{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T02:28:17Z","timestamp":1787711297105,"version":"build-2784847793"},"reference-count":64,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T00:00:00Z","timestamp":1590019200000},"content-version":"unspecified","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2020,3,30]]},"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Gestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use individual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>MEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>All IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, providing much needed evidence to inform clinical and public health actions in this area.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2020-036981","type":"journal-article","created":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T05:32:32Z","timestamp":1590125552000},"page":"e036981","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Metformin in Pregnancy Study (MiPS): protocol for a systematic review with individual patient data meta-analysis"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7356-4523","authenticated-orcid":false,"given":"Aya","family":"Mousa","sequence":"first","affiliation":[{"name":"Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tone","family":"L\u00f8vvik","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ij\u00e4s","family":"Hilkka","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Oulu and Oulu University Hospital, Medical Research Centre, PEDEGO Research Unit, Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven M","family":"Carlsen","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway"},{"name":"Department of Endocrinology, St Olavs Hospital, Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Morin-Papunen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Oulu and Oulu University Hospital, Medical Research Centre, PEDEGO Research Unit, Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristiina","family":"Tertti","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Turku, Turku, Finland"},{"name":"Department of Obstetrics and Gynecology, Turku University Hospital, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tapani","family":"R\u00f6nnemaa","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Turku University Hospital, Turku, Finland"},{"name":"Department of Medicine, University of Turku, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Argyro","family":"Syngelaki","sequence":"additional","affiliation":[{"name":"Fetal Medicine Research Unit, King's College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kypros","family":"Nicolaides","sequence":"additional","affiliation":[{"name":"Fetal Medicine Research Unit, King's College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Shehata","sequence":"additional","affiliation":[{"name":"Department of Maternal Medicine, Epsom Hospital, Epsom and St Helier University Hospitals NHS Trust, Epsom, Surrey, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christy","family":"Burden","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane E","family":"Norman","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Rowan","sequence":"additional","affiliation":[{"name":"Auckland District Health Board, Auckland, New Zealand"},{"name":"School of Medicine, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6363-4874","authenticated-orcid":false,"given":"Jodie M","family":"Dodd","sequence":"additional","affiliation":[{"name":"Robinson Research Institute, The University of Adelaide Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia"},{"name":"Women's and Babies Division, Women's and Children's Hospital, Adelaide, North Adelaide, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Hague","sequence":"additional","affiliation":[{"name":"Robinson Research Institute, The University of Adelaide Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia"},{"name":"Women's and Babies Division, Women's and Children's Hospital, Adelaide, North Adelaide, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eszter","family":"Vanky","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena J","family":"Teede","sequence":"additional","affiliation":[{"name":"Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2020,5,21]]},"reference":[{"key":"2025121403072830000_10.5.e036981.1","doi-asserted-by":"publisher","DOI":"10.3109\/14767058.2011.587921"},{"key":"2025121403072830000_10.5.e036981.2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1479-828X.2011.01356.x"},{"key":"2025121403072830000_10.5.e036981.3","doi-asserted-by":"publisher","DOI":"10.1097\/GRF.0b013e31815a61d6"},{"key":"2025121403072830000_10.5.e036981.4","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.2337\/diacare.26.4.1295","article-title":"Intrauterine hyperglycemia modifying the development of (monogenic) diabetes?","volume":"26","author":"Tuomi","year":"2003","journal-title":"Diabetes Care"},{"key":"2025121403072830000_10.5.e036981.5","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-1620"},{"key":"2025121403072830000_10.5.e036981.6","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-1282"},{"key":"2025121403072830000_10.5.e036981.7","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.h102"},{"key":"2025121403072830000_10.5.e036981.8","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k2477"},{"key":"2025121403072830000_10.5.e036981.9","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1007\/s00125-017-4351-y","article-title":"Metformin