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Daniel Lindbo,1 Linn Håkonsen Arendt,1,2 Andreas Ernst,1,3 Lea Lykke Harrits Lunddorf,1 Nis Brix,1,4 Cecilia Høst Ramlau-Hansen1 1Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 2Department of Obstetrics and Gynecology, Horsens Region Hospital, Horsens, Denmark; 3Department of Urology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Clinical Genetics, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Daniel Lindbo, Department of Public Health, Research Unit for Epidemiology, Aarhus University, Bartholins Allé 2, Aarhus, 8000, Denmark, Tel +45 21950102, Email lindbo0704@hotmail.comPurpose: Cryptorchidism and hypospadias share several prenatal risk factors. However, in published studies, boys exposed to cigarette smoking during pregnancy have a higher risk of cryptorchidism and a lower risk of hypospadias. Using Danish register-based data, we revisited these findings with a cohort and sibling-matched design to investigate the potential effect of shared time-stable factors.Patients and Methods: For the cohort study, we included 823,670 live-born, singleton boys born from 1991 to 2016. Crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression models for each genital anomaly according to maternal cigarette smoking during pregnancy. For the sibling-matched design, we included 399,258 brothers and used a stratified Cox regression model creating family-adjusted results.Results: In the cohort study, we found a higher risk of cryptorchidism (aHR = 1.18, 95% CI: 1.12, 1.24) and a lower risk of hypospadias (aHR = 0.84, 95% CI: 0.76, 0.93) when comparing boys exposed to cigarette smoking with non-exposed, and for increasing numbers of cigarettes smoked. In comparison, the sibling-matched analyses suggested a slightly weaker association for cryptorchidism and an association of similar magnitude for hypospadias, both in the same direction as in the cohort study.Conclusion: Shared, familial confounding does not seem to explain earlier findings of higher risk of cryptorchidism and lower risk of hypospadias.Keywords: cryptorchidism, hypospadias, epidemiology, fetal development

Ninna Hinchely Ebdrup,1– 3 Ulla Breth Knudsen,1,3 Jörg Schullehner,2,4 Linn Håkonsen Arendt,2,5 Zeyan Liew,6,7 Julie Lyngsø,2,5 Bjørn Bay,1,8 Pernille Jul Clemmensen,2 Torben Sigsgaard,2,9,10 Birgitte Hansen,4 Cecilia Høst Ramlau-Hansen2 1Department of Obstetrics and Gynecology, Horsens Regional Hospital, Horsens, Denmark; 2Department of Public Health, Aarhus University, Aarhus, Denmark; 3Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 4Geological Survey of Denmark and Greenland, Aarhus, Denmark; 5Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark; 6Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA; 7Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, CT, USA; 8Maigaard Fertility Clinic, Aarhus, Denmark; 9Centre for Integrated Register-based Research at Aarhus University, Aarhus, Denmark; 10Danish Big Data Centre for Environment and Health (BERTHA), Aarhus University, Aarhus, DenmarkCorrespondence: Ninna Hinchely Ebdrup, Department of Obstetrics and Gynecology, Horsens Regional Hospital, Regionshospitalet Horsens, Sundvej 30, Horsens, 8700, Denmark, Tel +4528472111, Email ninebd@rm.dkPurpose: No studies have investigated if drinking water nitrate affects human fecundity. Experimental studies point at detrimental effects on fetal development and on female and male reproduction. This cohort study aimed to explore if female and male preconception and long-term exposure to nitrate in drinking water was associated with fecundability measured as time to pregnancy (TTP) or use of medically assisted reproduction (MAR) treatment.Methods: The study population consisted of pregnant women recruited in their first trimester in 1996– 2002 to the Danish National Birth Cohort. Preconception drinking-water nitrate exposure was estimated for the pregnant women (89,109 pregnancies), and long-term drinking water nitrate exposure was estimated from adolescence to conception for the pregnant women (77,474 pregnancies) and their male partners (62,000 pregnancies) by linkage to the national drinking water quality-monitoring database Jupiter. Difference in risk of TTP > 12 months or use of MAR treatment between five exposure categories and log-transformed continuous models of preconception and long-term nitrate in drinking water were estimated. Binominal regression models for risk ratios (RR) were adjusted for age, occupation, education, population density, and lifestyle factors.Results: Nitrate in drinking water (median preconception exposure: 1.9 mg/L; median long-term exposure: 3.3 mg/L) was not associated with TTP > 12 months or use of MAR treatment, neither in the categorical nor in the continuous models.Conclusion: We found no association between preconception or long-term exposure to drinking water nitrate and fecundability.Keywords: environmental pollutant, subfecundity, time to pregnancy, public health, groundwater

Camilla Lomholt Kjersgaard,1 Linn Håkonsen Arendt,1,2 Andreas Ernst,1,3 Morten Søndergaard Lindhard,4,5 Jørn Olsen,1,6 Tine Brink Henriksen,5 Katrine Strandberg-Larsen,7 Cecilia Høst Ramlau-Hansen1 1Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 2Department of Obstetrics and Gynecology, Horsens Regional Hospital, Horsens, Denmark; 3Department of Urology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Pediatrics, Randers Regional Hospital, Randers, Denmark; 5Perinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark; 6Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 7Department of Public Health, Section of Epidemiology, Copenhagen University, Copenhagen, DenmarkCorrespondence: Camilla Lomholt KjersgaardDepartment of Public Health, Research Unit for Epidemiology, Aarhus University, Bartholins Allé 2, Aarhus, 8000, DenmarkTel +45 40 19 44 38Email ck@ph.au.dkPurpose: Hypospadias is one of the most frequent male congenital malformations. It remains controversial whether maternal lifestyle during pregnancy may affects the risk of having a son with hypospadias, especially for smoking with many suggesting lower risk. We assessed the individual and joint associations between maternal cigarette smoking, pre-pregnancy body mass index (BMI), alcohol consumption, binge drinking, and caffeine consumption and occurrence of hypospadias in sons.Patients and Methods: This cohort study utilized the Danish National Birth Cohort and the Aarhus Birth Cohort, holding detailed information on lifestyle factors in early pregnancy between 1989 and 2012. The Danish health registers were used to identify boys with hypospadias, according to International Classification of Diseases. Potential confounders and covariates were identified by literature search and use of directed acyclic graphs. Missing data were handled by multiple imputation and Cox proportional hazards models were applied to analyse data.Results: In total, 85,923 live-born singleton boys were included in the study of whom 502 (0.6%) were diagnosed with hypospadias. Maternal smoking in early pregnancy was associated with lower occurrence of hypospadias. An increase of one cigarette smoked per day was associated with lower risk of having a son with hypospadias (adjusted hazard ratio (HR) 0.97 (95% confidence interval (CI) 0.94, 1.00)). However, sub-analyses suggested that the results may be prone to unadjusted confounding. We found no association between pre-pregnancy BMI, alcohol consumption, binge drinking, or caffeine consumption and hypospadias.Conclusion: Maternal smoking during pregnancy was associated with lower occurrence of hypospadias but we cannot exclude uncontrolled confounding. The other investigated maternal lifestyle factors were not associated with hypospadias in sons.Keywords: smoking, prenatal exposures, alcohol, caffeine, BMI, birth defects

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

Mette Rahbek Bruun,1 Andreas Ernst,1,2 Linn Håkonsen Arendt,1,3 Cecilia Høst Ramlau-Hansen,1 Nis Brix1,4 1Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 2Department of Urology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Obstetrics and Gynecology, Regional Hospital Horsens, Horsens, Denmark; 4Department of Clinical Genetics, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Mette Rahbek Bruun Email mettebruun_90@hotmail.comPurpose: The objective of this study was to explore whether maternal nausea in pregnancy, a potential surrogate marker of endogenous estrogen levels, was associated with age at attaining pubertal milestones in sons and daughters.Materials and Methods: The study included a total of 14,612 boys and girls born in 2000– 2003, from the Danish National Birth Cohort. Information on nausea was reported by mothers during pregnancy in telephone interviews scheduled around gestational week 12 and 30. Their children were invited every six months from 11 years of age until 18 years of full maturation to provide information on current pubertal status. Pubertal milestones included pubic hair, axillary hair and acne for both sexes, besides genital development, voice break and first ejaculation for boys, and breast development and menarche for girls. Mean monthly differences in age at attaining several pubertal milestones for boys and girls were estimated according to duration of nausea in the first trimester (0, 1– 6, 7– 11, 12 weeks). Further, we explored whether duration of nausea in the first two trimesters (0, 1– 8, 9– 15 or 16– 28 weeks) and severity (measured by co-existence of vomiting and weight loss) were associated with pubertal timing.Results: Neither maternal nausea in the first trimester nor duration or severity of nausea in the first two trimesters were associated with pubertal timing.Conclusion: Our study does not support the hypothesis that nausea in pregnancy – as a surrogate marker of endogenous estrogen levels – is associated with age at attaining pubertal milestones in children.Keywords: maternal exposure, prenatal exposure delayed effects, nausea, puberty, estrogen

