Psychosocial job strain and risk of congenital malformations in offspring--a Danish National cohort study.

OBJECTIVE: To investigate if maternal exposure to psychosocial job strain at work (high demands and low control) measured by questionnaire early in pregnancy (median week 15) is associated with malformations in the offspring. DESIGN: Population-based cohort study. SETTING: The Danish National Birth Cohort. POPULATION: A cohort of 60,386 singleton children with full information on mother's occupational status, exposure to psychosocial job strain and all covariates during pregnancy. METHODS: Logistic regression analysis was used to calculate the odds of congenital malformations as a function of job strain with adjustment for maternal age, body mass index, parity, smoking, alcohol use, manual versus nonmanual work, maternal serious disease and gestational age at interview. MAIN OUTCOME MEASURES: Circulatory malformation, musculoskeletal malformation or any malformation. RESULTS: Logistic regression analyses, both crude and adjusted, indicated no associations between working under high strain and giving birth to a child with circulatory malformation (adjusted odds ratio [OR] 1.04, 95% confidence interval [95% CI] 0.75-1.44), musculoskeletal malformation (aOR 0.88, 95% CI 0.71-1.10) or any malformation (aOR 0.99, 95% CI 0.85-1.15). Supplementary analyses including restriction to first-borns and a stratified analysis with respect to manual and nonmanual work did not change the results. CONCLUSIONS: Association between exposure to high job strain during pregnancy and elevated risk of circulatory, muscle and any malformations is not supported by this study.

Maternal pre-pregnancy body mass index and pubertal development among sons.

Maternal overweight and obesity in pregnancy has been associated with earlier age of menarche in daughters as well as reduced semen quality in sons. We aimed at investigating pubertal development in sons born by mothers with a high body mass index (BMI). The study included 2522 sons of mothers that during pregnancy in 1984-1987 were enrolled in a mother-child cohort and gave information on their pre-pregnancy height and weight from which we calculated their BMI. Information on sons' pubertal development, assessed by age when starting regular shaving, voice break, acne and first nocturnal emission, was obtained from web-based questionnaires in 2005, when sons were 18-21 years old. Multiple linear regression analyses showed that sons of obese mothers on average started to shave regularly 8.3 (95% confidence interval: 2.5-14.0) months earlier than sons of normal weight mothers. For the three other indicators of pubertal development, results also indicated earlier pubertal development among sons of obese mothers. After excluding sons of underweight mothers in a subanalysis, we observed an inverse trend between maternal pre-pregnancy BMI and age at regular shaving, acne and first nocturnal emission. In conclusion, maternal pre-pregnant obesity may be related to earlier timing of pubertal milestones among sons. More research, preferably based on prospectively collected information about pubertal development, is needed to draw firm conclusions.

Maternal cigarette smoking during pregnancy and pubertal development in sons. A follow-up study of a birth cohort.

Epidemiological studies have raised concern about the reproductive consequences of prenatal cigarette smoking exposure, possibly affecting semen quality and onset of pubertal development of the offspring. The aim of this study was to further investigate pubertal development in young men exposed to cigarette smoking in foetal life. In a Danish pregnancy cohort, information on maternal smoking during pregnancy was available from questionnaires administered in 1984-1987, and information on pubertal development, assessed by age at first nocturnal emission, acne, voice break and regular shaving, was obtained from a follow-up questionnaire administered in 2005 to the young men (age: 18-21). We found no significant association between prenatal cigarette smoking exposure and earlier onset of puberty, but we did observe a tendency towards earlier age of first nocturnal emission, acne and voice break, indicating an accelerated age of pubertal development. Men exposed to ≥15 cigarettes/day had 3.1 months (95% CI: -6.4; 0.2) earlier age at acne and 2.2 months (95% CI: -7.3; 3.0) earlier age at first nocturnal emission, 1.2 months (95% CI: -4.6; 2.2) earlier age at voice break, however, 1.3 months (95% CI: -1.6; 4.3) later age at regular shaving, compared with unexposed men. Prenatal cigarette smoking exposure may induce an earlier age at onset of puberty in young men, but larger studies with prospectively collected data on pubertal development are needed to explore this hypothesis further.