use in pregnancy: promises and uncertainties","volume":"60","author":"Lindsay","year":"2017","journal-title":"Diabetologia"},{"key":"2025121403072830000_10.5.e036981.10","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.ebiom.2018.08.047","article-title":"Metformin from mother to unborn child - Are there unwarranted effects?","volume":"35","author":"Nguyen","year":"2018","journal-title":"EBioMedicine"},{"key":"2025121403072830000_10.5.e036981.11","doi-asserted-by":"publisher","DOI":"10.1007\/BF01221950"},{"key":"2025121403072830000_10.5.e036981.12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-5491.2007.02053.x"},{"key":"2025121403072830000_10.5.e036981.13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0707193"},{"key":"2025121403072830000_10.5.e036981.14","first-page":"Cd011967","article-title":"Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes","volume":"33","author":"Brown","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"2025121403072830000_10.5.e036981.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2010.06.044"},{"key":"2025121403072830000_10.5.e036981.16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0064585"},{"key":"2025121403072830000_10.5.e036981.17","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1055\/s-0032-1326994","article-title":"Metformin compared with insulin in the treatment of pregnant women with overt diabetes: a randomized controlled trial","volume":"30","author":"Hickman","year":"2013","journal-title":"Am J Perinatol"},{"key":"2025121403072830000_10.5.e036981.18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-0528.2010.02763.x"},{"key":"2025121403072830000_10.5.e036981.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2013.06.006"},{"key":"2025121403072830000_10.5.e036981.20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00404-014-3566-0","article-title":"Effect comparison of metformin with insulin treatment for gestational diabetes: a meta-analysis based on RCTs","volume":"292","author":"Li","year":"2015","journal-title":"Arch Gynecol Obstet"},{"key":"2025121403072830000_10.5.e036981.21","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000007939","article-title":"Comparative efficacy and safety of oral antidiabetic drugs and insulin in treating gestational diabetes mellitus: an updated PRISMA-compliant network meta-analysis","volume":"96","author":"Liang","year":"2017","journal-title":"Medicine"},{"key":"2025121403072830000_10.5.e036981.22","first-page":"327","article-title":"Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: a randomised blinded trial","volume":"4","author":"Mesdaghinia","year":"2013","journal-title":"Int J Prev Med"},{"key":"2025121403072830000_10.5.e036981.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2012.09.031"},{"key":"2025121403072830000_10.5.e036981.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2013.03.022"},{"key":"2025121403072830000_10.5.e036981.25","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12017"},{"key":"2025121403072830000_10.5.e036981.26","first-page":"866","article-title":"Efficacy of metformin versus insulin in the management of pregnancy with diabetes","volume":"23","author":"Waheed","year":"2013","journal-title":"J Coll Physicians Surg Pak"},{"key":"2025121403072830000_10.5.e036981.27","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1111\/bcp.12672","article-title":"Metformin versus insulin for gestational diabetes mellitus: a meta-analysis","volume":"80","author":"Zhao","year":"2015","journal-title":"Br J Clin Pharmacol"},{"key":"2025121403072830000_10.5.e036981.28","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2019-029808"},{"key":"2025121403072830000_10.5.e036981.29","doi-asserted-by":"crossref","first-page":"833","DOI":"10.3109\/09513590.2015.1041906","article-title":"Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis","volume":"31","author":"Feng","year":"2015","journal-title":"Gynecol Endocrinol"},{"key":"2025121403072830000_10.5.e036981.30","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.327.7421.951"},{"key":"2025121403072830000_10.5.e036981.31","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmm026"},{"key":"2025121403072830000_10.5.e036981.32","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j138"},{"key":"2025121403072830000_10.5.e036981.33","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000004526","article-title":"Effects of metformin on pregnancy outcomes in women with polycystic ovary syndrome: a meta-analysis","volume":"95","author":"Zeng","year":"2016","journal-title":"Medicine"},{"key":"2025121403072830000_10.5.e036981.34","first-page":"797","article-title":"The efficacy of metformin in pregnant women with polycystic ovary syndrome: a meta-analysis of clinical trials","volume":"36","author":"Zheng","year":"2013","journal-title":"J Endocrinol Invest"},{"key":"2025121403072830000_10.5.e036981.35","doi-asserted-by":"crossref","first-page":"120","DOI":"10.25011\/cim.v39i4.27091","article-title":"Effect of metformin treatment during pregnancy on women with PCOS: a systematic review and meta-analysis","volume":"39","author":"Tan","year":"2016","journal-title":"CIM"},{"key":"2025121403072830000_10.5.e036981.36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/381231","article-title":"Effect of metformin intervention during pregnancy on the gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and