Congenital Tooth Agenesis and Risk of Early-Onset Cancer.

Importance: There is some evidence that tooth agenesis (congenital absence of 1 or more teeth) is associated with cancer risk, especially carcinomas of the colon and ovaries, but results of previous studies are conflicting, and associations have not yet been evaluated in a population-based setting. Objective: To examine the association between tooth agenesis and specific cancer types before 40 years of age. Design, Setting, and Participants: This population-based cohort study used linking data from nationwide registries in Denmark to assess all Danish live-born singletons born from January 1, 1977, to December 31, 2018, and followed up for up to 40 years. Data were analyzed from January through June 2023. Exposure: Tooth agenesis as documented by the Danish Central Registry of Odontology (Danish municipal pediatric dental care) from January 1, 1988, to December 31, 2018, and from hospital encounters in the Danish National Patient Registry within the entire study period. Main Outcome and Measures: The primary outcome was first cancer diagnosis before 40 years of age obtained from the Danish Cancer Registry. Associations between tooth agenesis and specific cancers were estimated by Cox proportional hazards regression as hazard ratios (HRs) with 95% CIs. Analyses were split into age groups: younger than 1 year, 1 to younger than 3 years, 3 to younger than 10 years, 10 to younger than 20 years, 20 to younger than 30 years, and 30 to younger than 40 years. Associations with nonsyndromic tooth agenesis were evaluated after exclusion of individuals with known syndromes. Results: Among 2 501 715 included individuals (1 284 292 [51.3%] male), 70 288 (2.8%) had a diagnosis of tooth agenesis (mean [SD] age at diagnosis, 13.2 [4.1] years) and 26 308 (1.1%) had a diagnosis of early-onset cancer within the study period; 778 individuals had co-occurrence of tooth agenesis and cancer. Overall, tooth agenesis was positively associated with several cancer types, including neuroblastoma (age 1 to <3 years; HR, 4.20; 95% CI, 2.24-7.88), nephroblastoma (age 1 to <3 years; HR, 4.59; 95% CI, 2.37-8.91), hepatoblastoma (age 1 to <3 years; HR, 7.10; 95% CI, 2.70-18.68), osteosarcoma (age 10 to <20 years; HR, 2.19; 95% CI, 1.11-4.32), colorectal carcinomas (age 30 to <40 years; HR, 2.81; 95% CI, 1.38-5.71), and carcinomas of bladder (age 20 to <30 years; HR, 3.35; 95% CI, 1.35-8.30). Conclusions and Relevance: This cohort study found associations between congenital tooth agenesis and several cancer types, from childhood to early adulthood. Further evaluation of these associations is needed to assess possible clinical implications.

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

Congenital heart disease and the risk of impaired fertility: A Danish nationwide cohort study using time to pregnancy.

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.

Congenital Heart Disease and Fertility: A Danish Nationwide Cohort Study Including Both Men and Women.

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.

Maternal age at menarche and reproductive health in young adult men: a cohort study.

