Mortality patterns in a Danish nationwide cohort of persons with intellectual disabilities.

Mortality disparities among persons with intellectual disability are important to guide health-care practices. The objective was to evaluate mortality patterns of persons with intellectual disability in a nationwide study from 1976 to 2020. This study establishes a Danish nationwide cohort of persons with intellectual disability and age- and sex-matched reference cohort through linkage between several registers. We established a cohort of 79,114 persons with intellectual disability. Standardized mortality ratios were increased for persons with intellectual disability, most pronounced among younger persons and among females. Life expectancies were markedly lower; among persons with intellectual disability 63.6 years among females and 59.8 years among males in 2016-2020 compared to 82.4 and 78.7 years among females and males in the reference cohort. Life expectancies decreased with severity of intellectual disability. This study reports the establishment of a nationwide Danish cohort of persons with intellectual disability.

Is Sedentary Lifestyle Associated With Testicular Function? A Cross-Sectional Study of 1,210 Men.

Based on cross-sectional data on 1,210 healthy young Danish men, we investigated whether sedentary lifestyle was associated with testicular function (semen quality and reproductive hormones) independent of physical activity. The men were invited to participate in the study between 2008 and 2012, when they attended a compulsory medical examination to determine their fitness for military service. Information on sedentary behavior (television watching and computer time) and physical activity was obtained by questionnaire. The men had a physical examination, delivered a semen sample, and had a blood sample drawn. Time spent watching television, but not time sitting in front of a computer, was associated with lower sperm counts. Men who watched television more than 5 hours/day had an adjusted sperm concentration of 37 million/mL (95% confidence interval (CI): 30, 44) versus 52 million/mL (95% CI: 43, 62) among men who did not watch television; total sperm counts in those 2 groups were 104 million (95% CI: 84, 126) and 158 million (95% CI: 130, 189), respectively. Furthermore, an increase in follicle-stimulating hormone and decreases in testosterone and the testosterone/luteinizing hormone ratio were detected in men watching many hours of television. Self-rated physical fitness, but not time spent on physical activity, was positively associated with sperm counts.

Association of sleep disturbances with reduced semen quality: a cross-sectional study among 953 healthy young Danish men.

Several studies have found an association between sleep duration and morbidity and mortality, but no previous studies have examined the association between sleep disturbances and semen quality. We conducted a cross-sectional study among 953 young Danish men from the general population who were recruited in Copenhagen at the time of determination of fitness for military service between January 2008 and June 2011. All of the men delivered a semen sample, had a blood sample drawn, underwent a physical examination, and answered a questionnaire including information about sleep disturbances. Sleep disturbances were assessed on the basis of a modified 4-item version of the Karolinska Sleep Questionnaire, which includes questions on sleep patterns during the past 4 weeks. Sleep disturbances showed an inverse U-shaped association with sperm concentration, total sperm count, percent motile and percent morphologically normal spermatozoa, and testis size. Men with a high level of sleep disturbance (score >50) had a 29% (95% confidence interval: 2, 48) lower adjusted sperm concentration and 1.6 (95% confidence interval: 0.3, 3.0) percentage points' fewer morphologically normal spermatozoa than men with a sleep score of 11-20. This appears to be the first study to find associations between sleep disturbances and semen quality. In future studies, investigators should attempt to elucidate mechanistic explanations and prospectively assess whether semen quality improves after interventions restoring a normal sleeping pattern.

Temporal variability in urinary excretion of bisphenol A and seven other phenols in spot, morning, and 24-h urine samples.

Human exposure to modern non-persistent chemicals is difficult to ascertain in epidemiological studies as exposure patterns and excretion rates may show temporal and diurnal variations. The aim of this study was to assess the temporal variability in repeated measurements of urinary excretion of bisphenol A (BPA) and seven other phenols. All analytes were determined using TurboFlow-LC-MS/MS. Two spot, three first morning and three 24-h urine samples were collected from 33 young Danish men over a three months period. Temporal variability was estimated by means of intraclass correlation coefficients (ICCs). More than 70% of the urine samples had detectable levels of BPA, triclosan (TCS), benzophenone-3 (BP-3) and sum of 2,4-dichlorophenol and 2,5-dichlorophenol (ΣDCP). We found low to moderate ICCs for BPA (0.10-0.42) and ΣDCP (0.39-0.72), whereas the ICCs for BP-3 (0.69-0.80) and TCS (0.55-0.90) were higher. The ICCs were highest for the two spot urine samples, which were collected approximately 4 days apart, compared with the 24-h urine samples and the first morning urine samples, which were collected approximately 40 days apart. A consequence of the considerable variability in urinary excretion of BPA may be misclassification of individual BPA exposure level in epidemiological studies, which may lead to attenuation of the association between BPA and outcomes. Our data do not support that collection of 24-h samples will improve individual exposure assessment for any of the analysed phenols.

