The risk of attention deficit hyperactivity disorder in children exposed to maternal smoking during pregnancy - a re-examination using a sibling design.

BACKGROUND: Conventional cohort studies have consistently shown that exposure to maternal smoking in pregnancy is associated with about twice the risk of attention deficit hyperactivity disorder (ADHD) in the offspring. However, recent studies using alternative designs to disentangle the effect of social and genetic confounders have suggested that confounding may account for the association. In this study we aimed to estimate the association by a sibling design. METHODS: We used a design with half and full siblings in a Danish national register-based cohort on all singletons born between January 1991 and December 2006 and followed until January 2011. Data were available for 90% (N = 968,665) of the singleton live births in the period. We used the combination of the International Classification of Diseases (10th version) diagnosis of hyperkinetic disorder (HKD) and ADHD medication to identify children. We used sibling-matched (conditional) Cox regression to control social and genetic confounding. RESULTS: Using conventional cohort analyses, we found the expected association between pregnancy smoking and offspring ADHD (adjusted HR 2.01, 95% CI 1.94-2.07). In the sibling analysis, however, we did not detect such a strong association (adjusted HR 1.07, 95% CI 0.94-1.22). There was no difference between results for half- and full sibling analyses. The link between pregnancy smoking and low birth weight remained robust in the sibling design (adjusted OR 1.68, 95% CI 1.33-2.12). CONCLUSIONS: We found no support for prenatal smoking as a strong causal factor in ADHD. Our findings suggest that the strong association found in most previous epidemiological studies is likely to be due to a strong link between maternal smoking and maternal ADHD genetics or shared family environment. Pregnant women should still be encouraged to stop smoking because of other risks, but we have no reason to believe that this would reduce the risk of ADHD in the offspring.

The impact of comorbidity on outcome in 12 623 Danish head and neck cancer patients: a population based study from the DAHANCA database.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is primarily caused by smoking and alcohol. Besides having a carcinogenic effect, smoking also leads to other diseases and thus contributes to a high prevalence of comorbidities among HNSCC patients. Furthermore, the world population is becoming older resulting in more elderly patients with HNSCC. The aim of this study was to investigate the prevalence and impact of comorbidity in a retrospective nationwide population-based study of all Danish HNSCC patients diagnosed from 1992 to 2008. MATERIAL AND METHODS: A total of 12 623 patients diagnosed with HNSCC in the period from 1992 to 2008 were identified through the Danish Head and Neck Cancer group (DAHANCA) database. By linking to the Danish registers, information on somatic comorbidity present prior to the HNSCC diagnosis was obtained and adapted to the Charlson Comorbidity Index (CCI). The influence of comorbidity on overall survival and cancer specific death was evaluated and the type and prevalence of comorbidity described. RESULTS: In total, 36% of patients had comorbidity according to CCI. Increasing age was significantly associated with increasing CCI. In multivariate analyses, the CCI score remained a strong independent prognostic factor for overall survival, the HR being 1.16 (95% CI 1.08; 1.25), 1.34 (1.22; 1.46), 1.63 (1.51; 1.80) for patients with CCI score 1, 2, and 3+, respectively. The CCI score did not influence cancer specific death. CONCLUSION: Comorbidity is common among HNSCC patients and has a negative prognostic impact on overall survival. Cancer specific death was not affected by comorbidity suggesting that patients die from their comorbidities rather than their cancer. In the future, more elderly patients with comorbidity will require treatment which will demand a change in the healthcare system with a multidisciplinary approach required in order to take care of both their cancer and their comorbidities.

Perceived stress and semen quality.

BACKGROUND: Psychological stress is prevalent among reproductive-aged men. Assessment of semen quality for epidemiological studies is challenging as data collection is expensive and cumbersome, and studies evaluating the effect of perceived stress on semen quality are inconsistent. OBJECTIVE: To examine the association between perceived stress and semen quality. MATERIAL AND METHODS: We analyzed baseline data on 644 men (1,159 semen samples) from two prospective preconception cohort studies during 2015-2021: 592 in Pregnancy Study Online (PRESTO) and 52 in SnartForaeldre.dk (SF). At study entry, men aged ≥21 years (PRESTO) and ≥18 years (SF) trying to conceive without fertility treatment completed a questionnaire on reproductive and medical history, socio-demographics, lifestyle, and the 10-item version of the Perceived Stress Scale (PSS; interquartile range [IQR] of scores: 0-40). After enrollment (median weeks: 2.1, IQR: 1.3-3.7), men were invited to perform in-home semen testing, twice with 7-10 days between tests, using the Trak Male Fertility Testing System. Semen quality was characterized by semen volume, sperm concentration, and total sperm count. We fit generalized estimating equation linear regression models to estimate the percent difference in mean log-transformed semen parameters by four PSS groups (<10, 10-14, 15-19, ≥20), adjusting for potential confounders. RESULTS: The median PSS score and IQR was 15 (10-19), and 136 men (21.1%) had a PSS score ≥20. Comparing men with PSS scores ≥20 with <10, the adjusted percent difference was -2.7 (95% CI: -9.8; 5.0) for semen volume, 6.8 (95% CI: -10.9; 28.1) for sperm concentration, and 4.3 (95% CI: -13.8; 26.2) for total sperm count. CONCLUSION: Our findings indicate that perceived stress is not materially associated with semen volume, sperm concentration, or total sperm count.