Maternal smoking during pregnancy and reproductive health of daughters: a follow-up study spanning two decades.

STUDY QUESTION: Does in utero exposure to constituents of cigarette smoke have a programming effect on daughters' age of menarche and markers of long-term reproductive health? SUMMARY ANSWER: In utero exposure to constituents of cigarette smoke was associated with earlier age of menarche and--to a lesser extent--changes in the testosterone profile of the young women. WHAT IS KNOWN ALREADY: Studies observe potential effects of in utero exposure to constituents of cigarette smoke on the intrauterine formation of female gonads, but the consequences on long-term reproductive health in daughters remain unclear. STUDY DESIGN, SIZE AND DURATION: A prospective cohort study was designed using data from 965 pregnant women enrolled prior to a routine 30th-week antenatal examination at a midwifery practice in Denmark from 1988 to 1989 and a follow-up of their 19-21-year-old daughters in 2008. PARTICIPANTS/MATERIALS, SETTING AND METHODS: The pregnant women provided information on lifestyle factors during pregnancy, including the exact number of cigarettes smoked per day during the first and the second trimesters. A total of 438 eligible daughters were asked to complete a web-based questionnaire on reproductive health and subsequently invited to participate in a clinical examination during 2008. Of the 367 daughters (84%) who answered the questionnaire, 267 (61%) agreed to further examination. Information on menstrual pattern was provided at examination, blood samples were drawn to be analyzed for serum levels of reproductive hormones [FSH, LH, estradiol (E(2)), sex hormone-binding globulin, anti-Müllerian hormone, dehydroepiandrosterone-sulphate (DHEAS), free testosterone and free E(2)] and number of follicles (2-9 mm) were examined by transvaginal ultrasound. The daughters were divided into three exposure groups according to the level of maternal smoking during first trimester [non-exposed (reference), low-exposed (mother smoking >0-9 cigarettes/day) and high-exposed (mother smoking ≥ 10 cigarettes/day)]. Data were analyzed by multiple regression analyses in which we adjusted for potential confounders. Both crude and adjusted test for trend were carried out using maternal smoking during the first trimester as a continuous variable. MAIN RESULTS AND THE ROLE OF CHANCE: We observed an inverse association between in utero exposure to constituents of cigarette smoke and age of menarche (P = 0.001). Daughters exposed to >0-9 cigarettes/day debuted with -2.7 [95% confidence interval (CI) -5.2 to -0.1] percentage earlier age of menarche, whereas daughters exposed to ≥ 10 cigarettes/day had -4.1 (95% CI: -6.6 to -1.5) percentage earlier age of menarche corresponding to 6.5 (95% CI: -10.7 to -2.2) months. There was a non-significant tendency towards lower levels of testosterone and DHEAS with increasing in utero exposure to constituents of cigarette smoke but no associations with follicle number, cycle length or serum levels of the other reproductive hormones were observed. LIMITATIONS AND REASONS FOR CAUTION: We collected information on age of menarche retrospectively but the recall time was relatively short (2-10 years) and the reported values were within the normal range of Caucasians. Analyses of reproductive hormones are presented only for the group of daughters who were non-users of hormonal contraceptives because users were excluded, leaving only a low number of daughters available for the analyses (n = 75), as reflected in the wide CIs. The analyses of hormones were further adjusted for menstrual phase at time of clinical examination (follicular, ovulation and luteal phase) because blood samples were not collected on a specific day of the menstrual cycle. WIDER IMPLICATIONS OF THE FINDINGS: This study supports the limited evidence of an inverse association between maternal smoking during pregnancy and age of menarche and further addresses to what extent reproductive capacity and hormones may be programmed by maternal smoking during pregnancy. A trend toward earlier maturation of females is suggested to have implications on long-term reproductive function. STUDY FUNDING/COMPETING INTEREST(S): Supported by a scholarship from The Lundbeck Foundation (R93-A8476). No conflict of interest declared.

Male-mediated infertility in sons of building painters and gardeners: a nationwide register-based follow-up study.

