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Maternal vitamin D levels during pregnancy may be important for reproductive health in male offspring by regulating cell proliferation and differentiation during development. We conducted a follow-up study of 827 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, nested in the Danish National Birth Cohort to investigate if maternal vitamin D levels were associated with measures of reproductive health in adult sons. These included semen characteristics, testes volume, and reproductive hormone levels and were analysed according to maternal vitamin D (25(OH)D3) levels during pregnancy. In addition, an instrumental variable analysis using seasonality in sun exposure as an instrument for maternal vitamin D levels was conducted. We found that sons of mothers with vitamin D levels 75nmol/L. Continuous models, spline plots and an instrumental variable analysis supported these findings. Low maternal vitamin D levels were associated with lower testes volume and lower total sperm count with indications of dose-dependency. Maternal vitamin D level above 75nmol/L during pregnancy may be beneficial for testes function in adult sons.

BACKGROUND: Poor male fecundity is of concern, and a prenatal origin has been proposed. Folate, a methyl donor involved in DNA methylation, is essential for normal fetal development by regulating gene expression during different periods of fetal development. Thus, prenatal exposure to low maternal folate intake might have a programing function of the developing reproductive organs.OBJECTIVES: To examine the association between maternal intake of folate from diet and folic acid from supplements during pregnancy and markers of fecundity in young men.MATERIALS AND METHODS: We conducted a follow-up study using a Danish mother-son cohort of 787 young men born 1998-2000. Percentage differences in semen characteristics, testes volume, and reproductive hormone levels were analyzed according to total folate calculated as dietary folate equivalents from diet and supplements in midpregnancy, using multivariable negative binomial regression models. Total folate was analyzed in quintiles, continuous per standard deviation decrease (SD: 318 μg/day) and as restricted cubic splines.RESULTS: Low maternal intake of total folate was associated with lower total sperm count (-5% (95% confidence intervals [CI]: -11%; 2%)), a lower proportion of non-progressive and immotile spermatozoa (-5% [95% CI: -8%; -3%]), and lower testes volume (-4% [95% CI: -6%; -2%]) per SD decrease in total folate intake. Spline plots supported these findings.DISCUSSION: The finding of a lower proportion of non-progressive and immotile spermatozoa, and hence a higher proportion of motile spermatozoa, in men of mothers with a lower intake of total folate in midpregnancy was surprising and may be a chance finding.CONCLUSION: Lower maternal intake of total folate in midpregnancy was associated with lower sperm count and lower testes volume, however, also with a lower proportion of non-progressive and immotile spermatozoa in adult men. Whether this actually affects the ability to obtain a pregnancy warrants further investigation.

Male fecundity may be largely determined through fetal programming and therefore potentially be sensitive to exposure to maternal alcohol intake during pregnancy. We investigated whether maternal alcohol intake in early pregnancy was associated with biomarkers of fecundity in adult sons. In total, 1058 sons from the Fetal Programming of Semen Quality (FEPOS) cohort nested in the Danish National Birth Cohort (DNBC) provided blood and semen samples at around 19 years of age. Information on maternal weekly average alcohol intake (0 drinks [ref], >0–1 drinks, >1–3 drinks, >3 drinks) and binge drinking episodes (intake of ≥5 drinks on one occasion: (0 [ref], 1–2, ≥3 episodes)) was self-reported at around gestational week 17. Outcomes included semen characteristics, testes volume and reproductive hormones. We found some small tendencies towards lower semen characteristics and an altered hormone level profile in sons of mother who had an intake of > 3 drinks/week in early pregnancy and sons of mother who had ≥ 3 episodes of binge drinking in pregnancy. However, the effect estimates were overall small and inconsistent and with no indication of a dose dependent association. Due to the limited number of mothers with a high weekly alcohol intake, we cannot exclude whether prenatal exposure to higher doses than 4.5 drinks/week of alcohol in early pregnancy might have a detrimental effect on the biomarkers of fecundity in adult sons.. Male fecundity may be largely determined through fetal programming and therefore potentially be sensitive to exposure to maternal alcohol intake during pregnancy. We investigated whether maternal alcohol intake in early pregnancy was associated with biomarkers of fecundity in adult sons. In total, 1058 sons from the Fetal Programming of Semen Quality (FEPOS) cohort nested in the Danish National Birth Cohort (DNBC) provided blood and semen samples at around 19 years of age. Information on maternal weekly average alcohol intake (0 drinks [ref], >0-1 drinks, >1-3 drinks, >3 drinks) and binge drinking episodes (intake of ≥5 drinks on one occasion: (0 [ref], 1-2, ≥3 episodes)) was self-reported at around gestational week 17. Outcomes included semen characteristics, testes volume and reproductive hormones. We found some small tendencies towards lower semen characteristics and an altered hormone level profile in sons of mother who had an intake of > 3 drinks/week in early pregnancy and sons of mother who had ≥ 3 episodes of binge drinking in pregnancy. However, the effect estimates were overall small and inconsistent and with no indication of a dose dependent association. Due to the limited number of mothers with a high weekly alcohol intake, we cannot exclude whether prenatal exposure to higher doses than 4.5 drinks/week of alcohol in early pregnancy might have a detrimental effect on the biomarkers of fecundity in adult sons..

OBJECTIVE: To investigate if timing of puberty is associated with semen characteristics, testicular volume, and reproductive hormone levels.DESIGN: Cohort study.SUBJECTS: The Danish National Birth Cohort (DNBC) and its sub-cohort, the Fetal Programming of Semen Quality (FEPOS) cohort of 1,058 young men.EXPOSURE: Self-reported information on timing (younger, same age, older than peers) of the pubertal markers: voice break (primary exposure), pubic hair growth, regular shaving, and axillary hair growth.MAIN OUTCOME MEASURES: We estimated the relative differences with 95% confidence intervals (CI) for semen characteristics (semen volume, sperm concentration, total sperm count, sperm motility, percentage of morphologically normal spermatozoa), testicular volume, and reproductive hormones (follicle stimulating hormone [FSH], luteinizing hormone [LH], sex hormone-binding globulin [SHBG], testosterone, estradiol, free androgen index [FAI]) obtained at a median age of 19.2 years according to timing of pubertal development.RESULTS: Compared to men reporting voice break 'same age as peers', men reporting voice break 'older than peers' tended to have lower total sperm count (-12% [-25%, 4%]) and lower percent morphologically normal spermatozoa (-10% [-20%, 2%]), whereas men reporting voice break 'younger than peers' tended to have lower proportion of non-progressive and immotile spermatozoa (-6% [-13%, 1%]) and larger testicular volume (7% [1%, 13%]). The pattern was less consistent for the other pubertal markers.For reproductive hormones, voice break 'older than peers' tended to have higher FSH (24% [-1%, 55%]), higher SHBG (7% [0%, 15%]), lower estradiol (-14% [-23%, -5%]) and lower FAI (-8% [-14%, -1%]), whereas voice break 'younger than peers' tended to have higher LH (4% [-2%, 11%]), higher testosterone (5% [0%, 11%]), higher estradiol (17% [6%, 29%]) and higher FAI (4% [-2%, 11%]). When the categorical pubertal markers were analyzed as a linear term to assess for dose-dependency, older age at pubertal development were associated with higher FSH, higher SHBG, lower testosterone, lower estradiol and lower FAI for most pubertal markers.CONCLUSION: These results lend weak support to the hypothesis that older age at pubertal development is associated with markers of reduced male fecundity, especially reproductive hormone levels, although associations with semen characteristics and testicular volume were statistically insignificant.

Background Season of birth has been associated with age at menarche. Maternal vitamin D levels in pregnancy may explain this effect. We investigated whether the season of first trimester or maternal 25-hydroxyvitamin D3 [25(OH)D3] levels were associated with pubertal timing in children. Methods We conducted a follow-up study of 15 819 children born in 2000–03 from the Puberty Cohort, nested in the Danish National Birth Cohort (DNBC). Mean differences in attaining numerous pubertal markers, including a combined estimate for the average age at attaining all pubertal markers, were estimated for low (November–April) relative to high (May–October) sunshine exposure season in the first trimester using multivariable interval-censored regression models. Moreover, we conducted a two-sample instrumental variable analysis using season as an instrument for maternal first-trimester 25(OH)D3 plasma levels obtained from a non-overlapping subset (n = 827) in the DNBC. Results For the combined estimate, girls and boys of mothers who had their first trimester during November–April had earlier pubertal timing than girls and boys of mothers whose first trimester occurred during May–October: –1.0 months (95% CI: –1.7 to –0.3) and –0.7 months (95% CI: –1.4 to –0.1), respectively. In the instrumental variable analysis, girls and boys also had earlier pubertal timing: respectively, –1.3 months (95% CI: –2.1 to –0.4) and –1.0 months (95% CI: –1.8 to –0.2) per SD (22 nmol/L) decrease in 25(OH)D3. Conclusions Both first pregnancy trimester during November–April and lower 25(OH)D3 were associated with earlier pubertal timing in girls and boys.