Linn Håkonsen Arendt,1– 3 Lars Henning Pedersen,1,4 Lars Pedersen,5 Per Glud Ovesen,1,6 Tine Brink Henriksen,7 Morten Søndergaard Lindhard,8 Jørn Olsen,2,5 Henrik Toft Sørensen,5 Cecilia Høst Ramlau-Hansen2 1Department of Obstetrics and Gynecology, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 3Department of Obstetrics and Gynecology, Regional Hospital Horsens, Horsens, Denmark; 4Department of Biomedicine, Aarhus University, Aarhus, Denmark; 5Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 6Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; 7Department of Child and Adolescent Health, Aarhus University Hospital, Aarhus, Denmark; 8Department of Child and Adolescent Health, Regional Hospital Randers, Aarhus, DenmarkCorrespondence: Linn Håkonsen ArendtDepartment of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark; Department of Public Health, Research Unit for Epidemiology, Aarhus, DenmarkTel +45 27 21 09 81Email lha@clin.au.dkPurpose: To study the occurrence of major congenital abnormalities in children of women with type 1 and type 2 diabetes and investigate the association between glycated haemoglobin (HbA1c) and major congenital malformations according to type 1 diabetes and type 2 diabetes separately.Patients and methods: In this register-based study, all singletons born alive from January 1, 2000 to December 31, 2015 in the North Denmark and Central Denmark regions of Denmark and their mothers were included. We used data from Danish health registers and the LABKA database. Logistic regression models were used to compute crude and adjusted prevalence odds ratios (cORs and aORs) with 95% confidence intervals (CIs) for major congenital malformations overall and for subtypes, by type of maternal pre-existing diabetes and HbA1c levels.Results: Among 314,245 infants included, 2020 (0.64%) had mothers with type 1 diabetes and 498 (0.16%) had mothers with type 2 diabetes. We found an aOR of 2.9 (95% CI: 2.5, 3.5) and 1.9 (95% CI: 1.3; 2.8) for major malformations for type 1 and type 2 diabetes, respectively. The highest occurrence was seen for major congenital heart diseases, but we also observed higher occurrence of several other non-cardiac malformations. For both type 1 and type 2 diabetes, the prevalence of major congenital malformations increased with higher levels of maternal HbA1c with no safe threshold level. Mothers with type 1 diabetes had higher risks than those without diabetes irrespective of HbA1c, and women with HbA1c levels ≥ 9.5% had 8 times the odds of major congenital malformations [aOR 8.7 (95% CI: 5.4; 14.5)].Conclusions: The prevalence of major congenital malformations progressively increased with poorer glycemic control during pregnancy, with no obvious safe threshold level, for both type 1 and type 2 diabetes.Keywords: congenital heart diseases, diabetes, epidemiology, malformations, pregnancy, register-based research

Camilla Kjersgaard,1 Linn Håkonsen Arendt,1,2 Andreas Ernst,1 Morten Søndergaard Lindhard,2 Jørn Olsen,1,3 Tine Brink Henriksen,2 Katrine Strandberg-Larsen,4 Cecilia Høst Ramlau-Hansen1 1Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, 2Perinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital, Aarhus, 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 4Department of Public Health, Section of Social Medicine, Copenhagen University, Copenhagen, Denmark Purpose: Cryptorchidism is the most frequent congenital malformation in boys and is associated with low sperm count, infertility and testicular cancer. Unhealthy maternal lifestyle during pregnancy such as smoking, high prepregnancy body mass index (BMI) as well as alcohol and caffeine intake may constitute possible risk factors for cryptorchidism, but results from the few previous studies are conflicting. We aimed to explore the association between maternal lifestyle factors and occurrence of cryptorchidism in sons.Patients and methods: The Danish National Birth Cohort and the Aarhus Birth Cohort provided information on maternal lifestyle from early pregnancy. Data were linked to several Danish health registers, multiple imputation was used to handle missing data and Cox proportional hazards models were used to adjust for potential confounders.Results: In total, 85,923 boys were included, and of them, 2.2% were diagnosed with cryptorchidism. We observed the strongest associations between maternal tobacco smoking and prepregnancy BMI and cryptorchidism. Sons of women who smoked 10–14 cigarettes/day had the highest hazard ratio (HR) for cryptorchidism (1.37; 95% CI: 1.06–1.76), and for maternal BMI ≥30 kg/m2, the HR was 1.32 (95% CI: 1.06–1.65). Binge drinking was associated with an HR

Linn Håkonsen Arendt,1,2,* Andreas Ernst,1,3,* Morten Søndergaard Lindhard,2 Anne Aggerholm Jønsson,1 Tine Brink Henriksen,2 Jørn Olsen,4 Jorgen Thorup,5 L Henning Olsen,3 Cecilia Høst Ramlau-Hansen1 *These authors contributed equally to this work 1Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark; 2Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark; 3Department of Urology, Section for Paediatric Urology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 5Department of Paediatric Surgery, Rigshospitalet and Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Purpose: The Danish National Health registers provide a valuable data source that offers unique opportunities for observational research, including studies on the congenital anomaly hypospadias. The accuracy of the diagnosis and surgical treatment registration of hypospadias in the Danish National Patient Register (DNPR) remains unknown. Patients and methods: We randomly sampled 500 patients diagnosed with hypospadias in the DNPR from January 1, 1995 to December 31, 2012. Among these, 384 patients were also registered with surgical treatment for hypospadias. Medical records were collected and reviewed independently by two investigators. Any classification disagreements were resolved by consensus. Using the medical records as the gold standard, we estimated positive predictive values (PPVs) with 95% confidence intervals (CIs) for the hypospadias diagnoses and surgical treatment registrations overall, as well as for the clinical subtypes. Results: We were able to retrieve medical records for 463 (92.6%) patients with hypospadias diagnoses and for 329 (85.7%) patients registered with surgical treatment. Presence of hypospadias was confirmed in 450 of 463 patients, yielding an overall PPV (95% CI) of 97.6% (95.8%–98.7%). For subtypes of hypospadias, the PPVs ranged between 37.5% and 72.7%. For surgical treatment of hypospadias, the overall PPV was 99.7% (97.9%–99.9%). Conclusion: The validity of the registration of hypospadias diagnoses as well as surgical treatment for hypospadias in the DNPR is overall very high. For the specific subtypes of hypospadias diagnoses codes and the specific surgical treatment codes, the PPVs are lower and cautious use is warranted. However, the DNPR remains a valuable tool for future observational research on hypospadias. Keywords: data quality, epidemiology, hospital register diagnoses, ICD-10, positive predictive value

