Preeclampsia, antihypertensive medication use in pregnancy and risk of childhood cancer in offspring.

PURPOSE: Preeclampsia is a serious pregnancy complication that presents a significant risk to both the mother and the fetus. Preeclampsia and medications associated with its treatment are potentially linked to increased childhood cancer risk. Therefore, we examined the association between preeclampsia, antihypertensive medications, and childhood cancer in offspring. METHODS: Cases (n = 6,420) and controls (n = 160,484) were obtained from Danish national registries. We performed conditional logistic regression analyses to estimate the association between preeclampsia and childhood cancer risk, and examined the effects of antihypertensive medication use in pregnancy in relation to childhood cancer risk in the offspring with adjustment for relevant covariates. RESULTS: We observed an increased risk of acute lymphoblastic leukemia (ALL) among those whose mothers had preeclampsia (OR = 1.36, 95% CI 1.03, 1.79), especially for severe preeclampsia (OR = 2.36, 95% CI 1.37, 4.08). We also estimated an increased cancer risk in children born to mothers who were prescribed diuretics during pregnancy [OR = 2.09, 95% confidence interval (CI) 1.39, 3.14]. Intake of other antihypertensive medications was not associated with childhood cancer (OR = 0.78, 95% CI 0.50, 1.23). Among women who did not take diuretics in pregnancy, preeclampsia was associated with neuroblastoma (OR = 2.22, 95% CI 1.08, 4.55). CONCLUSION: Our findings suggested an increased risk for certain types of cancer in the offspring of mothers with preeclampsia and an increased risk of cancer with diuretic intake during pregnancy.

Tattoo-Associated Skin Reactions: A Danish Population-Based Survey in 5,914 Tattooed Individuals.

BACKGROUND: In Europe, Australia, and the USA, the estimated overall prevalence of tattooing is around 10-20%. Tattoo ink often comprises harmful chemicals and epidemiological studies on adverse effects of tattoos are lacking. OBJECTIVES: We aimed to estimate the prevalence of tattoo-associated skin reactions in the general Danish population and describe individuals with tattoo-associated skin reactions by socio-demographic factors and tattoo characteristics. METHODS: The study was based on respondents aged 16 years or older from a population-based 2021 survey entitled "How are you?" conducted in the Central Denmark Region (n = 33,925). Logistic regression was used to characterise individuals with tattoo-associated skin reactions by socio-demographic factors (gender, age, educational level, and ethnic background). Also, the relationship between size, age and colour of the tattoo, and tattoo-associated skin reactions was studied. Model 1 was adjusted for all socio-demographic variables (gender, age, educational level, and ethnic background); model 2, for all socio-demographic variables and tattoo characteristics (size, age, and colour). RESULTS: In total, 21.1% reported that they had at least one tattoo, 10.2% hereof reported that they had experienced tattoo-associated skin reactions (itching, pain, inflammation, and swelling) beyond the first 3 weeks after the tattoo was made. Lower age (16-44 years) (adjusted odds ratio (AOR) ≥1.75), larger tattoos (AOR ≥1.61) and having had tattoos for more than 10 years (AOR = 2.92, 95% confidence interval 1.45-5.88) increased the odds of tattoo-associated skin reactions. In general, tattooed individuals with colours other than black had higher odds of tattoo-associated skin reactions. CONCLUSION: Among participants with at least one tattoo, 10.2% had experienced tattoo-associated skin reactions beyond the first 3 weeks after their tattoo was made. This finding highlights the need for safer tattoo inks to prevent the adverse health problems experienced by many individuals with tattoos.

Maternal migraine and risk of pediatric cancers.

BACKGROUND: Maternal migraine has been linked to adverse birth outcomes including low birth weight and preterm birth, as well as congenital anomalies in offspring. It has been speculated that this may be due to the use of medications in pregnancy, but lifestyle, genetic, hormonal, and neurochemical factors could also play a role. There is evidence for varying cancer incidences among adults with migraine. Here, we utilized data from national registries in Denmark to examine associations between maternal diagnoses of migraine and risk for cancer in offspring. METHODS: We linked several national registries in Denmark to identify cases from the Cancer Registry among children less than 20 years (diagnoses 1996-2016) and controls from the Central Population Register, matched to cases by birth year and sex (25:1 matching rate). Migraine diagnoses were identified from the National Patient Register using International Classification of Diseases, versions 8 and 10 codes and migraine-specific acute or prophylactic treatment recorded in the National Pharmaceutical Register. We used logistic regression to estimate the risk of childhood cancers associated with maternal migraine. RESULTS: Maternal migraine was positively associated with risk for non-Hodgkin lymphoma (odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.01-2.86), central nervous system tumors ([OR = 1.31, 95% CI: 1.02-1.68], particularly glioma [OR = 1.64, 95% CI: 1.12-2.40]), neuroblastoma (OR = 1.75, 95% CI: 1.00-3.08), and osteosarcoma (OR = 2.60, 95% CI: 1.18-5.76). CONCLUSIONS: Associations with maternal migraine were observed for several childhood cancers, including neuronal tumors. Our findings raise questions about the role of lifestyle factors, sex hormones, genetic, and neurochemical factors in the relationship between migraine and childhood cancers.