BACKGROUND: Folate is essential for normal foetal development as it plays an important role for gene expression during different periods of foetal development. Thus, prenatal exposure to folate may have a programming effect on pubertal timing.OBJECTIVES: To study the association between maternal intake of folate during pregnancy and pubertal timing in girls and boys.METHODS: We studied 6585 girls and 6326 boys from a Danish population-based Puberty Cohort, 2000-2021. Information on maternal intake of folate from diet and folic acid from supplements was obtained from a food-frequency questionnaire in mid-pregnancy, and total folate was calculated as dietary folate equivalents. Information on age at menarche in girls, age at first ejaculation and voice break in boys, and Tanner stages, acne and axillary hair in both girls and boys was obtained every 6 months throughout puberty. We estimated mean monthly differences according to exposure groups for each pubertal milestone in addition to a combined estimate for the average age at attaining all pubertal milestones using multivariable interval-censored regression models. Total folate was analysed in quintiles, continuous and as restricted cubic splines.RESULTS: Maternal intake of total folate in mid-pregnancy was not associated with pubertal timing in girls (combined estimate for overall pubertal timing per standard deviation (SD 325 μg/day) decrease in maternal intake of total folate: -0.14 months (95% confidence interval [CI] -0.51, 0.22)). Boys had slightly later overall pubertal timing per standard deviation (SD 325 μg/day) decrease in maternal intake of total folate (combined estimate: 0.40 months, 95% CI 0.01, 0.72). Spline plots supported these findings.CONCLUSIONS: Prenatal exposure to low maternal intake of total folate in mid-pregnancy was not associated with pubertal timing in girls but associated with slightly later pubertal timing in boys. This minor delay is likely not of clinical importance.

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

Anne Gaml-Sørensen,1 Nis Brix,1,2 Gunnar Toft,3,4 Tine Brink Henriksen,5 Andreas Ernst,1,6 Linn Håkonsen Arendt,1,7 Sandra Søgaard Tøttenborg,8 Katia Keglberg Hærvig,8,9 Karin Sørig Hougaard,9,10 Jens Peter Ellekilde Bonde,8,9 Cecilia Høst Ramlau-Hansen1 1Department of Public Health, Research Unit for Epidemiology, Bartholins Allé 2, Aarhus University, Aarhus C, 8000, Denmark; 2Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, 8200, Denmark; 3Department of Clinical Epidemiology, Aarhus University, Aarhus N, 8200, Denmark; 4Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, 8200, Denmark; 5Perinatal Epidemiology Research Unit, Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus N, 8200, Denmark; 6Department of Urology, Aarhus University Hospital, Aarhus N, 8200, Denmark; 7Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus N, 8200, Denmark; 8Department of Occupational and Environmental Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen NV, 2400, Denmark; 9Department of Public Health, University of Copenhagen, København K, 1014, Denmark; 10National Research Centre for the Working Environment, Copenhagen East, 2100, DenmarkCorrespondence: Anne Gaml-Sørensen,Department of Public Health, Research Unit for Epidemiology, Bartholins Allé 2, Aarhus University, Aarhus C, 8000, Denmark, Tel +45 40868183, Email ags@ph.au.dkPurpose: Parental separation may be a stressful life event with the potential to influence hormonal regulation of offspring reproductive health and thereby affect semen quality in young men. We aimed to study the association between parental separation in pregnancy or in childhood and semen quality in young men and to study whether the timing of parental separation in childhood was important.Patients and Methods: We conducted a follow-up study of 1058 young men born 1998– 2000 from the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort. Data on parental separation were obtained longitudinal by self-report. Parental separation in pregnancy was dichotomized, and parental separation in childhood was both dichotomized and categorized according to the timing of parental separation (from birth, from early childhood (0– 5 years), and from late childhood (6– 10 years)). Semen volume, concentration, total sperm count, motility, morphology, and testes volume were analysed using multivariable negative binomial regression models.Results: Parental separation in pregnancy was not associated with semen quality. The association between parental separation in childhood and semen quality differed with the timing of parental separation. Parental separation from birth was associated with higher semen volume of 25%, 95% CI (− 5; 64); higher total sperm count of 62%, 95% CI (− 6; 179); and higher proportion of morphologically normal spermatozoa of 59%, 95% CI (20; 111). Parental separation in early childhood was associated with lower semen volume of − 14%, 95% CI (− 24; − 3); lower concentration of − 15%, 95% CI (− 28; 1); lower total sperm count of − 17%, 95% CI (− 32; 2) and lower testes volume of − 11%, 95% CI (− 18; − 3).Conclusion: The timing of parental separation was important, and parental separation from birth was associated with higher semen quality, and parental separation in early childhood was associated with lower semen quality.Keywords: stressful life-events, parental divorce, semen analysis, sperm quality, male infertility, epidemiology

STUDY QUESTION Is there risk of selection bias in etiological studies investigating prenatal risk factors of poor male fecundity in a cohort of young men? SUMMARY ANSWER The risk of selection bias is considered limited despite a low participation rate. WHAT IS KNOWN ALREADY Participation rates in studies relying on volunteers to provide a semen sample are often very low. Many risk factors for poor male fecundity are associated with participation status, and as men with low fecundity may be more inclined to participate in studies of semen quality, a risk of selection bias exists. STUDY DESIGN, SIZE, DURATION A population-based follow-up study of 5697 young men invited to the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998–2019. PARTICIPANTS/MATERIALS, SETTING, METHODS Young men (age range: 18 years, 9 months to 21 years, 4 months) born 1998–2000 by mothers included in the DNBC were invited to participate in FEPOS. In total, 1173 men answered a survey in FEPOS (n = 115 participated partly); of those, 1058 men participated fully by also providing a semen and a blood sample at a clinical visit. Differential selection according to parental baseline characteristics in the first trimester, the sons’ own characteristics from the FEPOS survey, and urogenital malformations and diseases in reproductive organs from the Danish registers were investigated using logistic regression. The influence of inverse probability of selection weights (IPSWs) to investigate potential selection bias was examined using a predefined exposure-outcome association of maternal smoking in the first trimester (yes, no) and total sperm count analysed using adjusted negative binomial regression. A multidimensional bias analysis on the same association was performed using a variety of bias parameters to assess different scenarios of differential selection. MAIN RESULTS AND THE ROLE OF CHANCE Participation differed according to most parental characteristics in first trimester but did not differ according to the prevalence of a urogenital malformation or disease in the reproductive organs. Associations between maternal smoking in the first trimester and male fecundity were similar when the regression models were fitted without and with IPSWs. Adjusting for other potential risk factors for poor male fecundity, maternal smoking was associated with 21% (95% CI: −32% to −9%) lower total sperm count. In the bias analysis, this estimate changed only slightly under realistic scenarios. This may be extrapolated to other exposure-outcome associations. LIMITATIONS, REASONS FOR CAUTION We were unable to directly assess markers of male fecundity for non-participants from, for example an external source and therefore relied on potential proxies of fecundity. We did not have sufficient power to analyse associations between prenatal exposures and urogenital malformations. WIDER IMPLICATIONS OF THE FINDINGS The results are reassuring when using this cohort to identify causes of poor male fecundity. The results may be generalized to other similar cohorts. As the young men grow older, they can be followed in the Danish registers, as an external source, to examine, whether participation is associated with the risk of having an infertility diagnosis. STUDY FUNDING/COMPETING INTEREST(S) The project was funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis’s Grant, Axel Muusfeldt’s Foundation (2016-491), AP Møller Foundation (16-37), the Health Foundation, Dagmar Marshall’s Fond, Aarhus University and Independent Research Fund Denmark (9039-00128B). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

Introduction Pregabalin is an antiepileptic drug frequently prescribed to pregnant women. Risks of adverse birth and postnatal neurodevelopmental outcomes following prenatal exposure to pregabalin are uncertain. Objective To investigate the association between prenatal exposure to pregabalin and the risks of adverse birth and postnatal neurodevelopmental outcomes. Methods This study was conducted using population-based registries in Denmark, Finland, Norway, and Sweden (2005–2016). We compared pregabalin exposure against no exposure to antiepileptics and against active comparators lamotrigine and duloxetine. We obtained pooled propensity score-adjusted estimates of association using fixed-effect and Mantel–Haenszel (MH) meta-analyses. Results The total number of pregabalin-exposed births was 325/666,139 (0.05%) in Denmark, 965/643,088 (0.15%) in Finland, 307/657,451 (0.05%) in Norway, and 1275/1,152,002 (0.11%) in Sweden. The adjusted prevalence ratios (aPRs) with 95% confidence interval (CI) following pregabalin exposure versus no exposure were 1.14 (0.98–1.34) for major congenital malformations and 1.72 (1.02–2.91) for stillbirth, which attenuated to 1.25 (0.74–2.11) in MH meta-analysis. For the remaining birth outcomes, the aPRs were close to or attenuated toward unity in analyses using active comparators. Adjusted hazard ratios (95% CI) contrasting prenatal pregabalin exposure versus no exposure were 1.29 (1.03–1.63) for ADHD and attenuated when using active comparators, 0.98 (0.67–1.42) for autism spectrum disorders, and 1.00 (0.78–1.29) for intellectual disability. Conclusions Prenatal exposure to pregabalin was not associated with low birth weight, preterm birth, small for gestational age, low Apgar score, microcephaly, autism spectrum disorders, or intellectual disability. On the basis of the upper value of the 95% confidence interval, increased risks greater than 1.8 were unlikely for any major congenital malformation and ADHD. For stillbirth and most groups of specific major congenital malformations, the estimates attenuated in MH meta-analysis. Prenatal exposure to pregabalin, birth outcomes and neurodevelopment - a population-based cohort study in four Nordic countries

