Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease: A Nationwide Cohort Study

doi:10.1161/CIRCULATIONAHA.115.017465

Comparative Study

. 2016 Jun 7;133(23):2243-53.

doi: 10.1161/CIRCULATIONAHA.115.017465. Epub 2016 May 10.

Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease: A Nationwide Cohort Study

Nina Øyen¹, Lars J Diaz², Elisabeth Leirgul², Heather A Boyd², James Priest², Elisabeth R Mathiesen², Thomas Quertermous², Jan Wohlfahrt², Mads Melbye²

Affiliations

¹ From Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark (N.Ø., L.J.D., H.A.B., J.W., M.M.); Department of Global Public Health and Primary Care, Faculty of Medicine and Dentistry, University of Bergen, Norway (N.Ø., E.L.); Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway(N.Ø.); Department of Cardiology, Haukeland University Hospital, Bergen, Norway (E.L.); Cardiovascular Institute, Stanford University School of Medicine, CA (J.P., T.Q.); Center for Pregnant Women with Diabetes, Department of Endocrinology, University of Copenhagen, Denmark (E.R.M.); Department of Medicine, Stanford University School of Medicine, CA (M.M.); and Department of Clinical Medicine, University of Copenhagen, Denmark (M.M.). noy@ssi.dk.
² From Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark (N.Ø., L.J.D., H.A.B., J.W., M.M.); Department of Global Public Health and Primary Care, Faculty of Medicine and Dentistry, University of Bergen, Norway (N.Ø., E.L.); Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway(N.Ø.); Department of Cardiology, Haukeland University Hospital, Bergen, Norway (E.L.); Cardiovascular Institute, Stanford University School of Medicine, CA (J.P., T.Q.); Center for Pregnant Women with Diabetes, Department of Endocrinology, University of Copenhagen, Denmark (E.R.M.); Department of Medicine, Stanford University School of Medicine, CA (M.M.); and Department of Clinical Medicine, University of Copenhagen, Denmark (M.M.).

PMID: 27166384
PMCID: PMC4890838
DOI: 10.1161/CIRCULATIONAHA.115.017465

Comparative Study

Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease: A Nationwide Cohort Study

Nina Øyen et al. Circulation. 2016.

. 2016 Jun 7;133(23):2243-53.

doi: 10.1161/CIRCULATIONAHA.115.017465. Epub 2016 May 10.

Authors

Nina Øyen¹, Lars J Diaz², Elisabeth Leirgul², Heather A Boyd², James Priest², Elisabeth R Mathiesen², Thomas Quertermous², Jan Wohlfahrt², Mads Melbye²

Affiliations

¹ From Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark (N.Ø., L.J.D., H.A.B., J.W., M.M.); Department of Global Public Health and Primary Care, Faculty of Medicine and Dentistry, University of Bergen, Norway (N.Ø., E.L.); Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway(N.Ø.); Department of Cardiology, Haukeland University Hospital, Bergen, Norway (E.L.); Cardiovascular Institute, Stanford University School of Medicine, CA (J.P., T.Q.); Center for Pregnant Women with Diabetes, Department of Endocrinology, University of Copenhagen, Denmark (E.R.M.); Department of Medicine, Stanford University School of Medicine, CA (M.M.); and Department of Clinical Medicine, University of Copenhagen, Denmark (M.M.). noy@ssi.dk.
² From Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark (N.Ø., L.J.D., H.A.B., J.W., M.M.); Department of Global Public Health and Primary Care, Faculty of Medicine and Dentistry, University of Bergen, Norway (N.Ø., E.L.); Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway(N.Ø.); Department of Cardiology, Haukeland University Hospital, Bergen, Norway (E.L.); Cardiovascular Institute, Stanford University School of Medicine, CA (J.P., T.Q.); Center for Pregnant Women with Diabetes, Department of Endocrinology, University of Copenhagen, Denmark (E.R.M.); Department of Medicine, Stanford University School of Medicine, CA (M.M.); and Department of Clinical Medicine, University of Copenhagen, Denmark (M.M.).

PMID: 27166384
PMCID: PMC4890838
DOI: 10.1161/CIRCULATIONAHA.115.017465

Abstract

Background: Maternal diabetes mellitus is associated with an increased risk of offspring congenital heart defects (CHD); however, the causal mechanism is poorly understood. We further investigated this association in a Danish nationwide cohort.

Methods and results: In a national cohort study, we identified 2 025 727 persons born from 1978 to 2011; among them were 7296 (0.36%) persons exposed to maternal pregestational diabetes mellitus. Pregestational diabetes mellitus was identified by using the National Patient Register and individual-level information on all prescriptions filled in Danish pharmacies. Persons with CHD (n=16 325) were assigned to embryologically related cardiac phenotypes. The CHD prevalence in the offspring of mothers with pregestational diabetes mellitus was 318 per 10 000 live births (n=232) in comparison with a baseline risk of 80 per 10 000; the adjusted relative risk for CHD was 4.00 (95% confidence interval, 3.51-4.53). The association was not modified by year of birth, maternal age at diabetes onset, or diabetes duration, and CHD risks associated with type 1 (insulin-dependent) and type 2 (insulin-independent) diabetes mellitus did not differ significantly. Persons born to women with previous acute diabetes complications had a higher CHD risk than those exposed to maternal diabetes mellitus without complications (relative risk, 7.62; 95% confidence interval, 5.23-10.6, and relative risk, 3.49; 95% confidence interval, 2.91-4.13, respectively; P=0.0004). All specific CHD phenotypes were associated with maternal pregestational diabetes mellitus (relative risk range, 2.74-13.8).