meta-analysis","volume":"2014","author":"Zhuo","year":"2014","journal-title":"J Diabetes Res"},{"key":"2025121403072830000_10.5.e036981.37","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/S2213-8587(19)30002-6","article-title":"Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial","volume":"7","author":"L\u00f8vvik","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2025121403072830000_10.5.e036981.38","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/S2213-8587(15)00219-3","article-title":"Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial","volume":"3","author":"Chiswick","year":"2015","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2025121403072830000_10.5.e036981.39","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S2213-8587(18)30310-3","article-title":"Effect of metformin in addition to dietary and lifestyle advice for pregnant women who are overweight or obese: the grow randomised, double-blind, placebo-controlled trial","volume":"7","author":"Dodd","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2025121403072830000_10.5.e036981.40","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1509819"},{"key":"2025121403072830000_10.5.e036981.41","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/jog.13477","article-title":"Metformin as a prophylactic treatment of gestational diabetes in pregnant patients with pregestational insulin resistance: a randomized study","volume":"44","author":"Vald\u00e9s","year":"2018","journal-title":"J Obstet Gynaecol Res"},{"key":"2025121403072830000_10.5.e036981.42","unstructured":"Higgins JPT . Cochrane Handbook for systematic reviews of interventions. Cichester, UK: The Cochrane Library, John Wiley & Sons, 2006."},{"key":"2025121403072830000_10.5.e036981.43","unstructured":"Finding the evidence . Centre for evidence based medicine. Oxford: University of Oxford, 2014."},{"key":"2025121403072830000_10.5.e036981.44","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.3656"},{"key":"2025121403072830000_10.5.e036981.45","unstructured":"MCHRI . Evidence synthesis program templates for critical appraisal and risk of bias (adapted from critical appraisal templates, centre for clinical effectiveness, southern health, Melbourne, 2010. Monash University and Monash Health, 2013."},{"key":"2025121403072830000_10.5.e036981.46","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.d5928"},{"key":"2025121403072830000_10.5.e036981.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2012.12.017"},{"key":"2025121403072830000_10.5.e036981.48","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4040"},{"key":"2025121403072830000_10.5.e036981.49","doi-asserted-by":"crossref","first-page":"431.e1","DOI":"10.1016\/j.jclinepi.2006.09.009","article-title":"Evidence synthesis combining individual patient data and aggregate data: a systematic review identified current practice and possible methods","volume":"60","author":"Riley","year":"2007","journal-title":"J Clin Epidemiol"},{"key":"2025121403072830000_10.5.e036981.50","doi-asserted-by":"publisher","DOI":"10.1002\/sim.3165"},{"key":"2025121403072830000_10.5.e036981.51","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.28.4.888"},{"key":"2025121403072830000_10.5.e036981.52","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-2733"},{"key":"2025121403072830000_10.5.e036981.53","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-9920"},{"key":"2025121403072830000_10.5.e036981.54","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.315.7109.629"},{"key":"2025121403072830000_10.5.e036981.55","doi-asserted-by":"publisher","DOI":"10.2307\/2533446"},{"key":"2025121403072830000_10.5.e036981.56","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.d7762","article-title":"Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: a database survey","volume":"344","author":"Ahmed","year":"2011","journal-title":"BMJ"},{"key":"2025121403072830000_10.5.e036981.57","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.d4002"},{"key":"2025121403072830000_10.5.e036981.58","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.328.7454.1490"},{"key":"2025121403072830000_10.5.e036981.59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1000097"},{"key":"2025121403072830000_10.5.e036981.60","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2012.96"},{"key":"2025121403072830000_10.5.e036981.61","doi-asserted-by":"crossref","DOI":"10.1186\/s12916-017-0925-2","article-title":"Gestational diabetes mellitus-right person, right treatment, right time?","volume":"15","author":"Lindsay","year":"2017","journal-title":"BMC Med"},{"key":"2025121403072830000_10.5.e036981.62","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62229-1"},{"key":"2025121403072830000_10.5.e036981.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2003.08.009"},{"key":"2025121403072830000_10.5.e036981.64","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c221"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2020-036981","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T11:07:35Z","timestamp":1765710455000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2020-036981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5]]},"references-count":64,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5,21]]},"published-print":{"date-parts":[[2020,5]]}},"alternative-id":["10.1136\/bmjopen-2020-036981"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2020-036981","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5]]}}}