Breast Cancer Screening Among Women With Intellectual Disability in Denmark.

Importance: Breast cancer-specific mortality is increased among women with intellectual disability (ID), and knowledge about participation in breast cancer screening in this group is needed. Objective: To examine participation in the Danish national breast cancer screening program among women with ID compared with women without ID. Design, Setting, and Participants: This dynamic population-based cohort study assessed participation in the Danish national breast cancer screening program initiated in 2007, targeting women aged 50 to 69 years with a screening interval of 2 years. In all, 6357 women with ID born between 1941 and 1967 and eligible for the screening program were identified in national registers. Women entered the study between January 1, 2007, and December 31, 2017. Subsequently, 273 women were excluded due to a history of carcinoma in situ or breast cancer, and 489 due to registration errors in registers. Each woman was individually age-matched with 10 women without ID (reference group). All women were followed up until March 31, 2021, or censoring (due to death, carcinoma in situ, or breast cancer). Data were analyzed from December 1, 2021, to June 31, 2022. Exposures: Intellectual disability was defined as being registered with an ID diagnosis or a diagnosis most likely leading to ID or residing at an institution for persons with ID. Main Outcomes and Measures: Participation in breast cancer screening (fully, partly, and never). Results: A total of 5595 women with ID and 49 423 age-matched women in the reference group were included in the analysis. Of these, 2747 women with ID (49%) and 24 723 in the reference group (50%) were 50 years of age at study entry; for those older than 50 years, the median age was 51 years (IQR, 50-58 years) in both groups. In all, 1425 women with ID (25%) were fully screened according to guidelines for the Danish breast cancer screening program compared with 30 480 women in the reference group (62%). Women with ID had nearly 5 times higher odds of never being screened compared with the reference group (odds ratio, 4.90 [95% CI, 4.60-5.22]). In all, 2498 women with ID (45%) and 6573 in the reference group (13%) were never screened. The proportion of never-screened women increased with severity of ID, from 834 of 2287 (36%) among women with mild ID to 173 of 212 (82%) among women with profound ID. Conclusions and Relevance: The findings of this cohort study suggest that women with ID are markedly less likely to participate in breast cancer screening compared with women without ID. These findings further suggest a need for tailored guidelines and approaches for breast cancer screening in this group of women.

Trends in rates of natural conceptions among Danish women born during 1960-1984.

STUDY QUESTION: The aim of the study was to analyse trends in the rate of natural conceptions (RNC) among birth cohorts of women born during the period 1960-1984. SUMMARY ANSWER: In this nationwide study of Danish-born female cohorts born during the period 1960-1984, we found a gradual decline in the RNC with successive birth cohorts. WHAT IS KNOWN ALREADY: Our results confirm the findings from a previous study on trends in RNC among native Danish women. STUDY DESIGN, SIZE, DURATION: This is a register-based cohort study. Our data set included 803 435 native Danish women born in 1960-1984, of whom 68.2% had conceived at least one child as of 1 January 2008, by which time the follow-up was terminated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from Danish national registers were linked at the individual level using unique personal numbers assigned at birth to each resident. We analysed the data for the cohorts of native Danish women born in 1960-1984 and resident in Denmark in 2008. For these cohorts, we estimated the RNC per woman, defined as the mean number of live births minus live births after assisted reproductive technology (ART) plus the mean number of induced abortions. Births, abortions and births after ART were partly projected for the younger cohorts who had not finished their reproductive years before 2008. In addition, we looked at trends in hormonal contraception use. MAIN RESULTS: In the main projection scenario, the RNC gradually declined with successive cohorts from 2.39 among women born in 1960 to 2.15 among women born in 1984, with stable values of 2.15-2.16 projected in the youngest cohorts analysed, 1979-1984. The projected decline was a consequence of a decrease in induced abortion rates and an increase in the use of ART among the younger cohorts. Furthermore, we projected a cohort increase in the share of women without natural conceptions. LIMITATIONS, REASONS FOR CAUTION: A considerable portion of the results was based on projections, which involve uncertainty, especially concerning the results for women born in 1980 and later. In addition, information on IUI could not be included, which led to underestimation of the frequency of births after ART treatment. WIDER IMPLICATIONS OF THE FINDINGS: The results of our study contribute new insights to the research field of declining fertility rates in Europe and many other parts of the world.