It has been proposed that poor semen quality may have its origins from fetal programming due to environmental factors. We investigated whether maternal coffee consumption during early pregnancy was associated with biomarkers of reproductive health in adult sons in the Fetal Programming of Semen Quality (FEPOS) cohort. In 2017-2019, 1058 young men provided a semen and blood sample and self-measured their testis volume. Daily maternal coffee consumption was reported by the mothers around gestational week 17. We estimated relative percentage differences with 95 % confidence intervals (CI) for semen quality measures, testis volume, and reproductive hormone levels according to maternal coffee consumption during pregnancy. Maternal coffee consumption (yes/no (reference)) was associated with lower semen volume (-7.0 % (95 % CI:-12.9;-0.7)), lower proportion of morphologically normal spermatozoa (-8.3 % (95 % CI:-16.5;0.8)), higher proportion of non-progressive and immotile spermatozoa (4.3 % (95 % CI:-1.5;10.3)), and lower testis volume (-4.8 % (95 % CI:-9.0;-0.4)). No indication of a dose-response association or threshold effects was observed in the categorized and continuous analyses. No associations with reproductive hormone levels were observed in any of the analyses. Overall, the study does not provide obvious indications that maternal coffee consumption in early pregnancy deteriorates male offspring fecundity. While some minor changes were observed, most estimates were small with confidence intervals overlapping the null. Future studies, preferably with greater exposure contrast, are warranted before a conclusion can be drawn as to whether maternal coffee consumption during pregnancy constitutes a risk for reproductive health in adult sons., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cecilia Ramlau-Hansen reports financial support was provided by European Research Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe the duration, timing, tempo, and synchronicity of puberty, as well as the correlation between timing and tempo of puberty., Methods: Overall, 15,819 of 22,439 invited children participated in the Puberty Cohort within the Danish National Birth Cohort. Participants completed a web-based questionnaire every 6 months through maturation with questions on current pubertal status. Girls reported current Tanner stage of breast and pubic hair development, and timing of menarche. Boys reported current Tanner stage of genital and pubic hair development, timing of first ejaculation, and vocal changes. While accounting for this interval-censored puberty information, we estimated the duration of puberty. Then, we used a nonlinear mixed effect growth model to estimate timing, tempo, synchronicity of puberty, and correlation between timing and tempo of puberty., Results: In girls, the average duration of breast development was longer, whereas the average tempo was slower than pubic hair development. The average timing of breast development was earlier than the average timing of pubic hair development. The majority of girls had asynchronous puberty. In boys, the average duration was longer and average tempo slower for genital than pubic hair development. The average timing of genital and pubic hair development were comparable; hence, the majority had synchronous pubertal development. Adolescents who had earlier timing also tended to have a faster tempo., Discussion: Being one of the largest puberty cohorts worldwide, these unique contemporary data can help physicians, parents, and children to understand and anticipate expected progression through pubertal development., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

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: This large population-based cohort study found no significant evidence for an adverse effect on semen quality in adult sons born by CS., (© 2024. The Author(s).)

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%, 11%]). When the categorical pubertal markers were analyzed as a linear term to assess dose dependence, older age at pubertal development was associated with higher FSH levels, higher SHBG levels, lower testosterone levels, lower estradiol levels, and lower FAI for most pubertal markers., Conclusion(s): 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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: High parental age is associated with adverse birth and genetic outcomes, but little is known about fecundity in male offspring., Objectives: We investigated if high parental age at birth was associated with biomarkers of male fecundity in a large population-based sample of young men., Materials and Methods: We conducted a study of 1057 men from the Fetal Programming of Semen Quality (FEPOS) cohort, a sub-cohort of sons born 1998-2000 into the Danish National Birth Cohort. Semen characteristics and reproductive hormone concentrations were measured in samples provided by the men 2017-2019. Testis volume was determined by self-measurement. Data on the parental age was drawn from registers. Adjusted relative difference in percentage with 95% confidence intervals were estimated for each outcome according to pre-specified maternal and paternal age groups (< 30 (reference), 30-34 and ≥ 35) as well as for combinations of parental age groups, using multivariable negative binomial regression models., Results: We did not observe consistent associations between parental age and biomarkers of fecundity, although sons of mothers ≥ 35 years had lower sperm concentration (-15% (95% CI: -30, 3)) and total sperm count (-10% (95% CI: -25, 9)). The analysis with parental age combinations showed lower sperm concentration with high age of the parents (both ≥ 35 years: -27%, 95% CI: -40, -19) when compared to the reference where both parents were below 30 years., Discussion and Conclusion: We found no strong association between higher parental age and biomarkers of fecundity in young men. However, we cannot exclude poorer semen characteristics in sons born by older mothers or with high age of both parents., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: The number of women with congenital heart disease (CHD) becoming pregnant are increasing. Although menstrual irregularities appear to occur more often in these patients, knowledge on their fertility is limited. In this nationwide cohort study, we evaluated the risk of impaired fertility in women with CHD compared with unaffected women using time to pregnancy (TTP)., Methods: The Danish National Birth Cohort (DNBC) of pregnant women constituted the study population. Information on TTP and use of medically assisted reproduction (MAR) treatment was reported at a first trimester interview. Women with CHD were identified by linkage to the Danish National Patient Registry. TTP was divided into three categories; 0-5 months, 6-12 months (i.e. subfertile), and > 12 months or use of MAR treatment (i.e. infertile). Relative risk ratios (RRR) for subfertility and infertility with 95% confidence intervals were estimated using multinomial logistic regression., Results: Among 93,832 pregnancies in 84,922 women, CHD was diagnosed in 333 women (0.4%), contributing with 360 pregnancies. The CHD was of simple complexity in 291 women (87.4%). No association was found between CHD and longer TTP (RRR of 1.02 (95% CI: 0.75-1.40) for subfertility, and RRR of 0.86 (95% CI: 0.61-1.20) for infertility). Similar was observed when comparing women with simple CHD and unaffected women. The number of women with complex CHD was too low for evaluation., Conclusions: Women with CHD had no increased risk of impaired fertility, assessed by TTP, when compared with unaffected women. Separate analysis of women with complex CHD was hampered by low numbers., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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.., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Exposures in utero are suggested to play a role in the etiology of endometriosis and adenomyosis, although the current evidence is inconclusive. Knowledge about potential prenatal programming and early life exposures that may affect this risk is of high importance, to focus potential preventive strategies for the diseases already during pregnancy. The aim of this study was to review systematically the literature of the association between measures of fetal growth and preterm birth and endometriosis and adenomyosis in adult life., Material and Methods: A systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines and by search on PubMed and EMBASE was carried out. We included published case-control and cohort studies. We excluded studies without a reference group, eg case series, case reports as well as commentaries, letters and editorials. The quality of the studies was assessed using the Newcastle-Ottawa Scale. Meta-analyses using a random-effect inverse variance weighted model were performed. PROSPERO registration number is CRD42021249322., Results: A total of 11 studies were included. In general, the quality scores of the studies were moderate. We found that the risk of endometriosis was 26% higher in women born with a birthweight <2.5 kg (pooled odds ratio [pOR] 1.26, 95% confidence interval [CI] 1.05-1.52) and 32% higher in women born preterm (pOR 1.32, 95% CI 1.01-1.72) than in the reference groups. The studies on adenomyosis pointed towards no association, but a meta-analysis was unfeasible due to the small number of studies., Conclusions: This systematic review and meta-analysis found that low birthweight and being born preterm were associated with endometriosis in adult life, but the results must be interpreted cautiously. No solid conclusion could be made regarding adenomyosis due to a limited number of published studies, but the studies included found no association. The results support the hypothesis of a potential early programming effect of endometriosis. However, the body of evidence is sparse and this hypothesis needs to be investigated further., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

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)D 3 ) 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., (© 2023. Springer Nature B.V.)

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., (© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background Despite an increasing number of patients with congenital heart disease (CHD) reaching reproductive age, the fertility of these patients remains undescribed. Therefore, the aim of the study was to evaluate the fertility in men and women with CHD by estimating the risk of infertility and comparing the birth rates, proportions of individuals becoming parents or remaining childless, and the number of children per parent with unaffected individuals. Methods and Results The study population consisted of individuals born between 1977 and 2000. Information on CHD, infertility, and live born children were obtained from the Danish health registries. Hazard ratios for infertility were analyzed using a Cox regression model. Differences of proportions and birth rates were calculated and compared between groups. Among 1 385 895 individuals, a total of 8679 (0.6%) were diagnosed with CHD. Men and women with simple or moderate CHD had no increased risk of infertility when compared with the reference population. Estimates for complex CHD groups were too imprecise for evaluation. Individuals with CHD were more often childless with consequently lower birth rates compared with unaffected individuals. However, those becoming parents had the same number of children as the reference population. Conclusions Men and women with simple or moderate CHD had the same risk of infertility as the reference population. Despite patients with CHD more often being childless, those becoming parents had the same number of children as parents without CHD. The current findings increase the knowledge regarding fertility in the CHD population.

