{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:47:43Z","timestamp":1790819263202,"version":"4.1.0"},"reference-count":31,"publisher":"American Diabetes Association","issue":"8","license":[{"start":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T00:00:00Z","timestamp":1687305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,8,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>To assess the risk of major congenital malformations with metformin versus insulin in pregnancies with type 2 diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>This cohort study used four Nordic countries\u2019 nationwide registers of live and stillborn infants exposed to metformin or insulin during first trimester organogenesis. Main exclusion criteria were type 1 diabetes, polycystic ovary syndrome, fertility treatment, and exposure to other diabetes drugs. Adjusted risk ratios (RRs) and 95% CIs were estimated for any and cardiac malformations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Of 3,734,125 infants in the source population, 25,956 were exposed to metformin or insulin in the first trimester, and 4,023 singleton infants were included. A malformation was diagnosed in 147 (4.7%) of 3,145 infants with exposure to any metformin (alone or in addition to insulin) and 50 (5.7%) of 878 infants with exposure to insulin alone (RR 0.84, 95% CI 0.46\u20131.54). Among 2,852 infants exposed to metformin alone and 293 infants exposed to metformin in addition to insulin 127 (4.4%) and 20 (6.8%), respectively, had a malformation. The adjusted risk was not increased for either metformin alone (0.83, 0.44\u20131.58) or both metformin and insulin (0.98, 0.56\u20131.69) versus insulin alone. Corresponding RRs for cardiac malformations were 1.01 (0.55\u20131.84) for any metformin, 0.92 (0.47\u20131.81) for metformin alone, and 1.72 (0.76\u20133.91) for both metformin and insulin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>No evidence of an increased malformation risk with metformin versus insulin in the first trimester was found. Results should be interpreted with caution since information on glycemic control was missing.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc23-0256","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T18:42:04Z","timestamp":1687372924000},"page":"1556-1564","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":25,"title":["Metformin Versus Insulin and Risk of Major Congenital Malformations in Pregnancies With Type 2 Diabetes: A Nordic Register-Based Cohort Study"],"prefix":"10.2337","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2033-736X","authenticated-orcid":false,"given":"Lars J.","family":"Kjerpeseth","sequence":"first","affiliation":[{"name":"1Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn E.","family":"Cesta","sequence":"additional","affiliation":[{"name":"2Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Furu","sequence":"additional","affiliation":[{"name":"1Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway"},{"name":"3Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Engeland","sequence":"additional","affiliation":[{"name":"1Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway"},{"name":"4Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Gissler","sequence":"additional","affiliation":[{"name":"5Department of Knowledge Brokers, Finnish Institute for Health and Welfare, Helsinki, Finland"},{"name":"6Academic Primary Health Care Centre, Region Stockholm, Stockholm, Sweden"},{"name":"7Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden"},{"name":"8Research Centre for Child Psychiatry, University of Turku, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanne L.","family":"Gulseth","sequence":"additional","affiliation":[{"name":"9Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d8ystein","family":"Karlstad","sequence":"additional","affiliation":[{"name":"1Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarit K.","family":"Leinonen","sequence":"additional","affiliation":[{"name":"5Department of Knowledge Brokers, Finnish Institute for Health and Welfare, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Pazzagli","sequence":"additional","affiliation":[{"name":"2Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga","family":"Zoega","sequence":"additional","affiliation":[{"name":"10School of Population Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia"},{"name":"11Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjav\u00edk, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Cohen","sequence":"additional","affiliation":[{"name":"1Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway"},{"name":"3Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2023,6,21]]},"reference":[{"key":"2023072018562801700_B1","doi-asserted-by":"crossref","first-page":"e000221","DOI":"10.1136\/bmjdrc-2016-000221","article-title":"Trends in diabetes in pregnancy in Sweden 1998-2012","volume":"4","author":"Fadl","year":"2016","journal-title":"BMJ Open Diabetes Res Care"},{"key":"2023072018562801700_B2","doi-asserted-by":"crossref","first-page":"615","DOI":"10.2147\/CLEP.S298748","article-title":"Glycemic