Mode of birth and long-term maternal mental health: A follow-up study in the Danish National Birth Cohort.

BACKGROUND: Cesarean birth has been associated with increased risks of short-term mental health problems. Little is known about whether these associations persist in the long term. This study aimed to estimate the associations between mode of birth and maternal mental health in midlife while considering mental health before and during pregnancy. METHODS: Cohort study among mothers in the Danish National Birth Cohort. Birth mode for each woman's entire reproductive history was obtained from Danish national registries. Symptoms of depression and stress in midlife were self-reported using validated scales. Log binomial regression was used to calculate risk ratios (RR) with 95% confidence intervals (CI) for the association between birth mode and depressive symptoms. Linear regression was used to calculate mean difference in stress score by birth mode. RESULTS: Among 42,872 women, 15.5% reported depressive symptoms at follow-up, where they were, on average, 43.9 years and 11.2 years after their last birth. Compared with women who only ever had spontaneous vaginal births, women who only had cesarean births, or had both cesarean and vaginal births with the last birth by cesarean, reported slightly more symptoms of depression (RR 1.10, 95% CI 1.01;1.20) and stress (mean difference 0.68 on a 100-point scale, 95% CI 0.10;1.26). CONCLUSION: Whether due to the birth experience or underlying factors, depression and stress in midlife were more frequent in women with only cesarean births or whose last birth was by cesarean compared with women with vaginal births.

Maternal diabetes and childhood cancer risks in offspring: two population-based studies.

BACKGROUND: The effect of maternal diabetes on childhood cancer has not been widely studied. METHODS: We examined this in two population-based studies in Denmark (N = 6420 cancer cases, 160,484 controls) and Taiwan (N = 2160 cancer cases, 2,076,877 non-cases) using logistic regression and Cox proportional hazard regression adjusted for birth year, child's sex, maternal age and birth order. RESULTS: Gestational diabetes in Denmark [odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.71-1.35] or type II and gestational diabetes in Taiwan (type II: hazard ratio (HR) = 0.81, 95% CI: 0.63-1.05; gestational diabetes: HR = 1.06, 95% CI: 0.92-1.22) were not associated with cancer (all types combined). In Denmark, maternal type I diabetes was associated with the risk of glioma (OR = 2.33, 95% CI: 1.04-5.22), while in Taiwan, the risks of glioma (HR = 1.59, 95% CI: 1.01-2.50) were elevated among children whose mothers had gestational diabetes. There was a twofold increased risk for hepatoblastoma with maternal type II diabetes (HR = 2.02, 95% CI: 1.02-4.00). CONCLUSIONS: Our results suggest that maternal diabetes is an important risk factor for certain types of childhood cancers, emphasising the need for effective interventions targeting maternal diabetes to prevent serious health effects in offspring.

Maternal polycystic ovarian syndrome and pubertal development in daughters and sons: a population-based cohort study.

