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Objective: To investigate whether maternal stress in pregnancy is associated with pubertal timing in girls and boys and to explore potential mediation by childhood body mass index (BMI) and childhood psychosocial stress., Design: Cohort study., Setting: Not applicable., Patients: In total, 14,702 girls and boys from the Puberty Cohort, nested within the Danish National Birth Cohort., Intervention: Maternal stress was obtained from a computer-assisted telephone interview in gestational weeks 30-32 as maternal life stress and emotional distress in pregnancy using questions on the basis of validated screening tools. Maternal life stress and emotional distress in pregnancy were analyzed separately and in an interaction analysis., Main Outcome Measures: Pubertal timing was measured half-yearly from age 11 years and throughout pubertal development and assessed as Tanner stages 1-5 (breast and pubic hair development in girls and genital and pubic hair development in boys), menarche in girls, voice break and first ejaculation in boys, and occurrence of acne and axillary hair in both girls and boys. A combined estimate for overall pubertal timing was derived using Huber-White robust variance estimation. Mean differences in age at attaining the pubertal milestones according to prenatal exposure to no (reference), low-, moderate-, or high-maternal stress in pregnancy were estimated using a multivariable censored regression model. Potential mediation by childhood BMI and childhood psychosocial stress was investigated in separate models., Results: After adjustment for potential confounding factors, prenatal exposure to high-maternal life stress (combined estimate: -1.8 months [95% CI, -2.7 to -0.8] and -0.9 months [95% CI, -1.8 to 0.0]), high maternal emotional distress (combined estimate: -1.5 months [95% CI, -2.5 to -0.5] and -1.7 months [95% CI, -2.8 to -0.7]), and both high-maternal life stress and emotional distress (combined estimate: -2.8 months [95% CI, -4.2, to -1.4] and -1.7 months [95% CI, -3.1 to -0.2]) were associated with earlier pubertal timing in girls and boys, respectively. The associations were not mediated by childhood BMI or childhood psychosocial stress., Conclusions: Prenatal exposure to maternal stress in pregnancy was associated with earlier pubertal timing in girls and boys in a dose-dependent manner. The associations were not mediated by childhood BMI or childhood psychosocial stress., Competing Interests: Declaration of Interests A.G.S. has nothing to disclose. N.B. has nothing to disclose. T.B.H. has nothing to disclose. C.H.R.H. has nothing to disclose., (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.)

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., (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.

Background: There is considerable public and scientific interest in the declining age of pubertal timing. Prenatal and postnatal stress has been proposed to relate with earlier pubertal timing, but it remains unknown whether intrapartum stress may affect pubertal timing as well., Objective: This study aims to examine the potential effect of caesarean delivery on pubertal timing in boys and girls., Methods: This study was based upon the nationwide Puberty Cohort nested within the Danish National Birth Cohort (DNBC) from 2000 to 2003. A total of 15,731 mother-child pairs with complete information on delivery mode and puberty were included in the main analysis. The delivery mode was categorised into non-instrumental vaginal delivery (reference), instrumental vaginal delivery, elective caesarean delivery before labour, emergency caesarean delivery during labour and un-specified caesarean delivery. Children's pubertal development were self-reported in web-based questionnaires from 11 years of age and every 6 months throughout puberty (2012-2019), including Tanner stages 2-5, menarche, voice break, first ejaculation, axillary hair growth and the onset of acne. Regression models for censored, normally distributed time-to-event data were used to estimate mean monthly differences in age at attaining the different pubertal milestones and the average of all these estimates for each sex (a combined indicator of pubertal timing)., Results: A total of 2810 participants were born by caesarean delivery (17.9%). Neither elective nor emergency caesarean delivery was associated with earlier age at achieving the pubertal milestones in boys or in girls. For the combined indicator, the mean age differences for elective caesarean delivery and emergency caesarean delivery were 0.1 (95% CI -1.1, 1.4) months and -0.7 (95% CI -2.0, 0.5) months in boys and 0.7 (95% CI -0.7, 2.0) and 0.2 (95% CI -1.3, 1.7) in girls., Conclusions: This study does not suggest a clinically important effect of caesarean delivery on children's pubertal timing., (© 2021 John Wiley & Sons Ltd.)