BackgroundMaternal fever during pregnancy has been associated with an increased risk of genital malformations, but the implication for long-term reproductive health in the offspring is unknown.ObjectivesTo investigate associations between timing, duration, and temperature of fetal exposure to maternal fever and sons’ semen quality, testicular volume, and levels of reproductive hormones in early adulthood. Further, to examine whether concurrent use of antipyretics and/or antibiotics modified the effect.Materials and methodsWe used the Fetal Programming of Semen Quality cohort consisting of men born to women enrolled in the Danish National Birth Cohort. Self-reported information on maternal fever was collected twice during pregnancy (median 16 and 31 pregnancy weeks) and categorized as any fever during pregnancy, fever during early pregnancy (weeks 1–15), and fever exclusively during late pregnancy (weeks 16–42). Semen quality and concentrations of reproductive hormones were measured at a clinical examination at the age of 18.9 years. We used negative binomial regression to examine the associations, adjusting for maternal age at birth, maternal smoking, family occupational status, and precision variables related to semen quality and hormonal levels, for example, abstinence time.Results986 men were included in the study, of which 23% had mothers reporting at least one episode of fever. We found no strong indications of associations between maternal fever during pregnancy and male reproductive health in young men. Concurrent use of antipyretics and antibiotics did not modify the association.DiscussionStrengths include the large sample size, prospectively collected data, and the adjustment for maternal factors during pregnancy and important precision variables. A limitation is the crude self-reported information on maternal fever.ConclusionWe found no evidence to support that timing, duration, or temperature of maternal fever during pregnancy has a long-term impact on semen characteristics, testicular volume, or level of reproductive hormones in male offspring Background: Maternal fever during pregnancy has been associated with an increased risk of genital malformations, but the implication for long-term reproductive health in the offspring is unknown. Objectives: To investigate associations between timing, duration, and temperature of fetal exposure to maternal fever and sons’ semen quality, testicular volume, and levels of reproductive hormones in early adulthood. Further, to examine whether concurrent use of antipyretics and/or antibiotics modified the effect. Materials and methods: We used the Fetal Programming of Semen Quality cohort consisting of men born to women enrolled in the Danish National Birth Cohort. Self-reported information on maternal fever was collected twice during pregnancy (median 16 and 31 pregnancy weeks) and categorized as any fever during pregnancy, fever during early pregnancy (weeks 1–15), and fever exclusively during late pregnancy (weeks 16–42). Semen quality and concentrations of reproductive hormones were measured at a clinical examination at the age of 18.9 years. We used negative binomial regression to examine the associations, adjusting for maternal age at birth, maternal smoking, family occupational status, and precision variables related to semen quality and hormonal levels, for example, abstinence time. Results: 986 men were included in the study, of which 23% had mothers reporting at least one episode of fever. We found no strong indications of associations between maternal fever during pregnancy and male reproductive health in young men. Concurrent use of antipyretics and antibiotics did not modify the association. Discussion: Strengths include the large sample size, prospectively collected data, and the adjustment for maternal factors during pregnancy and important precision variables. A limitation is the crude self-reported information on maternal fever. Conclusion: We found no evidence to support that timing, duration, or temperature of maternal fever during pregnancy has a long-term impact on semen characteristics, testicular volume, or level of reproductive hormones in male offspring.

STUDY QUESTION Is maternal age at menarche associated with reproductive health in sons measured by semen quality, testes volume and reproductive hormone levels? SUMMARY ANSWER Later maternal age at menarche was associated with impaired semen characteristics, lower testes volume and altered levels of reproductive hormones, while earlier maternal age at menarche was not strongly associated with reproductive outcomes in sons. WHAT IS KNOWN ALREADY Both earlier and later maternal age at menarche may be associated with altered male reproductive health outcomes. This is the first study to investigate the potential association between maternal age at menarche and semen quality, testes volume and reproductive hormone levels in sons. STUDY DESIGN, SIZE, DURATION In this population-based cohort study, we used data from the Fetal Programming of Semen Quality Cohort nested within the Danish National Birth Cohort. In total, 5697 sons born in 1998–2000 were invited to participate in the cohort in 2017–2019. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 1043 (18% of the invited) young men with information on maternal age at menarche provided a semen and blood sample, measured their testes volume, and filled in a questionnaire on health behavior and pubertal development. Maternal age at menarche was reported by the mothers during pregnancy and examined categorically (as earlier, at the same time or later than their peers), continuously and modeled as splines. We estimated relative percentage differences in the reproductive outcomes using negative binomial regression models. Further, we did a mediation analysis to investigate the potential mediating role of timing of the sons’ pubertal development. MAIN RESULTS AND THE ROLE OF CHANCE Sons whose mothers had age at menarche later than peers had 15% lower (95% CI: −27%; 0%) sperm concentration, 14% lower (95% CI: −28%; 1%) total sperm count, 7% higher (95% CI: 0%; 14%) proportion of nonprogressive or immotile spermatozoa, 6% lower (95% CI: −11%; 0%) testes volume, 6% lower (95% CI: −12%; 1%) luteinizing hormone, 6% lower (95% CI: −12%; 1%) sex hormone-binding globulin and 5% lower (95% CI: −9%; 0%) testosterone levels compared with sons whose mothers had age at menarche at the same time as peers. Our study did not suggest that earlier maternal age at menarche was strongly associated with semen quality, testes volume or reproductive hormones in sons. However, the spline analyses indicated a potential inverted U-shaped association for sperm concentration and testes volume, and levels of sex hormone-binding globulin and testosterone. We found no strong evidence of mediation by timing of the sons’ own pubertal development. LIMITATIONS, REASONS FOR CAUTION There was a rather low participation rate in the Fetal Programming of Semen Quality Cohort and we tried to counter it by applying selection weights. Maternal age at menarche was recalled during pregnancy, which may introduce misclassification, most likely nondifferential. Inaccuracy of the sons’ recalled pubertal development years after the event may result in underestimation of the possible mediating role of pubertal timing. WIDER IMPLICATIONS OF THE FINDINGS Our findings may represent a degree of shared heritability of reproductive health or be a result of an underlying epigenetic profile or unknown shared environmental, cultural or dietary exposure, causing both altered age at menarche and impaired reproductive health outcomes in sons. However, the exact mechanism for the investigated association remains unknown. STUDY FUNDING/COMPETING INTEREST(S) This article is part of the ReproUnion collaborative study, cofinanced by the European Union, Intereg V ÖKS (20200407). The FEPOS project was further funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis’s Grant, Axel Muusfeldt’s Foundation (2016-491), A.P. Møller Foundation (16-37), the Health Foundation and Dagmar Marshall’s Fond. Additionally, this study received funding from Aarhus University. There are no competing interests. TRIAL REGISTRATION NUMBER N/A.

BackgroundParacetamol (acetaminophen) is a frequently used nonprescription analgesic with suggested endocrine-disrupting properties. Epidemiological evidence on the effect of paracetamol on male fecundity is sparse.ObjectivesTo investigate if the use of paracetamol as an oral nonprescription mild analgesic was associated with semen quality in young men.Materials and methodsThis cross-sectional study was based on data from the Fetal Programming of Semen Quality (FEPOS; 2017–2019) cohort of 1058 young men (18–21 years) included in the Danish National Birth Cohort. Participants completed a comprehensive online questionnaire on health behavior including analgesic use and provided a semen sample. Negative binomial regression models were used to estimate the percentage differences (adjusted mean ratios [aMR]) in semen quality characteristics according to paracetamol use (no; yes) and frequency of use (almost never; ResultsIn total, 28% of the 913 participants with available data reported the use of paracetamol within the last 6 months. We found a slightly higher total sperm count (aMR 1.13 95% CI [0.99–1.30]) in users compared to nonusers but other semen characteristics were unaffected. The frequency of use was suggestive of lower total sperm count and morphologically normal sperm cells primarily among users ≥1/week, however, CIs were wide.DiscussionWe were unable to account for the underlying reason for paracetamol use, which may induce confounding by indication. Exposure misclassification due to recall is likely but probably nondifferential due to the participants’ young age and unawareness of semen quality. Due to the rapid plasma half-life of paracetamol and few frequent users, it was not possible to conclude on potential high-dose effects.ConclusionOur findings do not suggest any strong detrimental effect of paracetamol use on semen quality within this sample of young Danish men. However, the effects of high dose and frequent use cannot be excluded.

International audience; PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13–16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2–0.9) to 0.5 (95% CI, 0.3–1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8–1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.

