Pre-Pregnancy Diabetes and Offspring Risk of Congenital Heart Disease: A Nation-Wide Cohort Study
Background—Maternal diabetes is associated with an increased risk of offspring congenital heart disease (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 in 1978-2011, among them 7,296 (0.36%) persons exposed to maternal pre-gestational diabetes. Pre-gestational diabetes was identified 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 pre-gestational diabetes was 318 per 10,000 live births (n=232), compared with a baseline risk of 80 per 10,000; the adjusted relative risk (RR) for CHD was 4.00 (95% confidence interval (CI) 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 did not differ significantly. Persons born to women with previous acute diabetes complications had a higher CHD risk than those exposed to maternal diabetes without complications (RR 7.62, 95% CI 5.23-10.6, and RR 3.49, 95% CI 2.91-4.13, respectively, p=0.0004). All specific CHD phenotypes were associated with maternal pre-gestational diabetes (RR range: 2.74-13.8).
Conclusions—The profoundly increased CHD risk conferred by maternal pre-gestational diabetes neither changed over time nor differed by diabetes subtype. The association with acute pre-gestational diabetes complications was particularly strong, suggesting a role for glucose in the causal pathway.
- Received October 16, 2015.
- Revision received April 4, 2016.
- Accepted April 8, 2016.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.