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Background The caesarean section (CS) rate has increased worldwide and there is an increasing public and scientific interest in the potential long-term health consequences for the offspring. CS is related to persistent aberrant microbiota colonization in the offspring, which may negatively interfere with sex hormone homeostasis and thus potentially affect the reproductive health. It remains unknown whether adult sons’ semen quality is affected by CS. We hypothesize that CS is associated with lower semen quality. Methods This study was based on the Fetal Programming of Semen Quality cohort (FEPOS, enrolled from 2017 to 2019) nested within the Danish National Birth Cohort (DNBC, enrolled from 1996 to 2002). A total of 5697 adult sons of mothers from the DNBC were invited to the FEPOS cohort, and 1044 young men participated in this study. Information on mode of delivery was extracted from the Danish Medical Birth Registry, and included vaginal delivery, elective CS before labor, emergency CS during labor and unspecified CS. The young men provided a semen sample for analysis of semen volume, sperm concentration, motility and morphology. Negative binomial regression models were applied to examine the association between CS and semen characteristics with estimation of relative differences in percentages with 95% confidence intervals (CIs). Results Among included sons, 132 (13%) were born by CS. We found a slightly lower non-progressive sperm motility (reflecting higher progressive sperm motility) among sons born by CS compared to sons born by vaginal delivery [relative difference (95% CI): − 7.5% (− 14.1% to − 0.4%)]. No differences were observed for other sperm characteristics. When CS was further classified into elective CS, emergency CS and unspecified CS in a sensitivity analysis, no significant differences in non-progressive motility were observed among sons born by any of the three types of CS compared to sons born vaginally. C, BACKGROUND: The caesarean section (CS) rate has increased worldwide and there is an increasing public and scientific interest in the potential long-term health consequences for the offspring. CS is related to persistent aberrant microbiota colonization in the offspring, which may negatively interfere with sex hormone homeostasis and thus potentially affect the reproductive health. It remains unknown whether adult sons' semen quality is affected by CS. We hypothesize that CS is associated with lower semen quality.METHODS: This study was based on the Fetal Programming of Semen Quality cohort (FEPOS, enrolled from 2017 to 2019) nested within the Danish National Birth Cohort (DNBC, enrolled from 1996 to 2002). A total of 5697 adult sons of mothers from the DNBC were invited to the FEPOS cohort, and 1044 young men participated in this study. Information on mode of delivery was extracted from the Danish Medical Birth Registry, and included vaginal delivery, elective CS before labor, emergency CS during labor and unspecified CS. The young men provided a semen sample for analysis of semen volume, sperm concentration, motility and morphology. Negative binomial regression models were applied to examine the association between CS and semen characteristics with estimation of relative differences in percentages with 95% confidence intervals (CIs).RESULTS: Among included sons, 132 (13%) were born by CS. We found a slightly lower non-progressive sperm motility (reflecting higher progressive sperm motility) among sons born by CS compared to sons born by vaginal delivery [relative difference (95% CI): - 7.5% (- 14.1% to - 0.4%)]. No differences were observed for other sperm characteristics. When CS was further classified into elective CS, emergency CS and unspecified CS in a sensitivity analysis, no significant differences in non-progressive motility were observed among sons born by any of the three types of CS compared to sons born vaginally.CONCLUSIONS: Thi