Infertility is an increasing global health problem, affecting approximately 15% of couples worldwide , and male factor infertility is a major contributing factor. The decline in couple fecundity presumably is caused by biological, social, and behavioral aspects. It has been suggested that family planning and use of contraception during the past century have increased subfecundity. The most fecund couples have fewer children, whereas couples with low fecundity produce more children than before due to fertility treatment . This hypothesis assumes that intergenerational transmission of subfecundity is substantial, which is poorly documented Objective: To study the associations between parental subfecundity, assessed by time to pregnancy and use of medically-assisted reproduction, and reproductive health of young men.Design: Cohort study.Setting: Denmark.Patient(s): A total of 1,058 men in the Fetal Programming of Semen quality cohort, a subcohort of the Danish National Birth Cohort. Intervention(s): From 2017-2019, men were recruited and provided semen and blood samples. Information on parental time to pregnancy and use of medically-assisted reproduction (including type of treatment) as well as demographic, health, and lifestyle factors were available. We estimated the crude and adjusted relative percentage differences with 95% confidence intervals (CIs) in the outcomes according to time to pregnancy and use of medically-assisted reproduction, using multiple adjusted negative binomial regression analysis.Main Outcome Measure(s): Semen characteristics (semen volume, sperm concentration, total sperm count, sperm motility, and morphology), testicular volume, and reproductive hormone levels (follicle stimulating hormone, luteinizing hormone, testosterone, estradiol, sex hormone-binding globulin, and free androgen index). Result(s): Overall, semen quality and levels of reproductive hormones were not lower among sons of subfecund parents reporting a time to pregnancy >6 months or use of intrauterine insemination. Sons conceived after in vitro fertilization or intracytoplasmic sperm injection, had a higher semen concentration (29%; 95% CI, -7%-79%) and a higher percentage of sperm with normal morphology (20%; 95% CI, -8%-56%), but with 95% CI overlapping the null. Moreover, these sons had slightly higher estradiol levels (30%; 95% CI, 7%-57%). The absolute differences seen were small, and the clinical significance of these differences are unknown.Conclusion(s): We found no major difference in semen quality or reproductive hormones in sons conceived by subfertile couples or with the use of medically-assisted reproduction. (Fertil Sterile 2022;118:671-78. (c) 2022 by American Society for Reproductive Medicine.) El resumen esta disponible en Espanol al final del articulo.

BACKGROUND: Concerns remain about the human reproductive toxicity of the widespread per- and polyfluoroalkyl substances (PFAS) during early stages of development.OBJECTIVES: We examined associations between maternal plasma PFAS levels during early pregnancy and male offspring reproductive function in adulthood.METHODS: The study included 864 young men (age range:18.9-21.2 y) from the Fetal Programming of Semen Quality (FEPOS) cohort established between 2017 and 2019. Plasma samples from their mothers, primarily from the first trimester, were retrieved from the Danish National Biobank and levels of 15 PFAS were measured. Seven PFAS had detectable levels above the limit of detection in >80% of the samples and were included in analyses. Semen quality, testicular volume, and levels of reproductive hormones and PFAS were assessed in the young men. We used weighted quantile sum (WQS) regression to estimate the associations between combined exposure to maternal PFAS and reproductive function, and negative binomial regression to estimate the associations of single substances, while adjusting for a range of a priori-defined fetal and postnatal risk factors.RESULTS: By a 1-unit increase in the WQS index, combined maternal PFAS exposure was associated with lower sperm concentration (-8%; 95% CI: -16%, -1%), total sperm count (-10%; 95% CI: -17%, -2%), and a higher proportion of nonprogressive and immotile sperm (5%; 95% CI: 1%, 8%) in the young men. Different PFAS contributed to the associations with varying strengths; however, perfluoroheptanoic acid was identified as the main contributor in the analyses of all three outcomes despite the low concentration. We saw no clear association between exposure to maternal PFAS and testicular volume or reproductive hormones.DISCUSSION: In a sample of young men from the general Danish population, we observed consistent inverse associations between exposure to maternal PFAS and semen quality. The study needs to be replicated in other populations, taking combined exposure, as well as emerging short-chain PFAS, into consideration. https://doi.org/10.1289/EHP10285.

Background: Psychological stress is prevalent among reproductive-aged men. Assessment of semen quality for epidemiological studies is challenging as data collection is expensive and cumbersome, and studies evaluating the effect of perceived stress on semen quality are inconsistent. Objective: To examine the association between perceived stress and semen quality. Material and methods: We analyzed baseline data on 644 men (1,159 semen samples) from two prospective preconception cohort studies during 2015–2021: 592 in Pregnancy Study Online (PRESTO) and 52 in SnartForaeldre.dk (SF). At study entry, men aged ≥21 years (PRESTO) and ≥18 years (SF) trying to conceive without fertility treatment completed a questionnaire on reproductive and medical history, socio-demographics, lifestyle, and the 10-item version of the Perceived Stress Scale (PSS; interquartile range [IQR] of scores: 0–40). After enrollment (median weeks: 2.1, IQR: 1.3–3.7), men were invited to perform in-home semen testing, twice with 7–10 days between tests, using the Trak Male Fertility Testing System. Semen quality was characterized by semen volume, sperm concentration, and total sperm count. We fit generalized estimating equation linear regression models to estimate the percent difference in mean log-transformed semen parameters by four PSS groups (

OBJECTIVE: To study associations between maternal stress during pregnancy and reproductive function in young men.DESIGN: A cohort study nested in a population-based birth cohort.SETTING: Not applicable.PATIENTS: Young men (n = 1,052; response rate, 19%) participated in the Fetal Programming of Semen Quality cohort from 2017 to 2019. They were recruited from pregnancies in the Danish National Birth Cohort (1996-2001). The men completed an online questionnaire, clinical examination, and collection of blood and semen samples.EXPOSURES: Information on maternal life and emotional stresses was available from a telephone interview covering the interval from the beginning of pregnancy to approximately gestational week 30.MAIN OUTCOME MEASURE(S): We applied negative binomial, linear, and logistic regression to examine associations between life and emotional stress scores (range, 0-18) and reproductive function. The primary outcomes were measures of semen quality, and the secondary outcomes included reproductive hormone levels and testicular volume.RESULT(S): Overall, we observed no negative associations between maternal life or emotional stress and male reproductive function. Maternal emotional stress was associated with higher total sperm count (16% difference; 95% confidence interval [CI], 1-33), serum estradiol (11% difference; 95% CI, 2-21), and calculated free testosterone (β = 17.8; 95% CI, 1.26-34.3). The results were robust to inverse probability weighting introduced to account for selection.CONCLUSION(S): Although our findings may appear reassuring, further efforts to validate the measures of stress during pregnancy and improve our understanding of the full spectrum of fetal stress exposures and consequences for health later in life are needed.

Background Fetal exposure risk factors are associated with increased autism spectrum disorder (ASD) risk. New hypotheses regarding multigenerational risk for ASD have been proposed, but epidemiological evidence is largely lacking. We evaluated whether parental birth characteristics, including preterm birth and low birthweight, were associated with ASD risk in offspring. Methods We conducted a nationwide register-based cohort study that included 230 174 mother-child and 157 926 father-child pairs in Denmark. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for offspring ASD according to parental preterm ( Results Offspring of mothers or fathers with adverse birth characteristics had about 31–43% higher risk for ASD (maternal preterm birth, OR = 1.31, 95% CI= 1.12, 1.55; maternal low birthweight, OR = 1.35, 95% CI: 1.17,1.57; paternal preterm birth, OR = 1.43, 95% CI = 1.18, 1.73; paternal low birthweight, OR = 1.38, 95% CI= 1.13, 1.70). Parents born very preterm ( Conclusions Offspring of parents born with adverse characteristics had an elevated risk for ASD. Transmission of ASD risk through maternal and paternal factors should be considered in future research on ASD aetiology.

Background: Prenatal exposures may contribute to male infertility in adult life, but large-scale epidemiological evidence is still lacking. The Fetal Programming of Semen quality (FEPOS) cohort was founded to provide means to examine if fetal exposures can interfere with fetal reproductive development and ultimately lead to reduced semen quality and reproductive hormone imbalances in young adult men. Methods: Young adult men at least 18 years and 9 months of age born to women in the Danish National Birth Cohort living in relative proximity to Copenhagen or Aarhus and for whom a maternal blood sample and two maternal interviews during pregnancy were available were invited to FEPOS. Recruitment began in March 2017 and ended in December 2019. The participants answered a comprehensive questionnaire and underwent a physical examination where they delivered a semen, urine, and hair sample, measured their own testicular volume, and had blood drawn. Results: In total 21,623 sons fulfilled eligibility criteria of whom 5697 were invited and 1058 participated making the response rate 19%. Semen characteristics did not differ between sons from the Copenhagen and Aarhus clinics. When comparing the FEPOS semen parameters to similar cohorts, the median across all semen characteristics was slightly lower for FEPOS participants, although with smaller variation. Conclusion: With its 1058 young adult men, the FEPOS cohort is the largest population-based male-offspring cohort worldwide specifically designed to investigate prenatal determinants of semen quality. Wide-ranging information on maternal health, lifestyle, socioeconomic status, occupation, and serum concentrations of potential reproductive toxicants during pregnancy combined with biological markers of fertility in their sons collected after puberty allow for in-depth investigations of the ‘fetal origins of adult disease hypothesis’. (Less)

OBJECTIVE: To study the association between use of protein supplements (PS) and semen quality among young men.DESIGN: Cross-sectional study.SETTING: Not applicable PATIENT(S): We used data from the Fetal Programming of Semen Quality (FEPOS) cohort, which is a subsample of 778 men whose mothers enrolled in the Danish National Birth Cohort 1996-2002.INTERVENTION(S): Semen samples were collected from April 2017 to March 2019. Relative difference in semen characteristics according to self-reported PS use was estimated with negative binomial regression adjusting for lifestyle factors including exercise, body mass index, and use of anabolic steroids, and maternal and paternal factors potentially confounding the association between PS and semen quality.MAIN OUTCOME MEASURE(S): Negative binomial regression yielded the best fit and was used to estimate the percent difference with 95% confidence intervals in semen volume, sperm concentration, total sperm count, proportions of progressive, nonprogressive, and immotile sperm, and percentage of morphologically normal sperm in former and current users of PS relative to never users.RESULT(S): PS was used currently by 28% and formerly by 24% of participants. PS use was not associated with reduced semen quality in terms of semen volume, sperm concentration, total sperm count, morphology, or motility in either crude or adjusted analyses.CONCLUSION: This study showed no association between use of PS and semen quality characteristics. Still, we encourage others to repeat the study, as even a small harmful effect would have a large impact on the population level because of the widespread use of PS among young men.

