Early environmental risk factors and coeliac disease in adolescents: a population-based cohort study in Denmark.

OBJECTIVES: Our aim was to investigate the association between early environmental factors and the development of coeliac disease (CeD) in adolescents, recruited from a cohort nested in the Danish National Birth Cohort (DNBC). DESIGN: The study was designed as a prospective cohort study, nested in DNBC PARTICIPANTS: The Glutenfunen cohort comprises 1266 participants, nested in DNBC. All participants were screened for CeD, and in total, 28 cases of biopsy proven CeD were identified. Data about breastfeeding, timing of introduction to solid food in infancy, use of antibiotics, infections and symptoms were parentally reported prospectively at 6 months and 18 months, respectively. We estimated ORs and 95% CIs of CeD in adolescents using logistic regression analysis. RESULTS: Viral croup reported at 18 months of age was associated with CeD in adolescents with an OR of 3.2 (95% CI: 1.2 to 8.7). Furthermore, otitis media also reported at 18 months of age was linked with CeD with an OR of 3.2 (95% CI: 1.5 to 7.3). We were not able to find any statistical associations between CeD and breastfeeding, frequency of infections, parentally reported use of antibiotic and timing of solid foods. CONCLUSION: In this study, we present an overview of the relationship between early environmental factors and occurrence of CeD in adolescents. Our findings, despite limitations due to a limited number of cases of CeD, suggest a role of viral infections in the pathogenesis of CeD.

Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies.

BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence. METHODS AND FINDINGS: We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries. CONCLUSIONS: This study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term.

Fetal exposure to maternal cigarette smoking and male reproductive function in young adulthood.

Maternal smoking during pregnancy constitutes a potential, major risk factor for adult male reproductive function. In the hitherto largest longitudinal cohort, we examined biomarkers of reproductive function according to maternal smoking during the first trimester and investigated whether associations were mitigated by smoking cessation prior to the fetal masculinization programming window. Associations between exposure to maternal smoking and semen characteristics, testicular volume and reproductive hormones were assessed among 984 young men from the Fetal Programming of Semen Quality (FEPOS) cohort. Maternal smoking was assessed through interview data and measured plasma cotinine levels during pregnancy. We applied negative binomial, logistic and linear regression models to estimate differences in outcomes according to levels of maternal smoking. Sons of light smokers (≤ 10 cigarettes/day) had a 19% (95% CI - 29%, - 6%) lower sperm concentration and a 24% (95% CI - 35%, - 11%) lower total sperm count than sons of non-smokers. These estimates were 38% (95% CI - 52%, - 22%) and 33% (95% CI - 51%, - 8%), respectively, for sons of heavy smokers (> 10 cigarettes/day). The latter group also had a 25% (95% CI 1%, 54%) higher follitropin level. Similarly, sons exposed to maternal cotinine levels of  > 10 ng/mL had lower sperm concentration and total sperm count. Smoking cessation prior to gestational week seven was not associated with a higher reproductive capacity. We observed substantial and consistent exposure-response associations, providing strong support for the hypothesis that maternal smoking impairs male reproductive function. This association persisted regardless of smoking cessation in early pregnancy.

Indoor home environments of Danish children and the socioeconomic position and health of their parents: A descriptive study.