STUDY QUESTION: Is maternal age at menarche associated with reproductive health in sons measured by semen quality, testes volume and reproductive hormone levels? SUMMARY ANSWER: Later maternal age at menarche was associated with impaired semen characteristics, lower testes volume and altered levels of reproductive hormones, while earlier maternal age at menarche was not strongly associated with reproductive outcomes in sons. WHAT IS KNOWN ALREADY: Both earlier and later maternal age at menarche may be associated with altered male reproductive health outcomes. This is the first study to investigate the potential association between maternal age at menarche and semen quality, testes volume and reproductive hormone levels in sons. STUDY DESIGN, SIZE, DURATION: In this population-based cohort study, we used data from the Fetal Programming of Semen Quality Cohort nested within the Danish National Birth Cohort. In total, 5697 sons born in 1998-2000 were invited to participate in the cohort in 2017-2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1043 (18% of the invited) young men with information on maternal age at menarche provided a semen and blood sample, measured their testes volume, and filled in a questionnaire on health behavior and pubertal development. Maternal age at menarche was reported by the mothers during pregnancy and examined categorically (as earlier, at the same time or later than their peers), continuously and modeled as splines. We estimated relative percentage differences in the reproductive outcomes using negative binomial regression models. Further, we did a mediation analysis to investigate the potential mediating role of timing of the sons' pubertal development. MAIN RESULTS AND THE ROLE OF CHANCE: Sons whose mothers had age at menarche later than peers had 15% lower (95% CI: -27%; 0%) sperm concentration, 14% lower (95% CI: -28%; 1%) total sperm count, 7% higher (95% CI: 0%; 14%) proportion of nonprogressive or immotile spermatozoa, 6% lower (95% CI: -11%; 0%) testes volume, 6% lower (95% CI: -12%; 1%) luteinizing hormone, 6% lower (95% CI: -12%; 1%) sex hormone-binding globulin and 5% lower (95% CI: -9%; 0%) testosterone levels compared with sons whose mothers had age at menarche at the same time as peers. Our study did not suggest that earlier maternal age at menarche was strongly associated with semen quality, testes volume or reproductive hormones in sons. However, the spline analyses indicated a potential inverted U-shaped association for sperm concentration and testes volume, and levels of sex hormone-binding globulin and testosterone. We found no strong evidence of mediation by timing of the sons' own pubertal development. LIMITATIONS, REASONS FOR CAUTION: There was a rather low participation rate in the Fetal Programming of Semen Quality Cohort and we tried to counter it by applying selection weights. Maternal age at menarche was recalled during pregnancy, which may introduce misclassification, most likely nondifferential. Inaccuracy of the sons' recalled pubertal development years after the event may result in underestimation of the possible mediating role of pubertal timing. WIDER IMPLICATIONS OF THE FINDINGS: Our findings may represent a degree of shared heritability of reproductive health or be a result of an underlying epigenetic profile or unknown shared environmental, cultural or dietary exposure, causing both altered age at menarche and impaired reproductive health outcomes in sons. However, the exact mechanism for the investigated association remains unknown. STUDY FUNDING/COMPETING INTEREST(S): This article is part of the ReproUnion collaborative study, cofinanced by the European Union, Intereg V ÖKS (20200407). The FEPOS project was further funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis's Grant, Axel Muusfeldt's Foundation (2016-491), A.P. Møller Foundation (16-37), the Health Foundation and Dagmar Marshall's Fond. Additionally, this study received funding from Aarhus University. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Gender incongruence and timing of puberty: a population-based cohort study.

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

Semen quality and reproductive hormones in sons of subfertile couples: a cohort study.

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.

Maternal thyroid disease in pregnancy and timing of pubertal development in sons and daughters.

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.

Timing of Pubertal Development in Boys and Girls With Congenital Heart Defects: A Nationwide Cohort Study.

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.

Working life, health and well-being of parents: a joint effort to uncover hidden treasures in European birth cohorts.

OBJECTIVE: Birth cohorts collect valuable and under-utilized information on employment and health of parents before and during pregnancy, at birth, and sometimes after birth. In this discussion paper, we examine how these data could be exploited to study the complex relationships and interactions between parenthood, work, and health among parents themselves. METHODS: Using a web-based database of birth cohorts, we summarize information on maternal employment and health conditions and other potentially related variables in cohorts spread throughout Europe. This provided information on what data are available and could be used in future studies, and what was missing if specific questions are to be addressed, exploiting the opportunity to explore work-health associations across heterogenous geographical and social contexts. RESULTS: We highlight the many potentialities provided by birth cohorts and identify gaps that need to be addressed to adopt a life-course approach and investigate topics specific to the peri-pregnancy period, such as psychosocial aspects. We address the technical difficulties implied by data harmonization and the ethical challenges related to the repurposing of data, and provide scientific, ecological and economic arguments in favor of improving the value of data already available as a result of a serious investment in human and material resources. CONCLUSIONS: There is a hidden treasure in birth cohorts that deserves to be brought out to study the relationships between employment and health among working parents in a time when the boundaries between work and life are being stretched more than ever before.

Breast feeding and timing of puberty in boys and girls: A nationwide cohort study.

BACKGROUND: Breast feeding has been associated with improved infant health, but its impact on pubertal timing remains uncertain, particularly in boys. OBJECTIVE: The objective of this study was to investigate the association between duration of breast feeding and pubertal timing in boys and girls. METHODS: This population-based cohort study included 13 511 boys and girls from the Puberty Cohort nested within the Danish National Birth Cohort. The children gave half-yearly, self-reported information on pubertal development through questionnaires (Tanner stages, age at menarche, first ejaculation, voice break, axillary hair growth, and acne). Information on breast feeding was provided by the mothers when the children were 6 months of age. We estimated mean differences (in months) in age at attaining each pubertal marker and for overall timing of puberty (combined estimate) for every additional month of exclusive breast feeding. Furthermore, we estimated differences in pubertal age when comparing children never exclusively breastfed and exclusively breastfed <4 months using children exclusively breastfed ≥4 months as reference. In sub-analyses, we further adjusted for infant weight gain and childhood BMI at 7 years to investigate whether these variables mediated the association. RESULTS: Boys tended to reach pubertal markers later for every additional month of exclusive breast feeding (combined estimate: 0.2 (95% confidence interval [CI] 0.0, 0.4 months). Never exclusively breastfed boys reached pubertal markers earlier than the boys exclusively breastfed ≥4 months (combined estimate: -4.1 (95% CI -6.7, -1.6) months). Boys exclusively breastfed <4 months also reached pubertal markers earlier than those never exclusively breastfed but with smaller differences. In girls, duration of breast feeding was not associated with pubertal development. When including infant weight gain or childhood BMI, the results remained essentially unchanged. CONCLUSIONS: Shorter duration of exclusive breast feeding was associated with earlier pubertal development in boys but not in girls.