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., (© 2021 John Wiley & Sons Ltd.)

This cohort study, including 15,810 children born 2000-2003 in Denmark, aimed to investigate the association between father absence in pregnancy or during childhood and pubertal development in girls and boys. The children were followed from 11 years of age and throughout pubertal development. Mean age differences according to exposure groups were estimated for each pubertal marker separately and for a combined pubertal marker. The results suggested that father absence in pregnancy and during childhood was associated with earlier pubertal development in girls, and father absence from late childhood was associated with earlier pubertal development in boys. The paternal investment theory, the psychosocial acceleration theory and the energetics theory were explored, and did not seem to explain the observed associations., (© 2021 Society for Research in Child Development.)

Background: The placenta provides nutrients, oxygen, and hormonal support for adequate fetal growth and development of the hormonal axes, which are important for pubertal timing later in life., Objectives: We investigated if an indicator of poor placental function, low gestational age-specific Z-score for placental weight at birth, was associated with earlier pubertal timing., Methods: The study is based on a population-based cohort of 15 195 singleton boys and girls (68% of 22 439 invited) born 20 to 43 weeks of gestation (2000-2003) nested within the Danish National Birth Cohort. Placental Z-score was estimated from data collected at birth. Between 2012 and 2018, the children returned half-yearly web-based questionnaires from age of 11 years on status of the pubertal milestones: Tanner stages, voice break, first ejaculation, menarche, acne, and axillary hair. We estimated adjusted monthly differences in mean age at attaining the pubertal milestones and pubertal timing overall with placental Z-score continuously and as restricted cubic splines. Further, we explored whether growth by birthweight Z-score and body mass index Z-score around 7 years mediated the associations., Results: Placental Z-score was positively associated with age at attaining most of the pubertal milestones in girls, particularly for age at menarche, but not in boys. Effect sizes were modest, and when combining all pubertal milestones, one standard deviation increase in placental Z-score was associated with 0.5 months (95% confidence interval [CI] 0.2, 0.9) later pubertal timing overall in girls. The associations in girls were largely mediated through fetal growth., Conclusions: Assuming that placental Z-score correlates with placental function, these findings suggest that placental dysfunction (low placental Z-score) advances pubertal timing in girls slightly by reducing fetal growth. Future studies need to evaluate whether placental weight sufficiently captures intrauterine growth of importance for pubertal development and search for other potential candidates reflecting placental function., (© 2020 John Wiley & Sons Ltd.)