control in pregnancies complicated by pre-existing diabetes mellitus and congenital malformations: a Danish population-based study","volume":"13","author":"Arendt","year":"2021","journal-title":"Clin Epidemiol"},{"key":"2023072018562801700_B3","doi-asserted-by":"crossref","first-page":"e009494","DOI":"10.1136\/bmjopen-2015-009494","article-title":"A cohort study of trends in the prevalence of pregestational diabetes in pregnancy recorded in UK general practice between 1995 and 2012","volume":"6","author":"Coton","year":"2016","journal-title":"BMJ Open"},{"key":"2023072018562801700_B4","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1007\/s00125-012-2455-y","article-title":"Peri-conception hyperglycaemia and nephropathy are associated with risk of congenital anomaly in women with pre-existing diabetes: a population-based cohort study","volume":"55","author":"Bell","year":"2012","journal-title":"Diabetologia"},{"key":"2023072018562801700_B5","doi-asserted-by":"crossref","first-page":"e2030207","DOI":"10.1001\/jamanetworkopen.2020.30207","article-title":"Association of improved periconception hemoglobin A1c with pregnancy outcomes in women with diabetes","volume":"3","author":"Davidson","year":"2020","journal-title":"JAMA Netw Open"},{"key":"2023072018562801700_B6","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1177\/2042098618769831","article-title":"Metformin treatment of type 2 diabetes mellitus in pregnancy: update on safety and efficacy","volume":"9","author":"Polasek","year":"2018","journal-title":"Ther Adv Drug Saf"},{"key":"2023072018562801700_B7","doi-asserted-by":"crossref","first-page":"e000759","DOI":"10.1136\/bmjdrc-2019-000759","article-title":"Antidiabetic medication use during pregnancy: an international utilization study","volume":"7","author":"Cesta","year":"2019","journal-title":"BMJ Open Diabetes Res Care"},{"key":"2023072018562801700_B8","doi-asserted-by":"crossref","first-page":"S254","DOI":"10.2337\/dc23-S015","article-title":"15. Management of diabetes in pregnancy: Standards of Care in Diabetes\u20142023","volume":"46","author":"ElSayed","year":"2023","journal-title":"Diabetes Care"},{"key":"2023072018562801700_B9","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/jcpt.13503","article-title":"The efficacy and safety of metformin alone or as an add-on therapy to insulin in pregnancy with GDM or T2DM: a systematic review and meta-analysis of 21 randomized controlled trials","volume":"47","author":"He","year":"2022","journal-title":"J Clin Pharm Ther"},{"key":"2023072018562801700_B10","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1093\/humupd\/dmu022","article-title":"First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis","volume":"20","author":"Cassina","year":"2014","journal-title":"Hum Reprod Update"},{"key":"2023072018562801700_B11","doi-asserted-by":"crossref","first-page":"e002919","DOI":"10.1136\/bmjdrc-2022-002919","article-title":"Major malformations risk following early pregnancy exposure to metformin: a systematic review and meta-analysis","volume":"11","author":"Abolhassani","year":"2023","journal-title":"BMJ Open Diabetes Res Care"},{"key":"2023072018562801700_B12","doi-asserted-by":"crossref","first-page":"533","DOI":"10.2147\/CLEP.S314959","article-title":"Nordic health registry-based research: a review of health care systems and key registries","volume":"13","author":"Laugesen","year":"2021","journal-title":"Clin Epidemiol"},{"key":"2023072018562801700_B13","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1034\/j.1600-0412.2000.079006440.x","article-title":"Birthweight by gestational age in Norway","volume":"79","author":"Skjaerven","year":"2000","journal-title":"Acta Obstet Gynecol Scand"},{"key":"2023072018562801700_B14","unstructured":"European Commission . Guidelines for data registration. Accessed 18 March 2022. Available from https:\/\/eu-rd-platform.jrc.ec.europa.eu\/eurocat\/data-collection\/guidelines-for-data-registration_en"},{"key":"2023072018562801700_B15","doi-asserted-by":"crossref","unstructured":"Cohen JM , CestaCE, KjerpesethL, . A common data model for harmonization in the Nordic Pregnancy Drug Safety Studies (NorPreSS). Norsk Epidemiol2021;29(1\u20132). Accessed 4 October 2021. Available from https:\/\/www.ntnu.no\/ojs\/index.php\/norepid\/article\/view\/4053","DOI":"10.5324\/nje.v29i1-2.4053"},{"key":"2023072018562801700_B16","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1097\/EDE.0000000000000595","article-title":"A propensity-score-based fine stratification approach for confounding adjustment when exposure is infrequent","volume":"28","author":"Desai","year":"2017","journal-title":"Epidemiology"},{"key":"2023072018562801700_B17","doi-asserted-by":"crossref","first-page":"b2393","DOI":"10.1136\/bmj.b2393","article-title":"Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls","volume":"338","author":"Sterne","year":"2009","journal-title":"BMJ"},{"key":"2023072018562801700_B18","doi-asserted-by":"crossref","first-page":"S131","DOI":"10.1097\/MLR.0b013e318070c08e","article-title":"Increasing levels of restriction in pharmacoepidemiologic database