Study Question: Does maternal polycystic ovarian syndrome (PCOS) affect the timing of pubertal development in daughters and sons?, Summary Answer: Maternal PCOS was associated with earlier adrenarche in daughters., What Is Known Already: Female adolescents with PCOS often experience earlier adrenarche compared to adolescents without PCOS, due to hyperandrogenism. Likewise, they usually have hyperandrogenism during pregnancy, which might potentially affect the development of the foetus, including its future reproductive health., Study Design, Size, Duration: In this population-based cohort study, we included 15 596 mothers-child pairs from the Danish National Birth Cohort (DNBC) Puberty Cohort, who were followed from foetal life until full sexual maturation or 18 years of age., Participants/materials, Setting, Methods: Using register-based and self-reported information on maternal PCOS and menstrual irregularities, collected during pregnancy, we categorized the mothers as having PCOS (n = 251), oligomenorhoea (n = 134), 'other menstrual irregularities' (n = 2411) or no menstrual abnormalities (reference group, n = 12 800). The children provided self-reported information on pubertal development every 6 months from the age of 11 years. The main outcome measures were adjusted mean age differences (in months) at attaining several individual pubertal milestones using an interval-censored regression model, as well as the average difference in age at attaining all pubertal milestones combined into a single estimate using Huber-White robust variance estimation., Main Results and the Role of Chance: We found that maternal PCOS was associated with an accelerated pubertal development in daughters with an overall average difference of -3.3 (95% CI: -6.3; -0.4) months based on all pubertal milestones compared to the reference group. When further looking into the average difference for adrenarche only (pubarche, axillary hair and acne), the average difference was -5.4 (95% CI: -8.7; -2.1) months compared to the reference group; whereas thelarche and menarche did not occur earlier in daughters of mothers with PCOS (average difference: -0.8 (95% CI: -3.9; 2.4) months). Oligomenorrhoea and 'other menstrual irregularities' were not associated with pubertal development in daughters. Neither PCOS, oligomenorrhoea nor 'other menstrual irregularities' were associated with pubertal development in sons., Limitations, Reasons for Caution: We expect some degree of non-differential misclassification of maternal PCOS and menstrual irregularities as well as pubertal development in the children., Wider Implications of the Findings: Maternal PCOS might accelerate adrenarche in daughters. Whether this is due to genetics, epigenetics or prenatal programming by hyperandrogenism in foetal life remains unsolved. The results from the present study can be generalized to Caucasian populations., Study Funding/competing Interest(s): The study is funded by the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Nitrate contamination is seen in drinking water worldwide. Nitrate may pass the placental barrier. Despite suggestive evidence of fetal harm, the potential association between nitrate exposure from drinking water and pregnancy loss remains to be studied. We aimed to investigate if nitrate in drinking water was associated with the risk of pregnancy loss., Methods: We conducted a nationwide cohort study of 100,410 pregnancies (enrolled around gestational week 11) in the Danish National Birth Cohort (DNBC) during 1996-2002. Spontaneous pregnancy losses before gestational week 22 were ascertained from the Danish National Patient Registry and DNBC pregnancy interviews. Using the national drinking water quality-monitoring database Jupiter, we estimated the individual and time-specific nitrate exposure by linking geocoded maternal residential addresses with water supply areas. The nitrate exposure was analyzed in spline models using a log-transformed continuous level or classified into five categories. We used Cox proportional hazards models to estimate associations between nitrate and pregnancy loss and used gestational age (days) as the time scale, adjusting for demographic, health, and lifestyle variables., Results: No consistent associations were found when investigating the exposure as a categorical variable and null findings were also found in trimester specific analyses. In the spline model using the continuous exposure variable, a modestly increased hazard of pregnancy loss was observed for the first trimester at nitrate exposures between 1 and 10 mg/L, with the highest. adjusted hazard ratio at 5 mg/L of nitrate of 1.16 (95% CI: 1.01, 1.34). This trend was attenuated in the higher exposure ranges., Conclusion: No association was seen between drinking water nitrate and the risk of pregnancy loss when investigating the exposure as a categorical variable. When we modelled the exposure as a continuous variable, a dose-dependent association was found between drinking water nitrate exposure in the first trimester and the risk of pregnancy loss. Very early pregnancy losses were not considered in this study, and whether survival bias influenced the results should be further explored., (© 2022. The Author(s).)

Objective: To study whether maternal thyroid disease in pregnancy is associated with pubertal timing in sons and daughters., Design: Cohort study., Setting: National birth cohort and health registers., Patient(s): A total of 15,763 mothers and children from the Danish National Birth Cohort and its Puberty Cohort., Intervention(s): Register-based and self-reported information on maternal thyroid diseases during pregnancy (hyperthyroidism, hypothyroidism, benign goiter, or no thyroid disease [reference group])., Main Outcome Measure(s): The adjusted mean age difference (months) at attaining several self-reported pubertal milestones collected every 6 months using an interval-censored regression and the average difference in age at attaining all pubertal milestones using the Huber-White robust variance estimation (primary outcome)., Result(s): Sons of mothers with hyperthyroidism had earlier pubertal development (average difference, -2.9 [95% confidence interval (CI), -5.0 to -0.7] months) than unexposed sons. Maternal hypothyroidism was not associated with pubertal development in sons (average difference, -1.2 [95% CI, -5.1 to 2.7] months). We observed nonstatistically significant indications of earlier pubertal development in sons of mothers with benign goiter (average difference, -1.9 [95% CI, -4.6 to 0.9] months). Maternal thyroid disease was not associated with pubertal development in daughters (average difference (months), hyperthyroidism, -0.8 [95% CI, -2.8 to 1.2]; hypothyroidism, 0.3 [95% CI, -3.1 to 3.8]; and benign goiter, 0.7 [95% CI, -2.0 to 3.4])., Conclusion(s): We found indications of earlier pubertal development in sons of mothers with hyperthyroidism. More research is needed to further investigate the observed sex-specific association., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background Children with congenital heart defects (CHD) have an increased risk of developmental delay. It remains sparsely investigated if these patients also have a delayed pubertal development. In this nationwide cohort study, we evaluated if CHD was associated with timing of puberty using longitudinally collected data on pubertal milestones. Methods and Results We used data from the Danish nationwide Puberty Cohort. Information on CHD was obtained from the Danish National Patient Register. Information on pubertal development was obtained from 15 780 children through questionnaires answered half-yearly from 11 years until 18 years or full maturity. Using a multivariable regression model for censored time-to-event data, mean difference in age at attaining each pubertal milestone was estimated, including a combined pubertal marker. Compared with children without CHD, analyses were performed for both CHD overall and subdivided into simple and complex CHD. In a subanalysis, analyses were repeated in children born at term. In total, 137 children (62 boys and 75 girls) had a CHD diagnosis. Overall, no difference in age at pubertal timing was observed for children with CHD compared with unaffected children. The average differences were small for both boys (1.6 [95% CI, -2.6 to 5.7] months) and girls (1.0 [95% CI, -2.5 to 4.4] months). The same differences were observed when subdividing into simple or complex CHD and when restricting to children born at term. Conclusions We found no association between CHD and pubertal timing. For the group of children with complex CHD, we were unable to exclude a later pubertal timing.

