Maternal pre-pregnancy body mass index and risk of preterm birth: a collaboration using large routine health datasets.

BACKGROUND: Preterm birth (PTB) is a leading cause of child morbidity and mortality. Evidence suggests an increased risk with both maternal underweight and obesity, with some studies suggesting underweight might be a greater factor in spontaneous PTB (SPTB) and that the relationship might vary by parity. Previous studies have largely explored established body mass index (BMI) categories. Our aim was to compare associations of maternal pre-pregnancy BMI with any PTB, SPTB and medically indicated PTB (MPTB) among nulliparous and parous women across populations with differing characteristics, and to identify the optimal BMI with lowest risk for these outcomes. METHODS: We used three UK datasets, two USA datasets and one each from South Australia, Norway and Denmark, together including just under 29 million pregnancies resulting in a live birth or stillbirth after 24 completed weeks gestation. Fractional polynomial multivariable logistic regression was used to examine the relationship of maternal BMI with any PTB, SPTB and MPTB, among nulliparous and parous women separately. The results were combined using a random effects meta-analysis. The estimated BMI at which risk was lowest was calculated via differentiation and a 95% confidence interval (CI) obtained using bootstrapping. RESULTS: We found non-linear associations between BMI and all three outcomes, across all datasets. The adjusted risk of any PTB and MPTB was elevated at both low and high BMIs, whereas the risk of SPTB was increased at lower levels of BMI but remained low or increased only slightly with higher BMI. In the meta-analysed data, the lowest risk of any PTB was at a BMI of 22.5 kg/m2 (95% CI 21.5, 23.5) among nulliparous women and 25.9 kg/m2 (95% CI 24.1, 31.7) among multiparous women, with values of 20.4 kg/m2 (20.0, 21.1) and 22.2 kg/m2 (21.1, 24.3), respectively, for MPTB; for SPTB, the risk remained roughly largely constant above a BMI of around 25-30 kg/m2 regardless of parity. CONCLUSIONS: Consistency of findings across different populations, despite differences between them in terms of the time period covered, the BMI distribution, missing data and control for key confounders, suggests that severe under- and overweight may play a role in PTB risk.

Pregnancy and risk of COVID-19: a Norwegian registry-linkage study.

OBJECTIVE: To compare the risk of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and contact with specialist healthcare services for coronavirus disease 2019 (COVID-19) between pregnant and non-pregnant women. POPULATION OR SAMPLE: All women ages 15-45 living in Norway on 1 March 2020 (n = 1 033 699). METHODS: We linked information from the national birth, patient, communicable diseases and education databases using unique national identifiers. MAIN OUTCOME MEASURE: We estimated hazard ratios (HR) among pregnant compared to non-pregnant women of having a positive test for SARS-CoV-2, a diagnosis of COVID-19 in specialist healthcare, or hospitalisation with COVID-19 using Cox regression. Multivariable analyses adjusted for age, marital status, education, income, country of birth and underlying medical conditions. RESULTS: Pregnant women were not more likely to be tested for or to a have a positive SARS-CoV-2 test (adjusted HR 0.99; 95% CI 0.92-1.07). Pregnant women had higher risk of hospitalisation with COVID-19 (HR 4.70, 95% CI 3.51-6.30) and any type of specialist care for COVID-19 (HR 3.46, 95% CI 2.89-4.14). Pregnant women born outside Scandinavia were less likely to be tested, and at higher risk of a positive test (HR 2.37, 95% CI 2.51-8.87). Compared with pregnant Scandinavian-born women, pregnant women with minority background had a higher risk of hospitalisation with COVID-19 (HR 4.72, 95% CI 2.51-8.87). CONCLUSION: Pregnant women were not more likely to be infected with SARS-CoV-2. Still, pregnant women with COVID-19, especially those born outside of Scandinavia, were more likely to be hospitalised. TWEETABLE ABSTRACT: Pregnant women are at increased risk of hospitalisation for COVID-19.

Clinical characteristics including cardiovascular and metabolic risk factors in adolescents with psoriasis.

