Does metformin reduce excess birthweight in offspring of obese pregnant women?

Lead Research Organisation: University of Edinburgh
Department Name: UNLISTED

Abstract

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Technical Summary

Scientific Abstract|AIM: The aim of this study is to determine if metformin, administered to obese women during pregnancy, reduces the future life risk of obesity and metabolic syndrome in their babies. We will use high birthweight centile as a surrogate marker for future life events as its validity has been shown in large epidemiological studies [1-3]. Secondly, we will use metformin administration as a tool to explore the mechanism by which obesity causes adverse pregnancy outcomes, with a particular focus on insulin resistance (IR). |DESIGN: Double blind placebo controlled randomised clinical trial. |SETTING: Antenatal clinics specialising in the care of obese pregnant women in two large maternity hospitals in the UK (Edinburgh and Liverpool). |TARGET POPULATION: Obese pregnant women.|INTERVENTIONS BEING EVALUATED: Metformin, an insulin sensitising agent or matched placebo initiated between 12 and 16 weeks gestation. |PRIMARY OUTCOMES: (i) Efficacy outcome - z-score corresponding to the gestational age and sex adjusted birthweight centiles of the baby (ii) Mechanistic outcome - maternal insulin resistance (IR) at 36 weeks gestation which will be correlated with adverse pregnancy outcomes. |SECONDARY OUTCOMES: (A) More detailed measurements of neonatal body composition at birth including ponderal index; skinfold thicknesses; and (Edinburgh babies only) neonatal fat mass measured using air displacement plethysmography. (B) Biological mechanisms of metformin action including (i) change in IR; hepatic and skeletal insulin sensitivity (ii) maternal and neonatal inflammatory and lipid indices including CRP, IL-6, leptin, lipids, triglycerides and PAI1/PAI2 ratio (iii) placental glucocorticoid receptor expression (iv) maternal brachial arterial endothelial dependent flow mediated dilatation (FMD) (v) in vitro measurements of maternal myometrial contractility [4] (vi) changes in maternal anthrometry. (C) Adverse pregnancy outcomes as a composite; incidence of low birthweight centile. (D) Gas chromatography mass spectrometry measurements of metformin in maternal plasma to determine compliance.|MEASUREMENT OF OUTCOME AND DURATION OF FOLLOW UP. Birthweight will be measured by clinical staff, the result prospectively transferred from the clinical birth record to a case report form and Z score of birthweight centile calculated using www.gestation.net. Maternal IR at 36 weeks gestation will be expressed as the Matsuda index [5] (the best correlate with the gold standard the hyperinsulinaemic euglycaemic clamp in pregnant women)[6], and derived from multiple sampling during a glucose tolerance test. Change in IR will be expressed as changes in a logarithmic and reciprocal transformation of a single fasting glucose and insulin value (QUICKI), measured during a glucose tolerance test at baseline (prior to treatment), at 28 weeks and at 36 weeks gestation [6]. |In a subgroup of women (n = 20 in each group) insulin resistance will be measured by the hyperinsulinaemic euglycaemic clamp, to characterise the relative effects of metformin on hepatic and peripheral skeletal muscle insulin sensitivity. Endothelial dependent FMD will be measured in a subset (n = 30 each group) at 36 weeks gestation using a non invasive, validated, and reproducible method suitable for use in pregnancy [7 8]. Initial follow up will cease once the woman and baby have been discharged postnatally, although we anticipate further funding applications to continue neonatal follow up into early childhood.|SAMPLE SIZE: |(1) BIRTHWEIGHT CENTILE. In a previous study, the mean (SD) birthweight in a cohort of obese women (mean BMI 34) was 4.0kg (0.6kg)[9]. We hypothesise that metformin will reduce mean birthweight by 200g, corresponding to a reduction in birthweight centile of 0.3 SD. We believe that this reduction in birthweight centile is clinically relevant, but is a relatively conservative estimate of likely reduction in birthweight centile induced by metformin, given that m
 