Introduction: Emerging evidence shows that women with endometriosis face a higher risk of preterm birth. However, the pathways are unclear. The objective of this study is to further investigate at different gestational ages the association between endometriosis and different pathways of preterm birth including, medically indicated preterm birth, premature pre-labor rupture of membranes (PPROM), and spontaneous labor contractions., Material and Methods: In this population-based cohort study we linked singleton pregnancies from the Aarhus Birth Cohort to the Danish National Patient Registry, the Danish Medical Birth Registry, the Danish National Pathology Registry and Data Bank, and the Danish in vitro fertilization registry to gather information on endometriosis status, outcomes and maternal characteristics. We investigated preterm birth before 37 completed weeks of gestation and very preterm birth before 32 completed weeks of gestation. We explored different pathways including medically indicated preterm birth defined as induction of labor with intact membranes and no prior labor contractions, PPROM defined as rupture of membranes, and spontaneous labor contractions defined as contractions with intact membranes resulting in labor., Results: We found that women with endometriosis had an increased risk of preterm birth before 37 gestational weeks overall (adjusted hazard rate [aHR] 1.6, 95% confidence interval [CI] 1.3-1.9) and very preterm birth before 32 gestational weeks (aHR 1.8, 95% CI 1.1-2.9) compared with women without endometriosis. Medically indicated preterm birth was more prominent in women with endometriosis in deliveries before 37 gestational weeks (aHR 2.4, 95% CI 1.8-3.2) whereas spontaneous labor contractions were more common before 32 gestational weeks (aHR 2.2, 95% CI 1.1-4.5) in women with endometriosis compared with women without endometriosis. Further, in the analyses restricted to women with a histologically verified diagnosis of endometriosis, the results were strengthened overall and showed that women with endometriosis had an increased risk of PPROM before 32 gestational weeks (aHR 3.49, 95% CI1.36-8.98)., Conclusions: Endometriosis was associated with both preterm and very preterm birth; however, apparently through different pathways. Women with endometriosis were more prone to have medically indicated preterm births before 37 gestational weeks and spontaneous preterm births before 32 gestational weeks compared with women without endometriosis., (© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

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/m 2 ; 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/m 2 , 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/m 2 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., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: This systematic review and meta-analysis summarizes the evidence for the association between endometriosis and adverse pregnancy outcome, including gestational hypertension, pre-eclampsia, low birth weight, and small for gestational age, preterm birth, placenta previa, placental abruption, cesarean section, stillbirth, postpartum hemorrhage, spontaneous hemoperitoneum in pregnancy, and spontaneous bowel perforation in pregnancy., Methods: We performed the literature review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), by searches in PubMed and EMBASE, until 1 November 2020 (PROSPERO ID CRD42020213999). We included peer-reviewed observational cohort studies and case-control studies and scored them according to the Newcastle-Ottawa Scale, to assess the risk of bias and confounding., Results: 39 studies were included. Women with endometriosis had an increased risk of gestational hypertension, pre-eclampsia, preterm birth, placenta previa, placental abruption, cesarean section, and stillbirth, compared to women without endometriosis. These results remained unchanged in sub-analyses, including studies on spontaneous pregnancies only. Spontaneous hemoperitoneum in pregnancy and bowel perforation seemed to be associated with endometriosis; however, the studies were few and did not meet the inclusion criteria., Conclusions: The literature shows that endometriosis is associated with an increased risk of gestational hypertension, pre-eclampsia, preterm birth, placenta previa, placental abruption, cesarean section, and stillbirth.

Introduction: Length of hospital stay after birth has decreased during the last decades, but nationwide data on length of hospital stay after cesarean section are lacking. Elements of Enhanced Recovery Programs were reported to reduce the length of hospital stay. The aim of this nationwide study was to describe the length of hospital stay after cesarean section in Denmark from 2004 to 2016 taking into account birth- and health-related factors as well as demographic changes and, further, to assess potential differences between the five Danish regions., Material and Methods: Length of hospital stay was assessed in 164 209 deliveries by cesarean section in Denmark from 2004 to 2016. Data were obtained from the Danish National Patient Register. All deliveries by cesarean section at gestational age <22 weeks were excluded. Median length of hospital stay was reported based on crude and adjusted analyses., Results: The median length of hospital stay was significantly reduced by 39 hours (95% confidence interval [CI] 37.9-40.1), from 97 hours (4.0 days) in 2004 to 58 hours (2.4 days) in 2016. Reductions were observed among both planned and emergency cesarean sections. When birth- and health-related factors as well as demographic changes were accounted for, median length of hospital stay was reduced by 30 hours (95% CI 29.3-30.8) in the period. The decrease in length of hospital stay from 2004 to 2016 varied between the five Danish regions, with adjusted reductions between 19 and 46 hours., Conclusions: A nationwide decrease in length of hospital stay after cesarean section was observed from 2004 to 2016 across all five regions but with significant regional variations. Further studies on the optimal length of hospital stay are needed, especially with regard to implementation of enhanced recovery programs., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.)

Study Question: Do maternal hypertensive disorders affect pubertal development in daughters and sons?, Summary Answer: Pubertal development tended to occur earlier in daughters of mothers with 'preeclampsia, eclampsia or HELLP syndrome' (hemolysis, elevated liver enzymes and low blood platelets) or hypertension in pregnancy compared to daughters born of normotensive mothers., What Is Known Already: The existing literature suggests some or no association between preeclampsia and pubertal development in daughters, but not in sons. None of the previous studies has investigated the possible association between other types of hypertensive disorders (hypertension, eclampsia or HELLP syndrome) and pubertal timing in children., Study Design, Size, Duration: Longitudinal cohort study consisting of 15 819 mother-child pairs with information on maternal hypertensive disorders collected during pregnancy and information on pubertal development collected half-yearly from the age of 11 years and until fully developed or 18 years of age., Participants/materials, Setting, Methods: Participants are children from the Puberty Cohort nested within the Danish National Birth Cohort. The exposure was register-based and self-reported information on maternal hypertensive disorders during pregnancy. The outcomes were children's self-reported information on pubertal development, including Tanner stage 1-5 (pubic hair (both daughters and sons) and breast development (daughters) or genital development (sons)), first menstrual bleeding (daughters) or first ejaculation (sons), voice break episode (sons), axillary hair development and acne occurrence (both daughters and sons). The main outcome was mean difference in age at attaining each pubertal milestone and a combined pubertal marker in children of mothers with hypertensive disorders in pregnancy (either hypertension (n = 490), 'preeclampsia, eclampsia or HELLP syndrome' (n = 419) or 'unspecific hypertensive disorders' (n = 334) with unexposed children as reference (n = 14 576))., Main Results and the Role of Chance: In daughters of mothers with 'preeclampsia, eclampsia or HELLP syndrome', we observed tendencies of earlier pubertal timing (combined marker: -2.0 (95% CI: -3.9; 0.0) months). In daughters of mothers with hypertension, several pubertal milestones tended to occur earlier than in daughters of normotensive mothers; however, all 95% CIs overlapped the null resulting in a combined pubertal marker of -1.0 (95% CI: -3.2; 1.1) months. In sons of mothers with any of the hypertensive disorders, we observed no difference in pubertal timing (combined markers: 'preeclampsia, eclampsia or HELLP syndrome': 0.1 (95% CI: -2.0; 2.1) months; hypertension: -0.6 (95% CI: -2.3; 1.1) months; 'unspecific hypertensive disorders': 0.2 (95% CI: -1.9; 2.2) months)., Limitations, Reasons for Caution: The study is subject to non-differential misclassification of self-reported information on maternal hypertensive disorders in pregnancy and current pubertal status; possibly causing bias toward the null., Wider Implications of the Findings: Hypertensive disorders in pregnancy might accelerate pubertal timing in daughters; however, more studies are needed for causal conclusions., Study Funding/competing Interest(s): The study was funded by the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: RA and SLE are the most prevalent autoimmune rheumatic diseases affecting young women. Both diseases are characterized by systemic inflammation that may affect placental function and fetal development during pregnancy, and both diseases are associated with adverse pregnancy and child outcomes. We investigated the associations between maternal RA or SLE and the two genital malformations, cryptorchidism and hypospadias., Methods: In this nationwide register-based study including all male singleton live births in Denmark from 1995 to 2016, we assessed the occurrence of cryptorchidism and hypospadias according to the prenatal disease-state of the mothers. Using Cox proportional hazards models we calculated adjusted hazard ratios, accounting for varying age at diagnosis., Results: Among 690 240 boys, 1026 had a mother with RA and 352 had a mother with SLE. We found adjusted hazard ratios of 1.72 (95% CI: 1.15; 2.57) for cryptorchidism among boys born to mothers with RA and 1.46 (95% CI: 0.69; 3.06) for boys born to mothers with SLE, compared with the general population. As the number of hypospadias cases was low, multivariate analysis was not feasible. The crude hazard ratios were 0.51 (95% CI: 0.16; 1.58) and 1.00 (95% CI: 0.25; 4.03) for RA and SLE, respectively., Conclusion: Boys born to mothers with RA had higher risk of cryptorchidism, compared with unexposed boys. Boys born to mothers with SLE showed a similar tendency, however with less precision of the estimate. No conclusion could be reached on the risk of hypospadias, due to the low number of events., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In this review, we discuss genital herpes - a common sexually transmitted infection, which can be transmitted to the baby during birth. Neonatal herpes is a rare but serious infection. In 2019, the Danish Society of Obstetrics and Gynecology revised the guideline for management of genital herpes in pregnancy. Recommendations include antiviral therapy from gestational week 36 in case of primary- or recurrent infection in current pregnancy. Delivery by cesarean section is recommended in case of primary infection in the third trimester. Women with recurrent herpes can deliver vaginally, as risk of neonatal infection is low.