BACKGROUND: Impact of restorative proctocolectomy failure on fertility has not been studied and is greatly relevant.OBJECTIVE: The purpose of this study was to evaluate the impact of restorative proctocolectomy failure on birth rate in women and men, along with in vitro fertilization incidence and success.DESIGN: This was a retrospective registry-based cohort study over 17 years.SETTINGS: Records for parenting a child were cross-linked with patient records. In women, in vitro fertilization records were cross-linked. All data were prospectively registered.PATIENTS: Patients of fertile age with ulcerative colitis between 1994 and 2010 were identified in Danish national databases. Patients with restorative proctocolectomy and restorative proctocolectomy failure were identified as subgroups.MAIN OUTCOME MEASURES: Birth rate ratios and in vitro fertilization incidence and success were measured.RESULTS: We included 11,939 women and 13,569 men with ulcerative colitis. A total of 711 women and 730 men had restorative proctocolectomy; 114 women and 90 men had failure. Birth rate in women with failure was significantly reduced compared with women without (birth rate ratio = 0.50 (95% CI, 0.29-0.82)). In men with failure, birth rate tended to be lower compared with men without (birth rate ratio = 0.74 (95% CI, 0.51-1.05)). In vitro fertilization incidence was similar with and without failure (HRs adjusted for age at start of follow-up = 0.98 (95% CI, 0.58-1.67]). In vitro fertilization success was significantly lower with failure compared with ulcerative colitis (OR adjusted for age at start of follow-up = 0.36 (95% CI, 0.4-0.92)).LIMITATIONS: Information on patients leading up to restorative proctocolectomy failure is lacking. Failure patients may have had children during a period with pouch function. Therefore, the impact of failure may be underestimated.CONCLUSIONS: Restorative proctocolectomy failure impairs birth rate, primarily in women. Although in vitro fertilization incidence is similar in women with and without failure, the likelihood of giving birth after in vitro fertilization is reduced. See Video Abstract at http://links.lww.com/DCR/B202. IMPACTO SOBRE LA FERTILIDAD DESPUéS DEL FRACASO DE LA PROCTOCOLECTOMíA RESTAURADORA EN HOMBRES Y MUJERES CON COLITIS ULCEROSA: UN ESTUDIO DE COHORTE DE 17 AñOS: No se ha estudiado el impacto de la falla de la proctocolectomía restauradora en la fertilidad y es muy relevante.Evaluar el impacto del fracaso de la proctocolectomía restauradora en la tasa de natalidad en mujeres y hombres, junto con la incidencia y el éxito de la fertilización in vitro.Estudio de cohorte retrospectivo basado en el registro de más de 17 años.Los registros de crianza de un niño se cruzaron con los registros de pacientes. En las mujeres, los registros de fertilización in vitro se cruzarón. Todos los datos se regitraron de forma prospectiva.Los pacientes de edad fértil con colitis ulcerosa entre 1994-2010 fueron identificados en las bases de datos nacionales danesas. Los pacientes con proctocolectomía restauradora y fracaso de la proctocolectomía restauradora se identificaron como subgrupos.Tasas de natalidad e incidencia y éxito de la fertilización in vitro.Se incluyeron 11939 mujeres y 13569 hombres con colitis ulcerosa. 711 mujeres y 730 hombres tuvieron proctocolectomía restauradora; 114 mujeres y 90 hombres tuvieron fracaso. La tasa de natalidad en las mujeres con fracaso se redujo significativamente en comparación con las mujeres sin fracaso (tasa de natalidad: 0,50; IC del 95% [0,29; 0,82]). En los hombres con fracaso, la tasa de natalidad tendió a ser más baja en comparación con los hombres sin fracaso (tasa de natalidad: 0,74; IC del 95% [0,51; 1,05]). La incidencia de fertilización in vitro fue similar con y sin falla (aHR: 0.98, IC 95% [0.58; 1.67]). El éxito de la fertilización in vitro fue significativamente menor con el fracaso en comparación con la colitis ulcerosa (aOR: 0.36 IC 95% [0.4; 0.92]).Falta información sobre los pacientes que conducen al fracaso de la proctocolectomía restauradora. Los pacientes con fracaso pueden haber tenido hijos durante un período con función de bolsa. Por lo tanto, el impacto del fracaso puede ser subestimado.El fracaso de la proctocolectomía restauradora afecta la tasa de natalidad, principalmente en mujeres. Aunque la incidencia de la fertilización in vitro es similar en las mujeres con y sin fracaso, la probabilidad de dar a luz después de la fertilización in vitro se reduce. Consulte Video Resumen en http://links.lww.com/DCR/B202. (Traducción-Dr Gonzalo Hagerman).

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a large family of persistent industrial chemicals with endocrine disrupting properties.OBJECTIVES: To examine biomarkers of reproductive function in young adult males according to current environmental exposure to single and combined PFAS.METHODS: The study population consisted of young men (n = 1041, age 18-21) from the Fetal Programming of Semen Quality (FEPOS) cohort. These men were recruited from pregnancies included in the Danish National Birth Cohort (DNBC) between 1996 and 2002. From 2017 to 2019, participants answered an online questionnaire, completed a clinical examination and provided a blood and a semen sample. Exposure to 15 PFAS was measured in plasma. Six compounds were quantified above the limit of detection in at least 80% of the participants. We applied negative binomial regression and weighted quantile sum (WQS) regression models to assess associations between single and combined exposures to PFAS and measures of semen quality, testicular volume and reproductive hormones among the young men.RESULTS: We found no consistent associations between plasma concentrations of PFAS, semen quality and testicular volume. Higher levels of single and combined PFAS were associated with slightly higher levels of follicle-stimulating hormone (FSH) (WQS 4% difference, 95% confidence interval: 0, 9). Perfluorooctanoic acid (PFOA) was the main contributor to this finding with positive signals also from perfluorodecanoic acid (PFDA) and perfluorohexane sulfonic acid (PFHxS).DISCUSSION: We examined exposure to a range of common PFAS in relation to biomarkers of male reproductive function and found an association with higher levels of FSH among young men from the general population in Denmark. Further studies on especially combined exposure to PFAS are needed to expand our understanding of potential endocrine disruption from both legacy and emerging compounds in relation to male reproductive function.

Background: Existing literature suggests that frequent consumption of sugar-sweetened drinks may be associated with lower semen quality. Studies performed in mice suggest a dose-response relationship between intake of saccharin or aspartame, two artificial sweeteners, and sperm and testis function. Methods: A cross-sectional study based on data from The Fetal Programming of Semen Quality (FEPOS) Cohort, including 1047 young men (mean age = 19 years) was performed. Each male participant completed an online questionnaire on health, health behavior and diet, and provided a semen sample. The associations between consumption of sugar-sweetened or artificially sweetened beverages (moderate ≥ 3 days/week; infrequent < 3 days/week) and semen quality were analyzed using a multivariable, negative, binomial regression model. Results: Sugar-sweetened or artificially sweetened beverage consumption was not strongly associated with either semen volume, sperm concentration, total sperm count or total motility in young men. The proportion of morphologically normal sperm was 11% lower (0.89 (95% CI 0.76, 1.04)) for moderate (≥3 days/week) consumption of artificially sweetened beverages relative to infrequent (

Animal studies indicate deleterious effects of nitrate exposure on fecundity, but effects in humans are unknown, both for the prenatal and postnatal periods. We aimed to investigate if exposure to nitrate in maternal drinking water during the sensitive period of fetal life is associated with measures of fecundity in the adult sons. In a sub-analysis, the potential effects of nitrate exposure in adulthood were investigated. This cohort included 985 young adult men enrolled in The Fetal Programming of Semen Quality Cohort (FEPOS). Semen characteristics, testes volume and reproductive hormones were analyzed in relation to nitrate concentration in maternal drinking water, using a negative binomial regression model. The nitrate concentration in drinking water was obtained from monitoring data from Danish waterworks that were linked with the mothers’ residential address during pregnancy. The median nitrate concentration in maternal drinking water was 2 mg/L. At these low exposure levels, which are far below the World Health Organization’s (WHO) guideline value of 50 mg/L, we did not find indications of harmful effects of nitrate on the investigated measures of male fecundity Animal studies indicate deleterious effects of nitrate exposure on fecundity, but effects in humans are unknown, both for the prenatal and postnatal periods. We aimed to investigate if exposure to nitrate in maternal drinking water during the sensitive period of fetal life is associated with measures of fecundity in the adult sons. In a sub-analysis, the potential effects of nitrate exposure in adulthood were investigated. This cohort included 985 young adult men enrolled in The Fetal Programming of Semen Quality Cohort (FEPOS). Semen characteristics, testes volume and reproductive hormones were analyzed in relation to nitrate concentration in maternal drinking water, using a negative binomial regression model. The nitrate concentration in drinking water was obtained from monitoring data from Danish waterworks that were linked with the mothers' residential address during pregnancy. The median nitrate concentration in maternal drinking water was 2 mg/L. At these low exposure levels, which are far below the World Health Organization's (WHO) guideline value of 50 mg/L, we did not find indications of harmful effects of nitrate on the investigated measures of male fecundity.

