Preeclampsia and neonatal outcomes in pregnancies with maternal congenital heart disease: A nationwide cohort study from Norway.

INTRODUCTION: The prevalence of congenital heart disease (CHD) among women of reproductive age is rising. We aimed to investigate the risk of preeclampsia and adverse neonatal outcomes in pregnancies of mothers with CHD compared to pregnancies of mothers without heart disease. MATERIAL AND METHODS: In a nationwide cohort of pregnancies in Norway 1994-2014, we retrieved information on maternal heart disease, the course of pregnancy, and neonatal outcomes from national registries. Comparing pregnancies with maternal CHD to pregnancies without maternal heart disease, we used Cox regression to estimate the adjusted hazard ratio (aHR) for preeclampsia and log-binomial regression to estimate the adjusted risk ratio (aRR) for adverse neonatal outcomes. The estimates were adjusted for maternal age and year of childbirth and presented with 95% confidence intervals (CIs). RESULTS: Among 1 218 452 pregnancies, 2425 had mild maternal CHD, and 603 had moderate/severe CHD. Compared to pregnancies without maternal heart disease, the risk of preeclampsia was increased in pregnancies with mild and moderate/severe maternal CHD (aHR1.37, 95% CI 1.14-1.65 and aHR 1.62, 95% CI 1.13-2.32). The risk of preterm birth was increased in pregnancies with mild maternal CHD (aRR 1.33, 95% CI 1.15-1.54) and further increased with moderate/severe CHD (aRR 2.49, 95% CI 2.03-3.07). Maternal CHD was associated with elevated risks of both spontaneous and iatrogenic preterm birth. The risk of infants small-for-gestational-age was slightly increased with mild maternal CHD (aRR 1.12, 95% CI 1.00-1.26) and increased with moderate/severe CHD (aRR 1.63, 95% CI 1.36-1.95). The prevalence of stillbirth was 3.9 per 1000 pregnancies without maternal heart disease, 5.6 per 1000 with mild maternal CHD, and 6.8 per 1000 with moderate/severe maternal CHD. Still, there were too few cases to report a significant difference. There were no maternal deaths in women with CHD. CONCLUSIONS: Moderate/severe maternal CHD in pregnancy was associated with increased risks of preeclampsia, preterm birth, and infants small-for-gestational-age. Mild maternal CHD was associated with less increased risks. For women with moderate/severe CHD, their risk of preeclampsia and adverse neonatal outcomes should be evaluated together with their cardiac risk in pregnancy, and follow-up in pregnancy should be ascertained.

Maternal use of folic acid and multivitamin supplements and infant risk of birth defects in Norway, 1999-2013.

The association between folic acid supplementation and birth defects other than neural tube defects (NTD) remains unclear. We used a log-binomial regression model to investigate if periconceptional folic acid and/or multivitamin use was associated with birth defects in Norway with prospectively collected data from the Medical Birth Registry of Norway (MBRN) during 1999-2013. We used the European Surveillance of Congenital Anomalies (EUROCAT) classification system to define eleven organ-specific major birth defect groups (nervous system, eye, ear-face-neck, cardiovascular system, respiratory system, oral clefts, digestive system, abdominal wall, urinary system, genital organs and limb), with additional subgroups. Fetuses or infants whose mothers used folic acid and/or multivitamin supplements before and during pregnancy were classified as exposed. During the years 1999-2013, 888 294 (99·0 %) live-born infants, 6633 (0·7 %) stillborn infants and 2135 (0·2 %) fetuses from terminated pregnancies due to fetal anomalies were registered in the MBRN. Among the live- and stillborn infants of women who used vitamin supplements compared with infants of non-users, the adjusted relative risk (aRR) was 0·94 (95 % CI 0·91, 0·98) for total birth defects (n 18 382). Supplement use was associated with reduced risk of abdominal wall defects (aRR 0·58; 95 % CI 0·42, 0·80, n 377), genital organ defects (aRR 0·81; 95 % CI 0·72, 0·91, n 2299) and limb defects (aRR 0·81; 95 % CI 0·74, 0·90, n 3409). Protective associations were also suggested for NTD, respiratory system defects and digestive system defects although CI included the null value of 1. During the full study period, statistically significant associations between supplement use and defects in the eye, ear-face-neck, heart or oral clefts were not observed.

Intake of sucrose-sweetened soft beverages during pregnancy and risk of congenital heart defects (CHD) in offspring: a Norwegian pregnancy cohort study.

