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BMJ. 2018 Jun 25;361:k2477. doi: 10.1136/bmj.k2477.

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

Author information

1
Administrative Data Research Centre Northern Ireland, Ulster University, Belfast BT37 0QB, UK.
2
Institute of Nursing and Health Research, Ulster University, Belfast BT37 0QB, UK.
3
Paediatric Department, Hospital Lillebaelt, Kolding, DK-6000, Denmark.
4
Medical Genetics, CHUV, Lausanne, CH-1011, Switzerland.
5
University of Groningen, University Medical Center Groningen, Department of Genetics, Eurocat Northern Netherlands, 9700RB, Netherlands.
6
Registre des Malformations Congenitales de la Reunion, Saint-Pierre, BP350, Ile de la Reunion.
7
Directorate for Health Information and Research, Guardamangia, PTA 1313, Malta.
8
Division of Mental and Physical Health, Norwegian Institute of Public Health, Bergen, Norway.
9
Department of Global Public Health and Primary Care, University of Bergen, N-5018, Norway.
10
Inserm 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
Congenital Anomaly Register and Information Service for Wales, Public Health Wales, Swansea SA2 8QA, UK.
12
IMER Registry (Emilia Romagna Registry of Birth Defects), University of Ferrara and Azienda Ospedaliero Universitaria di Ferrara, Ferrara, 44100, Italy.
13
Tuscany Registry of Congenital Defects, Institute of Clinical Physiology, National Research Council/Fondazione Toscana Gabriele Monasterio, Pisa, 56126, Italy.
14
Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke University Magdeburg, Magdeburg, D-39120, Germany.

Abstract

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.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmj.org/cio_disclosure.pdf (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.

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