Background: Early puberty is a risk indicator for adult diseases. Identification of modifiable causes of earlier puberty is, therefore, warranted. We estimate the association between childhood body mass index (BMI) and pubertal timing in a cohort study and in a sibling-matched study to adjust for unobserved time-stable confounders shared within families., Methods: For the cohort study, 11 046 of 22 439 (49%) invited children, born 2000-203, from the Danish National Birth Cohort (DNBC) had information on childhood BMI at 7 years and self-reported, half-yearly puberty information from 11 years on Tanner stages, menarche, voice break, first ejaculation, acne, and axillary hair. For the sibling-matched study, 1700 brothers and sisters were included among 86 820 live-born singletons from the DNBC., Results: Childhood overweight (85th ≤ BMI < 95th percentile) and obesity (BMI ≥ 95th percentile) were associated with earlier age attaining the pubertal milestones in a dose-dependent manner in boys and girls. When modelling all pubertal milestones simultaneously, the pubertal milestones were attained earlier in: overweight boys: -3.1 [95% confidence interval (CI): -4.5, -1.7] months, overweight girls: -5.5 (95% CI: -7.1, -3.9) months, obese boys: -3.5 (95% CI: -5.1, -2.0) months, obese girls: -5.2 (95% CI: -7.1, -3.4) months compared with normal weight (BMI  < 85th percentile) children. In the sibling-matched study, higher BMI was associated with earlier age at attaining most pubertal milestones in girls, but only a tendency toward earlier pubertal timing was observed in boys., Conclusions: Childhood overweight and obesity were associated with earlier pubertal timing even after adjustment for unobserved time-stable confounders shared within families., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Early pubertal timing has been associated with adult diseases, and identifying preventable causes is of importance. In utero exposure to exogenous glucocorticoids, has been associated with changes in the reproductive hormonal axes in the children, which may influence pubertal timing. Exogenous glucocorticoids can be indicated for diseases such as asthma, allergy, skin diseases, as well as muscle and joint diseases. The aim was to explore the association between in utero exposure to glucocorticoids and pubertal timing in the children. This population-based study was conducted in the Puberty Cohort including 15,819 children, which is a sub-cohort of the Danish National Birth Cohort. Information on maternal glucocorticoid treatment was collected through interviews during pregnancy. Information on pubertal timing was obtained by questionnaires every 6 months throughout puberty, including Tanner Stages, axillary hair, acne, voice break, first ejaculation and menarche. The potential impact of confounding by indication was explored by stratifying on indication and treatment status. Overall, 6.8% of the children were exposed to glucocorticoids in utero. Exposure to glucocorticoids in utero was not associated with earlier puberty for neither boys nor girls with combined estimates of 0.4 months (95% CI: -1.5; 2.2) and -0.7 months (95% CI: -2.5; 1.2).

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

Background: In many countries, an increased prevalence of obesity in pregnancy has coincided with a declining pubertal age. We aimed to explore the potential effect of maternal pre-pregnancy overweight and obesity on timing of puberty in sons and daughters., Methods: Between 2012 and 2018, 15 819 of 22 439 invited children from the Danish National Birth Cohort, born 2000-03, provided half-yearly information from the age of 11 years on the pubertal milestones: Tanner stages, voice break, first ejaculation, menarche, acne and axillary hair. We estimated adjusted mean monthly differences (with 95% confidence intervals) in age at attaining the pubertal milestones for children exposed to maternal pre-pregnancy obesity [body mass index (BMI) ≥30.0 kg/m2] or overweight (BMI 25.0 to 29.9 kg/m2) with normal weight (BMI 18.5 to 24.9 kg/m2) as reference. In mediation analysis, we explored whether childhood BMI at age 7 years mediated the associations., Results: Maternal pre-pregnancy obesity was associated with earlier age at attaining most pubertal milestones in sons, and pre-pregnancy overweight and obesity were associated with earlier age at attaining all pubertal milestones in daughters. When combining all pubertal milestones, pre-pregnancy obesity [sons: -1.5 (-2.5, -0.4) months; daughters: -3.2 (-4.2, -2.1) months] and overweight [daughters only: -2.6 (-3.3, -1.8) months] were associated with earlier timing of puberty. The associations in sons were completely mediated by higher childhood BMI and partly so in daughters., Conclusions: Maternal pre-pregnancy obesity appears to lower timing of puberty through childhood obesity in sons and mainly through other mechanisms in daughters., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Earlier pubertal timing has been observed in many countries. We aimed to explore if prenatal exposure to maternal obesity, smoking, and alcohol intake was associated with timing of puberty by use of a novel marker of pubertal timing: 'the height difference in standard deviations' (HD:SDS)., Methods: HD:SDS is the difference between pubertal height in standard deviations and adult height in standard deviations, and it correlates well with age at peak height velocity. Pubertal height was measured by health care professionals at approximately 13 years in boys and 11 years in girls, and the children's adult height was predicted from parental height reported by the mothers during pregnancy. Information on HD:SDS was available for 42,849 of 56,641 eligible boys and girls from the Danish National Birth Cohort born 2000-2003. In a subsample, HD:SDS was validated against age at the following self-reported pubertal milestones: Tanner stages, menarche, first ejaculation, voice break, acne, and axillary hair. Prenatal exposures were reported by mothers during pregnancy., Results: HD:SDS correlated moderately with the pubertal milestones considered (correlation coefficients: - 0.20 to - 0.53). With normal weight (body mass index (BMI): 18.5-24.9 kg/m 2 ) as the reference, maternal pre-pregnancy obesity (BMI: 30.0+ kg/m 2 ) was associated with earlier pubertal timing: 0.23 (95% confidence interval (CI): 0.18, 0.28) higher HD:SDS in boys and 0.19 (95% CI, 0.14, 0.24) higher HD:SDS in girls. Maternal smoking was not associated with pubertal timing. Compared to alcohol abstainers, maternal intake of > 3 units of alcohol weekly was associated with later puberty in boys only: 0.14 (95% CI, 0.05, 0.24) lower HD:SDS., Conclusion: As correlations between HD:SDS and the considered pubertal milestones were comparable to those reported in the literature between age a peak height velocity and the considered pubertal milestones, the validity of HD:SDS seems acceptable. Maternal pre-pregnancy obesity was associated with earlier pubertal timing in both sexes, and maternal alcohol intake during pregnancy was associated with later pubertal timing in boys. Maternal smoking has been linked to earlier timing of puberty, but this was not replicated in our setting using HD:SDS as a marker of pubertal timing.

