Birth by caesarean section and semen quality in adulthood: a Danish population-based cohort study.

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.

Caesarean section is one of the most frequently used interventions during childbirth and global cesarean delivery rates continue to increase. The rising cesarean delivery rate has been reported to be related with series of adverse health outcomes in children, such as asthma, allergies, obesity, diabetes and even poor emotional, behavioral and educational outcomes. Still, it remains unknown whether children's reproductive health is affected by this delivery mode.Based on data from the Fetal Programming of Semen Quality cohort (FEPOS,) nested within the Danish National Birth Cohort, we have therefore analyzed the potential effect of caesarean section on son's semen quality in 1044 young men. We found a slightly higher progressive sperm motility among sons born by caesarean section compared to sons born by vaginal delivery. No differences, however, were observed for semen volume, sperm concentration and morphology between the two delivery modes.The FEPOS cohort is the largest population-based male offspring cohort worldwide. This is the first study aiming to examine the association between caesarean section and semen quality in adulthood. Although the findings need to be confirmed in other studies, it is reassuring that this large population-based cohort study finds no significant evidence for an adverse effect on semen quality in adult sons born by caesarean section.

Characteristics of Puberty in a Population-Based Sample of Danish Adolescents.

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.

Parental age at birth and biomarkers of fecundity in young Danish men.

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.

Measures of fetal growth and preterm birth and risk of endometriosis and adenomyosis in adult life: a systematic review and meta-analysis.

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.

Timing of puberty in relation to semen characteristics, testicular volume, and reproductive hormones: a cohort study.

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.

Maternal alcohol intake in early pregnancy and biomarkers of fecundity in adult sons: A cohort study.

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

Maternal vitamin D levels and male reproductive health: a population-based follow-up study.

Maternal vitamin D levels during pregnancy may be important for reproductive health in male offspring by regulating cell proliferation and differentiation during development. We conducted a follow-up study of 827 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, nested in the Danish National Birth Cohort to investigate if maternal vitamin D levels were associated with measures of reproductive health in adult sons. These included semen characteristics, testes volume, and reproductive hormone levels and were analysed according to maternal vitamin D (25(OH)D3) levels during pregnancy. In addition, an instrumental variable analysis using seasonality in sun exposure as an instrument for maternal vitamin D levels was conducted. We found that sons of mothers with vitamin D levels < 25 nmol/L had 11% (95% CI - 19 to - 2) lower testes volume and a 1.4 (95% CI 1.0 to 1.9) times higher risk of having low testes volume (< 15 mL), in addition to 20% (95% CI - 40 to 9) lower total sperm count and a 1.6 (95% CI 0.9 to 2.9) times higher risk of having a low total sperm count (< 39 million) compared with sons of mothers with vitamin D levels > 75 nmol/L. Continuous models, spline plots and an instrumental variable analysis supported these findings. Low maternal vitamin D levels were associated with lower testes volume and lower total sperm count with indications of dose-dependency. Maternal vitamin D level above 75 nmol/L during pregnancy may be beneficial for testes function in adult sons.

Maternal intake of folate and folic acid during pregnancy and markers of male fecundity: A population-based cohort study.

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.

Maternal polycystic ovarian syndrome and pubertal development in daughters and sons: a population-based cohort study.

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.

Drinking water nitrate and risk of pregnancy loss: a nationwide cohort study.

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.

Maternal Cigarette Smoking During Pregnancy and Genital Anomalies in Boys: A Register-Based Cohort and Sibling-Matched Design Study.

Purpose: 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.

Nitrate in Drinking Water and Time to Pregnancy or Medically Assisted Reproduction in Women and Men: A Nationwide Cohort Study in the Danish National Birth Cohort.

Purpose: 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.

Lifestyle in Pregnancy and Hypospadias in Sons: A Study of 85,923 Mother-Son Pairs from Two Danish Pregnancy Cohorts.

PURPOSE: 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.

Endometriosis and preterm birth: A Danish cohort study.

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.

Parental Separation and Semen Quality in Young Men: A Population-Based Cohort Study.

PURPOSE: 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.

Nausea During Pregnancy and Timing of Pubertal Development in Sons and Daughters: A Population-Based Cohort Study.

PURPOSE: 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.

Glycemic Control in Pregnancies Complicated by Pre-Existing Diabetes Mellitus and Congenital Malformations: A Danish Population-Based Study.

PURPOSE: 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.

Endometriosis and Risk of Adverse Pregnancy Outcome: A Systematic Review and Meta-Analysis.

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.

[Genital herpes simplex virus infection in pregnancy].

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.

Maternal rheumatoid arthritis and systemic lupus erythematosus and risk of cryptorchidism and hypospadias in boys: a Danish nationwide study.

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.