Female cigarette smoking and successful fertility treatment: A Danish cohort study.

INTRODUCTION: Despite smoking being a well-established risk factor for adverse pregnancy and neonatal outcomes, a substantial proportion of women of reproductive age smoke. Previously, meta-analyses have indicated a significantly negative impact of female smoking on outcomes of assisted reproduction, yet most of the included studies have several, essential methodological limitations. We aimed to investigate whether female cigarette smoking may affect the chance of achieving a clinical pregnancy and live birth among women and couples receiving medically assisted reproduction treatment. MATERIAL AND METHODS: A cohort study with longitudinally and repeatedly collected exposure information from 1 January 2010 to 31 August 2015, including data on 1708 women and potential partners initiating either intrauterine insemination, in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) or frozen embryo transfer treatment cycles at the public Fertility Clinic, Aarhus University Hospital, Denmark. Smoking was assessed from self-reported questionnaires completed before treatment. Outcomes were a clinical pregnancy and a live birth. Information on these was obtained from the Danish national health registries, allowing complete follow-up. To evaluate associations between female occasional/daily cigarette smoking and successful medically assisted reproduction treatments, a modified Poisson regression with robust standard errors was used. RESULTS: Female occasional/daily cigarette smoking was not associated with the chance of achieving a clinical pregnancy or a live birth in all intrauterine insemination or IVF/ICSI treatment cycles. When compared with nonsmokers, the adjusted relative risk for obtaining a live birth for those reporting smoking was 1.22 (0.70-2.12) among women initiating 1456 intrauterine insemination treatment cycles. Among women initiating 2788 IVF/ICSI treatment cycles, those reporting occasional/daily smoking had a relative risk for obtaining a live birth of 1.15 (0.82-1.60) when compared with nonsmokers. CONCLUSIONS: Occasionally/daily cigarette smoking women had similar chance of achieving a clinical pregnancy or a live birth as the nonsmokers when receiving medically assisted reproduction treatments. However, tobacco use before and during pregnancy remains a major cause of reduced fertility as well as maternal, fetal, and infant morbidity and mortality, and should strongly be discouraged.

Maternal pre-pregnancy overweight and infertility in sons and daughters: A cohort study.

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/m2 ; 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/m2 , 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/m2 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.

Hypertensive disorders in pregnancy and timing of pubertal development in daughters and sons.

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.

Prenatal exposure to antibiotics and timing of puberty in sons and daughters: A population-based cohort study.

OBJECTIVE: To investigate if prenatal exposure to antibiotics is associated with earlier timing of pubertal development in sons and daughters. STUDY DESIGN: This population-based cohort study is based upon the Puberty Cohort and includes a sample of 15,638 children born 2000-2003 in Denmark. Information on maternal use of antibiotics was collected around gestational week 30 and 6 months postpartum. The children were followed-up half-yearly from 11 years of age and throughout sexual maturation providing information on Tanner stages, acne and axillary hair, in addition to voice break and first ejaculation in sons and menarche in daughters. Due to the half-yearly collection of data on pubertal timing, the data was censored and therefore analysed using a multivariable censored time-to-event regression model. We examined both prenatal exposure to antibiotics at any time in pregnancy and trimester-specific prenatal exposure to antibiotics and pubertal timing, adjusting for maternal baseline socioeconomic and lifestyle characteristics. Mean age differences for the pubertal milestones between exposure groups were estimated. A combined estimate for overall pubertal timing was calculated based on combining all pubertal milestones into one model for sons and daughters, using Huber-White robust variance estimation which handles the risk of type 1 errors due to multiple testing of correlated outcomes. An active comparator approach with restriction to women reporting to have a urinary tract infection (cystitis) treated with either penicillin or sulfonamides was employed in a sub-analysis. RESULTS: The prevalence of any maternal use of antibiotics in pregnancy was 21.1 %. There was no association between prenatal exposure to antibiotics and timing of pubertal development for the individual milestones. The adjusted combined estimate for pubertal timing in sons prenatally exposed to antibiotics at any point in pregnancy was -0.4 (95 % confidence interval (CI): -1.2; 0.4) months compared to unexposed sons. The adjusted combined estimate for pubertal timing in daughters prenatally exposed to antibiotics at any point in pregnancy was -0.1 (95 % CI: -0.9; 0.7) months compared to unexposed daughters. Both the trimester-specific analyses and the active comparator analysis revealed similar results. CONCLUSION: Prenatal exposure to antibiotics was not associated with pubertal timing.

