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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.

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..

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.

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.

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.

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.

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

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.

To study whether the timing of puberty in adolescents who reported gender incongruence (incongruence between birth-assigned sex and self-identified gender) was different from those adolescents who reported gender congruence Objective: To study whether the timing of puberty in adolescents who reported gender incongruence (incongruence between birth -assigned sex and self-identified gender) was different from those adolescents who reported gender congruence.Design: Population-based cohort study using data from the Danish National Birth Cohort.Setting: Not applicable.Patient(s): Birth-assigned boys and girls born between 2000 and 2003, who self-reported gender incongruence at 11 years (N = 10,046) and their pubertal developmental stages from age 11 years to every 6 months throughout puberty were included.Intervention(s): Not applicable.Main Outcome Measure: Mean age differences in months at reaching Tanner stages 2-5 for breast or genital development and pubic hair, voice break, first ejaculation, menarche, axillary hair, acne, and the average difference at attaining all pubertal milestones (primary outcome).Result(s): In total, 549 (5.5% ) adolescents reported part or full gender incongruence at 11 years. Tendencies toward earlier timing of puberty were observed in adolescents who reported part gender incongruence (average difference, birth-assigned boys: -3.2 months [95% confidence interval {CI}: -6.7; 0.3]; birth-assigned girls: -2.0 months [95% CI: -3.9; -0.1]). Tendencies toward earlier timing of puberty were observed in adolescents who reported full gender incongruence (average difference, birth-assigned boys: -2.4 months [95% CI: -5.0; 0.4]; birth-assigned girls: -1.9 months [95% CI: -5.1; 1.2]).Conclusions: The results from this study indicated that birth-assigned boys and girls who reported either part or full gender incongruence tended to reach puberty slightly earlier than those adolescents who reported gender congruence at 11 years of age. Knowledge on the timing of puberty among adolescents who experience gender incongruence is essential to inform mutual decision-making in clinical settings. (Fertil Sterile 2022;118:938-45. (c) 2022 by American Society for Reproductive Medicine.)

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: 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.

BACKGROUND: There is considerable public and scientific interest in the declining age of pubertal timing. Prenatal and postnatal stress has been proposed to relate with earlier pubertal timing, but it remains unknown whether intrapartum stress may affect pubertal timing as well.OBJECTIVE: This study aims to examine the potential effect of caesarean delivery on pubertal timing in boys and girls.METHODS: This study was based upon the nationwide Puberty Cohort nested within the Danish National Birth Cohort (DNBC) from 2000 to 2003. A total of 15,731 mother-child pairs with complete information on delivery mode and puberty were included in the main analysis. The delivery mode was categorised into non-instrumental vaginal delivery (reference), instrumental vaginal delivery, elective caesarean delivery before labour, emergency caesarean delivery during labour and un-specified caesarean delivery. Children's pubertal development were self-reported in web-based questionnaires from 11 years of age and every 6 months throughout puberty (2012-2019), including Tanner stages 2-5, menarche, voice break, first ejaculation, axillary hair growth and the onset of acne. Regression models for censored, normally distributed time-to-event data were used to estimate mean monthly differences in age at attaining the different pubertal milestones and the average of all these estimates for each sex (a combined indicator of pubertal timing).RESULTS: A total of 2810 participants were born by caesarean delivery (17.9%). Neither elective nor emergency caesarean delivery was associated with earlier age at achieving the pubertal milestones in boys or in girls. For the combined indicator, the mean age differences for elective caesarean delivery and emergency caesarean delivery were 0.1 (95% CI -1.1, 1.4) months and -0.7 (95% CI -2.0, 0.5) months in boys and 0.7 (95% CI -0.7, 2.0) and 0.2 (95% CI -1.3, 1.7) in girls.CONCLUSIONS: This study does not suggest a clinically important effect of caesarean delivery on children's pubertal timing.