BACKGROUND: Clinical studies on psoriasis in adolescents have mainly been performed in patients with severe psoriasis. Population-based studies of clinical characteristics and risk factors for later cardiovascular and metabolic disease in children and adolescents are lacking. OBJECTIVES: To examine the clinical characteristics of adolescents with psoriasis nested in a general population cohort. Furthermore, to investigate cardiovascular and metabolic risk factors in the adolescents with psoriasis compared to parentally predisposed and non-predisposed adolescents without psoriasis from the same birth cohort. METHODS: We identified adolescents with and without psoriasis using a nationwide general population birth cohort in Denmark. A clinical examination included skin inspection and scoring of psoriasis severity, completion of a questionnaire on psoriasis and comorbidities, physical measurements, and blood sampling. Participants also completed self-administered questionnaires on quality of life and mental health. RESULTS: We included 81 adolescents with psoriasis and 234 controls (110 with genetic predisposition for psoriasis and 124 without predisposition). Median age was 15.6 (13.5-18.5) years, and in those with active psoriasis, median Psoriasis Area and Severity Index score was 1.2 (0.1-11.4). The scalp was the most common site of psoriasis, both at debut and at time of examination. Diaper rash in infancy was more frequent in the psoriasis group. No significant differences regarding quality of life, anxiety and depression were found. More adolescents with psoriasis were obese (8.6% vs. 1.7%, P = 0.008), and physical measures of abdominal obesity were also significantly higher. HbA1c was significantly higher (31.55 vs. 30.81 mmol/mol, P = 0.048), while no differences were found for blood pressure, lipids or high-sensitivity C-reactive protein. In a subgroup analysis, this was evident in the non-predisposed psoriasis-free controls only. CONCLUSIONS: Overall, adolescents with psoriasis from this general population had mild disease. Still, early markers of cardiovascular and metabolic disease were elevated.

Oral contraceptive use and genital anomalies in sons. A Danish cohort study.

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.

Associations between maternal socioeconomic position and psoriasis: a cohort study among the offspring of the Danish National Birth Cohort.

BACKGROUND: The socioeconomic determinants of paediatric-onset psoriasis have not been previously investigated. OBJECTIVE: To identify whether a social gradient exists for paediatric-onset psoriasis, using measures of maternal socioeconomic position. METHODS: Data on paediatric-onset psoriasis from 36 003 Danish National Birth Cohort offspring were cross-linked with nationwide registry data on maternal age and three measures of maternal socioeconomic position: maternal educational attainment, maternal labour market attachment and equivalized household income. Univariable and multivariable logistic regression analyses were conducted to estimate the odds ratios (ORs) of psoriasis in the offspring, in cohort analyses for data from the year of enrolment and cross-sectional analyses from the year of the 11-year follow-up. RESULTS: Maternal age at birth, maternal educational attainment and equivalized household income were inversely associated with psoriasis in the offspring. Low maternal educational attainment was associated with offspring psoriasis [adjusted OR 1·62, 95% confidence interval (CI) 1·20-2·18] after adjusting for maternal psoriasis and age in the cohort analysis. The crude OR of psoriasis in offspring of mothers in the highest quartile compared with mothers in the lowest quartile of equivalized household income was 0·57 (95% CI 0·43-0·76), and the adjusted OR was 0·59 (95% CI 0·44-0·80) after adjusting for maternal psoriasis and age. Similar results were observed for data on maternal socioeconomic position at enrolment and at follow-up. CONCLUSIONS: A steep social gradient in paediatric-onset psoriasis was observed. Maternal socioeconomic position may play a role in early-life exposure to modifiable risk factors for psoriasis. Future studies may help to elucidate which biological factors mediate the social gradient observed in our study.

The association between seasonal influenza-like illness cases and foetal death: a time series analysis.

It has been reported that foetal death follows a seasonal pattern. Influenza virus infection has been postulated as one possible contributor to this seasonal variation. This ecological study explored the temporal association between the influenza activity and the frequency of foetal death. Time series analysis was conducted using weekly influenza-like illness consultation proportions from the Danish sentinel surveillance system and weekly proportions of spontaneous abortions and stillbirths from hospital registers from 1994 to 2009. The association was examined in an autoregressive (AR) integrated (I) moving average (MA) model and subsequently analysed with cross-correlation functions. Our findings confirmed the well-known seasonality in influenza, but also seasonality in spontaneous abortion. No clear pattern of seasonality was found for stillbirths, although the analysis exposed dependency between observations. One final AR integrated MA model was identified for the influenza-like illness (ILI) series. We found no statistically significant relationship between weekly influenza-like illness consultation proportions and weekly spontaneous abortion proportions (five lags: P = 0.52; 11 lags: P = 0.91) or weekly stillbirths (five lags: P = 0.93; 11 lags: P = 0.40). Exposure to circulating influenza during pregnancy was not associated with rates of spontaneous abortions or stillbirths. Seasonal variations in spontaneous abortion were confirmed and this phenomenon needs further investigation.