STUDY QUESTION: Does maternal polycystic ovarian syndrome (PCOS) affect the timing of pubertal development in daughters and sons? SUMMARY ANSWER: Maternal PCOS was associated with earlier adrenarche in daughters. WHAT IS KNOWN ALREADY: Female adolescents with PCOS often experience earlier adrenarche compared to adolescents without PCOS, due to hyperandrogenism. Likewise, they usually have hyperandrogenism during pregnancy, which might potentially affect the development of the foetus, including its future reproductive health. STUDY DESIGN, SIZE, DURATION: In this population-based cohort study, we included 15 596 mothers-child pairs from the Danish National Birth Cohort (DNBC) Puberty Cohort, who were followed from foetal life until full sexual maturation or 18 years of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using register-based and self-reported information on maternal PCOS and menstrual irregularities, collected during pregnancy, we categorized the mothers as having PCOS (n = 251), oligomenorhoea (n = 134), 'other menstrual irregularities' (n = 2411) or no menstrual abnormalities (reference group, n = 12 800). The children provided self-reported information on pubertal development every 6 months from the age of 11 years. The main outcome measures were adjusted mean age differences (in months) at attaining several individual pubertal milestones using an interval-censored regression model, as well as the average difference in age at attaining all pubertal milestones combined into a single estimate using Huber-White robust variance estimation. MAIN RESULTS AND THE ROLE OF CHANCE: We found that maternal PCOS was associated with an accelerated pubertal development in daughters with an overall average difference of -3.3 (95% CI: -6.3; -0.4) months based on all pubertal milestones compared to the reference group. When further looking into the average difference for adrenarche only (pubarche, axillary hair and acne), the average difference was -5.4 (95% CI: -8.7; -2.1) months compared to the reference group; whereas thelarche and menarche did not occur earlier in daughters of mothers with PCOS (average difference: -0.8 (95% CI: -3.9; 2.4) months). Oligomenorrhoea and 'other menstrual irregularities' were not associated with pubertal development in daughters. Neither PCOS, oligomenorrhoea nor 'other menstrual irregularities' were associated with pubertal development in sons. LIMITATIONS, REASONS FOR CAUTION: We expect some degree of non-differential misclassification of maternal PCOS and menstrual irregularities as well as pubertal development in the children. WIDER IMPLICATIONS OF THE FINDINGS: Maternal PCOS might accelerate adrenarche in daughters. Whether this is due to genetics, epigenetics or prenatal programming by hyperandrogenism in foetal life remains unsolved. The results from the present study can be generalized to Caucasian populations. STUDY FUNDING/COMPETING INTEREST(S): The study is funded by the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Caesarean delivery and pubertal timing in boys and girls: A Danish population-based cohort study.

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

In utero exposure to perfluoroalkyl and polyfluoroalkyl substances and attention and executive function in the offspring: A study in the Danish National Birth Cohort.

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and accumulate in humans. PFAS are suspected to affect the neuropsychological function of children, but only few studies have evaluated the association with childhood attention and executive function. OBJECTIVES: To investigate the association between intrauterine exposure to PFAS and offspring attention and executive function. METHODS: A total of 1593 children from the Danish National Birth Cohort, born 1996-2003, were included. The levels of 16 PFAS were measured in maternal plasma during pregnancy. At 5 years of age, the Test of Everyday Attention for Children at Five (TEACh-5) and the Behavior Rating Inventory of Executive Function (BRIEF) were performed. TEACh-5 scores were standardized to a mean of 0 and standard deviation (SD) of 1. BRIEF scores were standardized to a mean of 50 and a SD of 10. The associations between levels of seven PFAS and TEACh-5 and BRIEF were examined by multivariable linear regression adjusted for potential confounders. RESULTS: Perfluorooctane sulfonamide (PFOSA) was associated with poorer selective attention [standardized mean difference (95% confidence interval) -0.5 (-0.7, -0.3), highest versus lowest quartile]. Other PFAS were not clearly associated with selective attention, and we found no clear associations between PFAS exposure and sustained attention. For parent rated executive function, perfluorooctanoate (PFOA) was associated with poorer scores, standardized mean difference 3.8 (95% confidence interval 1.6, 6.0), highest versus lowest quartile. Regarding other PFAS, the associations were less clear. We found no clear associations between any PFAS and executive function rated by preschool teachers. CONCLUSION: Intrauterine exposure to PFOSA was associated with poorer selective attention, while PFOA was associated with poorer executive function. Given the widespread nature of PFAS exposure, these findings may have public health implications, warranting further investigation.

The influence of parental age on timing of puberty: A study in the Danish National Birth Cohort.