Maternal salivary cortisol levels during pregnancy are positively associated with overweight children.

INTRODUCTION: Animal and human studies suggest that programing of the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the development of obesity, but human studies of biological indicators of HPA axis activity are lacking. We studied the association between levels of the stress hormone cortisol during pregnancy and overweight offspring during childhood into adolescence. METHODS: Salivary samples from 655 Danish pregnant women with singleton pregnancies (1989-1991) were collected once in the morning and once in the evening in their second and third trimester. We followed the offspring from two to 16 years of age with at least one measurement of height and weight, and classified their body mass index into overweight and normal weight. The adjusted relative difference in median salivary cortisol (with 95% confidence interval (CI)) during pregnancy (the four samples), in second and third trimester (morning and evening samples) between overweight and normal weight offspring was estimated. Furthermore, the adjusted median ratio between morning and evening maternal salivary cortisol level was estimated for normal weight and overweight children. All the analyses were stratified into the equal age groups: 2-6, 7-11, and 12-16 years. RESULTS: We found non-significant higher maternal cortisol levels during pregnancy in offspring that were overweight at the age of 2-6, 7-11 and 12-16 years than in normal weight peers; adjusted relative difference in median salivary cortisol 11% (95% CI: -2; 25), 6% (95% CI: -7; 20), and 9% (95% CI: -4; 24), respectively. A statistically significantly higher level of maternal cortisol was found in the second trimester in 2-6-year-old and 12-16-year-old overweight offspring; relative difference 19% (95% CI: 3; 37), and 20% (95% CI: 3; 41), respectively. The median ratio between morning and evening maternal salivary cortisol level was similar for overweight and normal weight children; e.g. at age 2-6 years in third trimester 4.31 (95% CI: 4.05; 4.60)nmol/l and 4.28 (95% CI: 3.60; 5.09)nmol/l, respectively (P=0.93). CONCLUSION: Our findings suggest a relatively consistent association between pregnancy cortisol levels and overweight offspring, especially in the second trimester.

Stoppage in Autism Spectrum Disorders.

Stoppage refers to changes in reproductive behavior following the birth of a child with a severe disease. The presence of stoppage can bias estimates of sibling recurrence risk if not properly addressed. If stoppage occurs non-randomly (differential stoppage), it is possibly an additional source of bias in sibling recurrence risk estimation. This study investigated whether stoppage occurs in Danish families with a firstborn child diagnosed with autism spectrum disorders, and if stoppage was differential. We found that stoppage occurs moderately in Danish families affected by autism spectrum disorders, and that stoppage is differential. However, differential stoppage is a minor source of estimation bias in Danish sibling recurrence risk studies of autism spectrum disorders.

Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study.

IMPORTANCE: To date, this is the first population-based study to examine the recurrence risk for autism spectrum disorders (ASDs), including time trends, and the first study to consider the ASDs recurrence risk for full- and half-siblings. OBJECTIVES: To estimate the relative recurrence risk for ASDs in a Danish population, including recurrence in full- and half-siblings, and to examine time trends in ASDs relative to the recurrence risk. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study in Denmark. All children (about 1.5 million) born in Denmark between January 1, 1980, and December 31, 2004, were identified and followed up to December 31, 2010. We identified a maternal sibling subcohort derived from mothers with at least 2 children and a paternal sibling subcohort derived from fathers with at least 2 children. EXPOSURES: Children having an older sibling with ASDs are compared with children not having an older sibling with ASDs. MAIN OUTCOMES AND MEASURES: The adjusted hazard ratio for ASDs among children having an older sibling with ASDs compared with children not having an older sibling with ASDs. RESULTS The overall relative recurrence risk for ASDs was 6.9 (95% CI, 6.1-7.8), and it did not change significantly over time; similar risks were observed in maternal and paternal full-siblings. The relative recurrence risks were 2.4 (95% CI, 1.4-4.1) for maternal half-siblings and 1.5 (95% CI, 0.7-3.4) for paternal half-siblings. CONCLUSIONS AND RELEVANCE: Our population-based recurrence risk estimate is lower than the recently reported estimates from clinical samples. Our results demonstrate no time trend in the ASDs recurrence risk as seen in the ASDs prevalence. The difference in the recurrence risk between full- and half-siblings supports the role of genetics in ASDs, while the significant recurrence risk in maternal half-siblings may support the role of factors associated with pregnancy and the maternal intrauterine environment in ASDs.

The International Collaboration for Autism Registry Epidemiology (iCARE): multinational registry-based investigations of autism risk factors and trends.

The International Collaboration for Autism Registry Epidemiology (iCARE) is the first multinational research consortium (Australia, Denmark, Finland, Israel, Norway, Sweden, USA) to promote research in autism geographical and temporal heterogeneity, phenotype, family and life course patterns, and etiology. iCARE devised solutions to challenges in multinational collaboration concerning data access security, confidentiality and management. Data are obtained by integrating existing national or state-wide, population-based, individual-level data systems and undergo rigorous harmonization and quality control processes. Analyses are performed using database federation via a computational infrastructure with a secure, web-based, interface. iCARE provides a unique, unprecedented resource in autism research that will significantly enhance the ability to detect environmental and genetic contributions to the causes and life course of autism.