BACKGROUND: Housing and indoor home environments are associated with the risk of infections and asthma in children. To better understand the determinants and characteristics of these environments, we aimed to describe the associations between parental health and socioeconomic position and housing and indoor home environments of children in Denmark, and the clustering of the factors within these environments. METHODS: Offspring in the Danish National Birth Cohort (DNBC) whose parents responded to the 11-year follow-up were eligible for inclusion. We included complete cases only. Data on the indoor and housing environments (i.e. variables on housing, sources of gaseous and particle pollution, mould and moisture, and pets) were collected through an online questionnaire responded to by a parent. Data on socioeconomic position were obtained through linkage with registry data on maternal education at offspring birth and household equivalized income at offspring birth. Data on parental health were obtained by linking self-reported data from the 11-year follow-up for mother and father with administrative registry data for the mother. We present descriptive statistics and exploratory factor analyses. RESULTS: A total of 42 723 offspring were included for analyses. The distributions of nearly all indoor and housing environments differed according to educational and income strata, with patterns similar for both education and income. Generally, higher parental educational and income strata had more favorable indoor and housing environments (less secondhand smoking, gas stove use, mould and condensation and higher house ownership, detached house dwellings and newer building age). However, candle use was approximately similar between strata, fireplace use among lower educational and income strata tended towards the extremes (none or daily), and water damage was more common among higher educational and income strata. Parental health was strongly associated with housing and indoor home environment factors - especially parental affective disorders was strongly associated with mould. Four factors were extracted from the exploratory factor analyses, relating primarily in order of extraction to: housing ownership, mould and moisture, candle use and household density. CONCLUSION: Parental health and socioeconomic position are strongly related to housing and indoor home environments. Additionally, several factors in these environments correlate strongly and cluster together. Observational studies on associations and causal effects of factors in the indoor and housing environments of children on their morbidity, must consider both of these conclusions to arrive at valid estimates and effects.

Use of Fertility Drugs and Risk of Malignant Melanoma: Results from a Large Danish Population-Based Cohort Study.

Fertility drugs have not definitively been linked to malignant melanoma. By the use of data from a large nationwide cohort of women aged 20.0-45.0 years and living in Denmark between January 1, 1995 and December 31, 2011, we assessed the association between the use of fertility drugs and the risk of malignant melanoma. Information on fertility status and the use of fertility drugs was obtained from the population-based Danish Infertility Cohort. Cox proportional hazard regression models were applied to estimate hazard ratios and 95% confidence intervals with adjustment for potential confounders. The study population comprised 1,330,954 women, of whom 86,231 (6.5%) were treated with fertility drugs. During a median follow-up of 21.0 years, 6,139 women were diagnosed with malignant melanoma. Compared with fertile women, women with fertility challenges who had used any fertility drugs had an increased risk of malignant melanoma (hazard ratio = 1.14; 95% confidence interval = 1.02-1.27). Furthermore, the use of specific types of fertility drugs (clomiphene, gonadotropins, human chorionic gonadotropin, gonadotropin-releasing hormone preparations, and progesterone) was also associated with an increased risk of malignant melanoma, with hazard ratios ranging between 1.09 and 1.13; however, the association did not reach statistical significance. Our findings indicate that the use of fertility drugs was associated with a modestly increased risk of malignant melanoma.

The effect of maternal pre-/early-pregnancy BMI and pregnancy smoking and alcohol on congenital heart diseases: a parental negative control study.

BACKGROUND: Congenital heart diseases (CHDs) are the most common congenital anomaly. The causes of CHDs are largely unknown. Higher prenatal body mass index (BMI), smoking and alcohol consumption are associated with increased risk of CHDs. Whether these are causal is unclear. METHODS AND RESULTS: Seven European birth cohorts including 232,390 offspring (2,469 CHD cases [1.1%]) were included. We applied negative exposure paternal control analyses to explore the intrauterine effects of maternal BMI, smoking and alcohol consumption during pregnancy, on offspring CHDs and CHD severity. We used logistic regression and combined estimates using a fixed-effects meta-analysis. Analyses of BMI categories resulted in similar increased odds of CHD in overweight (mothers OR: 1.15 (1.01, 1.31) and fathers 1.10 (0.96, 1.27)) and obesity (mothers OR: 1.12 (0.93, 1.36) and fathers 1.16 (0.90, 1.50)). The association of mean BMI with CHD was null. Maternal smoking was associated with increased odds of CHD (OR: 1.11 (0.97, 1.25)) but paternal smoking was not (OR: 0.96 (0.85, 1.07)). The difference increased when removing offspring with genetic/chromosomal defects (mothers OR: 1.15 (1.01, 1.32) and fathers 0.93 (0.83, 1.05)). The positive association with maternal pregnancy smoking appeared to be driven by non-severe CHD cases (OR: 1.22 (1.04, 1.44)). Associations with maternal (OR: 1.16 (0.52, 2.58)) and paternal (OR: 1.23 (0.74, 2.06)) moderate/heavy pregnancy alcohol consumption were similar. CONCLUSIONS: We found evidence of an intrauterine effect for maternal smoking on offspring CHDs, but no evidence for higher maternal BMI or alcohol consumption. Our findings provide further support for why smoking cessation is important during pregnancy.

Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.

BACKGROUND: Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. METHODS AND FINDINGS: We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. CONCLUSIONS: We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.

Prenatal, infantile, and childhood tobacco exposure and risk of pediatric psoriasis in the Danish National Birth Cohort offspring.

BACKGROUND: Tobacco smoking is implicated in psoriasis among adults. OBJECTIVE: To determine whether prenatal, infantile, and childhood tobacco exposure increase risk of pediatric psoriasis. METHODS: Data from Danish National Birth Cohort participants were collected at approximately gestational week 12 and when the children were approximately 6 months and 11 years of age. In total, 25 812 offspring with complete data from the Danish National Birth Cohort were included. We estimated the odds of pediatric psoriasis with tobacco exposure prenatally, from birth to age 6 months (early infancy), and at age 11 years (childhood). RESULTS: We observed an increased risk of pediatric psoriasis among offspring with prenatal tobacco exposure (adjusted odds ratio [OR], 1.39; 95% confidence interval [CI], 1.06-1.82). An exposure-response relationship was observed for increasing quantities of cigarettes smoked daily (≥16 cigarettes: adjusted OR, 2.92; 95% CI, 1.20-7.10; P for trend = .038). The associations with infantile (adjusted OR, 1.17; 95% CI, 0.76-1.79) and childhood (adjusted OR, 1.10; 95% CI, 0.77-1.58) tobacco exposure were attenuated after controlling for prenatal exposure. LIMITATIONS: Outcome status was maternally reported. CONCLUSIONS: Prenatal tobacco exposure may increase the risk of pediatric psoriasis in a monotonic fashion, indicating that smoking may play a causal role in psoriasis pathogenesis.

Cerebrovascular disease after placental abruption: A population-based prospective cohort study.

OBJECTIVE: To test whether abruption during pregnancy is associated with long-term cerebrovascular disease by assessing the incidence and mortality from stroke among women with abruption. METHODS: We designed a population-based prospective cohort study of women who delivered in Denmark from 1978 to 2010. We used data from the National Patient Registry, Causes of Death Registry, and Danish Birth Registry to identify women with abruption, cerebrovascular events, and deaths. The outcomes included deaths resulting from stroke and nonfatal ischemic and hemorrhagic strokes. We fit Cox proportional hazards regression models for stroke outcomes, adjusting for the delivery year, parity, education, and smoking. RESULTS: The median (interquartile range) follow-up in the nonabruption and abruption groups was 15.9 (7.8-23.8) and 16.2 (9.6-23.1) years, respectively, among 828,289 women with 13,231,559 person-years of follow-up. Cerebrovascular mortality rates were 0.8 and 0.5 per 10,000 person-years among women with and without abruption, respectively (hazard ratio [HR] 1.6, 95% confidence interval [CI] 0.9-3.0). Abruption was associated with increased rates of nonfatal ischemic stroke (HR 1.4, 95% CI 1.1-1.7) and hemorrhagic stroke (HR 1.4, 95% CI 1.1-1.9). The association of abruption and stroke was increased with delivery at <34 weeks, when accompanied by ischemic placental disease, and among women with ≥2 abruptions. These associations are less likely to have been affected by unmeasured confounding. CONCLUSION: Abruption is associated with increased risk of cerebrovascular morbidity and mortality. Disruption of the hemostatic system manifesting as ischemia and hemorrhage may indicate shared etiologies between abruption and cerebrovascular complications.