Fever in pregnancy and the risk of congenital malformations: a cohort study.

BACKGROUND: In a variety of animal species, hyperthermia in pregnancy has been recognized as teratogenic. Hyperthermia interferes with protein synthesis via heat-shock proteins, which can entail membrane disruption, cell death, vascular disruption, and placental infarction. This can induce severe fetal malformations or death. Fever during pregnancy, especially during embryogenesis, has also been associated with congenital malformations in human offspring. The purpose of this large cohort study of clinically recognized pregnancies was to investigate whether fever during first trimester was associated with an increased risk of congenital malformations in the offspring. METHODS: The Danish National Birth Cohort is a population-based cohort of 100,418 pregnant women and their offspring recruited in 1996 to 2002. Information on fever during pregnancy was collected prospectively by means of two telephone interviews. The study population comprised the 77,344 pregnancies enrolled in the Danish National Birth Cohort where self-reported information on fever during first trimester of pregnancy was available. Pregnancy outcomes were identified through linkage with the National Patient Registry. Congenital malformations within the first three and a half years of life were categorized according to EUROCAT's classification criteria. Logistic regression models were used to estimate the associations between fever in first trimester and overall congenital malformations and congenital malformations by subgroups. RESULTS: Eight thousand three hundred twenty-one women reported fever during first trimester (10.8%) and 2876 infants were diagnosed with a congenital malformation (3.7%). Fever during first trimester did not affect the risk of overall fetal congenital malformation (OR 0.99, 95% CI 0.88-1.12). The subgroup analyses indicated slightly higher risk of congenital anomalies in the eye, ear, face and neck (OR 1.29, 95% CI 0.78-2.12) and in the genitals (OR 1.17, 95% CI 0.79-1.12), whereas lower risk of malformations in the nervous system (OR 0.47, 95% CI 0.21-1.08), the respiratory system (OR 0.56, 95% CI 0.23-1.29) and in the urinary subgroup (OR 0.58, 95% CI 0.35-0.99) was suggested, the latter constituting the only statistically significant finding. CONCLUSIONS: Overall, this study did not show any association between maternal fever in pregnancy and risk of congenital anomalies.

Childhood psychopathology in children of women with eating disorders.

OBJECTIVE: We aimed to investigate the effect of maternal eating disorders (ED) on childhood psychopathology, early delays in cognitive, motor and language development, mother and child relationship, and child temperament in a community-based cohort: the Danish National Birth Cohort (DNBC). METHOD: Data were obtained prospectively on 48 403 children at 18 months and 46 156 children at 7 years. Data on cognitive, motor and language development, temperament and attachment were obtained at 18 months; data on child psychopathology were obtained at 7 years of age, using the Strengths and Difficulties Questionnaire (SDQ). Children of mothers with lifetime diagnosis of anorexia nervosa (AN, n = 931), lifetime diagnosis of bulimia nervosa (BN, n = 906) and both (AN & BN = 360) were compared to children of mothers without an ED (n = 46 206). RESULTS: Girls of women with lifetime AN had higher odds of having emotional problems, and girls of women with lifetime BN of having conduct problems compared with children of healthy women. Boys of women with lifetime AN had higher odds of total, emotional and conduct problems; boys of women with lifetime BN had higher odds of total, conduct, hyperactivity and peer difficulties compared to children of women without an ED. Boys of women with lifetime AN and BN had higher odds of total, emotional and peer problems compared to children of healthy women. CONCLUSION: Maternal ED is associated with childhood psychopathology in both boys and girls. Boys seemed at higher risk for psychopathology in this sample. Associations between emotional disorders across genders in children of mothers with lifetime AN, and hyperactivity and peer difficulties in boys of mothers with lifetime BN confirm and extend previous findings and point to possible shared risk between ED and other psychopathology.