Aims: Concerns have been raised about the potential negative biological effect of postponed parenthood upon the health of subsequent generations, including reproductive health. This study aimed to estimate if high parental age at birth was associated with accelerated pubertal timing in offspring. Methods: In this large-scale cohort 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 71%). Between 2012 and 2018, the children reported half-yearly information on pubertal status using web-based questionnaires from 11 years throughout puberty or 18 years of age. Information on parental age was drawn from nationwide registers. We estimated adjusted mean differences in months for age at attaining the pubertal milestones and pubertal timing overall between the pre-specified parental age groups: 20-29 (reference), 30-34 and advanced parental age groups (35-44 years for mothers and >35 years for fathers). Results: Overall, parental age at birth of the child was not associated with pubertal timing in daughters or sons. For sons of older fathers (>35 years), we observed indications towards slightly earlier pubertal timing in the range of 0.3-2.4 months for nearly all pubertal milestones, but all confidence intervals were wide, and many included the null. Conclusions: We found no strong association between parental age and timing of puberty, and we find it unlikely that the decreasing age in pubertal timing is a result of parental decision to delay childbearing.

Maternal hypertensive disorder of pregnancy and offspring early-onset cardiovascular disease in childhood, adolescence, and young adulthood: A national population-based cohort study.

BACKGROUND: The prevalence of cardiovascular disease (CVD) has been increasing in children, adolescents, and young adults in recent decades. Exposure to adverse intrauterine environment in fetal life may contribute to the elevated risk of early-onset CVD. Many studies have shown that maternal hypertensive disorders of pregnancy (HDP) are associated with increased risks of congenital heart disease, high blood pressure, increased BMI, and systemic vascular dysfunction in offspring. However, empirical evidence on the association between prenatal exposure to maternal HDP and early-onset CVD in childhood and adolescence remains limited. METHODS AND FINDINGS: We conducted a population-based cohort study using Danish national health registers, including 2,491,340 individuals born in Denmark from 1977 to 2018. Follow-up started at birth and ended at the first diagnosis of CVD, emigration, death, or 31 December 2018, whichever came first. Exposure of maternal HDP was categorized as preeclampsia or eclampsia (n = 68,387), gestational hypertension (n = 18,603), and pregestational hypertension (n = 15,062). Outcome was the diagnosis of early-onset CVD from birth to young adulthood (up to 40 years old). We performed Cox proportional hazards regression to evaluate the associations and whether the association differed by maternal history of CVD or diabetes before childbirth. We further assessed the association by timing of onset and severity of preeclampsia. The median follow-up time was 18.37 years, and 51.3% of the participants were males. A total of 4,532 offspring in the exposed group (2.47 per 1,000 person-years) and 94,457 in the unexposed group (2.03 per 1,000 person-years) were diagnosed with CVD. We found that exposure to maternal HDP was associated with an increased risk of early-onset CVD (hazard ratio [HR]: 1.23; 95% CI = 1.19 to 1.26; P < 0.001). The HRs for preeclampsia or eclampsia, gestational hypertension, and pregestational hypertension were 1.22 (95% CI, 1.18 to 1.26; P < 0.001), 1.25 (95% CI, 1.17 to 1.34; P < 0.001), and 1.28 (95% CI, 1.15 to 1.42; P < 0.001), respectively. We also observed increased risks for type-specific CVDs, in particular for hypertensive disease (HR, 2.11; 95% CI, 1.96 to 2.27; P < 0.001) and myocardial infarction (HR, 1.49; 95% CI, 1.12 to 1.98; P = 0.007). Strong associations were found among offspring of mothers with CVD history (HR, 1.67; 95% CI, 1.41 to 1.98; P < 0.001) or comorbid diabetes (HR, 1.56; 95% CI, 1.34 to 1.83; P < 0.001). When considering timing of onset and severity of preeclampsia on offspring CVD, the strongest association was observed for early-onset and severe preeclampsia (HR, 1.48, 95% CI, 1.30 to 1.67; P < 0.001). Study limitations include the lack of information on certain potential confounders (including smoking, physical activity, and alcohol consumption) and limited generalizability in other countries with varying disparities in healthcare. CONCLUSIONS: Offspring born to mothers with HDP, especially mothers with CVD or diabetes history, were at increased risks of overall and certain type-specific early-onset CVDs in their first decades of life. Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring.

Behavioral Problems at Age 11 Years After Prenatal and Postnatal Exposure to Acetaminophen: Parent-Reported and Self-Reported Outcomes.

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.

Parental occupation and childhood germ cell tumors: a case-control study in Denmark, 1968-2016.

