterine effect could result in a trans-generational spiral.

Publications

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Howe LJ (2019) Prenatal alcohol exposure and facial morphology in a UK cohort. in Drug and alcohol dependence

 
Description Citation in NIHR report for the Royal College of Midwives
Geographic Reach National 
Policy Influence Type Citation in clinical reviews
Impact Improved long term outcomes and quality of life of offspring of mothers who , as a result of these report, will avoid a number of toxic exposures while pregnant.
URL http://www.dc.nihr.ac.uk/themed-reviews/better-beginnings.htm
 
Description Presentation at All Party Parliamentary Group on Fetal Alcohol Spectrum Disorder
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL https://twitter.com/CLAHRC_West/status/935151647809994756
 
Guideline Title UK Chief Medical Officers' Alcohol Guidelines Review
Description revised alcohol in pregnancy guidelines
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
URL https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/490560/List__of_documents_...
 
Description Benjamin Meaker Visiting Professorship (LMIC)
Amount £4,000 (GBP)
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 08/2018
 
Description MRC IEU doctoral studentship
Amount £93,000 (GBP)
Organisation University of Bristol 
Department MRC Integrative Epidemiology Unit
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 09/2019
 
Description Medical Research Council Grant
Amount £1,378,535 (GBP)
Funding ID MR/L022206/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2015 
End 05/2019
 
Description University of Bristol International Strategic Fund
Amount £2,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Academic/University
Country United Kingdom
Start 01/2017 
End 09/2017
 
Description Knowledge transfer project on the current evidence of safety of alcohol use in pregnancy 
Organisation National Institute for Health Research
Department NIHR CLAHRC West
Country United Kingdom 
Sector Public 
PI Contribution initiated the collaboration, drafted a program of work, oversaw recruitment of a new post-doc to work on the project for 24 months, supervised (line-managed) the post-doc, supervised the completion of 2 papers submitted for publication, organised a PPI workshop for new mums to talk about implementation of new alcohol in pregnancy recommendations and their thoughts on this, contributed to revised UK Chief Medical Officer guidelines on alcohol in pregnancy by submitting an interim report on our evidence synthesis work
Collaborator Contribution gave input towards the general outline of the project, provided financial cover for the post-doc salary for 24 months, helped in recruiting the post-doc, supervised technical aspects of the evidence synthesis project
Impact A 24 months post-doc research contract has been issued for a post-doc to work on this knowledge-transfer project. Multi-disciplinary collaboration, involving : evidence synthesis of epidemiological research, searches and collation of current guidelines/advice from public health, healthcare practitioners and relevant societies, proposed revision of policies. 2 papers submitted for publication, 2 conference presentations, PPI workshop for new mums to talk about implementation of new alcohol in pregnancy recommendations and their thoughts on this, contributed to revised UK Chief Medical Officer guidelines on alcohol in pregnancy by submitting an interim report on our evidence synthesis work, contributed to NIHR Dissemination Centre's "Better Beginnings" publication with summary of evidence on effects of alcohol in pregnancy
Start Year 2014
 
Description alcohol consumption, ADH1B and cardiovascular disease 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Country United Kingdom 
Sector Academic/University 
PI Contribution Initiated the collaboration and co-designed the study, provided substantial intellectual input towards the conduct of the project, analysed data for a number of the collaborating studies, wrote sections of the manuscript and commented on several drafts
Collaborator Contribution Collated data from several collaborating studies, performed meta-analysis, drafted manuscript, developed new statistical methodology
Impact PMID: 25192829, PMID: 25011450, PMID: 28025256
Start Year 2010
 
Description alcohol consumption, ADH1B and cardiovascular disease 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Initiated the collaboration and co-designed the study, provided substantial intellectual input towards the conduct of the project, analysed data for a number of the collaborating studies, wrote sections of the manuscript and commented on several drafts
Collaborator Contribution Collated data from several collaborating studies, performed meta-analysis, drafted manuscript, developed new statistical methodology
Impact PMID: 25192829, PMID: 25011450, PMID: 28025256
Start Year 2010
 
