Elisabeth Leirgul

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

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.

Possible Common Aetiology behind Maternal Preeclampsia and Congenital Heart Defects in the Child: a Cardiovascular Diseases in Norway Project Study

BACKGROUND The aetiology of congenital heart defects (CHD) is mostly unknown, but maternal factors may modify the infant risk of CHD. We investigated the association between maternal preeclampsia and offspring risk of severe CHD in a nation-wide cohort study. METHODS Information on all births registered in the Medical Birth Registry of Norway, 1994-2009, was completed with information on CHD diagnoses from national health registries and the Cardiovascular Diseases in Norway Project (CVDNOR). RESULTS Among 914 703 singleton births without chromosomal abnormalities, 32 864 (3.6%) were born after a pregnancy with preeclampsia. The preeclampsia was diagnosed before the 34th week of pregnancy (early-onset preeclampsia) in 2618 (8.0% of preeclamptic pregnancies). CHDs were diagnosed in 10 691 infants; of these, 2473 had severe CHD. The risk of severe CHD was compared between births with and without maternal preeclampsia and estimated with binomial log-linear regression. When adjusting for year of birth, maternal age, parity, and pregestational diabetes, the risk ratio (RR) for severe CHD in offspring of mothers with any preeclampsia was 1.3 [95% confidence interval (CI) 1.1, 1.5], and in pregnancies with early-onset preeclampsia, the RR was 2.8 (95% CI 1.8, 4.4). The association between early-onset preeclampsia and specific types of severe CHD was stronger for atrioventricular septal defects (AVSD), with adjusted RR 13.5 (95% CI 6.8, 26.8). CONCLUSIONS Early-onset preeclampsia was strongly associated with infant risk of severe CHD, specifically; the risk of AVSD was 15-fold higher if the mother was diagnosed with early-onset preeclampsia, suggesting common aetiological factors for early-onset preeclampsia and erroneous fetal heart development.

Mortality and complications in 3495 children with isolated ventricular septal defects

Background Ventricular septal defects (VSDs) are the most common congenital heart defects (CHDs). Previous studies indicate an increased risk of endocarditis, aortic regurgitation, left ventricular outflow tract obstructions, pulmonary hypertension, arrhythmias and sudden death in patients with isolated VSDs. The present nationwide cohort study reports mortality and cardiac complications requiring hospitalisation or intervention in children with isolated VSDs. Methods and results Medical information concerning all 943 871 live births in Norway in 1994–2009 was retrieved from the Medical Birth Registry of Norway, the Cardiovascular Disease in Norway project, the Oslo University Hospitals Clinical Registry of Congenital Heart Defects and the Norwegian Cause of Death Registry. Isolated VSDs were identified in 3495 children without known chromosomal aberrations or extracardiac malformations. Surgical or catheter-based treatment of VSD was performed in 181 (5.2%) cases. Twelve (0.3%) children with VSDs died before 2013. There was no operative mortality, and no excess mortality in children with isolated VSDs compared with children without VSDs (adjusted HR 0.8 (0.5 to 1.4), p=0.48). The following conditions were recorded as possible cardiac complications of the VSDs: endocarditis in 3 children (0.9‰), aortic regurgitation in 12 children (3.4‰), left ventricular outflow tract obstructions in no children (0.0‰), pulmonary hypertension in 1 child (0.3‰) and arrhythmias in 16 children (4.6‰). Conclusions The entire group of children with isolated VSDs had a favourable prognosis without excess mortality. Cardiac complications requiring hospitalisation or intervention, including endocarditis, aortic regurgitation, left ventricular outflow tract obstructions, pulmonary hypertension and arrhythmias, were infrequent during childhood. Trial registration number NCT02026557.

Maternal Diabetes, Birth Weight, and Neonatal Risk of Congenital Heart Defects in Norway, 1994-2009.