AIM: To investigate whether sons of gardeners and building painters have increased risk of infertility in comparison with sons of bricklayers, carpenters and electricians. METHODS: Participants were men born 1965-1984 in Denmark whose fathers the year before birth had worked as gardeners, painters, bricklayers, carpenters or electricians (N=22,978). Cases of infertility were identified by Danish registers, and participants were followed-up for up to 24 years after their 20th birthday. RESULTS: Sons of gardeners did not have increased risk of infertility. Hazard ratios for sons of painters fluctuated around the null in main analyses but were 1.6 (98% CI: 1.0-2.5) and 1.7 (95% CI: 0.9-3.2) in the subset of participants with smallest risk of paternal exposure misclassification. CONCLUSIONS: Working as gardener or building painter was not related to increased risk of infertility among the next generation of males in main analyses. However, inherent limitations in data may have attenuated true associations.

Accuracy of cryptorchidism diagnoses and corrective surgical treatment registration in the Danish National Patient Registry.

PURPOSE: In recent years several Danish studies of the etiology, time trends and long-term health consequences of cryptorchidism have relied on diagnoses and surgical treatments registered in the National Patient Registry. We evaluated the diagnostic accuracy of these registry data. MATERIALS AND METHODS: According to the Danish National Patient Registry, 16,168 males were diagnosed with cryptorchidism and 9,244 surgical treatments for cryptorchidism were performed between January 1, 1995 and October 10, 2009. We randomly selected 500 diagnosed cases, of which 284 had been managed surgically. We requested the medical records from the departments making the diagnoses and performing the surgery. RESULTS: We successfully retrieved medical records for 452 diagnosed cases (90%) and 249 operations (88%). Overall positive predictive value of a registry diagnosis of cryptorchidism was 80% (95% CI 77-84) using the testicular position described by the physician performing the clinical examination as the gold standard. Similarly the positive predictive value of the surgical treatment registration was 99% (95% CI 98-100) using the type of procedure performed. CONCLUSIONS: The data on cryptorchidism in the Danish National Patient Registry are quite accurate. In etiological research the limited misclassification will in most cases only slightly attenuate estimates of the true relative association. Thus, the registry has the potential to serve as a valuable research tool, although caution should be exercised when studying time trends or geographical differences.

Does last week's alcohol intake affect semen quality or reproductive hormones? A cross-sectional study among healthy young Danish men.

The association between last 5 days of alcohol intake, semen quality and reproductive hormones was estimated in this cross-sectional study among 347 men. Conventional semen characteristics, DNA fragmentation index and reproductive hormones (testosterone, estradiol, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and inhibin B) were determined. There was a tendency towards lower semen characteristics at higher intake of alcohol past 5 days, albeit with no statistically significant dose-response association. The ratio between free estradiol and free testosterone was higher at higher alcohol intake during the 5 days preceding semen sampling. In conclusion, alcohol intake was associated with impairment of most semen characteristics but without a coherent dose-response pattern. The study indicates an association between recent alcohol intake and a hormonal shift towards higher estradiol/testosterone ratio. The hormonal changes observed may over time, lead to adverse effects on semen quality, but longitudinal studies are needed to study this.

Exposures that may affect sperm DNA integrity: two decades of follow-up in a pregnancy cohort.

Prenatal lifestyle exposures are linked to alterations in conventional semen characteristics. Sperm DNA integrity is another marker of semen quality shown to be altered in mice prenatally exposed to chemicals. From a Danish pregnancy cohort established in 1984-1987, sons were selected for a follow-up study in 2005-2006. We examined associations between prenatal and current lifestyle exposures and DNA fragmentation index (DFI) among 337 men. Sons of overweight mothers had 22% (95% CI: -3; 52) higher DFI than sons of normal weight mothers and sons of parents with a TTP >12 months had 14% (95% CI: -4; 34) higher DFI than sons of parents with a TTP of 0-6 months. Abstinence time was positively associated with DFI (p<0.005). Overweight men had higher DFI compared to normal weight men, however, statistically insignificantly. In conclusion, results indicate that DFI is affected by prenatal exposures, but confidence limits are wide and results statistically insignificant.

Does breastfeeding influence future sperm quality and reproductive hormones?