Study question Is exposure to maternal perceived stress during pregnancy associated with reproductive function in adult male offspring? Summary answer While maternal perceived stress was prevalent in the first trimesters of pregnancy, our preliminary findings indicate little association with reproductive function in young men. What is known already Though studies in animals point to a connection between prenatal exposure to maternal stress and reproductive function in offspring, the underlying biological mechanisms generating a deficit remain largely unclear. In humans, the few available studies focus on exposure to bereavement or other relatively strong objective stressful life events. Our individual perception of stress is, however, more likely the sum of a complex process involving both the actual input, previous experiences, coping strategies and support from our surroundings. Study design, size, duration Young men and their mothers were identified through records from the Danish National Birth Cohort (DNBC). Information on exposure, i.e. maternal perceived life and emotional stress, was available from telephone interviews conducted at approximately 30 weeks of gestation (1996 to 2001). Recruitment of the young men lasted from 2017 to 2019 with 1058 participants enrolled in the final FEPOS cohort. Participants/materials, setting, methods Each of the 1058 men in the FEPOS cohort completed an online questionnaire and clinical examinations and provided a blood and semen sample. Information on potential pre- and postnatal confounders was retrieved from the DNBC, the Danish National Patient Register and the Danish Medical Birth Register. We applied negative binomial regression models to examine associations between maternal perceived life and emotional stress scores and semen quality, testicular size and reproductive hormones among the young men. Main results and the role of chance Among the 1052 young men included in preliminary analyses, the majority was exposed to maternal perceived life and/or emotional stress (76% and 83%, respectively) during the first trimesters. Life stress was predominantly related to the actual pregnancy (48%), maternal disease (19%) or occupational conditions (33%). Emotional stress included especially being touchy (58%), sad (38%) or tense (36%), covering aspects of both stress, depression and anxiety. Overall, results indicate little association between maternal stress scores and measures of semen quality and testicular size. Our study involves a large cohort with prospectively collected exposure data and direct measures of several male reproductive outcomes. We applied inverse probability weighting to account for selection into the FEPOS cohort and included a range of a priori selected maternal confounders in our models. Limitations, reasons for caution The male fetus may be particularly sensitive to exposure during the differentiation of reproductive tissues (8–14 weeks of gestation). Our self-reported measures of exposure cover the first 30 weeks of gestation. Absence of association may, thus, be due to a lack of specific information on timing of symptoms. Wider implications of the findings: While our preliminary findings may appear reassuring, further efforts to improve our understanding of maternal stress in relation to fetal health and potential consequences later in life are needed. Trial registration number Not applicable

The potential adverse effects of prenatal exposure to endocrine disrupting chemicals (EDCs) on child behavior have been addressed in several recent studies and a review of 14 studies published the last 2 years (March 2017- March 2019) is provided. The published studies are focusing on several classes of EDCs including bisphenol A, phthalates, organochlorines, perfluoralkyl substances (PFAS) and polybrominated diphenyl ethers (PBDE). Several methods have been used to identify abnormal behavior, including questionnaires and registered diagnoses. Overall, the results indicate that abnormal behavior may be associated with several of the EDC exposures although not entirely consistent. The most convincing associations observed relate to phthalate exposures (four studies all showing adverse associations) and PFAS exposures where both of the two studies included also indicated an adverse association.

Introduction Overweight and obesity in pregnancy is increasing worldwide and may harm the developing fetus, including its future reproductive health. We therefore studied the association between in utero exposure to maternal overweight and obesity and infertility in adulthood. No studies have previously assessed this association. Material and methods We performed a cohort study with 9232 adult sons and daughters whose mothers were enrolled in the Danish Healthy Habits for Two cohort during pregnancy in 1984-87. Participants were sons and daughters followed in the Danish In-Vitro-Fertilization-Register and Danish National Patient Register until February 2018 for diagnoses of infertility. Results In total, 1203 (13%) sons and daughters were born to mothers with a body mass index (BMI) >25 kg/m2 ; 871 (9.4%) of the participants were identified as being infertile during follow-up. Sons of overweight mothers had slightly increased odds of infertility compared with sons of mothers with normal body weight (BMI 18.5-24.9 kg/m2 , adjusted odds ratio 1.4, 95% confidence interval [CI] 1.0-1.9). Cubic spline analyses with continuous BMI levels showed increasing odds with higher levels of BMI; however, for BMI >29 kg/m2 the confidence intervals were too wide to draw conclusions. No association between maternal overweight and infertility was found among daughters (adjusted odds ratio 0.9, 95% CI 0.7-1.2)). Conclusions Sons born to overweight mothers had higher odds of infertility compared with sons of normal weight mothers. No association between maternal overweight and infertility was observed in daughters. Prevention of overweight during pregnancy may be an important tool to preserve fecundity in future generations.

Bisphenol A (BPA) is considered an endocrine disruptor and has been associated with deleterious effects on spermatogenesis and male fertility. Bisphenol F (BPF) and S (BPS) are structurally similar to BPA, but knowledge of their effects on male fertility remains limited. In this cross–sectional study, we investigated the associations between exposure to BPA, BPF, and BPS and semen quality in 556 men 18–20 years of age from the Fetal Programming of Semen Quality (FEPOS) cohort. A urine sample was collected from each participant for determination of BPA, BPF, and BPS concentrations while a semen sample was collected to determine ejaculate volume, sperm concentration, total sperm count, sperm motility, and sperm morphology. Associations between urinary bisphenol levels (continuous and quartile–divided) and semen characteristics were estimated using a negative binomial regression model adjusting for urine creatinine concentration, alcohol intake, smoking status, body mass index (BMI), fever, sexual abstinence time, maternal pre–pregnancy BMI, and first trimester smoking, and highest parental education during first trimester. We found no associations between urinary bisphenol of semen quality in a sample of young men from the general Danish population.

Background: Fetal exposure risk factors are associated with increased ASD risk. New hypotheses regarding transgenerational risk for ASD have been proposed, but epidemiological evidence is still lac...

Personal care products (PCPs) may contain multiple chemicals capable of harming male reproductive function. The aim of this study was, therefore, to assess aggregated PCP exposure and potential associations with measures of semen quality in young men. Participants (n = 1058, age 18–21) were sampled among young men from the Danish National Birth Cohort (DNBC). Upon recruitment in 2017–2019, each man answered an online questionnaire and provided a semen sample. Exposure to 12 common types of PCPs was derived from the questionnaire, and the extent of use and co-use was analyzed. We applied a negative binomial regression model to estimate percentage differences in semen parameters between low, medium and high PCP exposure groups. All participants were exposed to at least one PCP more than once a week, resulting in a mean number (SD) of 5.3 (2.0) PCPs currently used. Most participants (92%) were also exposed to fragranced products on a weekly basis. Little association was observed between aggregated exposure to PCPs and sperm concentration, total sperm count, semen volume, sperm motility and morphology. Despite prevalent use of multiple PCPs, we found little indication of adverse effects of aggregated overall or fragranced PCP exposure on semen quality.

Background Routine clinical evidence is limited on clinical outcomes associated with anemia in patients with severe chronic kidney disease (CKD). Methods We linked population-based medical databases to identify individuals with severe CKD (eGFR 2) in Northern Denmark from 2000 to 2016, including prevalent patients as of 1 January 2009 or incident patients hereafter into the study. We classified patients as non-anemic (≥ 12/≥ 13 g/dl hemoglobin (Hgb) in women/men), anemia grade 1 (10–12/13 g/dl Hgb in women/men), 2 (8–10 g/dl Hgb), and 3+ ( Results We identified 16,972 CKD patients contributing with a total of 28,510 anemia patient profiles, of which 3594 had dialysis dependent (DD) and 24,916 had non-dialysis dependent (NDD) severe CKD. Overall, 14% had no anemia, 35% grade 1 anemia, 44% grade 2 anemia and 17% grade 3+ anemia. Compared to patients with no anemia, adjusted hazard ratios (HRs) for NDD patients with grade 3+ anemia were elevated for incident dialysis (1.91, 95% CI 1.61–2.26), any acute hospitalization (1.74, 95% CI 1.57–1.93), all-cause death (1.82, 95% CI 1.70–1.94), and MACE (1.14, 95% CI 1.02–1.26). Similar HRs were observed among DD patients. Conclusions Among NDD or DD patients with severe CKD, presence and severity of anemia were associated with increased risks of incident dialysis for NDD patients and with acute hospitalizations, death and MACE for all patients.