STUDY QUESTION Is maternal pre-pregnancy BMI associated with semen quality, testes volume, and reproductive hormone levels in sons? SUMMARY ANSWER Maternal pre-pregnancy BMI was associated with an altered reproductive hormone profile in young adult sons, characterized by higher levels of oestradiol, LH, and free androgen index (FAI) and lower levels of sex hormone-binding globulin (SHBG) in sons born of mothers with pre-pregnancy overweight and obesity. WHAT IS KNOWN ALREADY Evidence suggests that maternal pre-pregnancy BMI may influence reproductive health later in life. Only one pilot study has investigated the association between maternal pre-pregnancy BMI and reproductive health outcomes in sons, suggesting that a high BMI was associated with impaired reproductive function in the adult sons. STUDY DESIGN, SIZE, DURATION A population-based follow-up study of 1058 young men from the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998–2019, was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 1058 adult sons (median age 19 years, 2 months), born 1998–2000 by mothers included in the DNBC, participated in FEPOS. At a clinical examination, they provided a semen and blood sample, measured their testes volume, and had height and weight measured. Maternal pre-pregnancy BMI was obtained by self-report in early pregnancy. Semen characteristics, testes volume, and reproductive hormone levels were analysed according to maternal pre-pregnancy BMI categories and as restricted cubic splines using negative binomial and ordinary least square regression models. Mediation analyses examined potential mediation by the sons’ birthweight, pubertal timing, fat mass, and BMI. Additional analyses investigated the role of paternal BMI in the potential associations between maternal BMI and reproductive health outcomes. MAIN RESULTS AND THE ROLE OF CHANCE, STUDY QUESTION: Is maternal pre-pregnancy BMI associated with semen quality, testes volume, and reproductive hormone levels in sons?SUMMARY ANSWER: Maternal pre-pregnancy BMI was associated with an altered reproductive hormone profile in young adult sons, characterized by higher levels of oestradiol, LH, and free androgen index (FAI) and lower levels of sex hormone-binding globulin (SHBG) in sons born of mothers with pre-pregnancy overweight and obesity.WHAT IS KNOWN ALREADY: Evidence suggests that maternal pre-pregnancy BMI may influence reproductive health later in life. Only one pilot study has investigated the association between maternal pre-pregnancy BMI and reproductive health outcomes in sons, suggesting that a high BMI was associated with impaired reproductive function in the adult sons.STUDY DESIGN, SIZE, DURATION: A population-based follow-up study of 1058 young men from the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998-2019, was carried out.PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1058 adult sons (median age 19 years, 2 months), born 1998-2000 by mothers included in the DNBC, participated in FEPOS. At a clinical examination, they provided a semen and blood sample, measured their testes volume, and had height and weight measured. Maternal pre-pregnancy BMI was obtained by self-report in early pregnancy. Semen characteristics, testes volume, and reproductive hormone levels were analysed according to maternal pre-pregnancy BMI categories and as restricted cubic splines using negative binomial and ordinary least square regression models. Mediation analyses examined potential mediation by the sons' birthweight, pubertal timing, fat mass, and BMI. Additional analyses investigated the role of paternal BMI in the potential associations between maternal BMI and reproductive health outcomes.MAIN RESULTS AND THE ROLE OF CHANCE: We found no consistent ass

Objective To investigate whether the timing of puberty is associated with semen characteristics, testicular volume, and reproductive hormone levels. Design Cohort study. Setting Not applicable. Patients The Danish National Birth Cohort and its subcohort, the Fetal Programming of Semen Quality cohort of 1,058 young men. Intervention(s) Self-reported information on the 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(s) We estimated the relative differences with 95% confidence intervals 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, sex hormone-binding globulin [SHBG], testosterone, estradiol, and free androgen index [FAI]) obtained at a median age of 19.2 years according to timing of pubertal development. Result(s) Compared with 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 a lower proportion of nonprogressive 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 levels (24% [-1%, 55%]), higher SHBG levels (7% [0, 15%]), lower estradiol levels (-14% [-23%, -5%]), and lower FAI (-8% [-14%, -1%]), whereas voice break “younger than peers” tended to have higher luteinizing hormone levels (4% [-2%, 11%]), higher testosterone levels (5% [0%, Objective: To investigate whether the timing of puberty is associated with semen characteristics, testicular volume, and reproductive hormone levels. Design: Cohort study. Setting: Not applicable. Patients: The Danish National Birth Cohort and its subcohort, the Fetal Programming of Semen Quality cohort of 1,058 young men. Intervention(s): Self-reported information on the 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(s): We estimated the relative differences with 95% confidence intervals 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, sex hormone-binding globulin [SHBG], testosterone, estradiol, and free androgen index [FAI]) obtained at a median age of 19.2 years according to timing of pubertal development. Result(s): Compared with 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 a lower proportion of nonprogressive 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 levels (24% [-1%, 55%]), higher SHBG levels (7% [0, 15%]), lower estradiol levels (-14% [-23%, -5%]), and lower FAI (-8% [-14%, -1%]), whereas voice break “younger than peers” tended to have higher luteinizing hormone levels (4% [-2%, 11%]), higher testosterone levels (5% [0%, 11%]), higher estradiol levels (17% [6%, 29%]), and higher FAI (4% [-2

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..

