Sickness absence due to poor mental health is a common problem in many Western countries. To facilitate return to work, it may be important to identify individuals on sick leave and at risk of having a mental disorder and subsequently to offer appropriate treatment. Psychoeducation alone has not previously been used as a return to work intervention, but may be a promising tool to facilitate return to work. Therefore, the aim of the study is to evaluate the effectiveness of psychoeducation designed specifically to facilitate return to work for individuals on sick leave and at risk of having a mental disorder. The psychoeducation was a supplement to the various standard offers provided by the job centres.
The study is a randomised controlled trial, in which individuals on sick leave either receive psychoeducation and standard case management or standard case management alone. Participants were individuals with mental health symptoms, who had been on sick leave from part-time or full-time work or unemployment for about 4–8 weeks. The psychoeducational intervention was group-based and the course consisted of 2 hour sessions once a week for 6 weeks. The course was given by psychiatric nurses, a psychologist, a social worker, a physiotherapist and a person who had previously been on sick leave due to mental health problems. The sessions focused on stress and work life, and the purpose was to provide individuals on sick leave the skills to understand and improve their mental functioning.
The primary outcome is the duration of sickness absence measured by register data. Secondary outcomes include psychological symptoms, mental health-related quality of life, and locus of control. These outcomes are measured by questionnaires at the start of the intervention and at 3 and 6 months follow-up.
On the basis of this trial, the effect of psychoeducation for individuals on sick leave and at risk of having a mental disorder will be studied. The results will contribute to the continuing research on sickness absence and mental health. It will primarily show whether psychoeducation can lead to faster and sustainable return to work.
Clinical Trial.gov NCT01637363. Registered 6 July 2012.
Sickness absence; Psychoeducation; Mental health; Return to work; Psychological symptoms; Mental health-related quality of life; Locus of control
We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00×10−10), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38×10−5). An interaction test confirmed that these estimates differed from each other (P = 4.95×10−13). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.
We found that a single nucleotide polymorphism in the CHRNA5-A3-B4 gene cluster, which is known to influence smoking heaviness, is associated with lower body mass index (BMI) in current smokers, but higher BMI in never smokers. This difference in effects suggests that the variant influences BMI both via pathways other than smoking, and via the weight-reducing effects of smoking, in opposite directions. The overall effect on BMI would therefore be undetectable in an unstratified genome-wide association study, indicating that novel associations may be obscured by hidden population sub-structure.
To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach.
Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress.
Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA).
Primary outcome measures
Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis.
The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers.
Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.
Mendelian randomisation; Smoking; Depression; Anxiety
Growing evidence suggests that maternal prepregnancy weight and gestational weight gain are risk factors for perinatal complications and subsequent maternal and child health. Postpartum weight retention is also associated with adverse birth outcomes and maternal obesity. Clinical guidelines addressing healthy weight before, during, and after pregnancy have been introduced in some countries, but at present a systematic accounting for these policies has not been conducted. The objective of the present study was to conduct a cross-national comparison of maternal weight guidelines.
This cross sectional survey administered a questionnaire online to key informants with expertise on the subject of maternal weight to assess the presence and content of preconceptional, pregnancy and postpartum maternal weight guidelines, their rationale and availability. We searched 195 countries, identified potential informants in 80 and received surveys representing 66 countries. We estimated the proportion of countries with guidelines by region, income, and formal or informal policy, and described and compared guideline content, including a rubric to assess presence or absence of 4 guidelines: encourage healthy preconceptional weight, antenatal weighing, encourage appropriate gestational gain, and encourage attainment of healthy postpartum weight.
Fifty-three countries reported either a formal or informal policy regarding maternal weight. The majority of these policies included guidelines to assess maternal weight at the first prenatal visit (90%), to monitor gestational weight gain during pregnancy (81%), and to provide recommendations to women about healthy gestational weight gain (62%). Guidelines related to preconceptional (42%) and postpartum (13%) weight were less common. Only 8% of countries reported policies that included all 4 fundamental guidelines. Guideline content and rationale varied considerably between countries, and respondents perceived that within their country, policies were not widely known.