Prenatal exposure to perfluoroalkyl substances and anogenital distance at 3 months of age in a Danish mother-child cohort.

In the Odense child cohort, serum concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured in 638 pregnant women. Birth weight, head and abdominal circumferences and gestational age were determined. Anogenital distance (AGD), the distance from the anus to the genital organs, and penile width were measured 3 months after expected date of birth in 511 children. PFOS, PFHxS, PFNA and PFDA were associated with a decreased AGD in girls (p-trend<0.05) after adjusting for age and weight-for-age standard deviation score. PFOS in the highest quartile was associated with a 2.8mm (95% confidence intervals -4.5; -1.1) reduction in AGD in girls. No such tendencies were seen in boys. However, a tendency toward increased birth weight in girls and reduced birth weight in boys suggests that sex-dimorphic effects may occur from endocrine disrupting effects of these substances.

Prenatal exposure to perfluoroalkyl substances and anogenital distance at 3 months of age as marker of endocrine disruption.

In the Odense child cohort, serum concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured in 649 pregnant women at approximately 12 weeks of gestation. Birth weight, head and abdominal circumferences were measured, and gestational age determined. Anogenital distance (AGD), i.e., the distance from the anus to the genital organs, penile width and body weight were measured 3 months after the expected date of birth in 511 children. PFOS, PFHxS, PFNA and PFDA were associated with a decreased AGD in girls (p-trend<0.05) after adjusting for age and weight-for-age standard deviation score. Specifically, PFOS in the highest quartile was associated with a 2.8mm (95% confidence intervals -4.5;-1.1) reduction in AGD in girls. No such tendencies were seen in boys. However, a tendency toward increased birth weight in girls and reduced in boys suggests that sex-dimorphic effects may occur from endocrine disrupting effects of these substances.

Psychological stress and testicular function: a cross-sectional study of 1,215 Danish men.

OBJECTIVE: To study the associations between self-reported psychological stress, semen quality, and serum reproductive hormones among young Danish men. DESIGN: Cross-sectional study. SETTING: University hospital-based research center. PARTICIPANT(S): Danish men (median age 19 years) from the general population were investigated from 2008 to 2012. INTERVENTION(S): Participants completed a questionnaire on health and lifestyle, including a four-item questionnaire about self-rated stress, had a physical examination performed, delivered a semen sample, and had a blood sample drawn. MAIN OUTCOME MEASURE(S): Semen parameters (semen volume, sperm concentration, and percentages of motile and morphologically normal spermatozoa) and serum levels of reproductive hormones (LH, FSH, T, calculated free T, sex hormone-binding globulin, and inhibin B). RESULT(S): Poorer semen quality was detected among men with self-reported stress scores above an intermediate stress level, in a dose-response manner. For example, men with the highest stress levels had 38% (95% confidence interval [CI] 3%; 61%) lower sperm concentration, 34% (95% CI 59%; 106%) lower total sperm count, and 15% (95% CI 1%; 27%) lower semen volume than men with intermediate stress levels. No significant associations between self-reported stress and levels of reproductive hormones were detected. CONCLUSION(S): A negative association between self-reported stress and semen quality was detected. If causal, stress may be a contributing factor for suboptimal semen quality among otherwise healthy men.

Prenatal Triclosan Exposure and Anthropometric Measures Including Anogenital Distance in Danish Infants.