Studies report increased risk of congenital heart defects (CHD) in the offspring of mothers with diabetes, where high blood glucose levels might confer the risk. We explored the association between intake of sucrose-sweetened soft beverages during pregnancy and risk of CHD. Prospective cohort data with 88,514 pregnant women participating in the Norwegian Mother and Child Cohort Study was linked with information on infant CHD diagnoses from national health registers and the Cardiovascular Diseases in Norway Project. Risk ratios were estimated by fitting generalized linear models and generalized additive models. The prevalence of children with CHD was 12/1000 in this cohort (1049/88,514). Among these, 201 had severe and 848 had non-severe CHD (patent ductus arteriosus; valvular pulmonary stenosis; ventricular septal defect; atrial septal defect). Only non-severe CHD was associated with sucrose-sweetened soft beverages. The adjusted risk ratios (aRR) for non-severe CHD was 1.30 (95% CI 1.07-1.58) for women who consumed 25-70 ml/day and 1.27 (95% CI 1.06-1.52) for women who consumed ≥ 70 ml/day when compared to those drinking ≤ 25 ml/day. Dose-response analyses revealed an association between the risk of non-severe CHD and the increasing exposure to sucrose-sweetened soft beverages, especially for septal defects with aRR = 1.26 (95% CI 1.07-1.47) per tenfold increase in daily intake dose. The findings persisted after adjustment for maternal diabetes or after excluding mothers with diabetes (n = 19). Fruit juices, cordial beverages and artificial sweeteners showed no associations with CHD. The findings suggest that sucrose-sweetened soft beverages may affect the CHD risk in offspring.

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.

Paternal characteristics associated with maternal periconceptional use of folic acid supplementation.

BACKGROUND: Maternal predictors of folic acid (FA) supplementation use to reduce offspring risk of neural tube defects are well known, while paternal determinants for maternal FA use are less known. Such knowledge is important to increase women's compliance to recommended periconceptional FA use. METHODS: In a nation-wide study of 683,785 births registered in the Medical Birth Registry of Norway during 1999-2010, the associations between paternal characteristics (age, education, occupation, country of origin) and maternal FA use were estimated by relative risks (RR) with 95% confidence intervals (CI), using log-binomial regression. RESULTS: Maternal FA use before and during pregnancy (adequate FA use) was found in 16% of the births. The association between paternal age and adequate FA use was inversely U-shaped; adjusted RRs for adequate FA use were 0.35 (95% CI 0.28-0.43) and 0.72 (95% CI 0.71-0.74) for paternal age < 20 and ≥ 40 years, respectively, comparing age 30-34 years. Compulsory education (1-9 years) among fathers was compared to tertiary education; the RR was 0.69 (95% CI 0.68-0.71) for adequate FA use. The lower risk of adequate FA use for paternal compulsory education was present in all categories of maternal education. Occupation classes other than "Higher professionals" were associated with decreased risk of adequate FA use, compared with the reference "Lower professionals". RR for adequate FA use was 0.58 (95% CI 0.56-0.60) comparing fathers from "Low/middle-income countries" with fathers born in Norway. CONCLUSION: Adequate FA use in the periconceptional period was lower when fathers were younger or older than 30-34 years, had shorter education, had manual or self-employed occupations, or originated from low/middle-income countries. Partners may contribute to increase women's use of periconceptional FA supplementation.

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

AIM: 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. METHODS: National registers were used to identify Norwegian births (1994-2009) and deaths (1994-2014) and updated with hospital diagnoses. We estimated birth defect frequencies in Down syndrome and the general population, the association between CHDs and ECM and hazard ratios for death from different combinations of CHDs and ECM. RESULTS: Down syndrome was found in 1672 of 953 450 births (17.6 per 10 000). Of the 1251 live births (13.3 per 10 000), 58% had CHD and 9% ECM. CHDs were associated with oesophageal atresia (p = 0.02) and Hirschsprung's disease (p = 0.03) but with no other malformations. The five-year survival for Down syndrome increased from 91.8% (1994-1999) to 95.8% (2000-2009) (p = 0.006), and overall survival was 92.0% with CHD and 97.4% without. Compared with Down syndrome children without CHD or ECM, the five-year mortality was similar for those with nonsevere CHDs, without or with ECM, but 4-7 times higher in those with severe CHDs without ECM and 13-28 times higher in those with severe CHDs and ECM. CONCLUSION: Down syndrome childhood survival improved, but mortality remained high with severe CHDs and extracardiac defects.

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.

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.

Sudden unexpected death in children with congenital heart defects.