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., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: It remains unsettled whether prenatal exposure to perfluoroalkyl substances (PFASs) affects human reproductive health through potential endocrine disruption., Objectives: We aimed to explore the associations between prenatal exposure to several PFASs and various aspects of pubertal development in boys and girls., Methods: We studied two samples ([Formula: see text] and 445) from the Puberty Cohort, nested within the Danish National Birth Cohort (DNBC), measuring PFAS in maternal plasma from early gestation. Data on pubertal development were collected biannually from the age of 11 y until full maturation, using web-based questionnaires. Outcomes were age at menarche, voice break, first ejaculation, and Tanner stages 2 to 5 for pubic hair, breast, genital development, and a combined puberty indicator. A regression model for censored data was used to estimate mean difference (months) in age at achieving the pubertal outcomes across tertiles of PFAS concentrations and with a doubling of PFAS concentrations (continuous). For perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), a meta-analysis was used to provide a weighted average of the point estimates from samples 1 and 2., Results: Overall, prenatal exposure to PFOS, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PDFA) (girls) and PFHxS and PFHpS (boys) was associated with lower mean age at puberty marker onset. PFDA and PFNA exposure was associated with higher mean age at onset of puberty in boys. Nonmonotonic associations in girls (PFOS, PFHpS, PFDA) and boys (PFDA, PFNA) were observed, showing larger mean age differences for the combined puberty indicator in the middle tertile [girls: PFOS: [Formula: see text] mo, 95% confidence interval (CI): [Formula: see text], [Formula: see text]; PFHpS: [Formula: see text] mo, 95% CI: [Formula: see text], 1.85; PFDA: [Formula: see text] mo, 95% CI: [Formula: see text], 1.83; and boys: PFNA: 4.45 mo, 95% CI: [Formula: see text], 10.21; PFDA: 4.59 mo, 95% CI: [Formula: see text], 10.11] than in the highest tertile with the lowest as reference., Conclusions: Our population-based cohort study suggests sex-specific associations of altered pubertal development with prenatal exposure to PFASs. These findings are novel, and replication is needed. https://doi.org/10.1289/EHP3567.