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Pubertal development may be altered in boys with cryptorchidism and hypospadias, but existing knowledge is inconsistent. Therefore, we investigated the association between cryptorchidism and hypospadias and pubertal development in a large cohort study. Boys in the Puberty Cohort, a cohort nested within the Danish National Birth Cohort, were included in this study. Information on cryptorchidism and hypospadias was retrieved from the Danish National Patient Register. From 11 years until 18 years or full pubertal development, information on physical markers of pubertal development was provided biannually, including Tanner stages, axillary hair, acne, voice break, and first ejaculation. In multivariate regression models for interval censored data, the mean (95% confidence intervals [CIs]) differences in months in obtaining the pubertal markers between boys with and without the anomalies were estimated. Among 7698 boys, 196 (2.5%) had cryptorchidism and 60 (0.8%) had hypospadias. Boys with hypospadias experienced first ejaculation and voice break 7.7 (95% CI: 2.5-13.0) months and 4.5 (95% CI: 0.3-8.7) months later than boys without hypospadias. The age at attaining the Tanner stages for gonadal and pubic hair growth was also higher, though not statistically significant. Pubertal development seemed unaffected in boys with mild as well as severe cryptorchidism. In conclusion, hypospadias may be associated with delayed pubertal development, but pubertal development seems unaffected by cryptorchidism. The relation between hypospadias and later pubertal development may be due to the underlying shared in utero risk or genetic factors., Competing Interests: None

Study Question: Is female infertility predictive of a woman's future risk of early cardiovascular disease (CVD)?, Summary Answer: Female infertility does not seem to be predictive of early CVD during a mean follow-up of 9 years., What Is Known Already: Associations between infertility and comorbidity have been found in several studies, but data on the association between female infertility and risk of CVD are scarce and inconclusive., Study Design, Size, Duration: In this nationwide cohort study, we included 87 221 women registered in the Danish National IVF register, undergoing medically assisted reproduction (MAR) between 1st of January 1994 and 31st of December 2015. The cohort was followed for incident hospitalization due to CVD in the Danish National Patient Register from enrollment to 31 December 2015. Women with a history of CVD prior to enrollment were excluded. Cox proportional hazard models with age as the underlying time scale were used to estimate hazard ratios (HR) with 95% CI of CVD among women with an infertility diagnosis, compared to women without an infertility diagnosis. All analyses were adjusted for educational attainment., Participants/materials, Setting, Methods: Female infertility and the reason for infertility was diagnosed and registered in the IVF register by specialists in Danish public and private fertility clinics since 1st of January 1994. In our cohort, 53 806 women (61.7%) were diagnosed with female factor infertility, while 33 415 (38.3%) did not have a female factor infertility diagnosis and made up the reference group., Main Results and the Role of Chance: A total of 686 (1.3%) infertile women were hospitalized for CVD compared to 250 (0.7%) among women without an infertility diagnosis during a mean follow-up time of 9 years. We found no increased risk of early CVD in our analyses (adjusted HR 0.98, 95% CI: 0.85;1.14). Likewise, analyses stratified by specific infertility diagnosis, showed no risk difference., Limitations, Reasons for Caution: We were unable to adjust for confounding parameters such as body mass index, cigarette smoking or alcohol consumption. These results may not be generalizable to infertile women who do not seek out fertility treatment, or infertile women with other lifestyle characteristics than Danish women., Wider Implications of the Findings: Diagnosing female infertility or the time of MAR does not seem to be a window of opportunity where early screening for cardiovascular disease risk factors can have a prophylactic potential., Study Funding/competing Interest(s): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. None of the authors declare any conflict of interest., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: Maternal cancer may be associated with offspring mental and behavioural disorders through various biological pathways. When postnatally diagnosed, it may cause stress and changes in care, potentially influencing mental health. Prenatally diagnosed cancer could lead to maternal stress and treatment, or influence foetal neural development. This study investigates associations between prenatally or postnatally diagnosed maternal cancers and mental and behavioural disorders in children., Methods: The study composed of 2 158 430 children born in Denmark (1978-2012). Children were exposed if their mother received a cancer diagnosis prenatally (2 years prepartum, until birth) or postnatally (birth, until 18 years postpartum). Further analyses considered cancer types and diagnostic delays. Children were followed until 18 years of age or the first of the following: diagnosis of a mental or behavioural disorder, emigration, death, end of follow-up., Results: During follow-up 79 682 (3.7%) children were diagnosed with mental or behavioural disorders. There was an increased risk among offspring exposed to postnatally diagnosed cancers (HR 1.05; 95% CI, 1.00-1.11); for prenatally diagnosed cancers HR was 1.07 (0.87-1.31). The strongest associations for disorder types were for prenatal diagnoses with mood/affective disorders (HR 2.45; 1.02-5.89) and postnatal diagnoses with mood/affective disorders (HR 1.43; 1.14-1.79)., Conclusions: The results indicate a link between maternal cancer occurrence during pregnancy or early postnatal life, and mental and behavioural disorders in offspring. This association could be driven by common factors in the two periods, such as psychological stress or genetic factors. No specific foetal programming was identified., (© 2018 John Wiley & Sons, Ltd.)

