Nina Øyen

Recurrence of Congenital Heart Defects in Families

Background— Knowledge of the familial contribution to congenital heart diseases (CHD) on an individual and population level is sparse. We estimated an individual’s risk of CHD given a family history of CHD, as well as the contribution of CHD family history to the total number of CHD cases in the population. Methods and Results— In a national cohort study, we linked all Danish residents to the National Patient Register, the Causes of Death Register, the Danish Central Cytogenetic Register, and the Danish Family Relations Database, yielding 1 763 591 persons born in Denmark between 1977 and 2005, of whom 18 708 had CHD. Individuals with CHD were classified by phenotype. We estimated recurrence risk ratios and population-attributable risk. Among first-degree relatives, the recurrence risk ratio was 79.1 (95% confidence interval [CI] 32.9 to 190) for heterotaxia, 11.7 (95% CI, 8.0 to 17.0) for conotruncal defects, 24.3 (95% CI,12.2 to 48.7) for atrioventricular septal defect, 12.9 (95% CI, 7.48 to 22.2) for left ventricular outflow tract obstruction, 48.6 (95% CI, 27.5 to 85.6) for right ventricular outflow tract obstruction, 7.1 (95% CI, 4.5 to 11.1) for isolated atrial septal defect, and 3.4 (95% CI, 2.2 to 5.3) for isolated ventricular septal defect. The overall recurrence risk ratio for the same defect was 8.15 (95% CI, 6.95 to 9.55), whereas it was 2.68 (95% CI, 2.43 to 2.97) for different heart defects. Only 2.2% of heart defect cases in the population (4.2% after the exclusion of chromosomal aberrations) were attributed to CHD family history in first-degree relatives. Conclusions— Specific CHDs showed highly variable but strong familial clustering in first-degree relatives, ranging from 3-fold to 80-fold compared with the population prevalence, whereas the crossover risks between dissimilar cases of CHD were weaker. Family history of any CHD among first-degree relatives accounted for a small proportion of CHD cases in the population.

Size at birth and gestational age as predictors of adult height and weight

Background: Both birth length and birth weight are associated with height in adulthood and may have independent contributions to adult body size, but the effects of gestational age on these associations have not been fully evaluated. Our objective was to examine the independent contributions of gestational age, and of length and weight at birth, on adult (age 18 years) height and weight, with a special focus on the effects of being born preterm. Methods: In this nationwide cohort study, records of 348,706 male infants included in the Medical Birth Registry of Norway (1967–1979) were linked to the Norwegian Conscripts Service (1984–1999). Complete follow-up information, including deaths, emigration, and disability pension, was obtained for 94%. We analyzed length and weight at birth using standardized (z-scores) values and stratified by gestational age. Results: The positive association between birth length and adult height was stronger than between birth weight and adult weight (R2 = 7–9% compared with <0.1%, respectively). The strongest associations were seen among those born at gestational age 39 to 41 weeks. The effects of birth length on adult height, and of birth weight on adult weight, were considerably less among preterm births than among term births. Length and weight at birth each contributed independently to adult stature and body weight. The increase in adult weight per relative birth weight category was greatest for infants who were both heavy and long at birth. Conclusions: Birth length is perhaps a better predictor of adult height and weight than birth weight, and should be considered as a possible risk factor for adult morbidity and mortality.

A case-control study of smoking and sudden infant death syndrome in the Scandinavian countries, 1992 to 1995

AIM To establish whether smoking is an independent risk factor for sudden infant death syndrome (SIDS), if the effect is mainly due to prenatal or postnatal smoking, and the effect of smoking cessation. METHODS The analyses were based on data from the Nordic epidemiological SIDS study, a case-control study with 244 cases and 869 controls. Odds ratios were computed by conditional logistic regression analysis. RESULTS Smoking emerged as an independent risk factor for SIDS, and the effect was mainly mediated through maternal smoking in pregnancy (crude odds ratio 4.0 (95% confidence interval 2.9 to 5.6)). Maternal smoking showed a marked dose–response relation. There was no effect of paternal smoking if the mother did not smoke. Stopping or even reducing smoking was beneficial. SIDS cases exposed to tobacco smoke were breast fed for a shorter time than non-exposed cases, and feeding difficulties were also more common. CONCLUSIONS Smoking is an independent risk factor for SIDS and is mainly mediated through maternal smoking during pregnancy. Stopping smoking or smoking less may be beneficial in reducing the risk of SIDS.