Background: A secular trend towards earlier puberty has been observed in girls, while a similar trend has been more uncertain in boys. We estimated current ages at pubertal development in both boys and girls., Methods: In this population-based cohort study, 14 759 of 22 439 invited boys and girls born from 2000 to 2003 in the Danish National Birth Cohort gave half-yearly self-reported information on puberty from the age of 11.5 years and throughout puberty. This late start of follow-up limits the estimation of age at onset of puberty but not later pubertal milestones. We estimated mean age at attaining the following pubertal milestones in years with 95% confidence intervals (CI): age at menarche, voice break, first ejaculation of semen and Tanner stages for pubic hair development and breast development or genital development. Further, the difference in mean age at menarche between mothers and daughters was estimated., Results: In boys, voice break occurred at 13.1 (95% CI 13.0, 13.1) years, first ejaculation of semen occurred at 13.4 (95% CI 13.3, 13.4) years, and Tanner Genital Stage 5 occurred at 15.6 (95% CI 15.5, 15.6) years. In girls, age at menarche occurred at 13.0 (95% CI 13.0, 13.1) years and Tanner Breast Stage 5 occurred at 15.8 (95% CI 15.7, 15.9) years. Daughters had menarche 3.6 (95% CI 3.1, 4.2) months earlier than their mothers had., Conclusion: These data indicate that age at menarche has declined and to some extent support a decline in age at attaining other markers of pubertal development among boys., (© 2018 The Authors. Paediatric and Perinatal Epidemiology Published by John Wiley & Sons Ltd.)

This study explored the association between exposure to acetaminophen during pregnancy and pubertal development using data from 15,822 boys and girls in the longitudinal Puberty Cohort, nested within the Danish National Birth Cohort. Use of acetaminophen was reported 3 times during pregnancy and 6 months postpartum. In total, 54% of mothers indicated use at least once during pregnancy. Between 2012 and 2017, sons and daughters provided information on a wide range of pubertal milestones-including Tanner stages, axillary hair growth, and age at menarche or voice break and first ejaculation-every 6 months from 11 years of age until full sexual maturation. Data were analyzed using a regression model for interval-censored data, providing adjusted mean monthly differences in age at attaining the pubertal milestones according to intrauterine cumulative (weeks) and trimester-specific acetaminophen exposure. Our results suggested a tendency towards slightly earlier attainment of almost all studied markers of female pubertal development with increasing number of weeks of exposure (i.e., about 1.5-3 months earlier age at pubic hair, axillary hair, and acne development comparing unexposed with those prenatally exposed for more than 12 weeks). Male pubertal development had no strong association with acetaminophen exposure.

Because early puberty has been linked to diseases later in life, identification of modifiable causes of early puberty is of interest. We explored the possible associations between maternal smoking during pregnancy and pubertal development in sons and daughters. Between 2012 and 2017, 15,819 children from the Danish National Birth Cohort, born during 2000-2003, provided half-yearly information on puberty from the age of 11 years. We estimated adjusted age differences (in months) at attaining various pubertal milestones, including Tanner stages, per 10 daily cigarettes smoked in the first trimester of gestation. In sons, exposure to smoking in utero was associated with earlier genital development (Tanner 2, -1.3 months, 95% confidence interval (CI): -2.5, 0.0; Tanner 5, -3.7 months, 95% CI: -5.3, -2.0), pubic hair development (Tanner 2, -1.8 months, 95% CI: -2.9, -0.6; Tanner 5, -2.9 months, 95% CI: -4.2, -1.7), and voice break (-2.4 months, 95% CI: -3.6, -1.3). In daughters, maternal smoking was associated with earlier breast development (Tanner 2, -3.4 months, 95% CI: -5.3, -1.5; Tanner 5, -4.7 months, 95% CI: -6.5, -2.9), pubic hair development stages 3-5 (Tanner 5, -2.5 months, 95% CI: -4.1, -1.0), and menarche (-3.1 months, 95% CI: -4.0, -2.3). Fetal exposure to tobacco smoke might advance timing of puberty in boys and girls.