Impact of cystic fibrosis on birthweight: a population based study of children in Denmark and Wales.

BACKGROUND: Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). However, the impact of CF on intrauterine growth is unclear. We studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth. METHODS: We conducted national registry linkage studies in two countries, using data for 2.2 million singletons born in Denmark (between 1980 and 2010) and Wales (between 1998 and 2015). We used hospital inpatient and outpatient data to identify 852 children with CF. Using causal mediation methods, we estimated the direct and indirect (via gestational age) effect of CF on birth weight after adjustment for sex, parity and socioeconomic background. We tested the robustness of our results by adjusting for additional factors such as maternal smoking during pregnancy in subpopulations where these data were available. RESULTS: Babies with CF were more likely to be born preterm and with low birth weight than babies with no CF (12.7% vs 5% and 9.4% vs 5.8% preterm; 11.9% vs 4.2% and 11% vs 5.4% low birth weight in Denmark and Wales, respectively). Using causal mediation methods, the total effect of CF on birth weight was estimated to be -178.8 g (95% CI -225.43 to -134.47 g) in the Danish population and -210.08 g (95% CI -281.97 to -141.5 g) in the Welsh population. About 40% of this effect of CF on birth weight was mediated through gestational age. CONCLUSIONS: CF significantly impacts on intrauterine growth and leads to lower birth weight in babies with CF, which is only partially explained by shorter gestation.

Psoriasis as a Predictor of Cardiometabolic Comorbidity in Women: A Study Based on the Danish National Birth Cohort.

Psoriasis is associated with cardiometabolic comorbidity; however, whether this is due to common lifestyle-related risk factors is unclear. This study investigated the association between psoriasis and cardiometabolic comorbidity, taking body mass index and smoking into account. The population comprised expectant mothers in the Danish National Birth Cohort (established 1996-2002). During pregnancy, the women were asked about physician-diagnosed psoriasis. Any association with self-reported cardiometabolic comorbidity 11 years later was assessed using logistic regression. The cohort was also followed up for hospital-diagnosed comorbidity, including cardiac death, until 31 December 2014, and the risk was assessed using Cox regression. A total of 2,435 women with psoriasis (2.90%) and 81,388 women without were identified. Psoriasis was significantly associated with self-reported hypercholesterolaemia (adjusted odds ratio 1.31; 1.01-1.70) and hospital-diagnosed hypertension (adjusted hazard ratio 1.33; 1.08-1.65). Women with psoriasis have an increased risk of developing cardiometabolic comorbidity in early adult life.

Primary school achievement and socioeconomic attainment in individuals affected by parental cancer in childhood or adolescence: a Danish nationwide register-based study.

BACKGROUND: Children who experience parental cancer are at increased risk of developing emotional, social, cognitive and behavioural problems. Our aim was to investigate how experience of parental cancer in childhood or adolescence is associated with primary school achievement, educational attainment and income in early adult life. METHODS: This is a register-linkage, prospective study of children born in Denmark from 1978 through 1999 and their parents. Parental cancer experience before the ages of 15 and 18 was identified in the Danish National Patient Registry. Final grade point average (GPA) in ninth grade, educational attainment and disposable personal income at the age of 30 were identified in Statistics Denmark registers. General linear models and multinomial logistic regression were used to estimate beta estimates of GPA, and relative risk ratios (RRR) for lower educational and income levels compared with children without parental cancer, taking parental educational status into account. RESULTS: Children who had experienced parental cancer achieved a slightly lower final GPA in ninth grade and had a higher risk of low educational attainment (RRR: 1.20; 95% CI 1.14 to 1.25) and attenuated income at the age of 30 (RRR: 1.11; 95% CI 1.06 to 1.16). For all outcomes, analyses suggested substantial deterioration in achievements in subgroups of children whose parent had a severe cancer type (RRRLow education: 1.52; 95% CI 1.39 to 1.66) or if the parent died of cancer (RRRLow education: 1.61; 95% CI 1.49 to 1.75). CONCLUSION: Educational and socioeconomic attainments in early adulthood were affected negatively in individuals who had experienced parental cancer as children or adolescents. The associations appeared stronger the more severe the cancer was.

