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PURPOSE OF REVIEW: Acetaminophen (or paracetamol) is one of the most commonly used medications during pregnancy. We reviewed recent epidemiological evidence regarding intrauterine exposure to acetaminophen and risk for asthma, neurodevelopment disorders, and reproductive health in childhood.RECENT FINDINGS: An increasing number of cohort studies have suggested that maternal use of acetaminophen during pregnancy was associated with increased risk for asthma; neurodevelopmental disorders, especially ADHD and behavioral problems; and genital malformations in the offspring. Oxidative stress and inflammation or endocrine effects are plausible shared biological mechanisms for the exposure to influence multiple developmental outcomes. We discussed methodological challenges that can threaten the validity of these observational data, including confounding and measurement errors. Novel statistical methods and research designs that can be used to mitigate these issues were introduced. Given the high prevalence of use, findings regarding intrauterine exposure to acetaminophen on multiple child health outcomes raise concerns. Research on causal and non-causal mechanisms that might explain these associations should be a priority.

STUDY QUESTIONDo maternal hypertensive disorders affect pubertal development in daughters and sons?SUMMARY ANSWERPubertal 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 ALREADYThe 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, DURATIONLongitudinal 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, METHODSParticipants 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 CHANCEIn 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 CAUTIONThe 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 FINDINGSHypertensive 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 NUMBERN/A.

Author(s): Brix, Nis; Ernst, Andreas; Lauridsen, Lea Lykke Braskhoj; Parner, Erik Thorlund; Arah, Onyebuchi A; Olsen, Jorn; Henriksen, Tine Brink; Ramlau-Hansen, Cecilia Host | Abstract: BackgroundNon-participation in aetiologic studies of pubertal timing is frequent. However, little effort has been given to explore the risk and potential impact of selection bias in studies of pubertal timing.ObjectiveWe aimed to explore the risk of selection bias due to non-participation in a newly established puberty cohort.MethodsWe evaluated whether three maternal exposures chosen a priori (pre-pregnancy obesity, smoking, and alcohol drinking during pregnancy) were associated with participation, whether pubertal timing was associated with participation, and whether selection bias influenced the associations between these exposures and pubertal timing. In total, 22 439 children from the Danish National Birth Cohort born 2000-2003 were invited to the Puberty Cohort and 15 819 (70%) participated. Exposures were self-reported during pregnancy. Pubertal timing was measured using a previously validated marker, "the height difference in standard deviations" (HD:SDS), which is the difference between pubertal height and adult height, both in standard deviations. For this study, pubertal height at around 13 years in sons and around 11 years in daughters was obtained from an external database, and adult height was predicted based on parental height reported by mothers.ResultsParticipation was associated with most exposures but not with pubertal timing, measured by HD:SDS. The associations between exposures and HD:SDS were comparable for participants only and all invited for participation.ConclusionIn conclusion, the risk of selection bias in aetiologic studies on pubertal timing in the Puberty Cohort appears minimal.

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

Exposure to exogenous sex hormones with estrogenic or anti-androgen properties may influence intrauterine development of male genitals. This population-based cohort study based on data from 44,408 live-born singleton sons in the Danish National Birth Cohort (DNBC) aimed to investigate whether maternal use of oral contraceptives prior to or during early pregnancy increase the risk of cryptorchidism or hypospadias. We found no consistent association between use of oral contraceptives and cryptorchidism or hypospadias, neither in those exposed any time four months prior to conception [cryptorchidism: adjusted Odds Ratio (aOR): 1.06 (95% CI: 0.91; 1.23), hypospadias: 0.74 (95% CI: 0.53; 1.03)] nor in those exposed any time during the first trimester of pregnancy [cryptorchidism: aOR: 0.93 (95% CI: 0.53; 1.62), hypospadias: 1.02 (95% CI: 0.32; 3.23)]. Despite relatively strong exposure levels from oral contraceptive use in pregnancy, this study revealed no evidence of an increased risk of either two genital malformations.

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.

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.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.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.Childhood overweight and obesity were associated with earlier pubertal timing even after adjustment for unobserved time-stable confounders shared within families.

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.

Several studies have reported associations between prenatal acetaminophen exposure and behavioral outcomes in young children. We aimed to evaluate the associations of prenatal and postnatal exposures to acetaminophen with behavioral problems in children at age 11 years, using behavioral measures reported by parents and children. We studied 40,934 mother-child pairs from the Danish National Birth Cohort enrolled during 1996–2002. Parent-reported and child-reported Strengths and Difficulties Questionnaire (SDQ) responses were collected during the 11-year follow-up. We estimated risk ratios for behavioral problems including total difficulties as well as internalizing or externalizing behaviors following prenatal (during pregnancy) or postnatal (within the first 18 months after birth) acetaminophen exposure. Parent-reported and child-reported SDQ scores were moderately correlated; higher for externalizing (r = 0.59) than internalizing (r = 0.49) behaviors. Prenatal acetaminophen exposure was associated with 10%–40% higher risks for total difficulties and internalizing and externalizing problems based on parent- or child-reported SDQ, with the association being stronger for greater cumulative weeks of acetaminophen use. Postnatal exposure was associated with 16%–19% higher risks for parent-reported internalizing behaviors, but the associations were weak or null for child-reported scores except for prosocial behavior. Our study corroborates published associations between prenatal exposures to acetaminophen and behavioral problems and extends the literature to early adolescence.

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.

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.

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.

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

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.

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/m2) as the reference, maternal pre-pregnancy obesity (BMI: 30.0+ kg/m2) 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: Acetaminophen (paracetamol), a medication commonly used in pregnancy, has hormonal effects, as has been suggested in experimental studies. Developmental exposure to endocrine disruptors could predispose individuals to weight gain. This study evaluated the associations between prenatal acetaminophen exposure and overweight in childhood.METHODS: A total of 30,127 (age 7) and 24,934 (age 11) children in the Danish National Birth Cohort born during 1996 to 2002 were studied. Mothers reported acetaminophen use in telephone interviews conducted during pregnancy, and children's BMI and waist circumference were reported by parents at 7 and 11 years. Differences for BMI z score and waist circumference were estimated, as well as risk ratios for overweight in girls and boys adjusting for indications of use and other confounders.RESULTS: There were no consistent associations found for prenatal acetaminophen exposure and BMI z score or waist circumference in girls and boys at both ages. Prenatal acetaminophen exposure was associated with overweight in girls at age 11 (risk ratio 1.31, 95% CI: 1.10-1.56, if exposed in all three trimesters; P CONCLUSIONS: There was no strong association between prenatal acetaminophen exposure and childhood BMI, but the findings on frequent prenatal exposure to acetaminophen and overweight in girls warrant further investigation.

Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and thus, provide a new therapeutic option. Methods: To elucidate the mechanism leading to CTL activation we used the Hepa1-6 cell line in vitro and the mouse model of in vivo polymicrobial sepsis, following cecal-ligation and -puncture (CLP) in wildtype, myeloid specific NOX-2, global NOX2 and NOX4 knockout mice, and their survival as a final readout. In this in vivo setting, we also determined hepatic mRNA and protein expression as well as clinical parameters of liver damage - aspartate- and alanine amino-transaminases. Hepatocyte specific overexpression of PD-L1 was achieved in vivo by adenoviral infection and transposon-based gene transfer using hydrodynamic injection. Results: We observed downregulation of PD-L1 on hepatocytes in the murine sepsis model. Adenoviral and transposon-based gene transfer to restore PD-L1 expression, significantly improved survival and reduced the release of liver damage, as PD-L1 is a co-receptor that negatively regulates T cell function. Similar protection was observed during pharmacological intervention using recombinant PD-L1-Fc. N-acetylcysteine blocked the downregulation of PD-L1 suggesting the involvement of reactive oxygen species. This was confirmed in vivo, as we observed significant upregulation of PD-L1 expression in NOX4 knockout mice, following sham operation, whereas its expression in global as well as myeloid lineage NOX2 knockout mice was comparable to that in the wild type animals. PD-L1 expression remained high following CLP only in total NOX2 knockouts, resulting in significantly reduced release of liver damage markers. Conclusion: These results suggest that, contrary to common assumption, maintaining PD-L1 expression on hepatocytes improves liver damage and survival of mice during sepsis. We conclude that administering recombinant PD-L1 or inhibiting NOX2 activity might offer a new therapeutic option in sepsis.

The small GTPases H, K, and NRAS are molecular switches that are indispensable for proper regulation of cellular proliferation and growth. Mutations in this family of proteins are associated with cancer and result in aberrant activation of signaling processes caused by a deregulated recruitment of downstream effector proteins. In this study, we engineered novel variants of the Ras-binding domain (RBD) of the kinase CRAF. These variants bound with high affinity to the effector binding site of active Ras. Structural characterization showed how the newly identified mutations cooperate to enhance affinity to the effector binding site compared to RBDwt. The engineered RBD variants closely mimic the interaction mode of naturally occurring Ras effectors and as dominant negative affinity reagent block their activation. Experiments with cancer cells showed that expression of these RBD variants inhibits Ras signaling leading to a reduced growth and inductions of apoptosis. Using the optimized RBD variants, we stratified patient-derived colorectal cancer organoids according to Ras dependency, which showed that the presence of Ras mutations was insufficient to predict sensitivity to Ras inhibition.

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.

Author(s): Ernst, A; Lauridsen, LLB; Brix, N; Arah, OA; Olsen, J; Olsen, LH; Ramlau-Hansen, CH | Abstract: 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: g12 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.

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.

Summary: Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease. : Han et al. report that genetic depletion of IL-38 in mice delays the resolution of imiquimod-induced psoriasis by increasing the production of the inflammatory cytokine IL-17A by skin-infiltrating T cells. Depleting these T cells or the receptor that is targeted by IL-38 reduces psoriatic skin inflammation. Keywords: IL-38, IL1RAPL1, IL-17, γδ T cells, psoriasis, inflammation

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.

Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptor(s) remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. Therefore, we investigated cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38-knockout (IL-38 KO) mice showed delayed disease resolution due to exacerbated IL-17-mediated inflammation, which was reversed by administration of mature IL-38. Mechanistically, IL-38 antagonized X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1), which was upregulated upon γδ T cell activation to feed-forward amplify IL-17 production. Heightened activation of tumor-infiltrating γδ T cells was also observed in IL-38 KO oncogene-driven mammary carcinoma, accompanied by attenuated tumor growth. Our findings, which are supported by clinical data, highlight the connection between auto-inflammation and anti-tumor immunity and indicate IL-38 as a potential therapeutic target under these conditions.

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.

Summary Purpose The ventral aspect of the penis in boys with hypospadias is composed of dysplastic tissue of the skin and the urethra. The aim of this study was to assess the pre-operative size and biomechanical properties of urethrae in boys with and without hypospadias using a more objective catheter-based system. Materials & methods In this non-blinded clinical observation study, the study population consisted of 19 boys with hypospadias—the case group (median age 13.9 months [range: 12.2–21.3])—and seven boys without hypospadias—the control group (median age 8.5 months [range: 3.8–18.1]). Modified measurements of impedance were used to assess the size, compliance and viscoelasticity of the urethrae under stepwise increased pressures (between 0, 40 and 60 cmH2O) using a customised Endolumenal Functional Lumen Imaging probe (EndoFLIP®). Results The sizes of the urethrae in boys with hypospadias are variable but tend towards being narrower and less compliant than those of the control subjects i.e. median diameter for meatus urethra was 3.2 mm (range: 2.98–3.92) in the hypospadias group compared with 3.64 (range: 3.22–4.44) in the control group at 40 cmH2O, and the median change in diameter at meatus urethra was 0.08 mm (range: −0.02 to 0.52) in the hypospadias group compared with 0.23 mm (range: −0.02 to 0.34) when the pressure was increased from 40 to 60 cmH2O. This biomechanical analysis found that there was no significant viscoelasticity of the urethral meatus in both the groups, whereas the remainder of the urethral structure generally had viscoelastic properties in the control group, seen as a creep on the time/diameter curves (Figure). In the group of boys with hypospadias, evaluations of the urethrae revealed varying viscoelastic abilities, ranging from abilities that were comparable with those of the control subjects to no sign of viscoelasticity at all. Conclusions This study is the first to measure the biomechanical properties of the urethra in children, which might help to provide an understanding as to the structural and functional changes associated with hypospadias. The urethrae in the subjects with hypospadias were variable in diameter but tended to be narrower overall, especially in the distal portion of the urethra. Furthermore, the urethrae in boys with hypospadias were frequently less viscoelastic than those of controls. Clinical relevance The EndoFLIP® system may be a future way of objectively estimating the severity of a urethral obstruction and could potentially be included in the postoperative assessment of patients with signs of hampered voiding. Download : Download high-res image (169KB) Download : Download full-size image Figure . Time/diameter curves showing the diameter change in MU (meatus urethra) and 5, 10 and 15 mm proximally from MU in urethra in two control patients (a, b) and two hypospadias patients (c, d). The arrow indicates the time of pressure increase. Figures (a) and (b) show no viscoelasticity in MU but a creep in urethra indicating viscoelasticity. Figures (c) and (d) show no viscoelasticity in MU and also no viscoelasticity in urethra after pressure increase.

Objective To investigate the possible associations between maternal pre-pregnancy body mass index (BMI) and daughters' age of menarche and subsequent markers of reproductive health. Methods Nine hundred eighty-five pregnant women (80 %) were enrolled at their routine 30th week examinations in 1988-1989. In 2008, a follow-up questionnaire was completed for 365 daughters (83 %), while 267 daughters (61 %) participated in a subsequent clinical examination. Main outcome measures were age of menarche, reproductive hormone profile, and ovarian follicle count in daughters. Results Daughters of mothers in the highest pre-pregnancy BMI tertile (BMI ≥ 22.0 kg/m(2)) had an adjusted 4.1 (0.3; 8.0) months earlier menarche compared with the middle tertile group (BMI 20.0-21.9 kg/m(2)). Among non-users of hormonal contraceptives, daughters of mothers in the highest pre-pregnancy BMI tertile had non-significantly lower dehydroepiandrosterone-sulphate (DHEAS), estradiol, and free estrogen index (FEI), compared to the middle BMI tertile. This was supported by a sub-analysis using the WHO classification (underweight, BMI

ObjectivesThis study aims to estimate the association between pregnancy-associated maternal cancers, diagnosed both prenatally and postnatally, and birth outcomes.DesignPopulation-based register study.SettingNational registers of Denmark and Sweden.ParticipantsA total of 5 523 365 children born in Denmark (1977–2008) and Sweden (1973–2006).Primary and secondary outcome measures: gestational age, birth weight, size for gestational age, Apgar score, caesarean section and sex were the outcomes of interest. ORs and relative risk ratios (RRR) with 95% CIs were estimated using logistic regression and multinomial logistic regression, respectively.ResultsIn this study, 2% of children were born to mothers with a diagnosis of cancer. Children whose mothers received a prenatal cancer diagnosis had higher risk of being born preterm (RRR: 1.77, 95% CI 1.64 to 1.90); low birth weight (RRR 1.84, 95% CI 1.69 to 2.01); low Apgar score (OR 1.36, 95% CI 1.20 to 1.56); and by caesarean section (OR: 1.69, 95% CI 1.59 to 1.80). Associations moved towards the null for analyses using postnatal diagnoses, but preterm birth (RRR: 1.13, 95% CI 1.09 to 1.17) and low birth weight (RRR: 1.14, 95% CI 1.09 to 1.18) remained statistically significant, while risk of caesarean section became so (OR: 0.95, 95% CI 0.91 to 0.98). Additionally, statistical significance was reached for large for gestational age (RRR: 1.06, 95% CI 1.01 to 1.11), high birth weight (RRR: 1.04, 95% CI 1.01 to 1.06) and caesarean section (OR: 0.95, 95% CI 0.91 to 0.98).ConclusionsResults suggest an association between pregnancy-associated cancers and adverse birth outcomes in the offspring. While this is strongest for prenatally diagnosed cancers, some smaller associations exist for postnatally diagnosed cancers, indicating that cancer itself could affect fetal development, or that cancer and adverse birth outcomes share risk factors. Future studies on maternal cancer during pregnancy should consider including some postnatal years in their exposure window.

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

STUDY QUESTION Is age of menarche (AOM) associated with subfecundity and/or infertility in adulthood? STUDY ANSWER A late onset of menarche was associated with a slightly increased risk of subfecundity and infertility. WHAT IS KNOWN ALREADY Abnormal age at onset of menarche is a risk factor for several diseases later in life, but the effect on infertility is unknown. STUDY DESIGN, SIZE AND DURATION A cohort study of 73 107 pregnant Danish women enrolled in the Danish National Birth Cohort (DNBC) between 1996 and 2002 with self-reported data on AOM and waiting time to pregnancy (TTP). PARTICIPANTS/MATERIALS, SETTING AND METHODS Information on AOM and TTP was collected through a computer-assisted telephone interview scheduled in pregnancy Week 12. We estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) using multivariate logistic regression with TTP categorized as subfecundity (TTP ≥6 months) and infertility (TTP >12 months). Multiple imputation was performed to account for missing data. MAIN RESULTS AND THE ROLE OF CHANCE We found trends towards higher odds of subfecundity and infertility with increasing age of menarche, using 13 years as the starting point. Among women reaching menarche at 15 years, the odds for subfecundity were 1.09 (95% CI: 1.03-1.15), and 1.17 (95% CI: 1.09-1.25) for women reaching menarche later than 15 years compared with the reference group of girls reaching menarche at 13 years. Additionally, women reaching menarche older than 15 years had an OR of infertility of 1.18 (95% CI: 1.08-1.29). Women younger than 11 years at menarche had lower odds of subfecundity. The results were generally attenuated when adjusting for women's age of pregnancy, but the significant positive trend of higher OR for subfecundity persisted, as did the higher OR for subfecundity among women experiencing menarche older than 15 years. LIMITATIONS, REASONS FOR CAUTION We used retrospectively collected self-reported information on AOM and TTP. Information on male factors was limited in this cohort. We only included pregnant women and have therefore no data on women with untreated and unsuccessfully treated infertility, limiting the generalizability to women who became pregnant. WIDER IMPLICATION OF THE FINDINGS This study indicates that the onset of menarche at 15 years or later is associated with subfecundity and infertility. STUDY FUNDING/COMPETING INTERESTS The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the DNBC. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the DNBC is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Foundation. This specific study was supported by a scholarship from the Ministry of Science and Innovation. No conflict of interest declared.

Maternal cigarette smoking may affect the intrauterine hormonal environment during pregnancy and this early fetal exposure may have detrimental effects on the future trajectory of reproductive health. In this review, we discuss the epidemiological literature on the association between prenatal exposure to maternal cigarette smoking and several aspects of reproductive health. The literature points towards an increased risk of the urogenital malformation cryptorchidism, but a potential protective effect on the risk of hypospadias in sons following prenatal cigarette smoking exposure. Studies on sexual maturation find a tendency towards accelerated pubertal development in exposed boys and girls. In adult life, prenatally exposed men have impaired semen quality compared with unexposed individuals, but an influence on fecundability, that is, the biological ability to reproduce, is less evident. We found no evidence to support an association between prenatal cigarette smoking exposure and testicular cancer. Among adult daughters, research is sparse and inconsistent, but exposure to cigarette smoking in utero may decrease fecundability. In conclusion, prenatal exposure to cigarette smoking may cause some long-term adverse effects on the reproductive health.

STUDY QUESTION: Does in utero exposure to constituents of cigarette smoke have a programming effect on daughters' age of menarche and markers of long-term reproductive health? SUMMARY ANSWER: In utero exposure to constituents of cigarette smoke was associated with earlier age of menarche and--to a lesser extent--changes in the testosterone profile of the young women. WHAT IS KNOWN ALREADY: Studies observe potential effects of in utero exposure to constituents of cigarette smoke on the intrauterine formation of female gonads, but the consequences on long-term reproductive health in daughters remain unclear. STUDY DESIGN, SIZE AND DURATION: A prospective cohort study was designed using data from 965 pregnant women enrolled prior to a routine 30th-week antenatal examination at a midwifery practice in Denmark from 1988 to 1989 and a follow-up of their 19-21-year-old daughters in 2008. PARTICIPANTS/MATERIALS, SETTING AND METHODS: The pregnant women provided information on lifestyle factors during pregnancy, including the exact number of cigarettes smoked per day during the first and the second trimesters. A total of 438 eligible daughters were asked to complete a web-based questionnaire on reproductive health and subsequently invited to participate in a clinical examination during 2008. Of the 367 daughters (84%) who answered the questionnaire, 267 (61%) agreed to further examination. Information on menstrual pattern was provided at examination, blood samples were drawn to be analyzed for serum levels of reproductive hormones [FSH, LH, estradiol (E(2)), sex hormone-binding globulin, anti-Müllerian hormone, dehydroepiandrosterone-sulphate (DHEAS), free testosterone and free E(2)] and number of follicles (2-9 mm) were examined by transvaginal ultrasound. The daughters were divided into three exposure groups according to the level of maternal smoking during first trimester [non-exposed (reference), low-exposed (mother smoking >0-9 cigarettes/day) and high-exposed (mother smoking ≥ 10 cigarettes/day)]. Data were analyzed by multiple regression analyses in which we adjusted for potential confounders. Both crude and adjusted test for trend were carried out using maternal smoking during the first trimester as a continuous variable. MAIN RESULTS AND THE ROLE OF CHANCE: We observed an inverse association between in utero exposure to constituents of cigarette smoke and age of menarche (P = 0.001). Daughters exposed to >0-9 cigarettes/day debuted with -2.7 [95% confidence interval (CI) -5.2 to -0.1] percentage earlier age of menarche, whereas daughters exposed to ≥ 10 cigarettes/day had -4.1 (95% CI: -6.6 to -1.5) percentage earlier age of menarche corresponding to 6.5 (95% CI: -10.7 to -2.2) months. There was a non-significant tendency towards lower levels of testosterone and DHEAS with increasing in utero exposure to constituents of cigarette smoke but no associations with follicle number, cycle length or serum levels of the other reproductive hormones were observed. LIMITATIONS AND REASONS FOR CAUTION: We collected information on age of menarche retrospectively but the recall time was relatively short (2-10 years) and the reported values were within the normal range of Caucasians. Analyses of reproductive hormones are presented only for the group of daughters who were non-users of hormonal contraceptives because users were excluded, leaving only a low number of daughters available for the analyses (n = 75), as reflected in the wide CIs. The analyses of hormones were further adjusted for menstrual phase at time of clinical examination (follicular, ovulation and luteal phase) because blood samples were not collected on a specific day of the menstrual cycle. WIDER IMPLICATIONS OF THE FINDINGS: This study supports the limited evidence of an inverse association between maternal smoking during pregnancy and age of menarche and further addresses to what extent reproductive capacity and hormones may be programmed by maternal smoking during pregnancy. A trend toward earlier maturation of females is suggested to have implications on long-term reproductive function. STUDY FUNDING/COMPETING INTEREST(S): Supported by a scholarship from The Lundbeck Foundation (R93-A8476). No conflict of interest declared.

Summary Epidemiological studies have raised concern about the reproductive consequences of prenatal cigarette smoking exposure, possibly affecting semen quality and onset of pubertal development of the offspring. The aim of this study was to further investigate pubertal development in young men exposed to cigarette smoking in foetal life. In a Danish pregnancy cohort, information on maternal smoking during pregnancy was available from questionnaires administered in 1984–1987, and information on pubertal development, assessed by age at first nocturnal emission, acne, voice break and regular shaving, was obtained from a follow-up questionnaire administered in 2005 to the young men (age: 18–21). We found no significant association between prenatal cigarette smoking exposure and earlier onset of puberty, but we did observe a tendency towards earlier age of first nocturnal emission, acne and voice break, indicating an accelerated age of pubertal development. Men exposed to ≥15 cigarettes/day had 3.1 months (95% CI: −6.4; 0.2) earlier age at acne and 2.2 months (95% CI: −7.3; 3.0) earlier age at first nocturnal emission, 1.2 months (95% CI: −4.6; 2.2) earlier age at voice break, however, 1.3 months (95% CI: −1.6; 4.3) later age at regular shaving, compared with unexposed men. Prenatal cigarette smoking exposure may induce an earlier age at onset of puberty in young men, but larger studies with prospectively collected data on pubertal development are needed to explore this hypothesis further.

OBJECTIVES: Epidemiological studies have raised concerns about the reproductive consequences of in utero exposure to alcohol. Maternal lifestyle factors have been associated with altered pubertal development, but the impact of prenatal alcohol exposure on male puberty is unknown. Thus, the objective was to explore whether prenatal alcohol exposure alters pubertal development in boys.SETTING: Follow-up of a Danish pregnancy cohort.PARTICIPANTS: Sons (N=2522) of women who were enrolled in a Danish pregnancy cohort between 1984 and 1987.PRIMARY AND SECONDARY OUTCOME MEASURES: Indicators of pubertal development, assessed by age at first nocturnal emission, voice break, acne and regular shaving.RESULTS: We found a tendency towards a later age at first nocturnal emission and voice break following in utero exposure to binge drinking. Boys exposed to ≥5 binge drinking episodes during pregnancy experienced their first nocturnal emission 7.3 months (95% CI -2.8 to 17.4) later and voice break 4.9 months (95% CI -0.6 to 10.4) later than the unexposed boys. Results for average weekly alcohol consumption were in the same direction, but differences were smaller and not statistically significant.CONCLUSIONS: We found no strong support for the hypothesis that in utero exposure to weekly alcohol consumption is a risk factor for altered pubertal development, but a tendency towards delayed pubertal development among boys exposed to binge drinking during fetal life was observed. Longitudinal studies, with data collected as children go through puberty, are needed to explore this further.

The concentrations of delta sleep-inducing peptide (DSIP)-like (DSIP-LI) and P-DSIP-like (phosphorylated, Ser7) immunoreactivity (P-DSIP-LI) were measured by specific radioimmunoassay in the cerebrospinal fluid (CSF) of patients with senile dementia of the Alzheimer type [SDAT, subdivided into early (S1), middle (S2) and late dementia (S3)], multi-infarct dementia (MD), Parkinson's disease (PD), vascular disease (VD) and communicating hydrocephalus (H), as well as in control patients (C1, C2). Mean DSIP-LI and P-DSIP-LI concentrations were found to be significantly higher in the elderly control group (C1, mean age 83 +/- 5 years) than in the middle-aged control group (C2, mean age 40 +/- 16 years). DSIP-LI and P-DSIP-LI were positively correlated with age in both control groups. Significant decreases of DSIP-LI compared with age-matched controls (C1) were observed for S2, S3, MD, PD, VD and H. In contrast, no significant differences corresponding to pathology were found for P-DSIP-LI.