These results suggest that maternal weight is a concern throughout the world. However, we found a lack of international consensus on the content of guidelines. Further research is needed to understand which recommendations or interventions work best with respect to maternal weight in different country settings, and how pregnancy weight policies impact clinical practices and health outcomes for the mother and child.
Maternal weight policies; Key informant; International
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10−8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10−36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
Complications after cardiac implantable electronic device (CIED) treatment, including permanent pacemakers (PMs), cardiac resynchronization therapy devices with defibrillators (CRT-Ds) or without (CRT-Ps), and implantable cardioverter defibrillators (ICDs), are associated with increased patient morbidity, healthcare costs, and possibly increased mortality.
Methods and results
Population-based cohort study in all Danish patients who underwent a CIED procedure from May 2010 to April 2011. Data on complications were gathered on review of all patient charts while baseline data were obtained from the Danish Pacemaker and ICD Register. Adjusted risk ratios (aRRs) with 95% confidence intervals were estimated using binary regression. The study population consisted of 5918 consecutive patients. A total of 562 patients (9.5%) experienced at least one complication. The risk of any complication was higher if the patient was a female (aRR 1.3; 1.1–1.6), underweight (aRR 1.5; 1.1–2.3), implanted in a centre with an annual volume <750 procedures (0–249 procedures: aRR 1.6; 1.1–2.2, 250–499: aRR 2.0; 1.6–2.7, 500–749: aRR 1.5; 1.2–1.8), received a dual-chamber ICD (aRR 2.0; 1.4–2.7) or CRT-D (aRR 2.6; 1.9–3.4), underwent system upgrade or lead revision (aRR 1.3; 1.0–1.7), had an operator with an annual volume <50 procedures (aRR 1.9; 1.4–2.6), or underwent an emergency, out-of-hours procedure (aRR 1.5; 1.0–2.3).
CIED complications are more frequent than generally acknowledged. Both patient- and procedure-related predictors may identify patients with a particularly high risk of complications. This information should be taken into account both in individual patient treatment and in the planning of future organization of CIED treatment.
Complication; Predictors; Cardiac resynchronization therapy; Implantable cardioverter defibrillator; Pacemaker
The purpose of this nested case-control study in Denmark was to study the association between use of corticosteroids and risk of miscarriage.
We identified prescriptions for corticosteroids before the miscarriage/index date. We estimated odds ratios (ORs) for miscarriage and for early (<13 weeks) and late (13–21 weeks) miscarriage adjusting for age, history of diabetes and epilepsy, and nonsteroidal anti-inflammatory drug use.
We identified 10,974 women with miscarriage and 109,740 controls. Prevalence of inhaled corticosteroid use within 60 days before the index date was 1.3% among the cases and 1.0% among the controls (OR = 1.20; 95% confidence interval [CI] 1.01–1.44). Prevalence of oral corticosteroid use within 60 days before the index date was 0.3% for both cases and controls (OR = 0.78; 95% CI 0.53–1.15). For inhaled and oral corticosteroids, the ORs of early miscarriage were 1.22 (95% CI 1.01–1.49) and 0.81 (95% CI 0.55–1.20), respectively.
Use of inhaled corticosteroids was associated with a slightly increased risk of early miscarriage, but explanations alternative to causal ones were possible.
case-control study; corticosteroid hormones; epidemiology; miscarriage
Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of ‘age at first tooth’ and ‘number of teeth’ using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10−8) for ‘age at first tooth’ and 11 loci for ‘number of teeth’. Together, these associations explain 6.06% of the variation in ‘age of first tooth’ and 4.76% of the variation in ‘number of teeth’. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10−17). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.