Alcohol intake during pregnancy and timing of puberty in sons and daughters: A nationwide cohort study.

We explored whether maternal alcohol intake in early pregnancy is associated with pubertal timing in sons and daughters. In total, 15,819 children, born 2000-2003 within the Danish National Birth Cohort, gave half-yearly, self-reported information on pubertal development (Tanner stages, voice break, first ejaculation, menarche, acne, and axillary hair) from 11 years during 2012-2018. Information on maternal average alcohol intake in first trimester and binge drinking episodes (intake of ≥5 drinks on the same occasion) in first trimester was self-reported by mothers during pregnancy. Average alcohol intake of 5+ weekly drinks in first trimester was not associated with pubertal timing in sons (with no alcohol intake as the reference). A tendency towards earlier pubertal timing was observed in daughters (-2.0 (95 % confidence interval: -4.2, 0.3) months) when combining the estimates for all pubertal milestones. Binge drinking was not associated with pubertal timing in neither sons nor daughters.

Pubertal development after unintended intrauterine exposure to oral contraceptives: a nationwide cohort study.

OBJECTIVE: To study the associations between exposure to oral contraceptives before conception and early in pregnancy and pubertal timing in boys and girls. DESIGN: Population-based cohort study. SETTING: Not applicable. PATIENT(S): Overall, 15,800 children (70%) born during 2000-2003 into the Danish National Birth Cohort were categorized according to maternal use of combined oral contraceptive pills or progestin-only pills reported around gestational week 17: no exposure (reference), exposure 4 months before conception, and exposure in early pregnancy. Children self-assessed pubertal status using Web-based questionnaires from 11 years and biannually throughout puberty. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Adjusted mean age differences (months) for attaining individual pubertal milestones and overall pubertal timing. Proportion mediated by prepubertal body mass index. RESULT(S): In boys, intrauterine exposure to oral contraceptives showed a tendency toward slightly earlier mean age for voice break (months, -3.8; 95% confidence interval [CI] -6.5, -1.0) and first ejaculation (months, -2.9; 95% CI -5.9, 0.1) and a mean difference of -1.4 months (95% CI -3.3, 0.4) for overall pubertal timing. Girls with intrauterine exposure tended to have slightly earlier age at menarche (months, -1.9; 95% CI -4.0, 0.3) and Tanner breast stages and had a mean difference of -0.9 months (95% CI -2.7, 1.0) for overall pubertal timing. Exposure before conception was not associated with pubertal timing. Prepubertal body mass index did not play a mediating role. CONCLUSION(S): This study shows some evidence that intrauterine exposure to oral contraceptives might slightly affect pubertal timing.

Incidence and prevalence of keratoconus in Denmark - an update.

PURPOSE: To describe the annual incidence rate of keratoconus in Denmark 1995-2015 and prevalence of keratoconus in the National Danish Patient Register 1977-2015. METHODS: All patients diagnosed with keratoconus in the National Danish Patient Register 1977-2015 were included in the study. The annual incidence rates and the overall prevalence of diagnosed keratoconus in the register were calculated using life tables from the general Danish population. A sub-analysis excluding immigrants and descendants was performed. RESULTS: An increase in the annual incidence rate was seen from 1.24 per 100 000 person-years in 2003 to 3.83 per 100 000 in 2011. The average incidence rate 2011-2015 was 3.60 per 100 000 person-years. A survey of primary-sector ophthalmologists supported that the register data could be considered complete from 2011. The prevalence of diagnosed keratoconus in the National Patient Register 1977-2015 was 44 per 100 000 persons. Excluding immigrants and descendants yielded an average incidence rate 2011-2015 of 2.89 per 100 000 person-years and a prevalence of diagnosed keratoconus in the National Patient Register 1977-2015 of 40 per 100 000 persons. CONCLUSION: The present incidence rate (based on 2011-2015 data) has increased 2-3-fold during the last 10-15 years. The increase is possibly largely a consequence of more complete data due to the availability of corneal cross-linking, which has changed the referral pattern from the primary sector. Other factors such as better diagnostic tools and immigration may also play a role.

Mental and behavioural disorders in the children of mothers diagnosed with cancer: A Danish population-based register study.

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.