Risk of congenital anomalies after exposure to asthma medication in the first trimester of pregnancy - a cohort linkage study.

OBJECTIVE: To examine the effect of maternal exposure to asthma medications on the risk of congenital anomalies. DESIGN: Meta-analysis of aggregated data from three cohort studies. SETTING: Linkage between healthcare databases and EUROCAT congenital anomaly registries. POPULATION: 519 242 pregnancies in Norway (2004-2010), Wales (2000-2010) and Funen, Denmark (2000-2010). METHODS: Exposure defined as having at least one prescription for asthma medications issued (Wales) or dispensed (Norway, Denmark) from 91 days before to 91 days after the pregnancy start date. Odds ratios (ORs) were estimated separately for each register and combined in meta-analyses. MAIN OUTCOME MEASURES: ORs for all congenital anomalies and specific congenital anomalies. RESULTS: Overall exposure prevalence was 3.76%. For exposure to asthma medication in general, the adjusted OR (adjOR) for a major congenital anomaly was 1.21 (99% CI 1.09-1.34) after adjustment for maternal age and socioeconomic position. The OR of anal atresia was significantly increased in pregnancies exposed to inhaled corticosteroids (3.40; 99% CI 1.15-10.04). For severe congenital heart defects, an increased OR (1.97; 1.12-3.49) was associated with exposure to combination treatment with inhaled corticosteroids and long-acting beta-2-agonists. Associations with renal dysplasia were driven by exposure to short-acting beta-2-agonists (2.37; 1.20-4.67). CONCLUSION: The increased risk of congenital anomalies for women taking asthma medication is small with little confounding by maternal age or socioeconomic status. The study confirmed the association of inhaled corticosteroids with anal atresia found in earlier research and found potential new associations with combination treatment. The potential new associations should be interpreted with caution due to the large number of comparisons undertaken. TWEETABLE ABSTRACT: This cohort study found a small increased risk of congenital anomalies for women taking asthma medication.

Size at birth and preterm birth in women with lifetime eating disorders: a prospective population-based study.

OBJECTIVE: To investigate whether eating disorders are associated with lower size at birth, symmetric growth restriction, and preterm birth; and whether pregnancy smoking explains the association between anorexia nervosa and fetal growth. DESIGN: Longitudinal population-based cohort study. SETTING: Denmark. SAMPLE: Women from the Danish National Birth Cohort (n = 83 826). METHODS: Women with anorexia nervosa (n = 1609), bulimia nervosa (n = 1693) and both (anorexia + bulimia nervosa, n = 634) were compared with unexposed women (n = 76 724) (women with exposure data and singletons n = 80 660) using crude and adjusted linear and logistic regression models. MAIN OUTCOME MEASURES: Size at birth (birthweight, length, head and abdominal circumference and placental weight); gestational age; small- and large-for-gestational-age (SGA, LGA); ponderal index, abdominal/head circumference. RESULTS: Lifetime anorexia nervosa and lifetime anorexia + bulimia nervosa were prospectively associated with restricted fetal growth and higher odds of SGA [respectively, OR = 1.6 [95% CI 1.3-1.8] and OR = 1.5 [95% CI 1.2-1.9)] compared with unexposed women. Active anorexia nervosa was associated with lower birthweight, length, head and abdominal circumference, ponderal index, higher odds of SGA [OR = 2.90 (95% 1.98-4.26)] and preterm birth [OR = 1.77 (95% CI 1.00-3.12)] compared with unexposed women. Pregnancy smoking only partly explained the association between anorexia nervosa and adverse fetal outcomes. CONCLUSIONS: Maternal anorexia nervosa (both active and past) is associated with lower size at birth and symmetric growth restriction, with evidence of worse outcomes in women with active disorder. Women with anorexia nervosa should be advised about achieving full recovery before conceiving. Similarly, targeting smoking in pregnancy might improve fetal outcomes. TWEETABLE ABSTRACT: Anorexia nervosa predicts small size at birth, small-for-gestational-age and symmetric growth restriction.

Selective serotonin reuptake inhibitor prescribing before, during and after pregnancy: a population-based study in six European regions.