Background and Purpose:
Many researchers acknowledge the importance of “training errors” as the main cause of running‐related injuries. The purpose of this clinical commentary is to present a theoretical framework for the assumption that some running‐related injuries among rear‐foot strikers develop due to rapidly changing running volume, while others develop due to rapidly changing running pace.
Description of Topic with Related Evidence:
Evidence from clinical and experimental studies is presented to support the assertion that rapid change in running volume may lead to the development of patellofemoral pain syndrome, iliotibial band syndrome, and patellar tendinopathy, while change in running pace may be associated with the development of achilles tendinopathy, gastrocnemius injuries, and plantar fasciitis.
Discussion/Relation to Clinical Practice:
If this assertion is correct, bias may be prevented in future studies by categorizing injuries into volume or pacing injuries. However, more work is needed to provide further evidence in support of this approach. Future investigations of the link between training patterns and injury development should be designed as large‐scale prospective studies using objective methods to quantify training patterns.
Level of evidence:
Etiology; running pace; running‐related injury; training volume
Medications may be consumed periconceptionally before a woman knows she is pregnant. In this study, the authors evaluate the association of a prescription diet drug (Letigen) containing ephedrine (20 mg) and caffeine (200 mg) with spontaneous abortion (SAB) in the Danish National Birth Cohort.
Women were recruited during their first prenatal visit from 1996–2002. Pre-conception and early pregnancy medication use was reported on the enrollment form, and pregnancy outcome was determined by linking the mother's Civil Registration Number to the Medical Birth Registry and the National Hospital Discharge Register. Of 97,903 eligible pregnancies, 4,443 ended in SAB between 5 and 20 completed gestational weeks, inclusive. Letigen use was reported for 565 pregnancies. Cox regression models accounting for left truncation were fit to estimate the effect of pre-conception and early pregnancy Letigen use on SAB.
The estimated maternal age-adjusted hazard ratio for SAB was 1.1 (95% confidence interval 0.8–1.6) for any periconceptional Letigen use compared to no periconceptional use.
Although Letigen has high levels of caffeine (the recommended 3 pills/day are approximately equivalent to caffeine from 6 cups of coffee), periconceptional use does not appear to be associated with an appreciably increased hazard of clinically recognized SAB.
The aim of the present study was to identify predictors of nonparticipation in a Danish cohort of individuals on long-term sickness absence with a nonparticipation rate of 53.6%.
Data from Danish public registers were linked to all 2414 individuals initially recruited to the cohort. Information regarding social- and health-related characteristics was retrieved. Adjusted logistic regression was carried out to examine differences between participants and nonparticipants as well as to identify predictors of nonparticipation.
Nonparticipation was associated with being male, relatively young, having a vocational secondary education, and having a low income, whereas a recent somatic disease treated in hospital was a predictor for participation. Having had a psychiatric disorder in the past was generally a barrier for participation, while a recent psychiatric disorder was a positive factor for participation.
Individuals with low socioeconomic status and individuals with prior psychiatric disorders were less willing to participate in this cohort study of long-term sickness absence.
mental disorders; nonparticipation; nonresponse; sickness absence
Maternal smoking during pregnancy is associated with low birth weight. Common variation
at rs1051730 is robustly associated with smoking quantity and was recently shown to
influence smoking cessation during pregnancy, but its influence on birth weight is not
clear. We aimed to investigate the association between this variant and birth weight of
term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European
origin study participants by smoking status (women who smoked during pregnancy versus
women who did not smoke during pregnancy) and, in each stratum, analysed the association
between maternal rs1051730 genotype and offspring birth weight. There was evidence of
interaction between genotype and smoking (P = 0.007). In women who
smoked during pregnancy, each additional smoking-related T-allele was associated with a 20
g [95% confidence interval (95% CI): 4–36 g] lower birth weight
(P = 0.014). However, in women who did not smoke during
pregnancy, the effect size estimate was 5 g per T-allele (95% CI:
−4 to 14 g; P = 0.268). To conclude, smoking status
during pregnancy modifies the association between maternal rs1051730 genotype and
offspring birth weight. This strengthens the evidence that smoking during pregnancy is
causally related to lower offspring birth weight and suggests that population
interventions that effectively reduce smoking in pregnant women would result in a reduced
prevalence of low birth weight.