Description A pragmatic adaptive sequential placebo controlled randomised trial to determine the effectiveness of Glycerin trinitrate for retained placenta (Got-it trial).
Amount £1,712,000 (GBP)
Funding ID HTA/12/29/01 
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start 01/2014 
End 01/2018
 
Description An open randomised trial of the Arabin pessary to prevent preterm birth in twin pregnancy - STOPPIT- 2.
Amount £1,327,029 (GBP)
Funding ID HTA/13/04/22 
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start 11/2014 
End 11/2018
 
Description Centre funding Tommys (charity)
Amount £240,000 (GBP)
Organisation Guy’s & St Thomas’ Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2008 
End 03/2015
 
Description Effectiveness of progesterone to prevent miscarriage in women with early pregnancy bleeding: A randomised placebo-controlled trial (PRISM Trial
Amount £1,756,618 (GBP)
Funding ID HTA/12/167/26 
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start 12/2014 
End 12/2018
 
Description Glibenclamide and metfoRmin versus stAndard Care in gEstational diabeteS (GRACES) - a feasibility open label randomised trial
Amount £217,000 (GBP)
Funding ID CZH/4/1011 
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 03/2014 
End 04/2016
 
Description MICA: A pragmatic approach to the prevention of gestational diabetes and pre-eclampsia in obese pregnant women in resource poor settings
Amount £178,804 (GBP)
Funding ID MR/R019142/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2018 
End 01/2020
 
Description MRC Centre for Reproductive Health Centre grant
Amount £1,100,000 (GBP)
Funding ID G1002033 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2011 
End 04/2016
 
Description MRC Programme Grant - Poly(A)-binding proteins highlight the importance of regulated mRNA translation and stability in determining a functional materno-fetal interface.
Amount £1,494,000 (GBP)
Funding ID MR/J003069/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2012 
End 01/2017
 
Description My baby's movements study. NHMRC (Australia)
Amount $1,364,000 (AUD)
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 01/2014 
End 01/2018
 
Description Should we treat iron deficiency anaemia of pregnancy with lactoferrin? A randomised controlled trial.
Amount $2,050,000 (AUD)
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 01/2014 
End 01/2018
 
Description Small project grant - The clinical and short term NHS cost of maternal obesity.
Amount £58,000 (GBP)
Funding ID CZG/2/471 Denison 
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 08/2010 
 
Description Small project grant -Maternal obesity and programming of offspring obesity and cardiometabolic risk
Amount £49,000 (GBP)
Funding ID CZG/2/478 (Reynolds) 
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 09/2010 
 
Description Suture Type for Incompetent Cervix and effect on Health outcomes
Amount £1,090,069 (GBP)
Funding ID HTA/13/04/107 
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start 12/2014 
End 12/2018
 
Title iPPIC database 
Description This database is curated by John Allotey at Barts and the London, and is being used to generate a number of publications 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact No publications yet 
 
Description Collaboration between MD and PF 
Organisation University of Aberdeen
Department School of Medicine & Dentistry Aberdeen
Country United Kingdom 
Sector Academic/University 
PI Contribution intellectual input
Collaborator Contribution intellectual input
Impact PMID 21752894
Start Year 2010
 
Description Collaborative group for STOPPIT 2 study 
Organisation King's College London
Department Obstetrics and Gynaecology
Country United Kingdom 
Sector Academic/University 
PI Contribution Leadership of a research team for a grant to test a device to prevent preterm labour in twins.
Collaborator Contribution Members of a research team for a grant to test a device to prevent preterm labour in twins.
Impact Grant application not yet funded. Multidisciplinary: obstetrics statistics
Start Year 2012
 
Description Collaborative group for STOPPIT 2 study 
Organisation Newcastle University
Department Department of Obstetrics and Gynaecology
Country United Kingdom 
Sector Academic/University 
PI Contribution Leadership of a research team for a grant to test a device to prevent preterm labour in twins.
Collaborator Contribution Members of a research team for a grant to test a device to prevent preterm labour in twins.
Impact Grant application not yet funded. Multidisciplinary: obstetrics statistics
Start Year 2012
 