No human study has investigated the possible impact of breastfeeding on semen quality and levels of reproductive hormones, but a recent study of another hypothesis indicated an association with oligozoospermia. We investigated the association between breastfeeding, semen quality and levels of reproductive hormones. From a Danish pregnancy cohort established in 1984-1987, 347 sons were selected according to maternal smoking during pregnancy and followed up with questionnaires, semen analysis and blood sampling in 2005-2006. Complete data were available for 269 men aged 18-21 years. Breastfeeding was not statistically significantly associated with sperm concentration, total sperm count, sperm motility or morphology, oligozoospermia, follicle-stimulating hormone, inhibin B, luteinizing hormone, sex hormone-binding globulin (SHBG), the calculated level of free testosterone, free oestradiol, the free testosterone/free oestradiol ratio or the follicle-stimulating hormone/inhibin B ratio. Total testosterone and total oestradiol was 16% (p = 0.01) and 14% (p = 0.06), respectively, lower among men never breastfed in comparison with men breastfed exclusively for 1 month or longer. When taking SHBG into account, neither free testosterone nor free oestradiol was different between the two groups. This study shows no association between breastfeeding and sperm quality or reproductive hormones and a strong association is unlikely. A larger study would be needed to detect more subtle effects.

Does dissatisfaction with psychosocial work climate predict depressive, anxiety and substance abuse disorders? A prospective study of Danish public service employees.

BACKGROUND: The aim of this study was to examine if dissatisfaction with psychosocial work climate predicts psychiatrically diagnosed depressive, anxiety and substance abuse disorders. METHODS: In Aarhus County, Denmark, 13 423 public service employees at 683 workplace units answered a questionnaire survey assessing psychosocial work environment. An average workplace unit score of overall satisfaction with psychosocial working conditions, rated on a scale from 0-10 with 10 being most satisfied, was computed and assigned to the individual employees at each work unit. Aggregated satisfaction scores were divided into three levels, according to the 25-75 percentiles. Data on hospitalisations and outpatient treatments for depressive, anxiety and substance abuse disorders was obtained from the Danish Central Psychiatric Research Register. HRs and 95% CIs were computed for first onset of studied disorders, starting from the baseline survey at 1 January 2002 through to 30 April 2008. Risk estimates were adjusted for sociodemographic variables. RESULTS: A low satisfaction with psychosocial working conditions was associated with an increased risk of any mental health disorder, HR(adj) 1.71, 95% CI 1.04 to 2.82. The lower the satisfaction level, the higher was the risk of mental health disorders. Moreover, substance abuse disorders were more frequent among men dissatisfied with work climate, HR(adj) 3.53, 95% CI 1.55 to 8.03. CONCLUSION: Working in a dissatisfying psychosocial environment increases the risk of subsequent mental health disorders. Randomised, controlled intervention trials may help in resolving whether this association is causal.

Semen quality according to prenatal coffee and present caffeine exposure: two decades of follow-up of a pregnancy cohort.

BACKGROUND: A few studies have investigated the association between male caffeine consumption in adult life and semen quality with conflicting results, but so far no studies have explored the effect of prenatal coffee exposure. We studied the association between prenatal coffee and current caffeine exposure and semen quality and levels of reproductive hormones. METHODS: From a Danish pregnancy cohort established in 1984-1987, 347 sons out of 5109 were selected for a follow-up study conducted 2005-2006. Semen and blood samples were analyzed for conventional semen characteristics and reproductive hormones and were related to information on maternal coffee consumption during pregnancy and present caffeine consumption. Data were available for 343 men. RESULTS: There was a tendency toward decreasing crude median semen volume (P = 0.06) and adjusted mean testosterone (P = 0.06) and inhibin B (P = 0.09) concentrations with increasing maternal coffee consumption during pregnancy. Sons of mothers drinking 4-7 cups/day had lower testosterone levels than sons of mothers drinking 0-3 cups/day (P = 0.04). Current male caffeine intake was associated with increasing testosterone levels (P = 0.007). Men with a high caffeine intake had approximately 14% higher concentration of testosterone than those with a low caffeine intake (P = 0.008). CONCLUSIONS: The results observed in this study are only tentative, but they do not exclude a small to moderate effect of prenatal coffee exposure on semen volume and levels of reproductive hormones. Present adult caffeine intake did not show any clear associations with semen quality, but high caffeine intake was associated with a higher testosterone concentration.