AIMS: Congenital heart defects (CHDs) are the most common birth defects and are an important cause of death in children. The fear of sudden unexpected death has led to restrictions of physical activity and competitive sports. The aim of the present study was to investigate the rate of sudden unexpected deaths unrelated to surgery in children 2-18 years old with CHDs and, secondarily, to determine whether these deaths were related to cardiac disease, comorbidity, or physical activity. METHODS AND RESULTS: To identify children with CHDs and to determine the number of deaths, data concerning all 9 43 871 live births in Norway in 1994-2009 were retrieved from the Medical Birth Registry of Norway, the Cardiovascular Disease in Norway project, the Oslo University Hospital's Clinical Registry for Congenital Heart Defects and the Norwegian Cause of Death Registry. Survivors were followed through 2012, and information for the deceased children was retrieved from medical records at Norwegian hospitals. Among 11 272 children with CHDs, we identified 19 (0.2%) children 2-18 years old who experienced sudden unexpected deaths unrelated to cardiac surgery. A cardiac cause of death was identified in seven of these cases. None of the children died during physical activity, whereas two children survived cardiac arrest during sports. CONCLUSION: Sudden unexpected death was infrequent among children with CHDs who survived 2 years of age. Comorbidity was common among the children who died. This study indicates that sudden unexpected death in children with CHDs rarely occurs during physical activity.

Risk of Cardiomyopathy in Younger Persons With a Family History of Death from Cardiomyopathy: A Nationwide Family Study in a Cohort of 3.9 Million Persons.

BACKGROUND: Recommendations for presymptomatic screening of relatives of cardiomyopathy patients are based on findings from tertiary centers. Cardiomyopathy inheritance patterns are fairly well understood, but how cardiomyopathy in younger persons (<50 years) aggregates in families at the population level is unclear. In a nationwide cohort, we examined the risk of cardiomyopathy by family history of premature death (<60 years) from cardiomyopathy. METHODS AND RESULTS: By linking Danish national register data, we constructed a cohort of 3.9 million persons born from 1950 to 2008. We ascertained family history of premature (<60 years) death from cardiomyopathy or other conditions, and cohort members were followed from 1977 to 2008 for cardiomyopathy diagnosed at <50 years. We identified 3890 cardiomyopathies in 89 million person-years of follow-up. Using Poisson regression, we estimated incidence rate ratios for cardiomyopathy by family history of premature death. Premature cardiomyopathy deaths in first- and second-degree relatives were associated with 29- and 6-fold increases in the rate of cardiomyopathy, respectively. If the first-degree relative died aged <35 years, the rate of cardiomyopathy increased 100-fold; given ≥2 premature deaths in first-degree relatives, the rate increased more than 400-fold. In contrast, a family history of premature death from other cardiac or noncardiac conditions increased the rate of cardiomyopathy 3-fold at most. CONCLUSIONS: A family history of premature cardiomyopathy death was associated with an increase in risk of cardiomyopathy ranging from 6- to 400-fold, depending on age, kinship, gender and number of affected family members. Our general population-based results support recommendations for presymptomatic screening of relatives of cardiomyopathy patients.

Supplemental folic acid in pregnancy and childhood cancer risk.

BACKGROUND: We investigated the association between supplemental folic acid in pregnancy and childhood cancer in a nation-wide study of 687 406 live births in Norway, 1999-2010, and 799 children diagnosed later with cancer. METHODS: Adjusted hazard ratios (HRs) compared cancer risk in children by approximated periconceptional folic acid levels (folic acid tablets and multivitamins (0.6 mg), only folic acid (0.4 mg), only multivitamins (0.2 mg)) and cancer risk in unexposed. RESULTS: Any folic acid levels were not associated with leukemia (e.g., high-level folic acid HR 1.25; 95% CI 0.89-1.76, PTrend 0.20), lymphoma (HR 0.96; 95% CI 0.42-2.21, PTrend 0.51), central nervous system tumours (HR 0.68; 95% CI 0.42-1.10, PTrend 0.32), neuroblastoma (HR 1.05; 95% CI 0.53-2.06, PTrend 0.85), Wilms' tumour (HR 1.16; 95% CI 0.52-2.58, PTrend 0.76), or soft-tissue tumours (HR 0.77; 95% CI 0.34-1.75, PTrend 0.90). CONCLUSIONS: Folic acid supplementation was not associated with risk of major childhood cancers.

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.

Maternal use of folic acid supplements and infant risk of neural tube defects in Norway 1999-2013.

