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
Organisations
- University of Edinburgh (Lead Research Organisation)
- UNIVERSITY OF ABERDEEN (Collaboration)
- University of Manchester (Collaboration)
- Newcastle University (Collaboration)
- UNIVERSITY OF BIRMINGHAM (Collaboration)
- Norwegian Institute of Public Health (Collaboration)
- Perinatal Ireland (Collaboration)
- UNIVERSITY OF EXETER (Collaboration)
- KING'S COLLEGE LONDON (Collaboration)
People |
ORCID iD |
Jane Norman (Principal Investigator) |
Publications
Chiswick C
(2015)
Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial.
in The lancet. Diabetes & endocrinology
Chiswick C
(2016)
Does metformin reduce excess birthweight in offspring of obese pregnant women? A randomised controlled trial of efficacy, exploration of mechanisms and evaluation of other pregnancy complications
in Efficacy and Mechanism Evaluation
Chiswick CA
(2015)
Efficacy of metformin in pregnant obese women: a randomised controlled trial.
in BMJ open
Preston HM
(2016)
Repeated weighing during pregnancy is ineffective in minimising maternal weight gain.
in BJOG : an international journal of obstetrics and gynaecology
Yang L
(2022)
Metformin in obese pregnancy has no adverse effects on cardiovascular risk in early childhood.
in Journal of developmental origins of health and disease
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/ |