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 < 25 nmol/L had 11% (95% CI − 19 to − 2) lower testes volume and a 1.4 (95% CI 1.0 to 1.9) times higher risk of having low testes volume (< 15 mL), in addition to 20% (95% CI − 40 to 9) lower total sperm count and a 1.6 (95% CI 0.9 to 2.9) times higher risk of having a low total sperm count (< 39 million) compared with sons of mothers with vitamin D levels > 75 nmol/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 75 nmol/L during pregnancy may be beneficial for testes function in adult sons., 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 < 25 nmol/L had 11% (95% CI − 19 to − 2) lower testes volume and a 1.4 (95% CI 1.0 to 1.9) times higher risk of having low testes volume (< 15 mL), in addition to 20% (95% CI − 40 to 9) lower total sperm count and a 1.6 (95% CI 0.9 to 2.9) times higher risk of having a low total sperm count (< 39 million) compared with sons of mothers with vitamin D levels > 75 nmol/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 75 nmol/L during pregnancy may be beneficial for testes function in adult sons.

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, 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 lo

Is there risk of selection bias in etiological studies investigating prenatal risk factors of poor male fecundity in a cohort of young men?, 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

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% lo

In his letter to the editor regarding our paper,1 Abraham raises an important discussion about co-exposure to per- and polyfluoroalkyl substances (PFAS) and other persistent organic pollutants, in particular dioxins.2 In our paper we acknowledged that “there might be factors, such as other chemicals or lifestyle, that might be associated with PFAS exposure which also have an impact on reproductive function.”1 Dioxins potentially constitute such co-exposure, and, if associated with semen quality, the observed inverse associations between PFAS and semen quality could be at least partly due to dioxins. As we did not assess dioxin levels in our sample, we relied on other studies to elucidate the extend of covariation. Abraham states that he found dioxins significantly correlated with PFAS in blood sampled from 74 mothers 11 months after giving birth in the late 1990s.2 We have not identified other studies reporting correlations between PFAS and dioxins, but correlations between perfluorooctane sulfonic acid (PFOS) and 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB-153)—a chemical with kinetic properties similar to dioxins, for example, long half-life and accumulation in adipose tissue—were 0.62 in blood of 1,250 Greenlandic, Polish, and Ukrainian pregnant females sampled in 2002–2004.3 Stratification by country generally revealed that correlations were strongest for the Greenlandic sample: 0.52 for PFOS and polychlorinated biphenyl (PCB)-153 vs. 0.20 for Poland and 0.23 for Ukraine.3 Because PFAS bind mainly to proteins, whereas PCBs are lipid-soluble, a high correlation is not expected. We would expect correlations of PFAS and dioxins in the Fetal Programming of Semen Quality cohort (which provided the data used in our study) similar to the PFOS–PCB-153 correlation observed in Ukraine and Poland. Based on these small-to-moderate correlations, we have little reason to believe that PFAS and dioxins would be highly correlated in our sample. Although we acknowledge the pot

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 f

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.

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-assi

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 anal-yses. 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 mater-nal PFAS and semen quality. The study needs to be replicated in oth

Background Paracetamol (acetaminophen) is a frequently used nonprescription analgesic with suggested endocrine-disrupting properties. Epidemiological evidence on the effect of paracetamol on male fecundity is sparse. Objectives To investigate if the use of paracetamol as an oral nonprescription mild analgesic was associated with semen quality in young men. Materials and methods This 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; <1/month; ≥1/month; ≥1/week). Results In 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. Discussion We 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. Conclusion Our findings do not suggest any strong detrimental effect of paracetamol use on semen quality within this samp

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 (b = 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. ((C) 2022 by American Society for Reproductive Medicine.)

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.

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 exposure 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 (<3 days/week). Conclusion: Consumption of sugar-sweetened or artificially sweetened beverages, at the levels present in this study had limited effect on the measured markers of semen quality in young men.