Study Question: Is maternal age at menarche associated with pubertal development in sons and daughters?, Summary Answer: Maternal age at menarche was associated with pubertal development in both sons and daughters., What Is Known Already: Studies have shown that age at menarche is greatly inherited from mother to daughter, but it remains largely unknown to what extent age at menarche in mothers is associated with timing of puberty in sons., Study Design, Size, Duration: In this population-based study we used data from the Puberty Cohort nested within the Danish National Birth Cohort. Live-born singletons aged 11 were followed from 2012 to 2016., Participants/materials, Setting, Methods: In total, 15 822 children (7697 sons and 8125 daughters) gave half-yearly information on puberty from the age of 11 years until full sexual maturity or 18 years of age through self-administrated questionnaires (participation rate 71%). Information on maternal age at menarche was reported by the mothers during pregnancy. Maternal age at menarche was used both as a continuous and as a categorical variable (earlier, same time or later than peers). A multivariable regression model for interval-censored data was used., Main Results and the Role of Chance: Maternal age at menarche was positively associated with timing of genital development, pubic hair development, first ejaculation of semen, voice break, axillary hair development and acne in sons, and with timing of breast development, pubic hair development, menarche, axillary hair development and acne in daughters. In sons, the associations were of similar strength for all pubertal markers, whereas in daughters, the associations were strongest for breast development and menarche., Limitations, Reasons for Caution: Age at menarche was recalled during pregnancy. However, studies indicate that age at menarche is recalled moderately in adulthood. Information on puberty was self-reported, but inaccuracy of data would probably cause non-differential misclassification., Wider Implications of the Findings: Early maternal age at menarche was associated with earlier pubertal development, and late maternal age at menarche was associated with later pubertal development in both sons and daughters. The largest effect-estimates were for the associations between maternal age at menarche and the daughters' age at menarche and age at breast development., Study Funding/competing Interest(s): The study was funded by the Danish Council for Independent Research (4183-00152). There are no competing interests., Trial Registeration Number: N/A.

Background We evaluated the inter-rater agreement between self-assessed Tanner staging and clinical examination and the intra-individual agreement of self-assessed information on various puberty markers in late adolescents from the longitudinal nationwide Puberty Cohort, a sub-cohort of the Danish National Birth Cohort (DNBC). Methods We invited 715 children from the ongoing Puberty Cohort between June 2016 and January 2017. In total, 366 children (51%) returned an add-on questionnaire identical to the questionnaire used to collect information on puberty markers, including Tanner staging, in the Puberty Cohort. Of these, 197 (54%) also participated in a clinical examination with Tanner staging. We used percentage agreement and weighted kappa statistics to evaluate the inter-rater and intra-individual agreement. Results Due to late entry, more than 75% of children were Tanner stage 4 or above at clinical examination. In girls, the inter-rater agreement for pubic hair and breast staging was 54% and 52%, respectively, yielding weighted kappas of fair strength. In boys, pubic hair and genital staging agreed in 55% and 33%, respectively, corresponding to weighted kappas of fair to moderate strength. Boys tended to underestimate genitalia staging consistently. The intra-individual agreement on Tanner staging was 75-77% in girls and 69% in boys, whereas the intra-individual agreement on axillary hair and acne was above 92%. Conclusions Self-assessment of late stages of pubertal development may be misclassified, leading to random errors in studies of puberty timing. However, self-assessment continues to serve as an important time- and cost-saving tool in large prospective puberty cohorts.

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.)

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

Julie Jessen Hvidt, Nis Brix, Andreas Ernst, Lea Lykke Braskhøj Lauridsen, Cecilia Høst Ramlau-Hansen Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, DenmarkCorrespondence: Julie Jessen HvidtDepartment of Public Health, Section for Epidemiology, Aarhus University, Bartholins Allé 2, 8000 Aarhus C, DenmarkTel +45 2 721 0034Email Julie_Hvidt@hotmail.comPurpose: This study investigated whether size at birth and infant growth were associated with age of indicators of pubertal development in boys and girls. We hypothesized that restricted fetal growth and accelerated infant growth lead to earlier pubertal age.Patients and methods: In total, 15,822 boys and girls answered questionnaires half-yearly with information on pubertal development: age at menarche, first ejaculation, voice break, Tanner stages, axillary hair, and acne. Birth weight and gestational age were used to calculate birth weight Z-scores. Changes in infant weight Z-score from 0 to 5, 5 to 12, and 0 to 12 months were estimated. We estimated the mean monthly difference in timing of puberty between children born small-for-gestational age (SGA) and large-for-gestational age (LGA) with children born appropriate-for-gestational age (AGA) as reference. We further investigated whether increasing infant weight Z-scores were associated with age at attaining indicators of pubertal development.Results: Girls born SGA reached all pubertal markers at an earlier mean age than girls born AGA, as indicated by mean age differences below zero (eg, age at menarche: −2.3 months, 95% CI: −3.4, −1.2), except for breast development. Girls born LGA reached pubertal markers later than girls born AGA (eg, age at menarche: 1.7 months, 95% CI 0.5, 2.9). Boys born SGA and LGA achieved puberty earlier than boys born AGA, though with CIs crossing zero (eg, age at voice break for SGA: −0.7 months, 95% CI −2.1, 0.7 and for LGA: −0.7 months, 95% CI −2.1, 0.8). A 1-unit increase in weight Z-score from 0 to 12 months was associated with a mean age difference of −1.7 to −0.3 months for pubertal development in both sexes.Conclusion: Small size at birth and rapid infant growth were associated with early pubertal age, most consistent and pronounced in girls.Keywords: puberty, pubertal development, tanner stages, birth weight