Description alcohol genes, drinking in pregnancy and offspring cognition 
Organisation University of Oxford
Department National Perinatal Epidemiology Unit Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution I liaised with a colleague statistician to agree on a data analysis plan, conducted most of the analyses, obtained funding for genotyping of one variant, drafted and finalised two scientific papers (published, PMIDs 19687126 and 24065783). I also contributed to analyses and manuscript of another published scientific paper (PMID 23166662). In July 2013, I lead a bid for an MRC grant call together with our partner (Experimental Medicine call).
Collaborator Contribution Intellectual input in drafting the paper. Help in running advanced statistical analysis. Obtained funding. Contributed to drafting an outline call for an MRC Experimental Medicine grant call.
Impact Three papers were published to which this collaboration added a significant contribution (PMID 19687126, 24065783 and 23166662), and a grant application was submitted (outline only).
Start Year 2009
 
Description alcohol, adh1b and chronic disease (CVD and liver disease) 
Organisation Copenhagen University Hospital
Country Denmark 
Sector Hospitals 
PI Contribution I added intellectual content and helped draft 2 papers (one published, one submitted)
Collaborator Contribution Study design, analyses, paper drafting.
Impact PMID 23492672, PMID: 25503943
Start Year 2010
 
Description alcohol, adh1b and chronic disease (CVD and liver disease) 
Organisation Herlev Hospital
Country Denmark 
Sector Hospitals 
PI Contribution I added intellectual content and helped draft 2 papers (one published, one submitted)
Collaborator Contribution Study design, analyses, paper drafting.
Impact PMID 23492672, PMID: 25503943
Start Year 2010
 
Description alcohol, adh1b and chronic disease (CVD and liver disease) 
Organisation University of Bristol
Department School of Social and Community Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution I added intellectual content and helped draft 2 papers (one published, one submitted)
Collaborator Contribution Study design, analyses, paper drafting.
Impact PMID 23492672, PMID: 25503943
Start Year 2010
 
Description candidate genes and alcohol use 
Organisation Aarhus University
Country Denmark 
Sector Academic/University 
PI Contribution I reviewed the literature as background preparation for defining the research questions and planning details of data analysis. I drafted the analysis plan, applied for access to various data, conducted the statistical analysis and drafted the manuscript.
Collaborator Contribution De novo genotyping of one candidate genetic variant in two separate cohort studies and extraction of available in silico data for other studies, help with data handling. Intellectual and scientific input in refining a research question and drafting the manuscript for publication. Permission to use data to conduct analyses.
Impact PMID: 27902751
Start Year 2007
 
Description candidate genes and alcohol use 
Organisation International Agency for Research on Cancer (IARC)
Country France 
Sector Public 
PI Contribution I reviewed the literature as background preparation for defining the research questions and planning details of data analysis. I drafted the analysis plan, applied for access to various data, conducted the statistical analysis and drafted the manuscript.
Collaborator Contribution De novo genotyping of one candidate genetic variant in two separate cohort studies and extraction of available in silico data for other studies, help with data handling. Intellectual and scientific input in refining a research question and drafting the manuscript for publication. Permission to use data to conduct analyses.
Impact PMID: 27902751
Start Year 2007
 
Description candidate genes and alcohol use 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Department Faculty of Epidemiology and Population Health
Country United Kingdom 
Sector Academic/University 
PI Contribution I reviewed the literature as background preparation for defining the research questions and planning details of data analysis. I drafted the analysis plan, applied for access to various data, conducted the statistical analysis and drafted the manuscript.
Collaborator Contribution De novo genotyping of one candidate genetic variant in two separate cohort studies and extraction of available in silico data for other studies, help with data handling. Intellectual and scientific input in refining a research question and drafting the manuscript for publication. Permission to use data to conduct analyses.
Impact PMID: 27902751
Start Year 2007
 
Description candidate genes and alcohol use 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution I reviewed the literature as background preparation for defining the research questions and planning details of data analysis. I drafted the analysis plan, applied for access to various data, conducted the statistical analysis and drafted the manuscript.
Collaborator Contribution De novo genotyping of one candidate genetic variant in two separate cohort studies and extraction of available in silico data for other studies, help with data handling. Intellectual and scientific input in refining a research question and drafting the manuscript for publication. Permission to use data to conduct analyses.
Impact PMID: 27902751
Start Year 2007
 