OBJECTIVE: To explore the prescribing patterns of selective serotonin reuptake inhibitors (SSRIs) before, during and after pregnancy in six European population-based databases. DESIGN: Descriptive drug utilisation study. SETTING: Six electronic healthcare databases in Denmark, the Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the rest of the UK. POPULATION: All women with a pregnancy ending in a live or stillbirth starting and ending between 2004 and 2010. METHODS: A common protocol was implemented across databases to identify SSRI prescriptions issued (UK) or dispensed (non-UK) in the year before, during or in the year following pregnancy. MAIN OUTCOME MEASURES: The percentage of deliveries in which the woman received an SSRI prescription in the year before, during or in the year following pregnancy. We also compared the choice of SSRIs and changes in prescribing over the study period. RESULTS: In total, 721 632 women and 862,943 deliveries were identified. In the year preceding pregnancy, the prevalence of SSRI prescribing was highest in Wales [9.6%; 95% confidence interval (CI95 ), 9.4-9.8%] and lowest in Emilia Romagna (3.3%; CI95 , 3.2-3.4%). During pregnancy, SSRI prescribing had dropped to between 1.2% (CI95 , 1.1-1.3%) in Emilia Romagna and 4.5% (CI95 , 4.3-4.6%) in Wales. The higher UK pre-pregnancy prescribing rates resulted in higher first trimester exposures. After pregnancy, SSRI prescribing increased most rapidly in the UK. Paroxetine was more commonly prescribed in the Netherlands and Italian regions than in Denmark and the UK. CONCLUSIONS: The higher SSRI prescribing rates in the UK, compared with other European regions, raise questions about differences in the prevalence and severity of depression and its management in pregnancy across Europe.

Disparities in pre-eclampsia and eclampsia among immigrant women giving birth in six industrialised countries.

OBJECTIVE: To assess disparities in pre-eclampsia and eclampsia among immigrant women from various world regions giving birth in six industrialised countries. DESIGN: Cross-country comparative study of linked population-based databases. SETTING: Provincial or regional obstetric delivery data from Australia, Canada, Spain and the USA and national data from Denmark and Sweden. POPULATION: All immigrant and non-immigrant women delivering in the six industrialised countries within the most recent 10-year period available to each participating centre (1995-2010). METHODS: Data was collected using standardised definitions of the outcomes and maternal regions of birth. Pooled data were analysed with multilevel models. Within-country analyses used stratified logistic regression to obtain odds ratios (OR) with 95% confidence intervals (95% CI). MAIN OUTCOME MEASURES: Pre-eclampsia, eclampsia and pre-eclampsia with prolonged hospitalisation (cases per 1000 deliveries). RESULTS: There were 9,028,802 deliveries (3,031,399 to immigrant women). Compared with immigrants from Western Europe, immigrants from Sub-Saharan Africa and Latin America & the Caribbean were at higher risk of pre-eclampsia (OR: 1.72; 95% CI: 1.63, 1.80 and 1.63; 95% CI: 1.57, 1.69) and eclampsia (OR: 2.12; 95% CI: 1.61, 2.79 and 1.55; 95% CI: 1.26, 1. 91), respectively, after adjustment for parity, maternal age and destination country. Compared with native-born women, European and East Asian immigrants were at lower risk in most industrialised countries. Spain exhibited the largest disparities and Australia the smallest. CONCLUSION: Immigrant women from Sub-Saharan Africa and Latin America & the Caribbean require increased surveillance due to a consistently high risk of pre-eclampsia and eclampsia.

Risk factors for miscarriage from a prevention perspective: a nationwide follow-up study.

