Search

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-SørensenDepartment of Public Health, Research Unit for Epidemiology, Bartholins Allé 2, Aarhus University, Aarhus C, 8000, Denmark, Tel +45 40868183Email 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

Katia Keglberg Hærvig,1,2 Jens Peter Bonde,1,2 Cecilia Høst Ramlau-Hansen,3 Gunnar Toft,4 Karin Sørig Hougaard,2,5 Ina Olmer Specht,6 Aleksander Giwercman,7 Anne-Marie Nybo Andersen,2 Jørn Olsen,3 Christian Lindh,8 Birgit Bjerre Høyer,1,* Sandra Søgaard Tøttenborg1,* 1Department of Occupational and Environmental Medicine, Bispebjerg & Frederiksberg Hospital, Copenhagen, Denmark; 2Department of Public Health, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; 3Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 5National Research Centre for the Working Environment, Copenhagen, Denmark; 6The Parker Institute, Research Unit for Dietary Studies, Bispebjerg & Frederiksberg Hospital, Copenhagen, Denmark; 7Molecular Reproductive Medicine, Department of Translational Medicine, Lund University, Lund, Sweden; 8Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden*These authors contributed equally to this workCorrespondence: Sandra Søgaard TøttenborgDepartment of Occupational and Environmental Medicine, Bispebjerg & Frederiksberg Hospital, Bispebjerg Bakke 23F, Entrance 20F, 1st Floor, Copenhagen 2400, NV, DenmarkTel +45 23 35 58 85Email sandra.soegaard.toettenborg@regionh.dkBackground: 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’.Keywords: male infertility, prenatal exposure, fetal exposure, maternal-fetal exchange, semen quality, semen analysis

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. [ABSTRACT FROM AUTHOR]