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.

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.

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.

Placental weight Z-score and pubertal timing: A population-based cohort study.

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.

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.