studies of elderly and comparison with randomized trial results","volume":"45","author":"Schneeweiss","year":"2007","journal-title":"Med Care"},{"key":"2023072018562801700_B19","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1097\/EDE.0b013e3181a663cc","article-title":"High-dimensional propensity score adjustment in studies of treatment effects using health care claims data","volume":"20","author":"Schneeweiss","year":"2009","journal-title":"Epidemiology"},{"key":"2023072018562801700_B20","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1186\/s12884-020-03207-0","article-title":"Association of pregnancy outcomes in women with type 2 diabetes treated with metformin versus insulin when becoming pregnant","volume":"20","author":"Lin","year":"2020","journal-title":"BMC Pregnancy Childbirth"},{"key":"2023072018562801700_B21","doi-asserted-by":"crossref","first-page":"k2477","DOI":"10.1136\/bmj.k2477","article-title":"Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study","volume":"361","author":"Given","year":"2018","journal-title":"BMJ"},{"key":"2023072018562801700_B22","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1111\/bcp.13481","article-title":"Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services","volume":"84","author":"Panchaud","year":"2018","journal-title":"Br J Clin Pharmacol"},{"key":"2023072018562801700_B23","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1002\/bdr2.1199","article-title":"Metformin in the first trimester and risks for specific birth defects in the National Birth Defects Prevention Study","volume":"110","author":"Dukhovny","year":"2018","journal-title":"Birth Defects Res"},{"key":"2023072018562801700_B24","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.reprotox.2018.07.004","article-title":"Pregnancy outcome after first-trimester exposure to metformin: a prospective cohort study","volume":"81","author":"Scherneck","year":"2018","journal-title":"Reprod Toxicol"},{"key":"2023072018562801700_B25","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.reprotox.2018.05.007","article-title":"In-utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome: a prospective comparative observational study","volume":"80","author":"Diav-Citrin","year":"2018","journal-title":"Reprod Toxicol"},{"key":"2023072018562801700_B26","doi-asserted-by":"crossref","first-page":"e002363","DOI":"10.1136\/bmjdrc-2021-002363","article-title":"Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study","volume":"10","author":"Brand","year":"2022","journal-title":"BMJ Open Diabetes Res Care"},{"key":"2023072018562801700_B27","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/S2213-8587(20)30310-7","article-title":"Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial","volume":"8","author":"Feig","year":"2020","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2023072018562801700_B28","doi-asserted-by":"crossref","first-page":"e1003900","DOI":"10.1371\/journal.pmed.1003900","article-title":"Risks of specific congenital anomalies in offspring of women with diabetes: a systematic review and meta-analysis of population-based studies including over 80 million births","volume":"19","author":"Zhang","year":"2022","journal-title":"PLoS Med"},{"key":"2023072018562801700_B29","doi-asserted-by":"crossref","first-page":"e014972","DOI":"10.1136\/bmjopen-2016-014972","article-title":"Insulin analogues use in pregnancy among women with pregestational diabetes mellitus and risk of congenital anomaly: a retrospective population-based cohort study","volume":"8","author":"Wang","year":"2018","journal-title":"BMJ Open"},{"key":"2023072018562801700_B30","first-page":"62","article-title":"The role of propensity score matching in claims-based studies for achieving comparability in HbA1c levels between treatments in pregnant women with type 2 diabetes [abstract]","volume":"30","author":"Cesta","year":"2021","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"2023072018562801700_B31","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1001\/jama.2016.16435","article-title":"Confounding by indication in clinical research","volume":"316","author":"Kyriacou","year":"2016","journal-title":"JAMA"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/46\/8\/1556\/729552\/dc230256.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/46\/8\/1556\/729552\/dc230256.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T08:27:31Z","timestamp":1702628851000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/46\/8\/1556\/151609\/Metformin-Versus-Insulin-and-Risk-of-Major"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,21]]},"references-count":31,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,6,21]]},"published-print":{"date-parts":[[2023,8,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc23-0256","relation":{"has-preprint":[{"id-type":"doi","id":"10.2337\/figshare.23264624","asserted-by":"object"},{"id-type":"doi","id":"10.2337\/figshare.23264624.v1","asserted-by":"object"}]},"ISSN":["0149-5992","1935-5548"],"issn-type":[{"value":"0149-5992","type":"print"},{"value":"1935-5548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,21]]}}}