Atopic dermatitis (AD) is a common chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing AD are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 cases and 20,565 controls from 16 population-based cohorts and followed up the ten most strongly associated novel markers in a further 5,419 cases and 19,833 controls from 14 studies. Three SNPs met genome-wide significance in the discovery and replication cohorts combined: rs479844 upstream of OVOL1 (OR=0.88, p=1.1×10−13) and rs2164983 near ACTL9 (OR=1.16, p=7.1×10−9), genes which have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster on 5q31.1 (OR=1.11, p=3.8×10−8). We also replicated the FLG locus and two recently identified association signals at 11q13.5 (rs7927894, p=0.008) and 20q13.3 (rs6010620, p=0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in AD pathogenesis.
To assess whether onset of rheumatoid arthritis (RA) prior to conception is associated with a delayed time to pregnancy (TTP).
The study included pregnant women from across Denmark enrolled in the Danish National Birth Cohort (DNBC) between 1996 and 2002, who had planned or partly planned the cohort pregnancy. RA diagnosis was identified using the Danish National Hospital Discharge Registry. Self-reported data including TTP, maternal age, parity, pre-pregnancy height and weight, maternal occupational status, smoking and alcohol consumption were collected using a detailed computer-assisted telephone interview at approximately 16 weeks of gestation. We used logistic regression analyses as well as a complementary log regression model to examine whether TTP was influenced by RA, adjusting for the above-mentioned variables.
Overall, compared to women with no recorded RA (n=68,170), women with prevalent RA (onset prior to conception) (n=112) were slightly older (30.8±4.3 vs. 29.7±4.1 years), were more likely to have been treated for infertility (9.8% vs. 7.6%) and were more likely to have taken longer than 12 months to conceive (25.0% vs. 15.6%). The association between RA and TTP was borderline significant after adjusting for covariates in the regression analyses (OR=1.6, 95% CI: 1.0, 2.4). Similar results were obtained after restricting the analyses to women who had planned the pregnancy or those who were nulliparous before the cohort pregnancy.
Women with RA onset prior to conception had a slightly longer TTP compared to those who did not have RA, indicating a slight reduction in fecundity.
To examine whether prenatal exposure to parental type 1 diabetes, type 2 diabetes, or gestational diabetes is associated with an increased risk of malignant neoplasm or diseases of the circulatory system in the offspring.
We conducted a population-based cohort study of 1,781,576 singletons born in Denmark from 1977 to 2008. Children were followed for up to 30 years from the day of birth until the onset of the outcomes under study, death, emigration, or December 31, 2009, whichever came first. We used Cox proportional hazards model to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for the outcomes under study while adjusting for potential confounders. An increased risk of malignant neoplasm was found in children prenatally exposed to maternal type 2 diabetes (HR = 2.2, 95%CI: 1.5–3.2). An increased risk of diseases of the circulatory system was found in children exposed to maternal type 1 diabetes (HR = 2.2, 95%CI: 1.6–3.0), type 2 diabetes (HR = 1.4, 95%CI: 1.1–1.7), and gestational diabetes (HR = 1.3, 95%CI: 1.1–1.6), but results were attenuated after excluding children with congenital malformations. An increased risk of diseases of the circulatory system was also found in children exposed to paternal type 2 diabetes (HR = 1.5, 95%CI: 1.1–2.2) and the elevated risk remained after excluding children with congenital malformations.
This study suggests that susceptibility to malignant neoplasm is modified partly by fetal programming. Diseases of the circulatory system may be modified by genetic factors, other time-stable family factors, or fetal programming.