AIMS: Like most European countries, Norway has refrained from mandatory food fortification with folic acid to reduce the number of neural tube defects. We explored the role of folic acid and multivitamin supplements in the prevention of neural tube defects among newborn infants. METHODS: We used data from the Medical Birth Registry of Norway, 1999-2013. A total of 528,220 women had 880,568 pregnancies resulting in 896,674 live- and stillborn infants, of whom 270 had neural tube defects. Relative risks were estimated with log-binomial regression. RESULTS: From 1999 to 2013, intake of folic acid supplements increased from 4.8% to 27.4%. Vitamin supplement use was more frequent in older, married or cohabiting women and those with lower parity, as well as women who did not smoke during pregnancy. The overall adjusted relative risk of infant neural tube defects associated with maternal vitamin intake before pregnancy relative to no intake was 0.76 (95% confidence interval: 0.53-1.10). When we divided our study period in two (1999-2005 and 2006-2013), we found a significantly reduced risk of neural tube defects overall by vitamin use in the second time period, but not in the first: adjusted relative risk 0.54 (95% confidence interval: 0.31-0.91) and 1.02 (95% confidence interval: 0.63-1.65), respectively. CONCLUSIONS: OVER THE FULL STUDY PERIOD, WE FOUND NO STATISTICALLY SIGNIFICANT ASSOCIATION BETWEEN VITAMIN USE AND NEURAL TUBE DEFECTS OVERALL HOWEVER, VITAMIN USE WAS ASSOCIATED WITH A SIGNIFICANTLY LOWER RISK OF NEURAL TUBE DEFECTS IN THE SECOND HALF OF THE STUDY PERIOD, 2006-2013.

Folic acid supplements and risk for oral clefts in the newborn: a population-based study.

Results from previous studies on maternal folic acid intake and infant oral clefts are inconclusive. The aim of the present study was to investigate the association between women's use of folic acid and/or multivitamin supplements and the risk for oral cleft in the newborn. We used data from the Medical Birth Registry of Norway based on all births in Norway from 1999 to 2013. A total of 528 220 women had 880 568 pregnancies, resulting in 896 674 live births and stillbirths, of which 1623 had oral clefts (isolated oral clefts, n 1311; non-isolated oral clefts, n 312). Altogether, 21·5% of women were vitamin supplement users before pregnancy. The birth prevalence of oral clefts was 1·81/1000 live births and stillbirths. Relative risks (RR) were estimated with log-binomial regression. For pregnancies with maternal use of vitamins, the adjusted RR for clefts overall was 0·90 (95% CI 0·79, 1·04). The adjusted RR for cleft palate only (n 586) was 0·84 (95% CI 0·66, 1·06) and that for cleft lip with or without cleft palate (n 1037) was 0·94 (95% CI 0·79, 1·13). Associations were stronger for cleft cases that occurred in combination with other malformations (adjusted RR 0·63; 95% CI 0·45, 0·88), although vitamin supplements provided no protection against isolated clefts (adjusted RR 0·98; 95% CI 0·84, 1·15). In conclusion, our study demonstrates no statistically significant association between vitamin use and isolated oral clefts. However, we found lower risk for oral clefts that occurred in combination with other malformations.

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.

Birth prevalence of congenital heart defects in Norway 1994-2009--a nationwide study.

BACKGROUND: The reasons for decreasing birth prevalence of congenital heart defects (CHDs) in several European countries and Canada are not fully understood. We present CHD prevalence among live births, stillbirths, and terminated pregnancies in an entire nation over a period of 16 years. METHODS: Information on all births in the Medical Birth Registry of Norway, 1994-2009, was updated with information on CHD from the hospitals' Patient Administrative Systems, the National Hospital's clinical database for children with heart disease, and the Cause of Death Registry. Individuals with heart defects were assigned specific cardiac phenotypes. RESULTS: Among 954,413 births, 13,081 received a diagnosis of CHD (137.1 per 10,000 births, 133.2 per 10,000 live births). The prevalence per 10,000 births was as follows: heterotaxia, 1.6; conotruncal defects, 11.6; atrioventricular septal defects, 5.6; anomalous pulmonary venous return, 1.1; left outflow obstructions, 8.7; right outflow obstructions, 5.6; septal defects, 65.5; isolated patent ductus arteriosus, 24.6; and other specified or unspecified CHD, 12.7. Excluding preterm patent ductus arteriosus, the CHD prevalence was 123.4 per 10,000; per year, the prevalence increased with 3.5% (95% CI 2.5-4.4) in 1994-2005 and declined with 9.8% (-16.7 to -2.4) from 2005 onwards. Severe CHD prevalence was 30.7 per 10,000; per-year increase was 2.3% (1.1-3.5) in 1994-2004, and per-year decrease was 3.4% (-6.6 to -0.0) in 2004-2009. Numbers included severe CHD in stillbirths and terminated pregnancies. CONCLUSIONS: The birth prevalence of CHD declined from around 2005. Specifically, the prevalence of severe CHD was reduced by 3.4% per year from 2004 through 2009.