PURPOSE: To examine associations between parental occupation and childhood germ cell tumors (GCTs) in offspring while distinguishing by common histologic subtype (i.e., yolk sac tumor and teratoma). METHODS: This population-based case-control study included childhood GCT cases in Denmark diagnosed 1968-2015 (< 16 years old at diagnosis) and sex and birth year-matched controls. Demographic information and parental employment histories were obtained from Danish registries. Parental occupation was assessed by industry; job-exposure matrices were used to examine specific occupational exposures (i.e., potentially carcinogenic organic solvents and social contact). Conditional multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CIs). RESULTS: Overall, 178 childhood GCT cases (50 yolk sac tumors; 65 teratomas) and 4,355 controls were included for analysis. Maternal employment in education during pregnancy was associated with offspring GCTs (OR 2.45, 95% CI 1.23-4.90), especially yolk sac tumors (OR 5.27, 95% CI 1.94-14.28). High levels of both maternal and paternal occupational social contact were also associated with offspring yolk sac tumors across all exposure periods (ORs 2.30-4.63). No signals were observed for paternal occupational solvent exposure, while imprecise associations were estimated for maternal exposure (e.g., dichloromethane exposure during pregnancy, OR 1.51, 95% CI 0.77-2.95). CONCLUSION: Our findings suggest that parental occupation is associated with offspring GCTs, with most consistent evidence supporting an association between maternal employment in education or other high social contact jobs and offspring yolk sac tumors.

Maternal thyroid disease and adiposity in mother and child.

OBJECTIVE: Thyroid hormones are crucial developmental factors, and thyroid disease in pregnant women is a concern. Overweight and obesity are also important health concerns, and we hypothesized that in utero exposure to maternal thyroid disease could programme the foetus to development of adiposity. DESIGN: Cohort and case-cohort studies. PARTICIPANTS: Pregnant women from the Danish National Birth Cohort and their 7-year-old children. MEASUREMENTS: Maternal thyroid disease (hyperthyroidism and hypothyroidism) was assessed from registrations of diagnoses and treatment (n = 71 706) or from the measurement of thyroid-stimulating hormone (TSH) in a stored blood sample from the early pregnancy (n = 7624). Maternal prepregnancy body mass index (BMI) and child BMI at 7 years of age were used to define overweight and obesity, and associations were evaluated using regression models adjusting for potential confounders. RESULTS: No association was found between maternal thyroid disease in pregnancy and child overweight (hyperthyroidism: adjusted risk ratio (aRR): 1.02 (95% confidence interval (CI): 0.58-1.82); hypothyroidism: 1.31 (0.86-1.97)) or obesity (hyperthyroidism: 0.96 (0.53-1.75); hypothyroidism: 1.25 (0.76-2.05)). On the other hand, pregnant women with hypothyroidism in early pregnancy had a higher risk of being overweight (aRR: 1.20 (95% CI: 1.03; 1.41)) and obese (1.45 (1.07; 1.96)), whereas women with hyperthyroidism had a lower risk of being overweight (0.79 (0.64; 0.98)). CONCLUSIONS: Results provide no evidence that maternal thyroid disease in pregnancy programmes adiposity in the child, but corroborate an association between maternal thyroid disease and adiposity in the mother.

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

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

Prenatal nitrosatable prescription drug intake, drinking water nitrate, and the risk of stillbirth: a register- and population-based cohort of Danish pregnancies, 1997-2017.

BACKGROUND: Nitrosatable drugs commonly prescribed during pregnancy can react with nitrite to form N-nitroso compounds which have been associated with an increased risk of stillbirth. Whether maternal residential drinking water nitrate modifies this association is unknown. We investigated, if household drinking water nitrate was associated with stillbirth, and if it modified the association between nitrosatable prescription drug intake and the risk of stillbirth. METHODS: We conducted an individual-level register- and population-based cohort study using 652,810 women with the first recorded singleton pregnancy in the Danish Medical Birth Registry between 1997 and 2017. Nitrosatable drug exposure was recorded by use of the Danish National Patient Registry defined as women with a first redeemed prescription of a nitrosatable drug the first 22 weeks of pregnancy. The reference group was women with no redeemed prescription of a nitrosatable drug in this period. The average individual drinking water nitrate concentration level (mg/L) was calculated in the same period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios with 95% confidence intervals for stillbirth stratified into five categories of nitrate concentrations: ≤1 mg/L, > 1- ≤ 2 mg/L, > 2- ≤ 5 mg/L, > 5- ≤ 25 mg/L, and > 25 mg/L. RESULTS: Drinking water nitrate exposure in the population was not associated with the risk of stillbirth. Among 100,244 women who had a nitrosatable prescription drug redeemed ≤22 weeks of pregnancy of pregnancy, 418 (0.42%) had a stillbirth compared to 1993 stillbirths (0.36%) among 552,566 referent women. Women with any nitrosatable prescription drug intake and > 1- ≤ 2 mg/L nitrate concentration had an increased risk of stillbirth [adjusted hazard ratio 1.55 (95% confidence interval, 1.15-2.09)] compared with referent women. In the stratified analyses, the highest risk of stillbirth was found among women with secondary amine intake and > 25 mg/L nitrate concentrations [adjusted hazard ratio 3.11 (95% CI, 1.08-8.94)]. CONCLUSIONS: The association between nitrosatable prescription drug intake and the risk of stillbirth may depend on the level of nitrate in household drinking water. Evaluations of the effect of nitrosatable drug intake on perinatal outcomes might consider nitrate exposure from drinking water.

