Øyen Nina, Diaz Lars J, Leirgul Elisabeth, Boyd Heather A, Priest James, Mathiesen Elisabeth R, Quertermous Thomas, Wohlfahrt Jan, Melbye Mads
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.).
Circulation. 2016 Jun 7;133(23):2243-53. doi: 10.1161/CIRCULATIONAHA.115.017465. Epub 2016 May 10.
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.
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).
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.
母亲患糖尿病与后代先天性心脏病（CHD）风险增加相关；然而，其因果机制尚不清楚。我们在丹麦全国队列中进一步研究了这种关联。
在一项全国队列研究中，我们确定了1978年至2011年出生的2025727人；其中7296人（0.36%）暴露于母亲孕前糖尿病。孕前糖尿病通过国家患者登记册以及丹麦药房所有处方药的个人层面信息来确定。患有CHD的人（n = 16325）被分配到胚胎学相关的心脏表型。孕前糖尿病母亲的后代中CHD患病率为每10000例活产中有318例（n = 232），而基线风险为每10000例中有80例；CHD的调整后相对风险为4.00（95%置信区间，3.51 - 4.53）。这种关联不受出生年份、糖尿病发病时的母亲年龄或糖尿病病程的影响，并且与1型（胰岛素依赖型）和2型（非胰岛素依赖型）糖尿病相关的CHD风险没有显著差异。有既往急性糖尿病并发症的女性所生子女患CHD的风险高于暴露于无并发症的母亲糖尿病的子女（相对风险分别为7.62；95%置信区间，5.23 - 10.6，以及相对风险3.49；95%置信区间，2.91 - 4.13；P = 0.0004）。所有特定的CHD表型均与母亲孕前糖尿病相关（相对风险范围，2.74 - 13.8）。
母亲孕前糖尿病所带来的CHD风险显著增加，既不会随时间变化，也不因糖尿病亚型而有所不同。与孕前急性糖尿病并发症的关联尤为强烈，表明葡萄糖在因果途径中起作用。