Advanced paternal age and childhood cancer in offspring: A nationwide register-based cohort study.

Cancer initiation is presumed to occur in utero for many childhood cancers and it has been hypothesized that advanced paternal age may have an impact due to the increasing number of mutations in the sperm DNA with increasing paternal age. We examined the association between paternal age and specific types of childhood cancer in offspring in a large nationwide cohort of 1,904,363 children born in Denmark from 1978 through 2010. The children were identified in the Danish Medical Birth Registry and were linked to information from other national registers, including the Danish Cancer Registry. In total, 3,492 children were diagnosed with cancer before the age of 15 years. The adjusted hazard ratio of childhood cancer according to paternal age was estimated using Cox proportional hazards regressions. We found a 13% (95% confidence interval: 4-23%) higher hazard rate for every 5 years advantage in paternal age for acute lymphoblastic leukemia, while no clear association was found for acute myeloid leukemia (hazard ratio pr. 5 years = 1.02, 95% confidence interval: 0.80-1.30). The estimates for neoplasms in the central nervous system suggested a lower hazard rate with higher paternal age (hazard ratio pr. 5 years = 0.92, 95% confidence interval: 0.84-1.01). No clear associations were found for the remaining childhood cancer types. The findings suggest that paternal age is moderately associated with a higher rate of childhood acute lymphoblastic leukemia, but not acute myeloid leukemia, in offspring, while no firm conclusions could be made for other specific cancer types.

Is advanced paternal age a health risk for the offspring?

In this article we review the epidemiologic evidence for adverse health effects in offspring of fathers of advanced age. First the evidence regarding fetal survival is addressed, and afterward we review the evidence regarding morbidity in children with older fathers. The adverse conditions most consistently associated with increased paternal age are stillbirths, musculo-skeletal syndromes, cleft palate, acute lymphoblastic leukemia and retinoblastoma, and neurodevelopmental disorders in the autism spectrum and schizophrenia. Finally, we consider the public health impact of the increasing paternal age. We conclude that the adverse health effects in children that might be caused by the present increase in paternal age are severe but quantitatively of minor importance. However, identification of morbidities that are more frequent in offspring of older fathers, after having taken any maternal age effects and other confounding into account, may lead to a better understanding of the pathogenesis behind such conditions.

Validation of celiac disease diagnoses recorded in the Danish National Patient Register using duodenal biopsies, celiac disease-specific antibodies, and human leukocyte-antigen genotypes.

PURPOSE: The purpose of this study was to validate the celiac disease diagnoses recorded in the Danish National Patient Register. To validate the diagnoses, we used information on duodenal biopsies from a national register of pathology reports (the Patobank) and information on celiac disease-specific antibodies and human leukocyte antigen (HLA) genotypes obtained from patient medical records. PATIENTS AND METHODS: We included all the children who were born from 1995 to 2012 and who were registered as having celiac disease in the Danish National Patient Register. We reviewed all the pathology reports on duodenal biopsies in the Patobank and the information in the medical records on celiac disease-specific antibodies (ie, anti-tissue transglutaminase 2 IgA and IgG, endomysial antibodies IgA, and anti-deamidated gliadin peptide IgG) and HLA genotypes. RESULTS: We identified 2,247 children who were registered in the Danish National Patient Register with celiac disease. Duodenal biopsies for 1,555 of the children (69%) were registered in the Patobank; 1,127 (50%) had a biopsy that was compatible with celiac disease (ie, Marsh 2-3). We accessed the medical records of 95% of the children who were registered in the Danish National Patient Register with celiac disease. We found that 1,510 (67%) had one or more positive antibody-test results; 1,120 (50%) had anti-tissue transglutaminase 2, IgA at tenfold or greater the upper limit of the normal range and/or positive endomysial antibody results. The positive predictive value depended on the criteria used for validation and the types and numbers of registrations that were included in the analysis and ranged from 62% (95% confidence interval: 60%-64%) to 86% (95% confidence interval: 84%-87%). CONCLUSION: Our findings indicate that the Danish National Patient Register is a valuable source to identify patients who have been diagnosed with celiac disease. However, validation of the diagnoses is warranted before data on the patients are used for research purposes.