Menstrual pain and sexual health in mothers-A cross-sectional study in the Danish National Birth Cohort.

INTRODUCTION: Prevalence and consequences of menstrual pain have mainly been studied in younger women. We aimed to describe the prevalence of menstrual pain in mothers and its association with sexual problems. MATERIAL AND METHODS: A cross-sectional study using questionnaire data from the Maternal Follow Up (2013-2014) in the Danish National Birth Cohort (1996-2002). Of 82 569 eligible mothers, 43 639 (53%) completed the follow up. Of these, 24 000 women had a partner, and answered the questions on menstrual pain. Log binomial regression was used to calculate prevalence proportion ratios (PPR) with 95% CI for the association between menstrual pain and specific sexual problems. RESULTS: Menstrual pain was reported by 16 464 women (69%), and severe menstrual pain by 19%. Treatment had previously been requested by 19% of women with menstrual pain. The most common treatment was oral contraceptives, but for 18% of women seeking treatment, no treatment was given. Women with menstrual pain were more likely to report reduced sexual desire (PPR 1.22, 95% CI 1.15-1.29), vaginismus (PPR 1.31, 95% CI 0.96-1.78), and dyspareunia (PPR 1.63, 95% CI 1.47-1.81), in particular deep dyspareunia (PPR 1.92, 95% CI 1.67-2.20). CONCLUSIONS: A majority of Danish mothers in mid-life experienced menstrual pain, and these women more often reported reduced sexual desire, vaginismus, and deep dyspareunia. Few women sought and received treatment for menstrual pain. Healthcare practitioners should be aware that menstrual pain can affect parous women and co-occurs with sexual problems. Future studies should identify barriers to seeking and receiving adequate treatment for menstrual pain.

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

INTRODUCTION: Overweight and obesity in pregnancy is increasing worldwide and may harm the developing fetus, including its future reproductive health. We therefore studied the association between in utero exposure to maternal overweight and obesity and infertility in adulthood. No studies have previously assessed this association. MATERIAL AND METHODS: We performed a cohort study with 9232 adult sons and daughters whose mothers were enrolled in the Danish Healthy Habits for Two cohort during pregnancy in 1984-87. Participants were sons and daughters followed in the Danish In-Vitro-Fertilization-Register and Danish National Patient Register until February 2018 for diagnoses of infertility. RESULTS: In total, 1203 (13%) sons and daughters were born to mothers with a body mass index (BMI) >25 kg/m2 ; 871 (9.4%) of the participants were identified as being infertile during follow-up. Sons of overweight mothers had slightly increased odds of infertility compared with sons of mothers with normal body weight (BMI 18.5-24.9 kg/m2 , adjusted odds ratio 1.4, 95% confidence interval [CI] 1.0-1.9). Cubic spline analyses with continuous BMI levels showed increasing odds with higher levels of BMI; however, for BMI >29 kg/m2 the confidence intervals were too wide to draw conclusions. No association between maternal overweight and infertility was found among daughters (adjusted odds ratio 0.9, 95% CI 0.7-1.2)). CONCLUSIONS: Sons born to overweight mothers had higher odds of infertility compared with sons of normal weight mothers. No association between maternal overweight and infertility was observed in daughters. Prevention of overweight during pregnancy may be an important tool to preserve fecundity in future generations.

Parental occupational exposure to pesticides, animals and organic dust and risk of childhood leukemia and central nervous system tumors: Findings from the International Childhood Cancer Cohort Consortium (I4C).