Introduction: To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive. Objective: We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs. Methods: Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis. Results: A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education. Conclusion: We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444. This research was primarily supported by a grant from the European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement Developmental Neurotoxicity Assessment of Mixtures in Children (DENAMIC) no. 282957. M.-A.V. is the recipient of a Research Scholars J1 Award from the Fonds de recherche du Québec–Santé. Norwegian Human Milk Study (HUMIS) research was funded by a grant from the Norwegian Research Council, under the NEVRINOR program grant agreement no. 226402; by PROTECTion against Endocrine Disruptors: Detection, mixtures, health effects, risk assessment and communication, and by European Union (EU) Horizon 2020 Marie Skłodowska-Curie Actions Innovative Training Networks–European Training Network no. 722634. We thank Anteneh Desalegn for his work in the HUMIS biobank. The study was approved by the Regional Ethics Committee for Medical Research in Norway (ref. S-02122) and the Norwegian Data Inspectorate (refs. 2002/1398), and participation did not occur until after informed consent was obtained. The Infancia y Medio Ambiente (INMA) study was funded by grants from the EU: NEWGENERIS FP6-2003-Food-3-A-016320, FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1; and by grants from Spain: Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041, FIS-FEDER:PI 03/1615, PI04/1509, PI04/1112, PI04/1436, PI04/1931, PI/04/2018, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI/08/1151, PI09/02647, FIS-PI041436, FIS-PI081151, FISS-PI042018, FISS-PI09/02311, FISPI06/0867 FIS-PS09/00090, FIS-PI07/0252, PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663 and Miguel Servet-FEDER: CP11/00178, MS13/00054, and MSII16/00051), Generalitat de Catalunya-CIRIT 1999SGR 00241, La Fundació La Marató de TV3 (090430), Alicia Koplowitz Foundation 2017, Conselleria de Sanitat Generalitat Valenciana, Department of Health of the Basque Government (2005111093 and 2009111069), Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), Obra Social Cajastur, Universidad de Oviedo, Consejería de Salud de la Junta de Andalucía (grant no. 183/07), EU Commission (QLK4-1999-01422, QLK4-2002-00603, and CONTAMED FP7-ENV-212502), and Fundación Roger Torné. Global Health Institute Barcelona (ISGlobal) is a member of the CERCA Programme, Generalitat de Catalunya. A full roster of the INMA Project Investigators can be found at http://www.proyectoinma.org/presentacion-inma/listadoinvestigadores/en_listado-investigadores.html. The INUENDO study was funded by the European Commission’s Seventh and Fifth Framework Programmes (FP7-ENV-2008-1-226217 and QLK4-CT-2001-00202). The polychorinated biphenyl (PCB) cohort was funded by the U.S. National Institutes of Health (grants R01 CA096525 and R03 TW007152), the EU Seventh Framework Programme FP7/2007-2023 (grant agreement OBELIX, no. 227391), Slovak Research and Development Agency (grants APVT-21-016804, APVV-0571-12, APVV-0444-11), and by the ITMS project (no. 26240120033) based on the supporting operational research and development program from the European Regional Development Fund. This research was primarily supported by a grant from the European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement Developmental Neurotoxicity Assessment of Mixtures in Children (DENAMIC) no. 282957. M.-A.V. is the recipient of a Research Scholars J1 Award from the Fonds de recherche du Québec–Santé. Norwegian Human Milk Study (HUMIS) research was funded by a grant from the Norwegian Research Council, under the NEVRINOR program grant agreement no. 226402; by PROTECTion against Endocrine Disruptors: Detection, mixtures, health effects, risk assessment and communication, and by European Union (EU) Horizon 2020 Marie Skłodowska-Curie Actions Innovative Training Networks–European Training Network no. 722634. We thank Anteneh Desalegn for his work in the HUMIS biobank. The study was approved by the Regional Ethics Committee for Medical Research in Norway (ref. S-02122) and the Norwegian Data Inspectorate (refs. 2002/1398), and participation did not occur until after informed consent was obtained. The Infancia y Medio Ambiente (INMA) study was funded by grants from the EU: NEWGENERIS FP6-2003-Food-3-A-016320, FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1; and by grants from Spain: Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041, FIS-FEDER:PI 03/1615, PI04/1509, PI04/1112, PI04/1436, PI04/1931, PI/04/2018, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI/08/1151, PI09/02647, FIS-PI041436, FIS-PI081151, FISS-PI042018, FISS-PI09/02311, FISPI06/0867 FIS-PS09/00090, FIS-PI07/0252, PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663 and Miguel Servet-FEDER: CP11/00178, MS13/00054, and MSII16/00051), Generalitat de Catalunya-CIRIT 1999SGR 00241, La Fundació La Marató de TV3 (090430), Alicia Koplowitz Foundation 2017, Conselleria de Sanitat Generalitat Valenciana, Department of Health of the Basque Government (2005111093 and 2009111069), Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), Obra Social Cajastur, Universidad de Oviedo, Consejería de Salud de la Junta de Andalucía (grant no. 183/07), EU Commission (QLK4-1999-01422, QLK4-2002-00603, and CONTAMED FP7-ENV-212502), and Fundación Roger Torné. Global Health Institute Barcelona (ISGlobal) is a member of the CERCA Programme, Generalitat de Catalunya. A full roster of the INMA Project Investigators can be found at http://www.proyectoinma.org/presentacion-inma/listadoinvestigadores/en_listado-investigadores.html. The INUENDO study was funded by the European Commission’s Seventh and Fifth Framework Programmes (FP7-ENV-2008-1-226217 and QLK4-CT-2001-00202). The polychorinated biphenyl (PCB) cohort was funded by the U.S. National Institutes of Health (grants R01 CA096525 and R03 TW007152), the EU Seventh Framework Programme FP7/2007-2023 (grant agreement OBELIX, no. 227391), Slovak Research and Development Agency (grants APVT-21-016804, APVV-0571-12, APVV-0444-11), and by the ITMS project (no. 26240120033) based on the supporting operational research and development program from the European Regional Development Fund.

STUDY QUESTION Is birth weight for gestational age associated with infertility in adulthood among men and women? SUMMARY ANSWER Being born small for gestational age (SGA) was associated with infertility in adulthood among men. WHAT IS KNOWN ALREADY Fetal growth restriction may affect fertility, but results from previous studies have been inconsistent. STUDY DESIGN, SIZE, DURATION In this population-based cohort study, we used data from a Danish birth cohort, including 5594 men and 5342 women born between 1984 and 1987. Information on infertility was obtained from Danish health registers during the period from the participants’ 18th birthday and up until 31 December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were men and women born in two Danish municipalities, Aalborg and Odense. Information on birth weight and gestational age was obtained from birth records, and information on infertility diagnoses and fertility treatment was retrieved from the Danish National Patient Registry (NPR) and the Danish In Vitro Fertilisation (IVF) registry. Information on potential maternal confounders was obtained from questionnaires during pregnancy and was included in adjusted analyses. Logistic regression analysis was used to estimate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for infertility according to birth weight for gestational age. MAIN RESULTS AND THE ROLE OF CHANCE Men born SGA had a 55% higher risk of being diagnosed with or treated for infertility compared to men born appropriate for gestational age (AGA) (adjusted OR = 1.55, 95% CI: 1.09–2.21). The association attenuated after exclusion of men born with hypospadias or cryptorchidism (OR = 1.37, 95% CI: 0.93–2.01). No association was found between women’s birth weight for gestational age and risk of infertility (adjusted OR = 1.00, 95% CI: 0.73–1.37). LIMITATIONS, REASONS FOR CAUTION Estimation of gestational age is associated with some uncertainty and might have caused non-differential misclassification. The study design implicitly assumed similar distribution of reproductive and health-seeking behaviour across the groups that were compared. WIDER IMPLICATIONS OF THE FINDINGS Men born SGA had a higher risk of infertility. Genital malformations may account for part of the observed association, but this must be explored further. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by Health, Aarhus University. No competing interests are declared. TRIAL REGISTRATION NUMBER N/A

Background Perfluoroalkyl substances (PFAS) are suggested to interfere with thyroid hormone during pregnancy and influence fetal neurodevelopment. Epidemiological evidence regarding behavioral difficulties in childhood associated with prenatal PFAS exposure has been inconclusive. Objective We evaluated the association between prenatal PFAS exposure and behavioral difficulties at 7 and 11 years, and investigated the potential mediating role of maternal thyroid hormones. Methods Using pooled samples in the Danish National Birth Cohort established between 1996 and 2002, we estimated the associations between concentrations of six types of PFAS in maternal plasma (median, 8 gestational weeks) and child behavioral assessments from the Strength and Difficulties Questionnaire (SDQ), reported by parents at 7 years (n = 2421), and by parents (n = 2070) and children at 11 years (n = 2071). Behavioral difficulties were defined as having a composite SDQ score above the 90th percentile for total difficulties and externalizing or internalizing behaviors. We used logistic regression to estimate the adjusted Odds Ratio (OR) by doubling increase of prenatal PFAS (ng/ml). The possible mediating effect of maternal thyroid function classified based on thyroid stimulating hormone (TSH) and free thyroxine (fT4) levels were evaluated. Results Prenatal perfluorononanoic acid (PFNA) was consistently associated with total and externalizing behavioral difficulties in all three SDQ measures reported by parents (OR = 1.40, 95% CI: 1.14–1.73 for age 7; OR = 1.27, 95% CI: 1.05–1.53 for age 11) or children (OR = 1.32, 95% CI: 1.11–1.58) while no consistent associations were observed for other types of PFAS. A small magnitude of natural indirect effects via maternal thyroid dysfunction (ORs ranged from 1.01 to 1.03) of several PFAS were observed for parent-reported total and externalizing behaviors at 7 years only. Discussion Prenatal PFNA exposure was associated with externalizing behavioral difficulties in childhood in repeated SDQ measures at 7 and 11 years. The slight mediating effects of maternal thyroid hormones in early gestation warrant further evaluation.