Objectives: This study aims to estimate the association between pregnancy-associated maternal cancers, diagnosed both prenatally and postnatally, and birth outcomes., Design: Population-based register study., Setting: National registers of Denmark and Sweden., Participants: A total of 5 523 365 children born in Denmark (1977-2008) and Sweden (1973-2006).Primary and secondary outcome measures: gestational age, birth weight, size for gestational age, Apgar score, caesarean section and sex were the outcomes of interest. ORs and relative risk ratios (RRR) with 95% CIs were estimated using logistic regression and multinomial logistic regression, respectively., Results: In this study, 2% of children were born to mothers with a diagnosis of cancer. Children whose mothers received a prenatal cancer diagnosis had higher risk of being born preterm (RRR: 1.77, 95% CI 1.64 to 1.90); low birth weight (RRR 1.84, 95% CI 1.69 to 2.01); low Apgar score (OR 1.36, 95% CI 1.20 to 1.56); and by caesarean section (OR: 1.69, 95% CI 1.59 to 1.80). Associations moved towards the null for analyses using postnatal diagnoses, but preterm birth (RRR: 1.13, 95% CI 1.09 to 1.17) and low birth weight (RRR: 1.14, 95% CI 1.09 to 1.18) remained statistically significant, while risk of caesarean section became so (OR: 0.95, 95% CI 0.91 to 0.98). Additionally, statistical significance was reached for large for gestational age (RRR: 1.06, 95% CI 1.01 to 1.11), high birth weight (RRR: 1.04, 95% CI 1.01 to 1.06) and caesarean section (OR: 0.95, 95% CI 0.91 to 0.98)., Conclusions: Results suggest an association between pregnancy-associated cancers and adverse birth outcomes in the offspring. While this is strongest for prenatally diagnosed cancers, some smaller associations exist for postnatally diagnosed cancers, indicating that cancer itself could affect fetal development, or that cancer and adverse birth outcomes share risk factors. Future studies on maternal cancer during pregnancy should consider including some postnatal years in their exposure window., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To study if parental subfertility is related to the occurrence of the male genital anomalies, cryptorchidism and hypospadias., Design: Population-based cohort study., Setting: Not applicable., Patient(s): A total of 80,220 singleton boys and their mothers from the Danish National Birth Cohort and the Aarhus Birth Cohort., Intervention(s): None., Main Outcome Measure(s): The two congenital anomalies; cryptorchidism and hypospadias, registered within the Danish National Patient Register up until December 31, 2012., Result(s): By means of Cox regression analyses, we found no associations between waiting time-to-pregnancy (TTP) and cryptorchidism or hypospadias among those who conceived spontaneously. The highest hazard ratio for cryptorchidism was seen among boys of couples with a TTP>12 months who conceived after fertility treatment (adjusted hazard ratio [aHR] 1.19, 95% confidence interval 0.92-1.55). For hypospadias, we found that boys of couples with a TTP>12 months who conceived after fertility treatment, had a 71% higher risk of hypospadias (aHR 1.71, [95% confidence interval 1.24-3.36]) as compared with boys of couples with a TTP<5 months., Conclusion(s): The findings from this study showed that boys of couples with TTP>12 months who conceived after fertility treatment, had a higher occurrence of hypospadias than boys conceived spontaneously of couples with a short TTP. Among those who conceived spontaneously, TTP was not associated with hypospadias or cryptorchidism. These findings indicate that fertility treatment or severity of subfertility is related to hypospadias., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Although congenital abnormalities in the male reproductive tract are common, their causes remain poorly understood. We studied associations between hypertensive disorders of pregnancy (pregestational hypertension, gestational hypertension, and preeclampsia) and the genital anomalies, cryptorchidism (undescended testes), and hypospadias (ventrally displaced urethral meatus)., Methods: We established a population of 1,073,026 Danish boys born alive between 1 January 1978 and 31 December 2012. By means of Cox regression analyses, we estimated hazard ratios with 95% confidence intervals for cryptorchidism and hypospadias according to type and severity of hypertensive disorder. Further, we used restricted cubic spline analyses to investigate the association between gestational age at onset of severe and moderate preeclampsia and the two genital anomalies., Results: We found associations between pregestational hypertension and cryptorchidism (HR: 1.3; 95% CI = 1.1, 1.6) and hypospadias (HR: 1.7; 95% CI = 1.3, 2.3), whereas gestational hypertension was only associated with cryptorchidism (HR: 1.2; 95% CI = 1.1, 1.4). Boys of mothers with preeclampsia had the highest occurrence of cryptorchidism and hypospadias, increasing with preeclampsia severity. Women with HELLP syndrome faced the highest risk of having a child with both cryptorchidism (HR: 2.1; 95% CI = 1.4, 3.2) and hypospadias (HR: 3.9; 95% CI = 2.5, 6.1). Further, the occurrence increased with early onset of preeclampsia diagnosis., Conclusions: These findings support the hypotheses that preeclampsia and genital anomalies share common etiologic factors and that placental dysfunction and androgen deficiency in early pregnancy are important in the etiology of male genital anomalies.

Introduction: The objective of this systematic review and meta-analysis was to evaluate the risk of preterm delivery and having a small-for-gestational-age (SGA) child in women with endometriosis and adenomyosis compared with women without these two diseases., Material and Methods: Studies on endometriosis or adenomyosis and risk of preterm delivery and/or SGA infant were included. The systematic search was conducted for all published articles in PubMed and Embase published from 1950 to 2017 using specific search terms. After duplicates were removed, two authors independently reviewed all studies, initially based on title and subsequently based on abstract. Studies considered relevant were read in full text by both reviewers to identify if studies met the inclusion criteria., Results: The search found 21 studies on a total of 2 517 516 women meeting the inclusion criteria. Women with endometriosis had an increased odds of preterm delivery [odds ratio (OR) 1.47, 95% CI 1.28-1.69] and SGA infant (OR 1.26, 95% CI 1.04-1.549). Compared with endometriosis, adenomyosis implied an even higher odds of both preterm delivery (OR 3.09, 95% CI 1.88-5.09) and SGA infant (OR 3.23, 95% CI 1.71-6.09) as well., Conclusions: Women with endometriosis or adenomyosis had a higher odds of preterm delivery and having a child that was SGA compared with women without endometriosis or adenomyosis. The odds of both adverse birth outcomes was highest among women with adenomyosis. The results suggest a closer prenatal monitoring among pregnant women with endometriosis or adenomyosis., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Increasing evidence suggests that pregnant women with endometriosis have a higher risk of adverse obstetrical complications. The aim of this study was to systematically review the existing literature on this aspect. A PubMed/MEDLINE search was performed from its inception until September 2017 for studies on adverse obstetrical complications in pregnant women with endometriosis, including: preeclampsia, preterm birth, small for gestational age (SGA), antepartum hemorrhage, spontaneous hemoperitoneum, spontaneous bowel perforation, preterm birth, cesarean delivery, stillbirth and postpartum hemorrhage. Overall, the results showed an increased risk of preterm delivery, antepartum hemorrhage, delivery by cesarian section, and the rare complications of spontaneous hemorrhage in pregnancy and spontaneous bowel perforation. There is no firm evidence for any increased risk of preeclampsia, having a child born small for gestational age, stillbirth, or postpartum hemorrhage. In conclusion, pregnant patients with endometriosis should be offered special clinical attention., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: To study the association between maternal diabetes and timing of pubertal development in daughters and sons., Design: Prospective cohort study., Setting: Not applicable., Patient(s): A total of 15,822 mother-child pairs included in the Danish National Birth Cohort and the Puberty Cohort with prospectively collected, register-based and self-reported information on maternal diabetes and self-reported information on pubertal development., Intervention(s): None., Main Outcome Measure(s): Adjusted mean monthly difference in age at attaining pubertal milestones in children born of mothers with diabetes compared with children born of mothers without diabetes., Result(s): A total of 502 children were born of mothers with diabetes during pregnancy. In daughters exposed to gestational diabetes mellitus, we observed advanced onset in all pubertal milestones. The associations were statistically significant with regard to pubic hair Tanner stage 2 (-4.8 months) (95% confidence interval [CI] -7.7, -2.0), pubic hair Tanner stage 3 (-2.2 months) (95 % CI -4.4, 0.0), pubic hair Tanner stage 5 (-6.0 months) (95% CI -10.8, -1.2), and menarche (-2.5 months) (95 % CI -4.9, 0.0). We observed no tendencies between maternal type 1 or type 2 diabetes mellitus and pubertal development in daughters. We observed no associations between maternal diabetes and pubertal development in sons., Conclusion(s): Our findings suggest that gestational diabetes mellitus may accelerate the pubertal development in daughters. Our results did not support an association between type 1 or type 2 diabetes mellitus and daughters' pubertal development, as well as between any type of maternal diabetes and sons' pubertal development., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Pre-existing diabetes has been associated with an increased risk of congenital malformations overall, but studies on genital anomalies in boys are conflicting and possible causal mechanisms are not well understood. Previous studies have mainly assessed pregestational and gestational diabetes in combination. Yet considering the vulnerable time windows for the genital anomalies, associations could well differ between types of diabetes and between the 2 genital anomalies and we therefore aimed to study this further., Methods: A population-based cohort study of 2,416,246 singleton live-born boys from Denmark (1978-2012) and Sweden (1987-2012) was carried out using Danish and Swedish register-based data. Using Cox regression models, we estimated hazard ratios for hypospadias and cryptorchidism according to maternal diabetes. We considered type and severity of diabetes, as well as timing of diagnosis in relation to birth., Results: Pregestational type 1 diabetes was associated with a higher risk of both genital anomalies. The highest risks were seen for boys of mothers with diabetic complications (hazard ratio for hypospadias = 2.33 [95% confidence interval, 1.48, 3.66] and hazard ratio for cryptorchidism = 1.92 [95% confidence interval, 1.39, 2.65]). Gestational diabetes was associated with slightly increased risks of both genital anomalies., Conclusions: These results are consistent with the hypothesis that poor glycemic control may interfere with fetal genital development in the critical early period of organogenesis. Given the widespread and increasing occurrence of diabetes, these results are of public health importance.