Parental occupational exposures to pesticides, animals and organic dust have been associated with an increased risk of childhood cancer based mostly on case-control studies. We prospectively evaluated parental occupational exposures and risk of childhood leukemia and central nervous system (CNS) tumors in the International Childhood Cancer Cohort Consortium. We pooled data on 329,658 participants from birth cohorts in five countries (Australia, Denmark, Israel, Norway and United Kingdom). Parental occupational exposures during pregnancy were estimated by linking International Standard Classification of Occupations-1988 job codes to the ALOHA+ job exposure matrix. Risk of childhood (<15 years) acute lymphoblastic leukemia (ALL; n = 129), acute myeloid leukemia (AML; n = 31) and CNS tumors (n = 158) was estimated using Cox proportional hazards models to generate hazard ratios (HR) and 95% confidence intervals (CI). Paternal exposures to pesticides and animals were associated with increased risk of childhood AML (herbicides HR = 3.22, 95% CI = 0.97-10.68; insecticides HR = 2.86, 95% CI = 0.99-8.23; animals HR = 3.89, 95% CI = 1.18-12.90), but not ALL or CNS tumors. Paternal exposure to organic dust was positively associated with AML (HR = 2.38 95% CI = 1.12-5.07), inversely associated with ALL (HR = 0.55, 95% CI = 0.31-0.99) and not associated with CNS tumors. Low exposure prevalence precluded evaluation of maternal pesticide and animal exposures; we observed no significant associations with organic dust exposure. This first prospective analysis of pooled birth cohorts and parental occupational exposures provides evidence for paternal agricultural exposures as childhood AML risk factors. The different risks for childhood ALL associated with maternal and paternal organic dust exposures should be investigated further.

Hospital Records of Pain, Fatigue, or Circulatory Symptoms in Girls Exposed to Human Papillomavirus Vaccination: Cohort, Self-Controlled Case Series, and Population Time Trend Studies.

Human papillomavirus (HPV) vaccination has been associated with subsequent diffuse symptoms in girls, reducing public confidence in the vaccine. We examined whether girls have nonspecific outcomes of HPV vaccination, using triangulation from cohort, self-controlled case series (SCCS), and population time trend analyses carried out in Denmark between 2000 and 2014. The study population consisted of 314,017 HPV-vaccinated girls and 314,017 age-matched HPV-unvaccinated girls (cohort analyses); 11,817 girls with hospital records (SCCS analyses); and 1,465,049 girls and boys (population time trend analyses). The main outcome measures were hospital records of pain, fatigue, or circulatory symptoms. The cohort study revealed no increased risk among HPV vaccine-exposed girls, with incidence rate ratios close to 1.0 for abdominal pain, nonspecific pain, headache, hypotension/syncope, tachycardia (including postural orthostatic tachycardia syndrome), and malaise/fatigue (including chronic fatigue syndrome). In the SCCS analyses, we observed no association between HPV vaccination and subsequent symptoms. In time trend analyses, we observed a steady increase in these hospital records in both girls and (HPV-unvaccinated) boys, with no relationship to the 2009 introduction of HPV vaccine to Denmark's vaccination program. This study, which had nationwide coverage, showed no evidence of a causal link between HPV vaccination and diffuse autonomic symptoms leading to hospital contact.

Rheumatoid arthritis and risk of spontaneous abortion: a Danish nationwide cohort study.

OBJECTIVES: To investigate the influence of RA or preclinical RA on the risk of spontaneous abortion (SA) while taking age and duration of RA into consideration. METHODS: By linkage of data from Danish national registries, we established a nationwide cohort of pregnancies in Denmark from 1 January 1977 to 31 December 2014. We used multiple logistic regression to estimate; odds ratios (OR) for SA in women with RA or preclinical RA, compared with women without, and OR for SA by maternal age in women with RA or preclinical RA. RESULTS: A total of 2 612 529 pregnancies were included. Women aged <35 years diagnosed with RA <5 years before pregnancy had an increased risk of SA (OR = 1.25 95% CI: 1.07, 1.48), compared with women without RA aged <35. Women at the same age diagnosed with RA ≥5 years before pregnancy had an OR of 1.14 (0.96-1.34), compared with women without. Among women with RA aged ≥35 years and women with preclinical RA at time of pregnancy, no increased risk of SA was found. The risk of SA increased by maternal age in both women with RA, preclinical RA and in women without. CONCLUSION: Among women aged <35 years, the risk of SA was higher in women with RA compared with women without. After the age of 35 years, the risk of SA was no different from that among women without RA, even though the risk of SA increased with increasing age.