OBJECTIVE: To investigate the association between pregestational or gestational diabetes and offspring risk of congenital heart defects and the association between large-for-gestational-age birth weight and risk of cardiac defects in offspring of diabetic women. METHODS: Information on pregestational and gestational diabetes, cardiac defects, and birth weight among all births in Norway in 1994–2009 was ascertained from the Medical Birth Registry of Norway, national health registries, and the Cardiovascular Disease in Norway project. The relative risk (RR) compared offspring risk of cardiac defects for maternal diabetes with offspring risk in nondiabetic mothers adjusted for year of birth, maternal age, and parity. RESULTS: Among 914,427 births (live births, stillbirths, terminated pregnancies), 5,618 (0.61%) were complicated by maternal pregestational diabetes and 9,726 (1.06%) by gestational diabetes. Congenital heart defects were identified in 10,575 offspring. The prevalence of cardiac defects differed between groups: 344 of 10,000 births to women with pregestational diabetes, 172 of 10,000 to women with gestational diabetes, and 114 of 10,000 in women without diabetes (adjusted RRs 2.92, 95% confidence interval [CI] 2.54–3.36 and 1.47, 95% CI 1.26–1.71). During the study period, the adjusted RRs for congenital heart defects did not change. The risk of cardiac defects in neonates very large for gestational age (birth weight greater than 3 standard deviations above the mean) was compared with neonates with birth weight appropriate for gestational age. For pregestational diabetes, the prevalences of offspring cardiac defects were 561 compared with 248 per 10,000 births (adjusted RR 2.23, 95% CI 1.39–3.59) and for gestational diabetes 388 compared with 132 per 10,000 (adjusted RR 2.73, 95% CI 1.53–4.85). CONCLUSION: The increased risk of having a child with a congenital heart defect has not changed for diabetic women in Norway since 1994. Among women with pregestational or gestational diabetes, having a large-for-gestational-age neonate was associated with a two- to threefold increased risk of cardiac defects compared with neonates with normal birth weight.

Trends in Mortality of Congenital Heart Defects.

OBJECTIVE The aim of the present nationwide cohort study was to describe trends in 1-year mortality in live-born children with congenital heart defects in Norway 1994-2009 and to assess whether changes in the proportion of terminated pregnancies and altered operative mortality have influenced these trends. METHODS Medical information concerning all 954 413 live births, stillbirths, and late-term abortions in Norway, 1994-2009, was retrieved from the Medical Birth Registry of Norway, the Cardiovascular Disease in Norway project, the Oslo University Hospitals Clinical Registry for Congenital Heart Defects and the Norwegian Cause of Death Registry. Survivors were followed through 2012. RESULTS The 1-year cumulative mortality proportion during the study period was 17.4% for children with severe congenital heart defects and 3.0% for children with nonsevere congenital heart defects. The 1-year cumulative mortality proportion among live born children with severe congenital heart defects decreased 3.6% (95% CI: -5.4, -1.5) per year. The total mortality of severe congenital heart defects was unchanged when including stillbirths and late-term abortions with severe congenital heart defects. The proportion of stillbirths or terminated pregnancies with severe congenital heart defects among all pregnancies with severe congenital heart defects, was on average 8.8% over the entire period with an annually increase of 16.6% (11.4, 18.0). The mean operative mortality in children with severe congenital heart defects was 8.4% and decreased by 9.0% (-11.9, -5.9) per year. CONCLUSIONS The 1-year mortality of severe congenital heart defects among live births, 1994-2009, declined in Norway. The downward trend in mortality may be explained by a more frequent use of termination of affected pregnancies, and the reduced operative mortality of severe congenital heart defects.

Association Between Fetal Congenital Heart Defects and Maternal Risk of Hypertensive Disorders of Pregnancy in the Same Pregnancy and Across Pregnancies

Background: Both pregnant women carrying fetuses with heart defects and women with hypertensive disorders of pregnancy often exhibit angiogenic imbalances, suggesting that the same mechanisms are involved in the pathogenesis of the former and the pathophysiology of the latter. We conducted a register-based cohort study to determine whether offspring congenital heart defects are associated with an increased risk of hypertensive disorders of pregnancy and whether the mechanisms driving any association are primarily maternal or fetal. Methods: Among singleton pregnancies without chromosomal abnormalities lasting ≥20 weeks in Denmark from 1978 to 2011 (n= 1 972 857), we identified pregnancies complicated by offspring congenital heart defects or early preterm preeclampsia, late preterm preeclampsia, term preeclampsia, and gestational hypertension. We used polytomous logistic regression to estimate odds ratios (ORs) for associations between offspring congenital heart defects and maternal hypertensive disorders of pregnancy overall and for specific heart defects. Results: Offspring congenital heart defects were strongly associated with early preterm preeclampsia (OR, 7.00; 95% confidence interval [CI], 6.11–8.03) and late preterm preeclampsia (OR, 2.82; 95% CI, 2.38–3.34) in the same pregnancy and weakly associated with term preeclampsia (OR, 1.16; 95% CI, 1.06–1.27), but they were not associated with gestational hypertension (OR, 1.07; 95% CI, 0.92–1.25). Association strengths were consistent across heart defect types. Offspring congenital heart defects in a previous pregnancy were also strongly associated with preterm preeclampsia in subsequent pregnancies (early preterm preeclampsia: OR, 2.37; 95% CI, 1.68–3.34; late preterm preeclampsia: OR, 2.04; 95% CI, 1.52–2.75) but were only modestly associated with term preeclampsia and not associated with gestational hypertension. Similarly, preterm preeclampsia in a previous pregnancy, but not term preeclampsia or gestational hypertension, was associated with offspring congenital heart defects in later pregnancies (early preterm preeclampsia: OR, 7.91; 95% CI, 6.06–10.3; late preterm preeclampsia: OR, 2.83; 95% CI, 2.11–3.79; term preeclampsia: OR, 0.98; 95% CI, 0.88–1.10; gestational hypertension: OR, 1.13; 95% CI, 0.92–1.38). Conclusions: Linked pathophysiological mechanisms may be involved in some congenital heart defects and preterm preeclampsia. The strong associations across pregnancies support a predominantly maternal origin of effect.