Risk Factors for Hospitalization for Respiratory Syncytial Virus Infection: A Population-based Cohort Study of Danish Children.

BACKGROUND: The aim of this study is to identify the risk factors for hospitalization for respiratory syncytial virus (RSV) infection in Danish children. METHODS: This is a population-based cohort study with follow-up till 24 months of age. A total of 421,943 Danish children were divided into 5 groups based on gestational age (23-32, 33-35, 36, 37-41 and 42-45 weeks). RESULTS: In adjusted Cox regression models, chronic disease, asthma hospitalization before the RSV infection and siblings were associated with an increased risk of hospitalization for RSV infection in all children independent of gestational age. Plurality was associated with a decreased risk in children born between 23 and 36 weeks of gestation, whereas young maternal age, maternal asthma, single parenthood, maternal smoking, being born small for gestational age, Caesarian section, male gender and day care were associated with an increased risk of hospitalization for RSV infection in term children. In postterm children, young maternal age, male sex, being born small for gestational age and maternal smoking were associated with an increased risk of hospitalization for RSV. Asthma hospitalization before the RSV infection and siblings were associated with the highest measures of increased risk of hospitalization for RSV infection independent of gestational age. CONCLUSIONS: By 5 groups of gestational age, we provide estimates of the effects of 12 different factors, which can be regarded as add-on risk factors to those already known to increase the risk of hospitalization for RSV infection. Our study may help clinicians to precisely assess the risk profile in the individual child.

Determinants of developmental coordination disorder in 7-year-old children: a study of children in the Danish National Birth Cohort.

AIM: The aim of this study was to investigate early life determinants of developmental coordination disorder (DCD) in 7-year-old children. METHOD: The study was based on data from 33,354 women and their children who participated in the 7-year follow-up study of the Danish National Birth Cohort. Information on several potential determinants (maternal age at conception, maternal occupational status, smoking and alcohol consumption during pregnancy, child's sex, intrauterine growth restriction, degree of preterm birth, and age at walking) was obtained from population registries, from interviews during pregnancy and when the child was 18 months old. The outcome in this study was DCD at 7 years of age, measured by the validated Developmental Coordination Disorder Questionnaire. The associations between the potential determinants and DCD were estimated using logistic regression. RESULTS: The study population consisted of 17,065 males and 16,289 females (141 [0.4%] born very preterm [23(+0)-31(+6) wk]; 1281 [3.8%] born moderately preterm [32(+0)-36(+6) wk]; 29,044 [87.1%] were born term [37(+0)-41(+6) wk], and 2888 [8.7%] were born post-term [≥ 42(+0) wk]). Independently of each other, the following determinants were predictors of DCD: being a female (odds ratio [OR] 0.36 [95% confidence interval {CI} 0.31-0.41]); being born very preterm (OR 6.28 [95% CI 3.99-9.89]) or moderately preterm (OR 2.10 [95% CI 1.65-2.67]); being small for gestational age (OR 1.74 [95% CI 1.46-2.08]); being 15 months of age or more at walking attainment (OR 3.05 [95% CI 2.57-3.60]); and maternal occupational status (higher grade professionals (OR 1.28 [95% CI 1.02-1.61); economically inactive (OR 1.43 [95% CI 1.07-1.91]). Young maternal age and smoking were risk factors among term-born children. INTERPRETATION: The risk of DCD increases with decreasing gestational age. Intrauterine growth restriction is also a strong risk factor, as well as delayed walking.