OBJECTIVE: To identify modifiable risk factors for miscarriage and to estimate the preventable proportion of miscarriages that could be attributed to these. DESIGN: Nationwide observational follow-up study. SETTING: Denmark. POPULATION: Ninety-one thousand four hundred and twenty seven pregnancies included in the Danish National Birth Cohort between 1996 and 2002. METHODS: Information on potentially modifiable risk factors before and during pregnancy was collected by means of computer-assisted telephone interviews and linkage with Danish registers, ensuring almost complete follow-up of pregnancy outcome. Modifiable risk factors for miscarriage were identified by multiple Cox regression analysis, which provided the background for our estimations of population attributable fractions. In all, 88,373 pregnancies had full information on all covariates and were included in this analysis. MAIN OUTCOME MEASURES: Miscarriage before 22 completed weeks of gestation. RESULTS: The potentially modifiable pre-pregnant risk factors associated with increased miscarriage risk were: age of 30 years or more at conception, underweight, and obesity. During pregnancy the modifiable risk factors were: alcohol consumption, lifting of >20 kg daily, and night work. We estimated that 25.2% of the miscarriages might be prevented by reduction of all these risk factors to low risk levels. Modification of risk factors acting before and during pregnancy could lead to prevention of 14.7 and 12.5%, respectively, of the miscarriages. Maternal age at conception and alcohol consumption were the most important risk factors. CONCLUSIONS: Miscarriage risk is increased by multiple potentially modifiable risk factors and a considerable proportion of miscarriages may be preventable.

Prenatal exposure to alcohol, and gender differences on child mental health at age seven years.

BACKGROUND: It remains uncertain whether exposure to lower doses of alcohol is damaging to the developing fetus. The present study aimed to investigate associations for boys and girls between prenatal exposure to binge drinking and lower doses of alcohol in pregnancy, and parent-reported behavioural and emotional development at age seven. METHODS: This study used data from the Danish National Birth Cohort. Associations between cumulated alcohol exposure and binge drinking from full pregnancy and parent scores on the Strengths and Difficulties Questionnaire (SDQ) measured at age seven were investigated. The SDQ was used as continuous externalising/internalising scores, and as above/below cut-off for the specific scales of hyperactivity/inattention, conduct, emotional and peer problems. Inclusion criteria were information on alcohol exposure from three interviews, SDQ scores at age seven and being born full term (n=37 152). RESULTS: Controlling for relevant confounders, small positive associations were observed between binge drinking and internalising (relative change in mean: 1.04-1.06), externalising scores (relative change in mean: 1.01-1.07), and conduct scores (OR 1.12 to 1.23) for boys. No associations were observed with lower doses of alcohol. CONCLUSIONS: Exposure to binge drinking is weakly associated with impaired behavioural and emotional development measured at age seven. Large differences in background characteristics were observed between the groups defined by cumulated alcohol exposure, leaving the interpretations of findings uncertain.

Advanced paternal age and mortality of offspring under 5 years of age: a register-based cohort study.

STUDY QUESTION: Do children born to fathers of advanced age have an increased risk of dying before the age of 5 years? SUMMARY ANSWER: Children born to fathers aged 40 years or more have an increased risk of dying in early childhood due to an excess risk of fatal congenital anomalies, malignancies and external causes. WHAT IS KNOWN ALREADY: Advanced paternal age has previously been associated with adverse reproductive outcomes and some long-term health problems in the offspring. This is possibly due to specific point mutations, a condition known to increase in the sperm with increasing paternal age. STUDY DESIGN, SIZE, DURATION: A Danish population-based register study, designed as a prospective cohort study, of 1 575 521 live born children born from 1978 to 2004. The age of the child (in days) was used as the underlying time and the children entered the cohort the day they were born and were followed until 31 December 2009. The children were censored on date of turning 5 years, date of death or date of emigration, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from population-covering registers from Statistics Denmark including the Integrated Database for Labour Market Research, the Medical Birth Registry and the Registry of Causes of Death was linked using the unique civil registry number. Hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the risk of under-five mortality. The effect of paternal age was examined using restricted cubic splines and paternal age groups. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with children born to fathers aged 30-34 years, a statistically significant excess risk was found for children born to fathers aged 40-44 years [HR: 1.10 (95% CI: 1.00-1.21)] and children born to fathers aged 45+ years [HR: 1.16 (95% CI: 1.02-1.32)]. When only looking at 1-5 year olds, the relative risk (HR) among children born to fathers aged 40-44 years increased to 1.24 (95% CI: 1.00-1.53) and the risk in the oldest paternal age group (45+ years) rose to 1.65 (95% CI: 1.24-2.18). The results suggest that the elevated risk for children of fathers aged 40 years or more was primarily attributed to an elevated risk of dying from congenital malformations, malignancies and external causes. LIMITATIONS, REASONS FOR CAUTION: Specific causes of death might be misclassified; however, this is not likely to be dependent on paternal age. In some cases, the biological father may differ from the father registered. This misclassification is most likely non-differential. WIDER IMPLICATIONS OF THE FINDINGS: The excess risk of mortality among children born to older fathers is in accordance with the literature. The association needs further attention as it can provide valuable knowledge of the etiology of genetic diseases. Also, the association could become of greater importance in the future if the proportion of fathers aged 40+ years keeps growing. STUDY FUNDING/COMPETING INTEREST (S): None.