Parental subfecundity and risk of decreased semen quality in the male offspring: a follow-up study.

A few studies have found poor semen quality in sons whose mothers have received fertility treatment, but it is unknown whether the poor semen quality is related to the infertility treatment or to infertility per se, for example, whether it is caused by hereditable factors. Using data from a population-based, Danish follow-up study conducted in 2005-2006, the authors of the present study examined whether sons of subfertile couples who had not received fertility treatment had poorer semen quality than sons of fertile couples. Among the 311 participants, an inverse association between parental waiting time to pregnancy and both semen volume and total sperm count was observed (p trend = 0.04 and p trend = 0.046, respectively). Semen volume in sons of subfertile parents (pregnant after > or =1 years) was 19% lower in comparison with that in sons of parents whose waiting time to pregnancy was 0-6 months (p = 0.02). Additionally, sperm concentration and percentage of morphologically normal sperm were, respectively, 22% (p = 0.15) and 23% (p = 0.13) lower in sons of subfertile parents. Results suggest a small-to-moderate effect of parental subfecundity on semen quality in sons, comparable with the hypothesis that low fecundity has at least partly hereditable causes.

Maternal smoking in pregnancy and reproductive hormones in adult sons.

Smoking during pregnancy has been reported to alter levels of reproductive hormones in adult sons. From a Danish pregnancy cohort established in 1984-1987, 347 out of 5109 sons were selected according to their exposure to tobacco smoke in foetal life. From February 2005 to January 2006, a blood sample from each young man (18-21 years) was collected and analysed for reproductive hormones. There were no apparent trends of increasing or decreasing hormonal levels with increased exposure to maternal tobacco smoking during pregnancy. Only the free testosterone/free estradiol ratios increased with increased maternal smoking during pregnancy (p for trend = 0.05). No trends for increasing odds ratios for high follicle-stimulating hormone (> or =25 percentile) or low inhibin B (< or =25 percentile) in relation to maternal smoking were observed. We found no major indication of long-term effects of pre-natal exposure to tobacco smoke on the levels of reproductive hormones later in life, but the data may suggest a shift in the hypothalamo-pituitary-gonadal axis towards higher androgenicity. This result was, however, of only borderline significance and could be because of chance.

Is maternal obesity related to semen quality in the male offspring? A pilot study.

BACKGROUND: Obesity is a strong predictor of fecundity and maternal obesity may well program semen quality during pregnancy, but to our knowledge, no published studies have evaluated this hypothesis. METHODS: From a Danish pregnancy cohort established in 1984-87, 347 out of 5109 sons were selected for a follow-up study conducted from February 2005 to January 2006. Semen and blood samples were analyzed for conventional semen characteristics and reproductive hormones and related to information on maternal pre-pregnant body mass index (BMI) that was available for 328 men. Of these, 34 were sons of underweight, and 25 sons of overweight, mothers. RESULTS: Inhibin B decreased with increasing maternal BMI (P = 0.04) and the point estimates for sperm concentration, semen volume, percent motile sperm, testosterone and FSH suggested an impaired reproductive status among sons of overweight mothers, but none of the trends were statistically significant. CONCLUSIONS: The results suggest that there may be an effect of high maternal BMI on the sons' semen quality, but the study had only enough power to justify a critical evaluation of the hypothesis in a larger study.

Subfecundity in overweight and obese couples.

BACKGROUND: Recent studies indicate that not only women's but also men's obesity has adverse effects on fecundity and since fecundity is a couple concept, we examined fecundity in relation to overweight and obesity of the couple. We also examined the association between weight changes and fecundity over time. METHODS: Between 1996 and 2002, 64 167 pregnant women enrolled in the Danish National Birth Cohort were interviewed during and 18 months after pregnancy. Information on body mass index (BMI) and waiting time to pregnancy (TTP) was available for 47 835 couples. RESULTS: Among men and women with a BMI of 18.5 kg/m(2) or more, we found a dose-response relationship between increasing BMI group and subfecundity (a TTP of more than 12 months): Odds ratio (OR) = 1.32 (95% CI: 1.26-1.37) for women and OR = 1.19 (95% CI: 1.14-1.24) for men. Among 2374 women with an initial BMI of 18.5 kg/m(2) or more, who participated more than once in the Danish National Birth Cohort, each kilogram increment in weight between the two pregnancies was associated with a 2.84 (95% CI: 1.33-4.35) days longer TTP. CONCLUSIONS: Couples have a high risk of being subfecund if they are both obese.