Description Collaborative group for STOPPIT 2 study 
Organisation University of Aberdeen
Department Centre for Healthcare Randomised Trials
Country United Kingdom 
Sector Academic/University 
PI Contribution Leadership of a research team for a grant to test a device to prevent preterm labour in twins.
Collaborator Contribution Members of a research team for a grant to test a device to prevent preterm labour in twins.
Impact Grant application not yet funded. Multidisciplinary: obstetrics statistics
Start Year 2012
 
Description Collaborative group for STOPPIT 2 study 
Organisation University of Birmingham
Department Obstetrics and Gynaecology Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Leadership of a research team for a grant to test a device to prevent preterm labour in twins.
Collaborator Contribution Members of a research team for a grant to test a device to prevent preterm labour in twins.
Impact Grant application not yet funded. Multidisciplinary: obstetrics statistics
Start Year 2012
 
Description Collaborative group for STOPPIT 2 study 
Organisation University of Exeter
Department Obstetrics & Gynaecology
Country United Kingdom 
Sector Academic/University 
PI Contribution Leadership of a research team for a grant to test a device to prevent preterm labour in twins.
Collaborator Contribution Members of a research team for a grant to test a device to prevent preterm labour in twins.
Impact Grant application not yet funded. Multidisciplinary: obstetrics statistics
Start Year 2012
 
Description Scottish and Irish collaboration for stillbirth prevention study 
Organisation Norwegian Institute of Public Health
Department Department of International Public Health
Country Norway 
Sector Academic/University 
PI Contribution I initiated this collaboration to generate a proposal and later funding for a stillbirth prevention study
Collaborator Contribution Intellectual input
Impact Multidisciplinary grant application - obstetrics, midwifery, statistics, sociology
Start Year 2011
 
Description Scottish and Irish collaboration for stillbirth prevention study 
Organisation Perinatal Ireland
Country Ireland 
Sector Academic/University 
PI Contribution I initiated this collaboration to generate a proposal and later funding for a stillbirth prevention study
Collaborator Contribution Intellectual input
Impact Multidisciplinary grant application - obstetrics, midwifery, statistics, sociology
Start Year 2011
 
Description Scottish and Irish collaboration for stillbirth prevention study 
Organisation University of Manchester
Department Obstetrics
Country United Kingdom 
Sector Academic/University 
PI Contribution I initiated this collaboration to generate a proposal and later funding for a stillbirth prevention study
Collaborator Contribution Intellectual input
Impact Multidisciplinary grant application - obstetrics, midwifery, statistics, sociology
Start Year 2011
 
Title AFFIRM - Does promoting increased awareness of decreased fetal movements reduce stillbirth, a stepped wedge cluster randomised trial? 
Description Chief Scientist Office, Scottish Executive, (HSRC) and Sands 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact n/a 
URL http://www.crh.ed.ac.uk/affirm/
 
Title An open randomised trial of the Arabin pessary to prevent preterm birth in twin pregnancy - STOPPIT- 2. 
Description National Institute of Health, Health Technology Assessment Board 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact n/a 
URL https://w3.abdn.ac.uk/hsru/stoppit2/
 
Title EMPOWaR 
Description Use of metformin to reduce birthweight centile in obese pregnant women. Clinical trial called EMPOWaR funded by NIHR / EME Clinical trial - ISRCTN51279843 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2010
Development Status Under active development/distribution
Clinical Trial? Yes
Impact None yet 
URL http://www.controlled-trials.com/ISRCTN51279843
 
Title Glibenclamide and metfoRmin versus stAndard Care in gEstational diabeteS (GRACES) - a feasibility open label randomised trial 
Description Chief Scientist Office, Scottish Executive. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact n/a 
URL https://www.npeu.ox.ac.uk/graces
 