BACKGROUND: Styrene is an important industrial chemical that the general population is exposed to at low levels. Previous research has suggested increased occurrence of leukemia and lymphoma among reinforced plastics workers exposed at high levels of styrene.METHODS: We followed 73,036 workers of 456 small- and medium-sized Danish reinforced plastics companies from 1968 to 2011 and investigated the exposure-response relation between cumulative styrene exposure and incidence of lymphohematopoietic malignancies. We modeled styrene exposure from employment history, survey data, and historical styrene exposure measurements. We retrieved information on lymphohematopoietic malignancies from national cancer and patient registers.RESULTS: We identified 665 cases overall of 21 different lymphohematopoietic malignancies or combinations thereof, each with at least 20 cases, during 1,581,976 person-years of follow-up. Initial analyses suggested higher age, sex, and calendar year-adjusted incidence rate ratios (RRs) for acute myeloid leukemia, Hodgkin lymphoma, and T-cell lymphoma with higher estimates of cumulative styrene exposure. Accounting for time since exposure showed a trend by cumulative styrene exposure (P = 0.01) and a doubled risk (RR = 2.4; 95% CI, 1.2, 4.6) of acute myeloid leukemia following estimated high compared with estimated low cumulative exposure during the prior 15-29 years. We observed no increased risk following exposure during more recent years and less consistent risk patterns for Hodgkin lymphoma and T-cell lymphoma.CONCLUSIONS: This study, to our knowledge the largest epidemiologic study to date of occupational styrene exposure, suggests increased risk of acute myeloid leukemia following high styrene exposure with a latency period of about 15 years.

We examined associations between prenatal exposure to perfluorohexane sulfonic acid (PFHxS), perfluoroheptanoic acid (PFHpA), perfluorononanoic acid (PFNA), and perfluorodecanic acid (PFDA) - and child behaviour (SDQ-total) and hyperactivity (sub-scale) at 5-9years of age in birth cohorts from Greenland and Ukraine. Pregnancy serum samples (N=1023) were analysed for perfluoroalkyl substances (PFASs) and categorized into tertiles and also used as continuous exposure variables. Problem behaviour and hyperactivity were assessed, using the Strength and Difficulties Questionnaire (SDQ) and categorized as normal/borderline and abnormal. Associations were analysed using multiple logistic and linear regression. High compared to low prenatal PFHxS exposure was associated with 1.16 (95% confidence interval (CI): 0.08; 2.25) point higher SDQ-total (more problem behaviour) in Greenland and 0.80 (CI: 0.06; 1.54) point higher SDQ-total in the combined analyses, whereas no association was present in Ukraine alone. One natural log-unit increase in prenatal PFNA exposure was associated with 0.90 (CI: 0.10; 1.71) points higher SDQ-total in Greenland and 0.72 (CI: 0.13; 1.31) points higher in the combined analysis and no association in Ukraine. Prenatal PFAS exposure was unrelated to problem behaviour (abnormal SDQ-total). In the combined analysis, odds ratio (OR) (CI) for hyperactivity was 1.8 (1.0; 3.2) for one natural log-unit increase in prenatal PFNA and 1.7 (1.0; 3.1) for one natural log-unit increase in prenatal PFDA exposure. Findings are compatible with weak effects on child behaviour of prenatal exposure to some PFASs although spurious results are not entirely unlikely. The associations were strongest in Greenland.

PURPOSE OF REVIEW: The purpose of this review is to systematically review the literature linking di-2-ethylhexyl phthalate (DEHP) exposure with effects on reproductive health in adult males.RECENT FINDINGS: Thirty-three papers were included of which 28 were cross-sectional. Twenty-one papers investigated semen samples, 18 investigated reproductive hormones, and three studies investigated time to pregnancy. Studies revealed some but inconsistent indications that higher urinary DEHP metabolite levels are associated with an increase in the proportion of spermatozoa with damaged DNA and to a decrease in sperm concentration and motility. A negative association between DEHP metabolites and testosterone levels was more consistent. DEHP metabolites do not seem to be associated with a delay in time to pregnancy, but data are sparse. The studies on DEHP exposure and reproductive biomarkers in men converge to support the hypothesis that DEHP exposure is related to impaired male reproductive function. Longitudinal studies are needed to establish if the observed associations are causal.

Importance: Population-based data on educational and employment outcomes in adulthood among individuals diagnosed with autism spectrum disorder (ASD) in childhood are currently limited.Objective: To evaluate educational attainment and employment among individuals with and without a diagnosis of ASD before age 12 years in Denmark.Design, Setting, and Participants: This nationwide cross-sectional prevalence study was conducted using data from Danish registers. Individuals with a diagnosis of ASD recorded before age 12 years were identified among all individuals born in Denmark between January 1, 1989, and December 31, 1991, who were alive at age 25 years. Individuals with ASD were then matched on a 10:1 ratio by age, sex, and region of residence with a comparison population of individuals without a diagnosis of ASD at age 12 years. Data were analyzed from March 2019 to December 2020.Exposures: Autism spectrum disorder diagnosis and diagnostic subtype recorded before age 12 years.Main Outcomes and Measures: Adjusted prevalence ratios (aPRs) with 95% CIs for the completion of compulsory primary and lower secondary school (grade 9), upper secondary school (grades 10-12 or vocational), and tertiary school (university) and for employment by age 25 years were estimated using log-binomial regression analysis.Results: A total of 810 individuals with a diagnosis of ASD before age 12 years were matched with a comparison population of 8100 individuals without ASD. The prevalence of ninth-grade completion was similar among those with and without ASD (785 individuals [96.9%] and 7982 individuals [98.5%], respectively; aPR, 0.98; 95% CI, 0.97-1.00). Compared with those without ASD, persons with ASD had a lower prevalence of completing upper secondary school (6338 individuals [78.2%] vs 286 individuals [35.3%], respectively; aPR, 0.46; 95% CI, 0.42-0.50) and tertiary school (2185 individuals [27.0%] vs 70 individuals [8.6%]; aPR, 0.33; 95% CI, 0.26-0.41) and obtaining employment (4284 individuals [77.7%] vs 177 individuals [27.2%]; aPR, 0.35; 95% CI, 0.31-0.40) at age 25 years. A ninth-grade final examination score was available for 394 individuals (48.6%) with ASD and 7417 individuals (91.6%) without ASD. In an analysis stratified by ASD subtype, individuals diagnosed with childhood autism had lower educational attainment and employment than those diagnosed with Asperger syndrome or pervasive developmental disorder not otherwise specified. A total of 461 individuals (56.9%) with ASD were receiving public assistance or a pension (ie, disability benefits) at age 25 years compared with 1094 individuals (13.5%) without ASD in the comparison population.Conclusions and Relevance: In this population-based cross-sectional study, a diagnosis of ASD in childhood was not associated with the completion of compulsory primary and lower secondary education (ninth grade). An ASD diagnosis before age 12 years was associated with a lower prevalence of attaining education beyond ninth grade and obtaining employment by age 25 years, indicating a substantially higher risk of reliance on public assistance in young adulthood.

BACKGROUND: Occupational exposure to styrene is widespread and has been suggested to be carcinogenic. The aim of this study was to investigate whether occupational exposure to styrene increases the risk of cancer, in particular lymphohematopoietic cancers.METHODS: We established a study population of 72,292 workers employed in 443 small and medium-sized companies producing reinforced plastics 1964-2007 by utilizing several national registries, expert assessment, and worker survey data. We identified incident cancer cases from 1968 to 2012 in the national Danish cancer registry and computed standardized incidence rate ratios (SIRs) with 95% confidence intervals (95% CI) based on national rates.RESULTS: Increasing SIRs of Hodgkin lymphoma, myeloid leukemia, and cancer of nasal cavities and sinuses were inconsistently associated with increasing duration of employment, early year of first employment, or styrene exposure probability. No such trends were observed for cancer of the esophagus, pancreas, lung, kidney, or urinary bladder, which have previously been associated with styrene exposure. Lung cancer showed an overall increased risk that decreased by duration of employment CONCLUSION:: Occupational styrene exposure may be associated with Hodgkin lymphoma, myeloid leukemia, and cancer of nasal cavities and sinuses. Further studies are needed to evaluate if the observed associations are likely to be causal.