Conclusions: The profoundly increased CHD risk conferred by maternal pregestational diabetes mellitus neither changed over time nor differed by diabetes subtype. The association with acute pregestational diabetes complications was particularly strong, suggesting a role for glucose in the causal pathway.

Keywords: congenital abnormalities; diabetes mellitus; heart defects, congenital; insulin; pregnancy.

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Comment in

Pregestational Diabetes Mellitus and Congenital Heart Defects.
Correa A. Correa A. Circulation. 2016 Jun 7;133(23):2219-21. doi: 10.1161/CIRCULATIONAHA.116.022960. Epub 2016 May 10. Circulation. 2016. PMID: 27166385 No abstract available.

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References

1. Macintosh MC, Fleming KM, Bailey JA, Doyle P, Modder J, Acolet D, Golightly S, Miller A. Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study. BMJ. 2006;333:177. doi: 10.1136/bmj.38856.692986.AE. - PMC - PubMed
1. Eidem I, Vangen S, Hanssen KF, Vollset SE, Henriksen T, Joner G, Stene LC. Perinatal and infant mortality in term and preterm births among women with type 1 diabetes. Diabetologia. 2011;54:2771–2778. doi: 10.1007/s00125-011-2281-7. - PubMed
1. Eidem I, Stene LC, Henriksen T, Hanssen KF, Vangen S, Vollset SE, Joner G. Congenital anomalies in newborns of women with type 1 diabetes: nationwide population-based study in Norway, 1999-2004. Acta Obstet Gynecol Scand. 2010;89:1403–1411. doi: 10.3109/00016349.2010.518594. - PubMed
1. Jenkins KJ, Correa A, Feinstein JA, Botto L, Britt AE, Daniels SR, Elixson M, Warnes CA, Webb CL American Heart Association Council on Cardiovascular Disease in the Young. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115:2995–3014. doi: 10.1161/CIRCULATIONAHA.106.183216. - PubMed
1. Kumar SD, Dheen ST, Tay SS. Maternal diabetes induces congenital heart defects in mice by altering the expression of genes involved in cardiovascular development. Cardiovasc Diabetol. 2007;6:34. doi: 10.1186/1475-2840-6-34. - PMC - PubMed

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[1] Macintosh MC, Fleming KM, Bailey JA, Doyle P, Modder J, Acolet D, Golightly S, Miller A. Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study. BMJ. 2006;333:177. doi: 10.1136/bmj.38856.692986.AE. - PMC - PubMed

[2] Macintosh MC, Fleming KM, Bailey JA, Doyle P, Modder J, Acolet D, Golightly S, Miller A. Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study. BMJ. 2006;333:177. doi: 10.1136/bmj.38856.692986.AE. - PMC - PubMed

[3] Eidem I, Vangen S, Hanssen KF, Vollset SE, Henriksen T, Joner G, Stene LC. Perinatal and infant mortality in term and preterm births among women with type 1 diabetes. Diabetologia. 2011;54:2771–2778. doi: 10.1007/s00125-011-2281-7. - PubMed

[4] Eidem I, Vangen S, Hanssen KF, Vollset SE, Henriksen T, Joner G, Stene LC. Perinatal and infant mortality in term and preterm births among women with type 1 diabetes. Diabetologia. 2011;54:2771–2778. doi: 10.1007/s00125-011-2281-7. - PubMed

[5] Eidem I, Stene LC, Henriksen T, Hanssen KF, Vangen S, Vollset SE, Joner G. Congenital anomalies in newborns of women with type 1 diabetes: nationwide population-based study in Norway, 1999-2004. Acta Obstet Gynecol Scand. 2010;89:1403–1411. doi: 10.3109/00016349.2010.518594. - PubMed

[6] Eidem I, Stene LC, Henriksen T, Hanssen KF, Vangen S, Vollset SE, Joner G. Congenital anomalies in newborns of women with type 1 diabetes: nationwide population-based study in Norway, 1999-2004. Acta Obstet Gynecol Scand. 2010;89:1403–1411. doi: 10.3109/00016349.2010.518594. - PubMed

[7] Jenkins KJ, Correa A, Feinstein JA, Botto L, Britt AE, Daniels SR, Elixson M, Warnes CA, Webb CL American Heart Association Council on Cardiovascular Disease in the Young. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115:2995–3014. doi: 10.1161/CIRCULATIONAHA.106.183216. - PubMed

[8] Jenkins KJ, Correa A, Feinstein JA, Botto L, Britt AE, Daniels SR, Elixson M, Warnes CA, Webb CL American Heart Association Council on Cardiovascular Disease in the Young. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115:2995–3014. doi: 10.1161/CIRCULATIONAHA.106.183216. - PubMed

[9] Kumar SD, Dheen ST, Tay SS. Maternal diabetes induces congenital heart defects in mice by altering the expression of genes involved in cardiovascular development. Cardiovasc Diabetol. 2007;6:34. doi: 10.1186/1475-2840-6-34. - PMC - PubMed

[10] Kumar SD, Dheen ST, Tay SS. Maternal diabetes induces congenital heart defects in mice by altering the expression of genes involved in cardiovascular development. Cardiovasc Diabetol. 2007;6:34. doi: 10.1186/1475-2840-6-34. - PMC - PubMed

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Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease: A Nationwide Cohort Study

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Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease: A Nationwide Cohort Study

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