The evidence is scarce on the association between age at puberty and semen quality. A cohort of 320 Danish men aged 18-21 years enrolled in the "Healthy Habits for Two" birth cohort provided self-reported data on pubertal indicators and delivered semen and blood samples. The results indicated an association between older age at pubertal development and lower semen quality and altered reproductive hormones concentrations as measured in young adult life. Men who had their first nocturnal emission, start of pubic hair growth and first voice break episode when older than 15 years had 37.0%, 45.0% and 32.7% lower sperm concentration; 37.8%, 44.2% and 29.1% lower total sperm count; 7.4%, 13.4% and 15.3% lower testosterone concentration; and 21.3%, 1.5% and 3.7% lower inhibin B concentration, respectively, compared with the men who were younger than 13 years at their first pubertal indicators. Only few of the results were statistically significant, but similar tendencies were seen in several of the reproductive parameters suggesting an association between the timing of pubertal development and reproductive health later in life.

Objective: To investigate the association between maternal endometriosis and occurrence of the genital anomalies cryptorchidism and hypospadias in sons., Design: Population-based cohort study., Setting: Not applicable., Patient(s): All live-born singleton boys born from 1978 to 2012., Intervention(s): None., Main Outcome Measure(s): Cryptorchidism and hypospadias in boys based on information from the Danish National Patient Register., Result(s): The study included 1,073,026 live-born singleton boys. A total of 6,443 boys were sons of women diagnosed with endometriosis before pregnancy. Altogether, 27,342 boys were diagnosed with cryptorchidism, of whom 16,446 had corrective surgery. Hypospadias was diagnosed in 4,853 boys. As compared with unexposed boys, a tendency towards a slightly higher occurrence of cryptorchidism was observed among boys of women with endometriosis (adjusted hazard ratio [aHR] 1.18; 95% confidence interval [CI], 0.97, 1.44). When stratified by medically assisted reproduction (MAR) technologies, the association was slightly stronger among boys born to women with endometriosis who had conceived via MAR, yet it remained moderate and statistically insignificant (aHR 1.27; 95% CI, 0.86; 1.88). When women who conceived with MAR were excluded, the association between endometriosis and cryptorchidism disappeared. For hypospadias, we observed no association, either in the main analysis or the stratified analysis., Conclusion(s): The findings from this register-based study do not provide strong evidence for a higher occurrence of the studied genital anomalies among boys of women with endometriosis., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Overweight and obese pregnant women face higher risk of several critical birth outcomes, including an overall increased risk of congenital abnormalities. Only few studies have focused on associations between maternal overweight and the genital anomalies in boys, cryptorchidism and hypospadias, and results are inconclusive., Methods: We performed a population-based cohort study and assessed the associations between maternal body mass index (BMI) in early pregnancy and occurrence of cryptorchidism and hypospadias. All live-born singleton boys born in Sweden from 1992 to 2012 were included. From the Swedish Patient Register, information on cryptorchidism and hypospadias was available. Data were analysed using Cox proportional hazards regression adjusted for potential confounders. Mediation analyses were performed to estimate how much of the association between BMI and genital anomalies were mediated through obesity-related diseases., Results: Of the 1 055 705 live-born singleton boys born from 1992 to 2012, 6807 (6.4 per 1000) were diagnosed with hypospadias and 16 469 (15.6 per 1000) were diagnosed with cryptorchidism, of which 9768 (9.3 per 1000) underwent corrective surgery for cryptorchidism. We observed dose-response associations between maternal BMI and hypospadias and cryptorchidism. Boys of mothers with BMI ≥40.0 kg/m 2 had the highest adjusted hazard ratios for hypospadias (HR 1.35, 95% confidence interval [CI] 1.04, 1.76) and cryptorchidism (HR 1.25, 95% CI 1.00, 1.58). A substantial proportion of the associations between BMI and the genital anomalies were mediated through preeclampsia., Conclusion: This large register-based study adds to the current literature and indicates that the occurrence of hypospadias and cryptorchidism increase with maternal overweight and obesity severity., (© 2017 John Wiley & Sons Ltd.)

Several studies on pregnancy-associated cancers have suggested an association with congenital anomalies in offspring. Previous studies have included maternal cancers diagnosed up to 2 years after pregnancy; however, long latency periods of some cancers mean that cancers diagnosed many years postpartum might have been present during pregnancy in a preclinical state. This paper considers the association between maternal cancers diagnosed from 2 years prior to pregnancy until the mother reaches 50 years of age, and congenital anomalies, as diagnosed at birth or within the first year of life. The current population-based study looks at associations of cancers in mothers with congenital anomalies in their children. Children were followed up from birth to diagnosis of a congenital anomaly, death, emigration or end of follow-up (whichever occurred first). A total of 56,016 children (2.6%) were considered exposed to a maternal cancer of any type; and they had a hazard ratio (HR) of 1.04 (95% confidence interval [CI]: 1.00, 1.09) compared with unexposed children. The greatest HR was seen among children whose mothers had been diagnosed with cancers before or during pregnancy (HR: 1.37, 95% CI: 1.07, 1.75). Similar results were seen when paternal cancers were used as a 'negative control'. Statistically significant associations were seen for some specific congenital anomalies of organ systems (congenital anomalies of the musculoskeletal system [HR: 1.13, 95% CI: 1.02, 1.25]) and for some specific types of maternal cancer (leukaemia [HR: 1.31, 95% CI: 1.01, 1.61], The results of the main analyses suggest a small increase in risk of congenital anomalies in offspring of mothers diagnosed with cancer from 2 years before pregnancy, until the mother reaches 50 years of age; with the greatest increase seen for exposure in the pre-pregnancy and pregnancy period. These results may reflect shared causes for some cancers and some congenital anomalies. The similar results seen for paternal cancers indicate that the cause may be genetic or related to the families' social and environmental conditions.

Objective: To study the association between endometriosis and risk of pre-eclampsia, cesarean section, postpartum hemorrhage, preterm birth, and small for gestational age (SGA), in a large Danish birth cohort, while taking fertility treatment into account., Design: Population-based study., Setting: Not applicable., Patient(s): A total population of 82,793 singleton pregnancies from the Aarhus Birth Cohort (1989 through 2013); 1,213 women had a diagnosis of endometriosis, affecting 1,719 pregnancies., Intervention(s): None., Main Outcome Measure(s): Pre-eclampsia, cesarean section, postpartum hemorrhage, preterm birth, and SGA., Result(s): Endometriosis was associated with an increased risk of preterm birth (adjusted odds ratio [AOR] 1.67, 95% confidence interval [CI] 1.37-2.05), with the risk being highest for very preterm birth (AOR 1.91, 95% CI 1.16-3.15). Compared with unaffected women, women with endometriosis also had an increased risk of pre-eclampsia (AOR 1.37, 95% CI 1.06-1.77) and cesarean section (AOR 1.83, 95% CI 1.60-2.09). Assisted reproductive technology did not explain these findings. No association was found between endometriosis and postpartum hemorrhage or SGA., Conclusion(s): Women with endometriosis were at increased risk of pre-eclampsia, preterm birth, and cesarean section, irrespective of use of assisted reproductive technology., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The most consistently reported risk indicators for the male genital anomalies cryptorchidism and hypospadias are prematurity and low birth weight. Placental dysfunction has been hypothesized as a possible underlying cause, and an association between placental weight at birth and hypospadias has been indicated. In a population-based cohort of 388,422 Danish singleton boys born alive (1997-2008), we studied the association between placental weight and cryptorchidism and hypospadias. Missing data were handled with multiple imputation, and we estimated hazard ratios by means of Cox regression models. During follow-up, 1,713 boys were diagnosed with hypospadias and 6,878 with cryptorchidism (3,624 underwent corrective surgery). We observed an association between low placental weight and risk of both genital anomalies. Boys with a placental weight in the lowest decile (<10%) had higher risks of both cryptorchidism (hazard ratio = 1.52, 95% confidence interval: 1.31, 1.76) and hypospadias (hazard ratio = 1.97, 95% confidence interval: 1.59, 2.45) than boys in the reference decile (50.0-59.9%). In conclusion, we found higher risks of both genital malformations in boys born with a low placental weight. The relationship seemed stronger for hypospadias than for cryptorchidism. Taken together, our data support a role for placental dysfunction in the etiology of these anomalies., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)