Is smoking a risk factor for decreased semen quality? A cross-sectional analysis.

BACKGROUND: Previous studies suggest a deleterious effect of cigarette smoking on semen quality, but their results have not been consistent. We studied the association between current smoking and semen characteristics and hormonal levels in a large group of healthy men. METHODS: From 1987 to 2004, seven separate occupational or environmental semen quality studies were co-ordinated by our department. A total of 2562 men participated, each providing semen and blood sample and answering a questionnaire about lifestyle and factors related to health. Appropriate semen and smoking data were available for 2542 men. RESULTS: Adjusting for study, age and other covariates, we observed an inverse dose-response relation between smoking and semen volume, total sperm count and percentage motile sperm. Heavy smokers had a 19% lower sperm concentration than non-smokers. We found a positive dose-response relationship between smoking and testosterone, LH and the LH/free testosterone ratios. CONCLUSION: Current smoking in adult life moderately impairs the semen quality. It is well known that semen quality is associated to fecundity. Therefore, it would be sensible to advise men to abstain from smoking to avoid decreased fecundity.

Time to pregnancy as a function of male and female serum concentrations of 2,2'4,4'5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE).

BACKGROUND: Persistent organochlorine pollutants (POP) may affect both the female and male reproductive system in animals as well as in humans. METHODS: Blood samples were collected from pregnant women and their partners from Greenland, Warsaw and Kharkiv, and from a cohort of Swedish fishermen's wives. Blood samples were analysed for 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE). Information on the participants' fertility, measured as time to pregnancy (TTP), was collected. In total, 778 men and 1505 women were included in the analyses. RESULTS: The data from Warsaw, Kharkiv and the Swedish fishermen's wives indicated no effect of either male or female exposure to POP on TTP. However, among men and women from Greenland, there seemed to be an association between serum concentrations of CB-153 and p,p'-DDE and prolonged TTP. Due to the strong intra-individual correlation between CB-153 and p,p'-DDE in the Greenlandic population, it was not possible to determine whether the risk was associated with CB-153 or p, p'-DDE or was an interaction between the two compounds. CONCLUSIONS: The overall results of the present study create a somewhat ambiguous pattern, but give some support to the idea that dietary POP exposure might be harmful for couple fertility.

Lower sperm counts following prenatal tobacco exposure.

BACKGROUND: Recent findings have indicated that prenatal exposure to tobacco smoke may cause lower sperm concentration in ejaculates of adult men. To extend the research on this hypothesis we investigated the dose-dependency of the association, controlling for other prenatal exposures. METHODS: From 1987 to 1996, four separate occupational semen studies were conducted at three centres in Denmark. A total of 945 men provided semen and blood samples, and information on reproductive and lifestyle factors. In 2004, we collected data on the maternal smoking habits during pregnancy from 522 mothers of the participating men. RESULTS: Adjusting for study subgroup, abstinence time and other factors, we found statistically non-significant differences in mean sperm concentrations: 65.0 x 10(6)/ml [95% confidence interval (CI) 51, 81] among sons of non-smokers; 59.1 x 10(6)/ml (95% CI 46, 75) among sons of mothers who had smoked 1-10 cigarettes/day; and 57.7 x 10(6)/ml (95% CI 40, 81) among those whose mothers had smoked >10 cigarettes/day. The former group had a higher odds ratio (OR) for oligozoospermia (sperm concentration < or =20 x 10(6)/ml) of 1.5 (95% CI 0.9, 2.8), the latter group an OR of 2.6 (95% CI 1.2, 5.8). CONCLUSION: We observed a dose-dependent association between prenatal tobacco exposure, lower sperm concentration and higher risk of oligozoospermia.