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Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study

BMJ 2018; 361 doi: (Published 25 June 2018) Cite this as: BMJ 2018;361:k2477
  1. Joanne E Given, research associate1,
  2. Maria Loane, reader in public health2,
  3. Ester Garne, consultant paediatrician3,
  4. Marie-Claude Addor, clinical geneticist4,
  5. Marian Bakker, epidemiologist5,
  6. Bénédicte Bertaut-Nativel, midwife6,
  7. Miriam Gatt, programme director7,
  8. Kari Klungsoyr, professor8 9,
  9. Nathalie Lelong, project manager10,
  10. Margery Morgan, consultant obstetrician and gynaecologist11,
  11. Amanda J Neville, EUROCAT registry leader12,
  12. Anna Pierini, researcher13,
  13. Anke Rissmann, consultant paediatrician and registry leader14,
  14. Helen Dolk, professor of epidemiology and health services research15
  1. 1Administrative Data Research Centre Northern Ireland, Ulster University, Belfast BT37 0QB, UK
  2. 2Institute of Nursing and Health Research, Ulster University, Belfast BT37 0QB, UK
  3. 3Paediatric Department, Hospital Lillebaelt, Kolding, DK-6000, Denmark
  4. 4Medical Genetics, CHUV, Lausanne, CH-1011, Switzerland
  5. 5University of Groningen, University Medical Center Groningen, Department of Genetics, Eurocat Northern Netherlands, 9700RB, Netherlands
  6. 6Registre des Malformations Congenitales de la Reunion, Saint-Pierre, BP350, Ile de la Reunion
  7. 7Directorate for Health Information and Research, Guardamangia, PTA 1313, Malta
  8. 8Division of Mental and Physical Health, Norwegian Institute of Public Health, Bergen, Norway
  9. 9Department of Global Public Health and Primary Care, University of Bergen, N-5018, Norway
  10. 10Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité and DHU Risks in pregnancy, Paris Descartes University, Paris, 75014, France
  11. 11Congenital Anomaly Register and Information Service for Wales, Public Health Wales, Swansea SA2 8QA, UK
  12. 12IMER Registry (Emilia Romagna Registry of Birth Defects), University of Ferrara and Azienda Ospedaliero Universitaria di Ferrara, Ferrara, 44100, Italy
  13. 13Tuscany Registry of Congenital Defects, Institute of Clinical Physiology, National Research Council/Fondazione Toscana Gabriele Monasterio, Pisa, 56126, Italy
  14. 14Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke University Magdeburg, Magdeburg, D-39120, Germany
  15. 15Institute of Nursing and Health Research, Ulster University, Belfast BT37 0QB, UK
  1. Correspondence to: Joanne E Given je.given{at}
  • Accepted 4 May 2018


Objective To investigate whether exposure to metformin during the first trimester of pregnancy, for diabetes or other indications, increases the risk of all or specific congenital anomalies.

Design Population based exploratory case-control study using malformed controls. Cases of 29 specific subgroups of non-genetic anomalies, and all non-genetic anomalies combined, were compared with controls (all other non-genetic anomalies or genetic syndromes).

Setting 11 EUROmediCAT European congenital anomaly registries surveying 1 892 482 births in Europe between 2006 and 2013.

Participants 50 167 babies affected by congenital anomaly (41 242 non-genetic and 8925 genetic) including live births, fetal deaths from 20 weeks’ gestation, and terminations of pregnancy for fetal anomaly.

Main outcome measure Odds ratios adjusted for maternal age, registry, multiple birth, and maternal diabetes status.

Results 168 babies affected by congenital anomaly (141 non-genetic and 27 genetic) were exposed to metformin, 3.3 per 1000 births. No evidence was found for a higher proportion of exposure to metformin during the first trimester among babies with all non-genetic anomalies combined compared with genetic controls (adjusted odds ratio 0.84, 95% confidence interval 0.55 to 1.30). The only significant result was for pulmonary valve atresia (adjusted odds ratio 3.54, 1.05 to 12.00, compared with non-genetic controls; 2.86, 0.79 to 10.30, compared with genetic controls).

Conclusions No evidence was found for an increased risk of all non-genetic congenital anomalies combined following exposure to metformin during the first trimester, and the one significant association was no more than would be expected by chance. Further surveillance is needed to increase sample size and follow up the cardiac signal, but these findings are reassuring given the increasing use of metformin in pregnancy.


  • Contributors: JEG and HD had the idea for the study. JEG did the statistical analysis and wrote the first draft of the paper. ML advised on the conduct and coordination of the study, as well as interpretation of the results. EG and HD advised on interpretation of the results. EG, MCA, MB, MG, NL, KK, MM, AJN, AP, HR, and AR provided and verified the data. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. All authors commented on drafts and read and approved the final manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. JEG is the guarantor.

  • Funding: This work was supported by the Economic and Social Research Council grant number ESL/L007509/1 (Administrative Data Research Centre—Northern Ireland). EUROCAT registries are funded as fully described in Paper 6 of Report 9—EUROCAT Member Registries: Organisation and Activities: The funders of this research were not involved in the study design, data analysis, or manuscript preparation or publication decisions.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: JEG, ML, and HD received grants from the Economic and Social Research Council for the submitted work; ML and HD received grants from European Union Framework 7 for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Ethical approval was provided by the University of Ulster Nursing Research Governance Filter Committee.

  • Data sharing: EUROmediCAT aims to encourage the use of its data and networks for pharmacovigilance and drug safety research. Data sharing can be requested as per the ENCePP Code of Conduct—Implementation Guidance for Sharing of Study Data; see and for more information.

  • Transparency statement: The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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