Title STOPPIT baby follow up study: what effect does prophylactic progesterone in twin pregnancy have on childhood outcome? 
Description Chief Scientist Office, Scottish Executive Funding 
Type Therapeutic Intervention - Drug
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact n/a 
URL http://www.isrctn.com/ISRCTN35782581
 
Description 3. Developmental Programming - Does it Really Exist? Evidence from Human Studies 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Developmental Programming Symposium at Society of Reproductive Investigation Meeting, San Francisco,
Year(s) Of Engagement Activity 2015
 
Description 4. Metformin in Obese Women in Pregnancy: results of the EMPOWaR study 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited plenary lecture. British Maternal and Fetal Medicine Society annual meeting.
Year(s) Of Engagement Activity 2015
 
Description 53rd Annual Meeting of European Association for the Study of Diabetes, Lisbon, Portugal, 11-15 September 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Speaker, title of talk: Metformin in pregnancy
Year(s) Of Engagement Activity 2017
URL https://www.easd.org/annual-meeting/easd-2017.html
 
Description An Odyssey in pregnancy research - there and back again. Inaugural Lecture, University of Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Around 150 people attended this talk

Increased awareness of issues of maternal obesity
Year(s) Of Engagement Activity 2010
 
Description Article in Scotsman - Dieting, not eating for two 'benefits mother and baby' 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Scotsman newspaper has large circulation list in Scotland

Increased public awareness of obesity in pregnancy issues
Year(s) Of Engagement Activity 2012
 
Description Articles about EMPOWaR study 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Articles in the following papers and media outlets: 1/04/12: (The Daily Mail online) (The Herald Sun online (Australia) ) (Opposing Views online) (Christian Post online) (Active Quote) (Coventry Telegraph online) (Harborough Mail online) (Gather News online) (Halifax Courier online) (Skynews online) (The Herald) (The Star) (The Edinburgh Evening News) (The Daily Express) (Metro) (The Herald) (The Scotsman) (The Press and Journal) (Coventry Telegraph) (The Daily Telegraph) (The Daily Mail) (MedIndia online) (EsMas online) (Evening Herald online) (The Irish Independent) (Fox News online (USA)) (Magic Maman online) (Gulf News online ) (Perth Now) (News.com.au) (KSAZ-TV (Phoenix)) (Magic Maman online)

Increased public awareness of study
Year(s) Of Engagement Activity 2012
 
Description Excesses of modern societies. Optimal Pregnancy Environment Risk Assessment meeting 
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 Risk assessment meeting
Year(s) Of Engagement Activity 2015
 
Description Improving outcomes for pregnant women and babies in Scotland through research. Scottish Government Maternity Services Good Practice Event Edinburgh, May 2014. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk sparked questions and discussion afterwards

Talk sparked questions and discussion afterward
Year(s) Of Engagement Activity 2014
 
Description Inaugural lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 120 attendees

Interest in research into preterm birth
Year(s) Of Engagement Activity 2010
 
Description Maternal and infant nutrition and health - Holyrood Magazine meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Around 200 delegates, largely policy makers

Increased awareness of issues of maternal obesity
Year(s) Of Engagement Activity 2010
 
Description Medical Detective Series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Audience of 100 members of the public who asked questions about research into preterm birth and its prevention.


The lecture is available on You Tube at http://www.youtube.com/watch?v=TC43j2UJ-GI&feature=player_embedded. As of Nov 2011 it has had 1400 hits on "You tube".
Year(s) Of Engagement Activity 2010
 
Description Metformin in pregnancy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Speaking at international meeting - European Conference on Diabetes, Lisbon
Year(s) Of Engagement Activity 2017
 
Description Multiple media references to EMPOWaR 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Multiple media references to EMPOWaR and discussion of issues of obesity in pregnancy. Article in Daily Telegraph, Daily Mail, New York times etc.

Increased awareness of the issues of maternal obesity
Year(s) Of Engagement Activity 2011
 
Description Pint of Science Public Engagement Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Pint of Science Talk "Sex Drugs and Birth" 23.5.16
Year(s) Of Engagement Activity 2016
URL https://pintofscience.co.uk/