Description candidate genes and alcohol use 
Organisation University of Western Australia
Department Centre for Genetic Origins of Health and Disease (GOHaD)
Country Australia 
Sector Academic/University 
PI Contribution I reviewed the literature as background preparation for defining the research questions and planning details of data analysis. I drafted the analysis plan, applied for access to various data, conducted the statistical analysis and drafted the manuscript.
Collaborator Contribution De novo genotyping of one candidate genetic variant in two separate cohort studies and extraction of available in silico data for other studies, help with data handling. Intellectual and scientific input in refining a research question and drafting the manuscript for publication. Permission to use data to conduct analyses.
Impact PMID: 27902751
Start Year 2007
 
Description prenatal alcohol and growth trajectories 
Organisation University College Cork
Country Ireland 
Sector Academic/University 
PI Contribution intellectual contribution to study design, results interpretation and drafting paper
Collaborator Contribution designed study, ran analyses, drafted paper
Impact PMID: 26073790
Start Year 2013
 
Description prenatal alcohol, adh1b and child athopy and asthma 
Organisation Queen Mary University of London
Department Centre for Primary Care and Public Health
Country United Kingdom 
Sector Academic/University 
PI Contribution intellectual contribution to study and help in drafting paper
Collaborator Contribution designed study, ran analyses, drafted paper
Impact PMID 23806636
Start Year 2011
 
Description prenatal alcohol, adh1b and child balance 
Organisation St Michael's Hospital
Department Children's Hearing Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution intellectual content and help in drafting a published paper
Collaborator Contribution designed study, ran analyses, drafted paper
Impact PMID 23794556
Start Year 2011
 
Description prenatal alcohol, adh1b and child balance 
Organisation University of Bristol
Department School of Social and Community Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution intellectual content and help in drafting a published paper
Collaborator Contribution designed study, ran analyses, drafted paper
Impact PMID 23794556
Start Year 2011
 
Description prenatal alcohol, adh1b and fetal adh1a genotype and conduct problems 
Organisation University of Cambridge
Department Department of Public Health and Primary Care
Country United Kingdom 
Sector Academic/University 
PI Contribution intellectual contribution to study design, results interpretation and drafting paper; obtained funding and arranged genotyping
Collaborator Contribution designed study, ran analyses, drafted paper
Impact PMID: 26588883
Start Year 2013
 
Description prenatal alcohol, adh1b and fetal adh1a genotype and conduct problems 
Organisation University of Oxford
Department National Perinatal Epidemiology Unit Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution intellectual contribution to study design, results interpretation and drafting paper; obtained funding and arranged genotyping
Collaborator Contribution designed study, ran analyses, drafted paper
Impact PMID: 26588883
Start Year 2013
 
Description Interviews for national and international press 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Following a press-release for the publication of our systematic review on the effects of low levels of alcohol drinking in pregnancy, we received a huge amount of media interest and requests for comments and interviews (on the phone, via email and Skype). (PMID 28775124) Some of the reporting of our results in the media was inaccurate, therefore we also quickly mounted a counter-information campaign (mainly on social media but also by writing letters to relevant national newspapers) to set the record straight.
Year(s) Of Engagement Activity 2017
URL https://twitter.com/i/moments/912617139537940482
 
Description Live broadcast - TV and radio 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact In relation to the systematic review on the effects of low levels of alcohol use in pregnancy (PMID 28775124), we were interviewed on live TV for BBC1 Breakfast and the Victoria Derbyshire program. We were also interviewed by a number of national (eg Drivetime) and regional radio channels (eg BBC Scotland, BBC Bristol, BBC Birmingham etc). We took advantage of these interviews to set the record straight on some misleading press headlines that were not representatives of the study's findings.
Year(s) Of Engagement Activity 2017
 
Description media interest (prenatal alcohol exposure and cognition study) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact As a result of the press release, we received many calls/emails from journalists who wanted to run a story on our findings on prenatal alcohol exposure and childhood cognition.

A number of articles published in national/international newspapers and magazines.
Year(s) Of Engagement Activity 2012
 
Description participation to local radio program (BBC Bristol) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I successfully took part in a radio interview on a popular Saturday morning program about health issues, and discussed the general problems around conducting research into the effects of alcohol drinking, its safe limits, and some recent results from one of my collaborations.


Difficult to measure - there was no phone-in following the live radio interview
Year(s) Of Engagement Activity 2014