BACKGROUND: Triclosan (TCS) is widely used as an antibacterial agent in consumer products such as hand soap and toothpaste, and human exposure is widespread. TCS is suspected of having endocrine-disrupting properties, but few human studies have examined the developmental effects of prenatal TCS exposure. OBJECTIVES: We prospectively examined associations between prenatal TCS exposure and anthropometric measures at birth and anogenital distance (AGD) at 3 months of age. METHODS: Pregnant women from the Odense Child Cohort (n = 514) provided urine samples at approximately gestational week 28 (median 28.7 weeks, range 26.4-34.0), and urinary TCS concentration was measured by isotope dilution TurboFlow-liquid chromatography-tandem mass spectrometry. Multiple linear regression analysis was used to examine associations between prenatal TCS exposure and measures of size at birth (birth weight, length, head and abdominal circumference) and AGD at 3 months of age (median 3.3 months, range 2.3-6.7 months), controlling for potential confounders. RESULTS: Newborn boys in the highest quartile of prenatal TCS exposure had a 0.7-cm [95% confidence interval (CI): -1.2, -0.1, p = 0.01] smaller head circumference than boys in the lowest quartile. Additionally in boys, inverse associations of borderline statistical significance were observed between prenatal TCS exposure and abdominal circumference at birth and AGD at 3 months of age (p-values < 0.10). Prenatal TCS exposure was not significantly associated with any of the outcomes in girls. However, AGD was measured in fewer girls, and we observed no significant interactions between a child's sex and prenatal TCS exposure in anthropometric measures at birth. CONCLUSION: Prenatal TCS exposure was associated with reduced head and abdominal circumference at birth and with reduced AGD at 3 months of age in boys, although the last two findings were statistically nonsignificant. These findings require replication but are compatible with an anti-androgenic effect of prenatal TCS exposure on fetal growth in boys. CITATION: Lassen TH, Frederiksen H, Kyhl HB, Swan SH, Main KM, Andersson AM, Lind DV, Husby S, Wohlfahrt-Veje C, Skakkebæk NE, Jensen TK. 2016. Prenatal triclosan exposure and anthropometric measures including anogenital distance in Danish infants. Environ Health Perspect 124:1261-1268; http://dx.doi.org/10.1289/ehp.1409637.

Prenatal Exposure to Phthalates and Anogenital Distance in Male Infants from a Low-Exposed Danish Cohort (2010-2012).

BACKGROUND: Phthalates comprise a large class of chemicals used in a variety of consumer products. Several have anti-androgenic properties, and in rodents prenatal exposure has been associated with reduced anogenital distance (AGD)-the distance from the anus to the genitals in male offspring. Few human studies have been conducted, but associations between the anti-androgenic phthalates and male AGD have been reported. OBJECTIVE: We aimed to study the association between phthalate exposure in late pregnancy in Danish women pregnant in 2010-2012 and AGD in their male infants at 3 months of age (n = 273). METHODS: In the Odense child cohort study, urinary concentrations of 12 phthalate metabolites of diethyl, di-n-butyl, diisobutyl, di(2-ethylhexyl), butylbenzyl, and diisononyl phthalate (DEP, DnBP, DiBP, DEHP, BBzP, and DiNP, respectively) were measured among 245 mothers of boys at approximately gestational week 28 (range, 20.4-30.4) and adjusted for osmolality. AGD, penile width, and weight were measured 3 months after the expected date of birth. Associations between prenatal phthalate and AGD and penile width were estimated using multivariable linear regression adjusting for age and weight-for-age standard deviation score. RESULTS: Phthalate levels were lower in this population than in a recent Swedish study in which phthalates were measured in the first trimester. No consistent associations were seen between any prenatal phthalate and AGD or penile width. Most associations were negative for exposures above the first quartile, and for ln-transformed exposures modeled as continuous variables, but there were no consistent dose-response patterns, and associations were not statistically significant (p > 0.05). CONCLUSION: We found no significant trends towards shorter AGD in boys with higher phthalates exposures in this low exposed Danish population. CITATION: Jensen TK, Frederiksen H, Kyhl HB, Lassen TH, Swan SH, Bornehag CG, Skakkebaek NE, Main KM, Lind DV, Husby S, Andersson AM. 2016. Prenatal exposure to phthalates and anogenital distance in male infants from a low-exposed Danish cohort (2010-2012). Environ Health Perspect 124:1107-1113; http://dx.doi.org/10.1289/ehp.1509870.

Habitual alcohol consumption associated with reduced semen quality and changes in reproductive hormones; a cross-sectional study among 1221 young Danish men.