Background. Maternal distress during pregnancy increases the intrauterine level of glucocorticoids, which may have long-term health consequences for the child.
Objective. To examine if distress as a combined measure of anxiety, depression, and stress of the mother during pregnancy was associated with offspring childhood overweight at age 7.
Methods. We performed a cohort study using prospective data from 37,764 women and child dyads from the Danish National Birth Cohort (1996–2002). At a telephone interview at approximately 30 weeks gestation, the women reported whether they felt anxious, depressed, or stressed. The 95 percentile for body mass index in an international reference defined childhood overweight at any given age. Logistic regression was used for the analyses. Results. The prevalence of overweight children at 7 years of age was 9.9%. Prenatal exposure to maternal distress during pregnancy was not associated with childhood overweight at 7 years of age (adjusted OR 1.06 (95% CI 0.96; 1.18)). In analyses stratified on sex, a small tendency of overweight was seen in boys (OR 1.15 (0.99; 1.33)), but not in girls (OR 0.98 (0.85; 1.13)). Conclusions. Maternal distress during pregnancy appeared to have limited, if any, influence on the risk of overweight in offspring at 7 years of age.
Exposures during fetal life may have long-term health consequences including risk of childhood overweight. We investigated the associations between maternal recreational exercise during early and late pregnancy and the children's body mass index (BMI) and risk of overweight at 7 years. Data on 40,280 mother-child pairs from the Danish National Birth Cohort was used. Self-reported information about exercise was obtained from telephone interviews around gestational weeks 16 and 30. Children's weight and height were reported in a 7-year follow-up and used to calculate BMI and overweight status. Data was analyzed using multiple linear and logistic regression models. Recreational exercise across pregnancy was inversely related to children's BMI and risk of overweight, but all associations were mainly explained by smoking habits, socioeconomic status, and maternal pre-pregnancy BMI. Additionally, we did not find exercise intensity or changes in exercise habits in pregnancy related to the children's BMI or risk of overweight.
Thirty-two common variants associated with body mass index (BMI) have been identified in genome-wide association studies, explaining ∼1.45% of BMI variation in general population cohorts. We performed a genome-wide association study in a sample of young adults enriched for extremely overweight individuals. We aimed to identify new loci associated with BMI and to ascertain whether using an extreme sampling design would identify the variants known to be associated with BMI in general populations.
From two large Danish cohorts we selected all extremely overweight young men and women (n = 2,633), and equal numbers of population-based controls (n = 2,740, drawn randomly from the same populations as the extremes, representing ∼212,000 individuals). We followed up novel (at the time of the study) association signals (p<0.001) from the discovery cohort in a genome-wide study of 5,846 Europeans, before attempting to replicate the most strongly associated 28 SNPs in an independent sample of Danish individuals (n = 20,917) and a population-based cohort of 15-year-old British adolescents (n = 2,418). Our discovery analysis identified SNPs at three loci known to be associated with BMI with genome-wide confidence (P<5×10−8; FTO, MC4R and FAIM2). We also found strong evidence of association at the known TMEM18, GNPDA2, SEC16B, TFAP2B, SH2B1 and KCTD15 loci (p<0.001), and nominal association (p<0.05) at a further 8 loci known to be associated with BMI. However, meta-analyses of our discovery and replication cohorts identified no novel associations.
Our results indicate that the detectable genetic variation associated with extreme overweight is very similar to that previously found for general BMI. This suggests that population-based study designs with enriched sampling of individuals with the extreme phenotype may be an efficient method for identifying common variants that influence quantitative traits and a valid alternative to genotyping all individuals in large population-based studies, which may require tens of thousands of subjects to achieve similar power.