Maternal Diabetes and Cardiac Left Ventricular Structure and Function in the Infant: A Copenhagen Baby Heart Study.

OBJECTIVE: Prenatal exposure to maternal diabetes is associated with an increased risk of offspring heart defects. We evaluated associations with subtle infant cardiac changes. RESEARCH DESIGN AND METHODS: In a cohort of 25,486 infants with transthoracic echocardiography within 60 days of birth, we investigated associations between maternal preexisting diabetes and gestational diabetes mellitus (GDM) and infant left ventricular (LV) structural and functional parameters, using linear regression to estimate adjusted mean differences (aMDs) between groups. RESULTS: Infants exposed to maternal preexisting diabetes (n = 198) had thicker LV posterior walls (aMD 0.19 mm; 95% CI 0.11, 0.27), smaller LV internal diameters in systole (aMD -0.27 mm; 95% CI -0.45, -0.18) and diastole (aMD -0.37 mm; 95% CI -0.59, -0.09), reduced stroke volumes (aMD -0.36 mL; 95% CI -0.61, -0.11), and increased heart rates (aMD 3.14 bpm; 95% CI 1.10, 6.18) and mitral valve early peak velocities (aMD 2.17 cm/s; 95% CI 0.31, 4.04) than unexposed infants (n = 24,639). Infants born to mothers with GDM (n = 649) had significantly smaller LV internal diameters in systole (aMD -0.13 mm; 95% CI -0.22, -0.03) and similar structural and functional changes as children exposed to preexisting diabetes, albeit with smaller nonsignificant aMDs. Higher third-trimester HbA1c levels were associated with smaller LV internal diameters and stroke volumes in infants exposed to preexisting diabetes and with lower heart rates in infants exposed to GDM. CONCLUSIONS: Maternal preexisting diabetes and, to a lesser extent, GDM were associated with changes in infant LV structure and function.

Predictors of heart-focused anxiety in patients undergoing genetic investigation and counseling of long QT syndrome or hypertrophic cardiomyopathy: a one year follow-up.

Since Long QT syndrome and Hypertrophic cardiomyopathy are inherited cardiac disorders that may cause syncope, palpitations, serious arrhythmias, and sudden cardiac death, at-risk individuals may experience heart-focused anxiety. In a prospective multi-site study, 126 Norwegian patients attending genetic counseling were followed 1 year with multiple administration of questionnaires, including the Cardiac Anxiety Questionnaire, measuring three distinct symptoms of heart-focused anxiety- avoidance, attention, and fear-in mixed linear analyses. Overall, at 1-year follow-up, patients with clinical diagnosis as compared to patients at genetic risk had significantly higher scores of avoidance (p < .002), attention (p < .005), and fear (p < .007). Sudden cardiac death in close relatives, uncertainty whether other relatives previously had undergone genetic testing, patients' perceived general health, self-efficacy expectations and procedural satisfaction with genetic counseling were influential in predicting the different symptoms of heart-focused anxiety over time.

Risk of Congenital Heart Defects in Offspring of Affected Mothers and Fathers.

BACKGROUND: Smaller studies have reported a higher offspring risk of congenital heart defects (CHDs) for mothers with CHDs than for fathers with CHDs. In a large population-based study, we investigated whether offspring risk of CHD differed for mothers and fathers with CHDs. METHODS: All people born in Denmark, 1977 to 2011, with at least 1 registered parent, were included in our cohort (n=2 341 061). Parent-child recurrence of CHDs was evaluated using risk ratios (RRs) comparing risks of CHDs in individuals with and without a parent with a CHD, estimated using log-linear binomial regression. RESULTS: The RRs for any CHD in offspring were 5.39 (95% CI, 4.88-5.96) for mothers and 3.04 (95% CI, 2.59-3.57) for fathers affected with any CHD; the ratio of RRs for mothers versus fathers was 1.82 (P<0.0001). Recurrence RRs for the same cardiac phenotype in parent and offspring were significantly stronger for mothers than for fathers for conotruncal defects (ratio of RRs, 4.98), left ventricular outlet tract obstruction (ratio of RRs, 4.98), and ventricular septal defects (ratio of RRs, 2.51) but not for atrioventricular septal defects (ratio of RRs, 1.06). Birth rates among people with CHDs, relative to the general population, were 18% higher for women than for men, regardless of parental cardiac phenotype. CONCLUSIONS: Recurrence risks of CHDs were significantly greater in the offspring of affected women than in the offspring of affected men. The excess maternal recurrence risks could not be explained by the slightly higher birth rates in women with CHDs.