OBJECTIVE: Study associations between three measures of alcohol consumption (recent, typical/habitual, binging), semen quality and serum reproductive hormones. DESIGN: Cross-sectional population based study. SETTING AND PARTICIPANTS: 1221 young Danish men, aged 18-28 years were recruited when they attended a compulsory medical examination to determine their fitness for military service from 2008 to 2012. Total alcohol consumption: (1) in the week preceding (habitual/typical) the visit (recent alcohol intake), (2) in a typical week and (3) frequency of 'binge drinking' (consuming more than 5 units/day)) in the past 30 days was estimated. MAIN OUTCOME MEASURES: Semen quality (volume, sperm concentration, total sperm count, and percentages of motile and morphologically normal spermatozoa) and serum concentration of reproductive hormones (follicle-stimulating hormone, luteinising hormone, testosterone, sex hormone binding globulin, oestradiol, free testosterone and inhibin B). RESULTS: Sperm concentration, total sperm count and percentage of spermatozoa with normal morphology were negatively associated with increasing habitual alcohol intake. This association was observed in men reporting at least 5 units in a typical week but was most pronounced for men with a typical intake of more than 25 units/week. Men with a typical weekly intake above 40 units had a 33% (95% CI 11% to 59%) reduction in sperm concentration compared to men with an intake of 1-5 units/week. A significant increase in serum free testosterone with increasing alcohol consumption the week preceding the visit was found. Binging was not independently associated with semen quality. CONCLUSIONS: Our study suggests that even modest habitual alcohol consumption of more than 5 units per week had adverse effects on semen quality although most pronounced associations were seen in men who consumed more than 25 units per week. Alcohol consumption was also linked to changes in testosterone and SHBG levels. Young men should be advised to avoid habitual alcohol intake.

Urinary bisphenol A levels in young men: association with reproductive hormones and semen quality.

BACKGROUND: Few human studies have examined bisphenol A (BPA) exposure in relation to semen quality and reproductive hormones in men, and results are divergent. OBJECTIVES: We examined associations between urinary BPA concentration and reproductive hormones, as well as semen quality, in young men from the general population. METHODS: Our study population consisted of 308 young men from the general population. Urinary BPA concentration was measured by isotope dilution TurboFlow-liquid chromatography-tandem mass spectrometry. We used multiple linear regression analysis to estimate associations between BPA concentration and reproductive hormones and semen quality, adjusting for confounding factors. RESULTS: We found that 98% of the men had detectable urinary levels of BPA. Median (5th-95th percentiles) BPA concentration was 3.25 ng/mL (0.59-14.89 ng/mL). Men with BPA concentrations above the lowest quartile had higher concentrations of serum testosterone, luteinizing hormone (LH), estradiol, and free testosterone compared with the lowest quartile (p trend ≤ 0.02). Men in the highest quartile of BPA excretion had on average 18% higher total testosterone (95% CI: 8, 28%), 22% higher LH (95% CI: 6, 39%), and 13% higher estradiol (95% CI: 4, 24%) compared with lowest quartile. Men in the highest quartile of BPA also had significantly lower percentage progressive motile spermatozoa compared with men in the lowest quartile (-6.7 percentage points, 95% CI: -11.76, -1.63). BPA was not associated with other semen parameters. Adjusting for dietary patterns did not influence the results. CONCLUSIONS: The pattern of associations between BPA and reproductive hormones could indicate an antiandrogenic or antiestrogenic effect, or both, of BPA on the hypothalamic-pituitary-gonadal hormone feedback system, possibly through a competitive inhibition at the receptor level. However, additional research is needed to confirm our findings and to further test the suggested potential mechanisms.

Phthalate excretion pattern and testicular function: a study of 881 healthy Danish men.

BACKGROUND: In animals, some phthalates impair male reproductive development and function. Epidemiological studies have reported inconsistent evidence of associations between phthalates and markers of human testicular function. OBJECTIVES: We aimed to provide estimates of the effects of phthalate exposure on reproductive hormone levels and semen quality in healthy men. METHODS: A total of 881 men gave urine, serum, and semen samples. Serum levels of testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin-B; semen quality; and urinary concentrations of 14 phthalate metabolites, including metabolites of di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), were assessed. The proportions of DEHP and DiNP excreted as their respective primary metabolites [mono(2-ethylhexyl) phthalate (MEHP) and mono-isononyl phthalate (MiNP)] were calculated and expressed as percentages (%MEHP and %MiNP, respectively). RESULTS: The free androgen index was 15% lower [95% confidence interval (CI): -23, -8%] for men in the highest %MiNP quartile compared to the lowest quartile (p < 0.001) after adjusting for confounders, and 9% lower (95% CI: -16, -1%) in the highest %MEHP quartile (p = 0.02). %MEHP and %MiNP were negatively associated with the ratio of testosterone/LH and testosterone/FSH. %MEHP was negatively associated with total testosterone, free testosterone, and ratio of testosterone/E(2). %MiNP was positively associated with SHBG. There was little evidence of associations between urinary phthalate metabolites or sums of phthalates with reproductive hormones or semen quality. CONCLUSION: Our data suggest that both testosterone production and pituitary-hypothalamic feedback may be compromised in individuals excreting a high proportion of primary metabolites of long-chained phthalates relative to the proportion of secondary metabolites.