The sequence and timing of permanent tooth eruption is thought to be highly heritable and can have important implications for the risk of malocclusion, crowding, and periodontal disease. We conducted a genome-wide association study of number of permanent teeth erupted between age 6 and 14 years, analyzed as age-adjusted standard deviation score averaged over multiple time points, based on childhood records for 5,104 women from the Danish National Birth Cohort. Four loci showed association at P<5×10−8 and were replicated in four independent study groups from the United States and Denmark with a total of 3,762 individuals; all combined P-values were below 10−11. Two loci agreed with previous findings in primary tooth eruption and were also known to influence height and breast cancer, respectively. The two other loci pointed to genomic regions without any previous significant genome-wide association study results. The intronic SNP rs7924176 in ADK could be linked to gene expression in monocytes. The combined effect of the four genetic variants was most pronounced between age 10 and 12 years, where children with 6 to 8 delayed tooth eruption alleles had on average 3.5 (95% confidence interval: 2.9–4.1) fewer permanent teeth than children with 0 or 1 of these alleles.
While genome-wide association studies (GWAS) initially focused on the disease under investigation, additional findings in secondary traits have shown further benefits of having extensive phenotype data at hand. Using records from the nationwide dental registry for children and genotype data from two GWAS, we were able to identify four genomic loci associated with permanent tooth eruption in children. Two of the identified genomic regions had no previous GWAS findings, whereas two loci were reported in the context of primary dentition. A follow-up in an on-going GWAS showed that rs7924176 also plays a substantial role in primary dentition. During the age period of permanent tooth eruption many important developmental processes take place. Thus, we suggest following up the four reported SNPs in other growth-related traits to further elucidate the genetic background of maturation.
Preterm birth (PTB) has been associated with a later increased risk of maternal cardiovascular disease (CVD). We hypothesized a more pronounced relation between early or recurrent PTB and maternal CVD risk.
We related PTB severity (earlier gestational age at delivery) and recurrence (=2) among women with births from 1973–1983 in Denmark (n=427,765) to maternal CVD morbidity or mortality (1977–2006). Birth data were linked to CVD hospitalizations and deaths identified in national registers and data were analyzed using Cox proportional hazards models.
Women with a prior PTB had excess CVD after adjustment for age, parity, and education (HR 1.36 [95% CI 1.31, 1.41]). This was only modestly attenuated when women with preeclampsia or small for gestational age births were excluded, and the relationship was stronger for CVD mortality (HR 1.98 [1.73, 2.26]). Recurrent PTB was associated with higher CVD morbidity compared to women with one PTB, particularly for ischemic events (HR 1.78 [1.40, 2.27] vs. 1.22 [1.09, 1.36]). Risk was similarly elevated among women with early, moderate, and late PTB. Sensitivity analysis suggested that confounding by smoking only partly explained these associations.
Women with PTB, especially recurrent PTB, were at increased risk for CVD, suggesting common causes of these conditions.
Premature birth; cardiovascular disease; pregnancy; women
To describe patterns of prescribed drug use over time among primiparous women in Denmark.
Through the Danish Medical Birth Registry, we identified all primiparous women giving live birth or stillbirth at ≥ 22 gestational weeks in northern Denmark, from 1999 to 2009. From the Aarhus University Prescription Database we obtained information on the women’s prescriptions for reimbursed drugs filled from 30 days before conception until delivery.
Among 85,710 primiparous women, 47,982 (56.0%) redeemed at least one prescription from 30 days before conception until delivery. Women aged 35 years and older had the highest overall prevalence of prescription drug use (61.1%). Age-standardized prevalence of drug use was 54.7% in 1999 and 61.2% in 2009, prevalence ratio (PR) of 1.13 (95% confidence interval 1.10; 1.16), adjusted for age and smoking.
Over the 11-year period from 1999 to 2009, we found a modest increase in overall use of drugs by primiparous women in Denmark. This increase was not, however, explained by an increasing proportion of older first-time mothers. We noted changes in patterns of use of anti-infective drugs and antidepressants.
drug utilization; epidemiology; pregnancy
Exposure to infectious pathogens is a frequent occupational hazard for women who work with patients, children, animals or animal products. The purpose of the present study is to investigate if women working in occupations where exposure to infections agents is common have a high risk of infections and adverse pregnancy outcomes.