Prevalence of Coxiella burnetii in women exposed to livestock animals, Denmark, 1996 to 2002.

Q fever is a zoonotic infection which can pose a danger to pregnant women. To our knowledge, Denmark has never experienced a clinically verified Q fever outbreak. We aimed to quantify risk of infection in pregnant women occupationally and environmentally exposed to Coxiella burnetii. The Danish National Birth Cohort collected blood samples from 100,418 pregnant women in the period 1996 to 2002. We sampled 195 women with occupational exposure to livestock (veterinarians and female farmers), 202 women with domestic exposure (dairy cattle and/or sheep) and a random sample of 459 unexposed women. Samples were screened for antibodies against C. burnetii by commercial enzyme-linked immunosorbent assay. Positive samples were confirmed by immunofluorescence (cut-off titre ≥1:128). The proportion of seropositive women was higher in the occupationally exposed (47.2% seropositive; relative risk (RR): 9.8; 95% confidence interval (CI): 6.4­15.2) and the domestically exposed population (32.2% seropositive; RR: 6.7; 95% CI: 4.3­10.6) than in unexposed women (4.8% seropositive). We found a high prevalence of antibodies to C. burnetii among pregnant women with occupational or domestic exposure to cattle and/or sheep compared with unexposed pregnant women. Our findings suggest that contact to livestock is a risk factor for C. burnetii infection in Denmark.

Does the association of education with breast cancer replicate within twin pairs? A register-based study on Danish female twins.

BACKGROUND: A positive association between socio-economic position and breast cancer has been widely observed, but not hitherto within twin pairs, where shared familial factors were adjusted for. METHODS: We used data on education and other factors from the Danish Twin Registry, The Danish Cancer Registry, and official registers on a total of 16 310 twins. Unpaired and intrapair Cox regression analyses were compared. RESULTS: In the unpaired analysis, an educational gradient in breast cancer risk was found. Similar results were seen in the intrapair analyses of all twins, although no longer statistically significant. When intrapair analyses were stratified on zygosity, the effect of education was attenuated in the monozygotic twins. CONCLUSION: The main findings support an effect of education beyond shared familial factors.

Smoking and pregnancy-related pelvic pain.

OBJECTIVE: To investigate possible associations between smoking and pregnancy-related pelvic pain. DESIGN: Nested case-control study. SETTING: Denmark 2000-2001. POPULATION: The Danish National Birth Cohort. METHODS: The women were interviewed twice in pregnancy and twice after childbirth. The first pregnancy interview provided information on smoking and possible confounding factors,whereas the first interview after birth addressed case identification.Cases (n = 2302) were defined on the basis of self-reported pelvic pain, and controls were selected among women who did not report pelvic pain (n = 2692). Logistic regression analysis was used to estimate associations between smoking and pelvic pain. MAIN OUTCOME MEASURE: Pregnancy-related pelvic pain. RESULTS: Compared with non-smokers, women who smoked during pregnancy had an adjusted odds ratio of 1.2 (1.0-1.4) for overall pelvic pain, similar to women who stopped smoking in early pregnancy 1.3 (1.1-1.7). The equivalent adjusted odds ratio for severe pelvic pain was 1.2 (1.0-1.5) for smokers, and 1.5 (1.2-1.9)for women who stopped smoking. Smoking intensity, measured as number of cigarettes smoked per day, was associated with pelvic pain in a dose-response pattern. Information about smoking was collected prospectively, which makes it unlikely that differential recall alone explains the results. CONCLUSIONS: Smoking was associated with pregnancy-related pelvic pain, with a dose-response pattern between reported smoking intensity and pelvic pain. These findings suggest a possible new risk factor for a common ailment during pregnancy