Periconceptional Folic Acid Supplementation and Infant Risk of Congenital Heart Defects in Norway 1999-2009

BACKGROUND The birth prevalence of congenital heart defects (CHDs) has decreased in Canada and Europe. Recommended intake of folic acid in pregnancy is a suggestive risk-reducing factor for CHDs. We investigated the association between periconceptional intake of folic acid supplements and infant risk of CHDs. METHODS Information on maternal intake of folic acid supplements before and during pregnancy in the Medical Birth Registry of Norway 1999-2009 was updated with information on CHD diagnoses from national health registers and the Cardiovascular Diseases in Norway Project. The association between folic acid intake and infant risk of CHD was estimated as relative risk (RR) with binomial log linear regression. RESULTS Among 517 784 non-chromosomal singleton births, 6200 children were identified with CHD and 1153 with severe CHD. For all births, 18.4% of the mothers initiated folic acid supplements before pregnancy and 31.6% during pregnancy. The adjusted RR for severe CHD was 0.99 [95% confidence interval [CI] 0.86, 1.13] comparing periconceptional intake of folic acid with no intake. Specifically, RR for conotruncal defects was 0.99 [95% CI 0.80, 1.22], atrioventricular septal defects 1.19 [95% CI 0.78, 1.81], left ventricular outflow tract obstructions 1.02 [95% CI 0.78, 1.32], and right ventricular outflow tract obstructions 0.97 [95% CI 0.72, 1.29]. Birth prevalence of septal defects was higher in the group exposed to folic acid supplements with RR 1.19 [95% CI 1.10, 1.30]. CONCLUSIONS Periconceptional folic acid supplement use showed no association with severe CHDs in the newborn. An unexpected association with an increased risk of septal defects warrants further investigation.

Recurrence of congenital heart defects among siblings—a nationwide study

Congenital heart defects (CHD) constitute the largest group of congenital malformations. In most families, only one person has CHD; however, the risk of CHD increases for children born into families already affected. In this study, all births from 1994 through 2009 were identified in the Medical Birth Registry of Norway, including supplemental information on CHD from clinical and administrative registers, as part of the CVDNOR project. By using the unique personal identification number of each parent we were able to link 16,078 pairs of twins, 445,584 pairs of full siblings, and 106,840 pairs of half‐siblings. Sibling recurrence risk ratio (RRR) was calculated using CHD status in the oldest sibling as exposure and CHD status in the younger sibling as outcome, adjusted for year of birth, maternal age, and maternal diabetes. Among full sibling pairs with CHD in the older sibling, the younger sibling had CHD in 4.1% compared to 1.1% of the pairs without CHD in the older sibling (adjusted RRR 3.6; 95% confidence interval (CI) 3.1–4.1). In same‐sex twins the RRR was 14.0 (95% CI 10.6–18.6), and in opposite‐sex twins the RRR was 11.9 (95% CI 7.1–19.9). For half‐siblings the RRR was 1.5 (95% CI 0.8–2.8). When restricting to severe types of CHD, the RRR was 6.9 (95% CI 4.9–9.8) for full siblings. In 50% of the pairs with recurrent CHD, the siblings had similar types of CHD. The high relative risk of recurrence indicates that familial risk factors are important in the etiology of CHD.

The five-year survival of children with Down syndrome in Norway 1994-2009 differed by associated congenital heart defects and extracardiac malformations

We investigated the prevalence of Down syndrome in a nationwide birth cohort, focusing on congenital heart defects (CHDs), their associations with extracardiac malformations (ECM) and survival.

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

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.