We used data from the Danish National Birth Cohort, a population-based cohort study and studied the risk of Infection and adverse outcomes in pregnant women working with patients, with children, with food products or with animals. The regression analysis were adjusted for the following covariates: maternal age, parity, history of miscarriage, socio-occupational status, pre-pregnancy body mass index, smoking habit, alcohol consumption.
Pregnant women who worked with patients or children or food products had an excess risk of sick leave during pregnancy for more than three days. Most of negative reproductive outcomes were not increased in these occupations but the prevalence of congenital anomalies (CAs) was slightly higher in children of women who worked with patients. The prevalence of small for gestational age infants was higher among women who worked with food products. There was no association between occupation infections during pregnancy and the risk of reproductive failures in the exposed groups. However, the prevalence of CAs was slightly higher among children of women who suffered some infection during pregnancy but the numbers were small.
Despite preventive strategies, working in specific jobs during pregnancy may impose a higher risk of infections, and working in some of these occupations may impose a slightly higher risk of CAs in their offspring. Most other reproductive failures were not increased in these occupations.
We investigated associations between maternal postpartum distress covering anxiety, depression and stress and childhood overweight.
We performed a prospective cohort study, including 21 121 mother-child-dyads from the Danish National Birth Cohort (DNBC). Maternal distress was measured 6 months postpartum by 9 items covering anxiety, depression and stress. Outcome was childhood overweight at 7-years-of age. Multiple logistic regression analyses were performed and information on maternal age, socioeconomic status, pre-pregnancy BMI, gestational weight gain, parity, smoking during pregnancy, paternal BMI, birth weight, gestational age at birth, sex, breastfeeding and finally infant weight at 5 and 12 month were included in the analyses.
We found, that postpartum distress was not associated with childhood risk of overweight, OR 1.00, 95%CI [0.98–1.02]. Neither was anxiety, depression, or stress exposure, separately. There were no significant differences between the genders. Adjustment for potential confounders did not alter the results.
Maternal postpartum distress is apparently not an independent risk factor for childhood overweight at 7-years-of-age. However, we can confirm previous findings of perinatal determinants as high maternal pre-pregnancy BMI, and smoking during pregnancy being risk factors for childhood overweight.
The timing and frequency of periconceptional multivitamin use may be related to the risk of preeclampsia. Women in the Danish National Birth Cohort (1997–2003) reported multivitamin or folate-only supplement use during a 12-week periconceptional period (from 4 weeks prior to 8 weeks after the last menstrual period). Preeclampsia cases were identified by using International Classification of Diseases, Tenth Revision, codes. Cox regression was used to estimate the association of frequency (weeks of use) and timing (preconception and postconception) of use with preeclampsia risk. Overall, there were 668 cases of preeclampsia (2.3%), and 18,551 women (65%) reported periconceptional multivitamin use. After adjustment, regular use (12 of 12 weeks) was related to a reduced risk of preeclampsia among normal-weight women. Compared with nonusers with a body mass index of 22 kg/m2, regular multivitamin users with the same body mass index had a 20% reduced risk of preeclampisa (hazard ratio = 0.78, 95% confidence interval: 0.60, 0.99). In addition, regular use in the postconception period only was associated with reduced risk, a relation that also appeared to be limited to women with a body mass index of <25 kg/m2 (hazard ratio = 0.63, 95% confidence interval: 0.42, 0.93). Folate-only supplement use was unrelated to preeclampsia risk. Regular periconceptional multivitamin use was associated with a reduced risk of preeclampsia among normal-weight women, and the immediate postconception period appeared to be the relevant exposure window.
body mass index; dietary supplements; pre-eclampsia; pregnancy; vitamins; women