The decline in the incidence of SIDS in Scandinavia and its relation to risk‐intervention campaigns

A prospective case‐control study of sudden infant death syndrome (SIDS) in Norway, Denmark and Sweden between September 1,1992 and August 31,1995 comprised 244 cases and 869 matched controls. After the introduction of risk‐intervention campaigns, the SIDS incidence decreased from 2. 3/1000 live births in Norway, 1. 6 in Denmark and 1. 0 in Sweden to 0. 6/1000 or fewer in all the Scandinavian countries in 1995. The decrease paralleled a decline in the prone sleeping position and there was an accompanying parallel fall in total postneonatal mortality in all three countries. Thus, the risk‐reducing campaigns for SIDS have been successful not only in Norway and Denmark, starting from relatively high incidences, but also in Sweden, starting from a low incidence. During the study period, a gradual increase was observed for the effects of prone sleeping, smoking and bottle‐feeding as risk factors for SIDS.

National time trends in congenital heart defects, Denmark, 1977-2005

BACKGROUND Time trends in congenital heart defects (CHD) by specific phenotype and with long follow-up time are rarely available for an entire population. We present trends in national CHD prevalences over the past 3 decades. METHODS We linked information from the National Patient Register, the Causes of Death Register, and the Danish Cytogenetic Central Register for all persons born in Denmark, 1977 to 2005, and registered in the Civil Registration System, yielding a cohort of 1,763,591 persons-18,207 with CHD. Individuals with CHDs were classified by phenotype (heterotaxia, conotruncal defect, atrioventricular septal defect, anomalous pulmonary venous return, left and right ventricular outflow tract obstructions, septal defects, complex defects, associations, patent ductus arteriosus, unspecified, and other specified) by combining International Classification of Diseases codes using a hierarchical approach. RESULTS From 1977 to 2005, the overall CHD birth prevalence increased from 73 to 113 per 10,000 live births. Generally, prevalence increased for defects diagnosed in infancy, until 1996-1997, and then stabilized. For each 5-year interval, isolated septal defects and severe defects increased by 22% (95% CI, 20%-25%) and 5% (95% CI, 4%-7%), respectively. Among the severe defects, conotruncal defects and atrioventricular septal defect showed the largest prevalence increases. Women had a lower prevalence of severe defects during the 1980s. The CHD prevalence increase was unchanged when persons with extracardiac defects or chromosomal aberrations were excluded. CONCLUSIONS CHD birth prevalence increased from the beginning of the 1980s but stabilized in the late 1990s.

Familial Aggregation of Lone Atrial Fibrillation in Young Persons

OBJECTIVES This study investigated whether an individuals risk of developing lone atrial fibrillation (AF) before age 60 years is associated with lone AF in relatives. BACKGROUND Genetic factors may play a role in the development of lone AF. METHODS Using Danish national registers, a cohort was established of ~4 million persons born between 1950 and 2008, and those with a family history of lone AF (AF without preceding cardiovascular/endocrine diagnoses) were identified. Individuals were followed up until the first diagnosis of lone AF. Poisson regression was used to estimate incidence rate ratios (IRRs). RESULTS In ~92 million person-years of follow-up, 9,507 persons were identified as having lone AF. The IRRs for lone AF given an affected first- or second-degree relative were 3.48 (95% confidence interval [CI]: 3.08 to 3.93) and 1.64 (95% CI: 1.04 to 2.59), respectively. IRRs were higher for men than for women but were not associated with the affected relatives sex. IRR for lone AF was 6.24 (95% CI: 2.59 to 15.0), given at least 2 first-degree relatives affected with lone AF. The IRR for lone AF in persons aged <40 years given a first-degree relative affected at age <40 years was 5.42 (95% CI: 3.80 to 7.72), and 8.53 (95% CI: 3.82 to 19.0) in persons age <30 years given a first-degree relative affected at age <30 years. CONCLUSIONS A family history of lone AF is associated with substantial risk of lone AF, with the strongest risks associated with young age at onset, multiple affected relatives, and in first-degree relatives. These results suggest routine evaluation of the families of at least certain types of patients with lone AF.

Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers

Mutations in the KCNQ1, HERG, SCN5A, minK and MiRP1 genes cause long QT syndrome (LQTS), of which there are two forms: the Romano Ward syndrome and the Jervell and Lange‐Nielsen syndrome. We have performed DNA sequencing of the LQTS‐associated genes in 169 unrelated patients referred for genetic testing with respect to Romano Ward syndrome and in 13 unrelated patients referred for genetic testing with respect to Jervell and Lange‐Nielsen syndrome. A total of 37 different mutations in the 5 genes, of which 20 were novel, were identified. Among patients with the most stringent clinical criteria of Romano Ward syndrome, a mutation was identified in 71 %. Twelve of the 13 unrelated patients referred for genetic testing with respect to Jervell and Lange‐Nielsen syndrome were provided with a molecular genetic diagnosis. Cascade genetic screening of 505 relatives of index patients with molecularly defined LQTS identified 251 mutation carriers. The observed penetrance was 41 %. Although caution must be exerted, the prevalence of heterozygotes for mutations in the LQTS‐associated genes in Norway could be in the range 1/100–1/300, based on the prevalence of patients with Jervell and Lange‐Nielsen syndrome.

Familial Aggregation and Heritability of Pyloric Stenosis

CONTEXT Pyloric stenosis is the most common condition requiring surgery in the first months of life. Case reports have suggested familial aggregation, but to what extent this is caused by common environment or inheritance is unknown. OBJECTIVES To investigate familial aggregation of pyloric stenosis from monozygotic twins to fourth-generation relatives according to sex and maternal and paternal contributions and to estimate disease heritability. DESIGN, SETTING, AND PATIENTS Population-based cohort study of 1,999,738 children born in Denmark between 1977 and 2008 and followed up for the first year of life, during which 3362 children had surgery for pyloric stenosis. MAIN OUTCOME MEASURE Familial aggregation of pyloric stenosis, evaluated by rate ratios. RESULTS The incidence rate (per 1000 person-years) of pyloric stenosis in the first year of life was 1.8 for singletons and 3.1 for twins. The rate ratios of pyloric stenosis were 182 (95% confidence interval [CI], 70.7-467) for monozygotic twins, 29.4 (95% CI, 9.45-91.5) for dizygotic twins, 18.5 (95% CI, 13.7-25.1) for siblings, 4.99 (95% CI, 2.59-9.65) for half-siblings, 3.06 (95% CI, 2.10-4.44) for cousins, and 1.60 (95% CI, 0.51-4.99) for half-cousins. We found no difference in rate ratios for maternal and paternal relatives of children with pyloric stenosis and no difference according to sex of cohort member or sex of relative. The heritability of pyloric stenosis was 87%. CONCLUSION Pyloric stenosis in Danish children shows strong familial aggregation and heritability.

Risk Perception, Worry and Satisfaction Related to Genetic Counseling for Hereditary Cancer

In this multi center study, genetic counseling for hereditary cancer was evaluated by assessing patients’ worry, perceived risk of developing cancer and satisfaction with genetic counseling. An overall aim was to identify characteristics of vulnerable patients in order to customize genetic counseling. In addition, agreement between patients’ and counselors’ scores was measured. A total of 275 Norwegian patients were consecutively recruited, and 213 completed questionnaires before and after genetic counseling. Patients’ perceived risk decreased after the genetic counseling session. There was incongruence between risk perception expressed as a percentage and in words. Patients were significantly less worried after counseling. Higher levels of worry were predicted by low instrumental satisfaction with counseling, high degree of perceived risk of developing cancer and younger age. In conclusion, counselors met the patients’ psychological needs to a satisfactory degree during counseling. However, patients did not fully understand their risk of developing cancer.

Associations of birth size, gestational age, and adult size with intellectual performance: evidence from a cohort of Norwegian men.

The influences of prenatal and postnatal growth on intellectual performance are unclear. We examined the associations of birth size and gestational age with intellectual performance and explored whether these associations were influenced by adult body size and social factors. In this nationwide cohort study, the records of 317,761 male infants registered in the Medical Birth Registry of Norway (1967–1979) were linked to the Norwegian Conscript Service (1984–1999). The variation in intelligence test score at age 18 due to birth weight and birth length was evaluated using absolute and standardized (z scores) values. Mean intelligence score increased by gestational age, birth weight, and birth length. However, a decline in intellectual performance was observed for gestational age >41 wk and birth weight >4500 g. There was a strong interaction on intellectual performance between birth size and gestational age (p < 0.0005). Adjusting for adult size strongly attenuated the association of birth size with intellectual performance. The overall R2 of intellectual performance explained by birth size was <1%; however, adding adult body size and social factors to the model increased R2 to 12%. In conclusion, the association of birth size with intellectual performance was weak, but still present after adjustment for adult body size and social factors.