Occupational lifting of heavy loads and preterm birth: a study within the Danish National Birth Cohort.

OBJECTIVES: To examine the association between occupational lifting during pregnancy and preterm birth. The risk of preterm birth was estimated for total burden lifted per day and number of medium and heavy loads lifted per day. METHODS: In a study population of 62 803 pregnant women enrolled to the Danish National Birth Cohort from 1996 to 2002, the association between self-reported occupational lifting in the first part of pregnancy and preterm birth was analysed using logistic regression models with adjustment for age, parity, cervical cone biopsy, assisted reproduction and smoking. Associations between lifting and extremely (before 28 weeks), very (28-32 weeks) and moderately (33-37 weeks) preterm birth were analysed using Cox regression models. RESULTS: We found a dose-response relation between total daily burden lifted and preterm birth with an OR of 1.50 (95% CI 1.03 to 2.19) with loads over 1000 kg/day. No threshold value was found. The associations were strongest for extremely and very preterm birth with HRs (95% CIs) of 4.3 (1.4 to 13.8) and 1.7 (0.7 to 4.0), respectively. Lifting heavy loads (>20 kg) more than10 times/day was associated with preterm birth up to an OR of 2.03 (95% CI 1.14 to 3.62). CONCLUSION: In a society with social welfare and a highly regulated working environment, occupational lifting was associated with an increased risk of preterm birth.

Birth weight and polycystic ovary syndrome in adult life: a register-based study on 523,757 Danish women born 1973-1991.

OBJECTIVE: To study the association between birth weight and polycystic ovary syndrome (PCOS) in adult life in Danish women born 1973-1991. DESIGN: Register study. SETTING: Data were extracted from the Danish Medical Birth Register and the Danish National Patient Register (NPR). PATIENT(S): All female children born of Danish mothers in Denmark between 1973 and 1991 were included (n = 523,757) and followed for a total of 4,739,547 person-years at risk. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Information on birth weight was extracted from the Danish Medical Birth Register. The cohort was followed up in the NPR for PCOS diagnoses from age 15 years until the end of 2006. Furthermore, information on maternal diabetes diagnoses was extracted from the NPR. RESULT(S): The risk of PCOS was significantly increased in women with birth weight ≥4,500 g (incidence rate ratio, 1.57; 95% confidence interval 1.21-2.03) compared to women with birth weight 3,000-3,499 g. All women with birth weight ≥4,500 g were born large for gestational age and a birth weight of 4,500 g represented the 98.5th percentile of the birth weights. Women born of mothers diagnosed with diabetes were at increased risk of PCOS. In these women the risk of PCOS increased with decreasing birth weight. CONCLUSION(S): The risk of PCOS was increased in women born with birth weight ≥4,500 g. In women of diabetic mothers we found an increased risk of PCOS, which was inversely related to birth weight.

Does shared family background influence the impact of educational differences on early mortality?

The mechanisms behind social differences in mortality rates have been debated. The authors examined the extent to which shared family background and health in early life could explain the association between educational status and all-cause mortality rates using a sibling design. The study was register-based and included all individuals born in Denmark between 1950 and 1979 who had at least 1 full sibling born in the same time period (n = 1,381,436). All individuals were followed from 28 years of age until death, emigration, or December 2009. The authors used Cox regression analyses to estimate hazard ratios for mortality according to educational level. Conventional cohort and intersibling analyses were carried out and conducted separately for deaths occurring before and after the age of 45 years, respectively. The cohort analyses showed an inverse association between educational status and all-cause mortality that was strongest for males, increased with younger birth cohorts, and tended to be strongest in the analyses of death before 45 years of age. The associations were attenuated slightly in the intersibling analyses and after adjustment for serious health conditions in early life. Hence, health selection and confounding by factors shared by siblings explained only a minor part of the association between educational level and all-cause mortality.