Study questionDoes parental fertility, measured by time to pregnancy (TTP), or use of medically assisted reproduction (MAR) affect pubertal development in the offspring?Summary answerNeither TTP nor type of MAR treatment had clinically relevant implications for mean age at achieving individual pubertal milestones or overall timing of puberty in boys and girls.What is known alreadyParental TTP and MAR have been associated with impaired semen quality in adult sons. Timing of puberty reflects earlier signals of reproductive health, but it remains unclear whether parental fertility or MAR affects pubertal development, especially in the growing generation of children conceived by IVF or ICSI.Study design, size, durationIn this study, 15 819 children born by mothers in the Danish National Birth Cohort from 2000 to 2003 participated in a nationwide puberty cohort (participation rate = 70%). Parental TTP and use of MAR were reported by mothers in early pregnancy and children's pubertal development data was self-recorded in web-based questionnaires from 11 years of age and 6 monthly throughout puberty (2012-2018).Participants/materials, setting, methodsPubertal development in children (of planned pregnancies, n = 13 285) born by untreated subfecund (TTP: 6-12 months) (n =2038), untreated severely subfeund (TTP: >12 months) (n = 1242), treated subfecund (n = 230) and treated severely subfecund (n = 1234) parents were compared to children born to more fertile parents (TTP: ≤5 months). We estimated mean monthly differences in mean age at achieving individual pubertal milestones (i.e. age at menarche, voice break, first ejaculation and Tanner stages 2, 3, 4 and 5 for breast or genital development and pubic hair growth) and a combined indicator of timing of puberty. Further, we compared mean age at achieving the individual pubertal milestones in children born by use of IVF or ICSI (n = 480) with children born by controlled ovarian stimulation or ovulation induction with or without intrauterine insemination (n = 902).Main results and the role of chanceWe found tendencies towards slightly later mean age at male pubertal timing and slightly earlier mean age at female pubertal timing among children born by untreated subfecund, treated subfecund, untreated severely subfecund and treated severely subfecund parents. There were no specific patterns with increasing TTP, use of MAR nor type of MAR treatment, and the magnitude of the mean differences for individual milestones and overall timing of puberty were small, i.e. 0.9 months (95% CI: -1.0; 2.8) for first ejaculation and -0.5 months (95% CI: -2.0; 1.0) months for age at menarche in boys and girls, respectively, born by treated severely subfecund parents when compared with children born by more fertile parents.Limitations, reasons for cautionNon-differential misclassification of the self-reported information on parental TTP and pubertal development in the offspring may serve as an alternative explanation of the findings, possibly biasing the estimates towards the null. The information on pubertal development was collected from around 11 years of age and onwards.Wider implications of the findingsThis study adds to the growing body of literature suggesting only limited harmful effects of parental subfecundity and MAR on offspring's long-term growth and development.Study funding/competing interest(s)This work was supported by the Danish Council for Independent Research [DFF 4183-00152]; and the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose.