Congenital Tooth Agenesis and Risk of Early-Onset Cancer.

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

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

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

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

OBJECTIVE: To study the associations between parental subfecundity, assessed by time to pregnancy and use of medically-assisted reproduction, and reproductive health of young men. DESIGN: Cohort study. SETTING: Denmark. PATIENT(S): A total of 1,058 men in the Fetal Programming of Semen quality cohort, a subcohort of the Danish National Birth Cohort. INTERVENTION(S): From 2017-2019, men were recruited and provided semen and blood samples. Information on parental time to pregnancy and use of medically-assisted reproduction (including type of treatment) as well as demographic, health, and lifestyle factors were available. We estimated the crude and adjusted relative percentage differences with 95% confidence intervals (CIs) in the outcomes according to time to pregnancy and use of medically-assisted reproduction, using multiple adjusted negative binomial regression analysis. MAIN OUTCOME MEASURE(S): Semen characteristics (semen volume, sperm concentration, total sperm count, sperm motility, and morphology), testicular volume, and reproductive hormone levels (follicle stimulating hormone, luteinizing hormone, testosterone, estradiol, sex hormone-binding globulin, and free androgen index). RESULT(S): Overall, semen quality and levels of reproductive hormones were not lower among sons of subfecund parents reporting a time to pregnancy >6 months or use of intrauterine insemination. Sons conceived after in vitro fertilization or intracytoplasmic sperm injection, had a higher semen concentration (29%; 95% CI, -7%-79%) and a higher percentage of sperm with normal morphology (20%; 95% CI, -8%-56%), but with 95% CI overlapping the null. Moreover, these sons had slightly higher estradiol levels (30%; 95% CI, 7%-57%). The absolute differences seen were small, and the clinical significance of these differences are unknown. CONCLUSION(S): We found no major difference in semen quality or reproductive hormones in sons conceived by subfertile couples or with the use of medically-assisted reproduction.

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

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

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.

Maternal Smoking During Pregnancy and Timing of Puberty in Sons and Daughters: A Population-Based Cohort Study.

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.

Acetaminophen (Paracetamol) Exposure During Pregnancy and Pubertal Development in Boys and Girls From a Nationwide Puberty Cohort.

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.

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

OBJECTIVE: Maternal cancer may be associated with offspring mental and behavioural disorders through various biological pathways. When postnatally diagnosed, it may cause stress and changes in care, potentially influencing mental health. Prenatally diagnosed cancer could lead to maternal stress and treatment, or influence foetal neural development. This study investigates associations between prenatally or postnatally diagnosed maternal cancers and mental and behavioural disorders in children. METHODS: The study composed of 2 158 430 children born in Denmark (1978-2012). Children were exposed if their mother received a cancer diagnosis prenatally (2 years prepartum, until birth) or postnatally (birth, until 18 years postpartum). Further analyses considered cancer types and diagnostic delays. Children were followed until 18 years of age or the first of the following: diagnosis of a mental or behavioural disorder, emigration, death, end of follow-up. RESULTS: During follow-up 79 682 (3.7%) children were diagnosed with mental or behavioural disorders. There was an increased risk among offspring exposed to postnatally diagnosed cancers (HR 1.05; 95% CI, 1.00-1.11); for prenatally diagnosed cancers HR was 1.07 (0.87-1.31). The strongest associations for disorder types were for prenatal diagnoses with mood/affective disorders (HR 2.45; 1.02-5.89) and postnatal diagnoses with mood/affective disorders (HR 1.43; 1.14-1.79). CONCLUSIONS: The results indicate a link between maternal cancer occurrence during pregnancy or early postnatal life, and mental and behavioural disorders in offspring. This association could be driven by common factors in the two periods, such as psychological stress or genetic factors. No specific foetal programming was identified.

Pregnancy-associated cancers and birth outcomes in children: a Danish and Swedish population-based register study.

OBJECTIVES: This study aims to estimate the association between pregnancy-associated maternal cancers, diagnosed both prenatally and postnatally, and birth outcomes. DESIGN: Population-based register study. SETTING: National registers of Denmark and Sweden. PARTICIPANTS: A 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. RESULTS: In 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). CONCLUSIONS: Results 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.

Endometriosis and adenomyosis are associated with increased risk of preterm delivery and a small-for-gestational-age child: a systematic review and meta-analysis.

INTRODUCTION: The objective of this systematic review and meta-analysis was to evaluate the risk of preterm delivery and having a small-for-gestational-age (SGA) child in women with endometriosis and adenomyosis compared with women without these two diseases. MATERIAL AND METHODS: Studies on endometriosis or adenomyosis and risk of preterm delivery and/or SGA infant were included. The systematic search was conducted for all published articles in PubMed and Embase published from 1950 to 2017 using specific search terms. After duplicates were removed, two authors independently reviewed all studies, initially based on title and subsequently based on abstract. Studies considered relevant were read in full text by both reviewers to identify if studies met the inclusion criteria. RESULTS: The search found 21 studies on a total of 2 517 516 women meeting the inclusion criteria. Women with endometriosis had an increased odds of preterm delivery [odds ratio (OR) 1.47, 95% CI 1.28-1.69] and SGA infant (OR 1.26, 95% CI 1.04-1.549). Compared with endometriosis, adenomyosis implied an even higher odds of both preterm delivery (OR 3.09, 95% CI 1.88-5.09) and SGA infant (OR 3.23, 95% CI 1.71-6.09) as well. CONCLUSIONS: Women with endometriosis or adenomyosis had a higher odds of preterm delivery and having a child that was SGA compared with women without endometriosis or adenomyosis. The odds of both adverse birth outcomes was highest among women with adenomyosis. The results suggest a closer prenatal monitoring among pregnant women with endometriosis or adenomyosis.

Noise-Induced Hearing Loss - A Preventable Disease? Results of a 10-Year Longitudinal Study of Workers Exposed to Occupational Noise.

AIMS: To survey current, Danish industrial noise levels and the use of hearing protection devices (HPD) over a 10-year period and to characterise the association between occupational noise and hearing threshold shift in the same period. Furthermore, the risk of hearing loss among the baseline and the follow-up populations according to first year of occupational noise exposure is evaluated. MATERIALS AND METHODS: In 2001-2003, we conducted a baseline survey of noise- and hearing-related disorders in 11 industries with suspected high noise levels. In 2009-2010, we were able to follow up on 271 out of the 554 baseline workers (49%). Mean noise levels per industry and self-reported HPD use are described at baseline and follow-up. The association between cumulative occupational noise exposure and hearing threshold shift over the 10-year period was assessed using linear regression, and the risk of hearing loss according to year of first occupational noise exposure was evaluated with logistic regression. RESULTS: Over the 10-year period, mean noise levels declined from 83.9 dB(A) to 82.8 dB(A), and for workers exposed >85 dB(A), the use of HPD increased from 70.1 to 76.1%. We found a weak, statistically insignificant, inverse association between higher ambient cumulative noise exposure and poorer hearing (-0.10 dB hearing threshold shift per dB-year (95% confidence interval (CI): -0.36; 0.16)). The risk of hearing loss seemed to increase with earlier first year of noise exposure, but odds ratios were only statistically significant among baseline participants with first exposure before the 1980s (odds ratio: 1.90, 95% CI: 1.11; 3.22). CONCLUSIONS: We observed declining industrial noise levels, increased use of HPD and no significant impact on hearing thresholds from current ambient industrial noise levels, which indicated a successful implementation of Danish hearing conservation programs.

In utero exposure to persistent organochlorine pollutants and reproductive health in the human male.

Persistent organochlorine pollutants (POPs) are ubiquitous, bioaccumulative compounds with potential endocrine-disrupting effects. They cross the placental barrier thereby resulting in in utero exposure of the developing fetus. The objective of this study was to investigate whether maternal serum concentrations of polychlorinated biphenyls (PCBs) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) during pregnancy are associated with son's semen quality and reproductive hormone levels. During 2008-2009, we recruited 176 male offspring from a Danish cohort of pregnant women who participated in a study in 1988-1989. Each provided semen and blood samples that were analyzed for sperm concentration, total sperm count, motility, and morphology, and reproductive hormone levels, respectively. The maternal blood samples were collected in pregnancy week 30 and were analyzed for the concentrations of six PCBs (PCB-118, -138, -153, -156, -170, and -180) and p,p'-DDE. The potential associations between in utero exposure to ΣPCBs (pmol/ml), Σdioxin like-(DL) PCBs (PCB-118 and -156) (pmol/ml), and p,p'-DDE and semen quality and reproductive hormone levels were investigated using multiple regression. Maternal median (range) exposure levels of ΣPCB, ΣDL-PCB, and p,p'-DDE were 10.0 (2.1-35.0) pmol/ml, 0.8 (0.2-2.7) pmol/ml, and 8.0 (0.7-55.3) pmol/ml, respectively, reflecting typical background exposure levels in the late 1980s in Denmark. Results suggested that in utero exposure to ΣPCB, ΣDL-PCB, and p,p'-DDE was not statistically significantly associated with semen quality measures or reproductive hormone levels. Thus, results based on maternal PCB and p,p'-DDE concentrations alone are not indicative of long-term consequences for male reproductive health; however, we cannot exclude that these POPs in concert with other endocrine-modulating compounds may have adverse effects.

Having children with multiple partners is associated with reduced risk of malignant melanoma: an observation seeking a plausible explanation.

OBJECTIVE: We examined the association between the number of partners that mothers and fathers have children with and occurrence of cutaneous malignant melanoma (CMM). METHODS: We conducted a complete registry-based follow-up of all Danish mothers born after 1935 from the birth of their second child until CMM, death, emigration, or end of study in 2002. We conducted a similar follow-up of the corresponding fathers. Incidence rate ratios (IRR) and confidence intervals (CI) were estimated by Poisson regression. RESULTS: THIS STUDY CORROBORATES THAT WOMEN HAVING CHILDREN WITH THREE OR MORE MEN ARE HALF AS LIKELY TO HAVE CMM AS WOMEN WHO HAVE CHILDREN WITH ONE MAN: incidence rate ratio (IRR) = 0.51, 95% CI: 0.29, 0.91; having children by two fathers reduces risk among women by 20%: IRR = 0.80, 95% CI: 0.70, 0.91. Fathers with multiple partners tend to face a similar risk reduction. CONCLUSION: The similar patterns of mothers and fathers challenge us to consider and propose likely mechanisms common to both sexes. The patterns of reduced risk have now been reported in two large independent complete population-based studies in Sweden and Denmark.