Trends in antidepressant use among children and adolescents: a Scandinavian drug utilization study.

OBJECTIVE: To compare antidepressant utilization in individuals aged 5-19 years from the Scandinavian countries. METHODS: A population-based drug utilization study using publicly available data of antidepressant use from Denmark, Norway, and Sweden. RESULTS: In the study period from 2007 to 2017, the proportion of antidepressant users increased markedly in Sweden (9.3-18.0/1000) compared to Norway (5.1-7.6/1000) and Denmark (9.3-7.5/1000). In 2017, the cumulated defined daily doses (DDD) of selective serotonin reuptake inhibitors were 5611/1000 inhabitants in Sweden, 2709/1000 in Denmark, and 1848/1000 in Norway. The use of 'other antidepressants' (ATC code N06AX) also increased in Sweden with a higher DDD in 2017 (497/1000) compared to Denmark (225/1000) and Norway (170/1000). The use of tricyclic antidepressants was generally low in 2017 with DDDs ranging between 30-42 per 1000. The proportion of antidepressant users was highest among 15- to 19-year-old individuals. Girls were more likely to receive treatment than boys, and the treated female/male ratios per 1000 were similar in Sweden (2.39), Denmark (2.44), and Norway (2.63). CONCLUSION: Even in highly comparable healthcare systems like the Scandinavian countries', variation in antidepressant use is considerable. Swedish children and adolescents have a markedly higher and still increasing use of antidepressants compared to Danish and Norwegian peers.

Low-to-moderate alcohol consumption and success in fertility treatment: a Danish cohort study.

STUDY QUESTION: Does female weekly alcohol intake and binge drinking impact the chance of a successful fertility treatment? SUMMARY ANSWER: Low-to-moderate weekly alcohol drinking and binge drinking were not associated with the chance of achieving a clinical pregnancy or a live birth among women and couples undergoing medically assisted reproduction (MAR) treatments. WHAT IS KNOWN ALREADY: Alcohol consumption is common among women of reproductive age, even though health authorities advise women trying to conceive to abstain from drinking. A growing number of couples struggle with infertility, but it is unknown whether low-to-moderate levels of alcohol consumption and alcohol binge drinking impair success in fertility treatment. STUDY DESIGN, SIZE, DURATION: Cohort study with prospectively collected exposure information including 1708 women and potential partners undergoing fertility treatment at the public fertility clinic, Aarhus University Hospital, 1 January 2010 to 31 August 2015. In total, data on 1511 intrauterine insemination (IUI) cycles, 2870 in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles and 1355 frozen embryo transfer cycles. PARTTICIPANTS/MATERIALS, SETTING, METHODS: Exposure to weekly average alcohol intake was assessed from questionnaires completed by participants before the start of treatment. Outcome measures are the achievement of a clinical pregnancy and live birth in consecutive treatment cycles in the Danish national health registries, enabling complete follow-up. A modified Poisson regression with robust standard errors was used to evaluate associations between a weekly average alcohol intake and MAR outcomes, adjusting for female age, body mass index, cigarette smoking, coffee consumption, chronic diseases, level of education, and cycle number. When evaluating the association between binge drinking in the month prior to baseline and MAR outcomes the analyses were further adjusted for average weekly alcohol consumption. MAIN RESULTS AND THE ROLE OF CHANCE: Low-to-moderate average weekly alcohol intake was not statistically significantly associated with the chance of achieving a clinical pregnancy or a live birth following IUI or IVF/ICSI treatment cycles. Compared to women abstaining from alcohol, the adjusted relative risks for achieving a live birth among those reporting 1-2, 3-7, and >7 drinks per week were 1.00 (95% CI 0.66; 1.53), 1.20 (0.76; 1.91), and 1.48 (0.56; 3.93), respectively, among women initiating IUI treatments. Among those initiating IVF/ICSI treatments, the chance for achieving a live birth among those reporting 1-2, 3-7, and >7 drinks per week were 1.00 (0.83; 1.21), 0.95 (0.75; 1.20), and 0.89 (0.53; 1.51), respectively. The chance of achieving a live birth in the first IUI or IVF/ICSI treatment cycle was unrelated to the number of binge drinking episodes in the month preceding baseline. LIMITATIONS, REASONS FOR CAUTION: The risk of non-differential exposure misclassification, confounding, or chance cannot be ruled out. In addition, due to the low number of women reporting an intake of >7 drinks/week, the potential effect of high alcohol consumption should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: Although it remains unsettled if and how alcohol affects female reproduction, our results indicate that is not necessary to abstain from alcohol when striving for a successful outcome following fertility treatment. STUDY FUNDING/COMPETING INTEREST(S): J.L. is supported by a fully financed Ph.D. scholarship from Aarhus University and has received funds from the A.P. Møller foundation. The funding sources had no involvement in the conduct of the article. Dr Kesmodel reports personal fees from MSD and Ferring Pharmaceuticals outside the submitted work. All other authors have no conflicts of interest to declare and all have completed the ICMJE disclosure form. TRIAL REGISTRATION NUMBER: Not relevant.

Fever and infections during pregnancy and psychosis-like experiences in the offspring at age 11. A prospective study within the Danish National Birth Cohort.

BACKGROUND: Maternal exposures to fever and infections in pregnancy have been linked to subsequent psychiatric morbidity in the child. This study examined whether fever and common infections in pregnancy were associated with psychosis-like experiences (PLEs) in the child. METHODS: A longitudinal study of 46 184 children who participated in the 11-year follow-up of the Danish National Birth Cohort was conducted. Pregnant women were enrolled between 1996 and 2002 and information on fever, genitourinary infections, respiratory tract infection, and influenza-like illness during pregnancy was prospectively collected in two interviews during pregnancy. PLEs were assessed using the seven-item Adolescent Psychotic-Like Symptom Screener in a web-based questionnaire completed by the children themselves at age 11. RESULTS: PLEs were reported among 11% of the children. Multinomial logistic regression models with probability weights to adjust for potential selection bias due to attrition suggested that maternal fever, genitourinary infections and influenza-like illness were associated with a weak to moderate increased risk of subclinical psychosis-like symptoms in the offspring, whereas respiratory tract infections were not. No clear pattern was observed between the strengths of the associations and the timing of exposure, or the type of psychosis-like symptom. CONCLUSIONS: In this study, maternal exposures to fevers and common infections in pregnancy were generally associated with a subtle excess risk of PLEs in the child. A more pronounced association was found for influenza-like illness under an a priori definition, leaving open the possibility that certain kinds of infections may constitute important risk factors.

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.

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.

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.

Maternal alcohol consumption during pregnancy and semen quality in the male offspring: two decades of follow-up.

BACKGROUND: Concurrent alcohol exposure has been associated with reduced fecundity, but no studies have estimated the effect of prenatal alcohol exposure on male fecundity. The aim of this study was to investigate the association between maternal alcohol consumption during pregnancy, semen quality and levels of reproductive hormones in young, adult men. METHODS: From a Danish pregnancy cohort established in 1984-1987, 347 sons were selected for a follow-up study conducted in 2005-2006. Semen and blood samples were analyzed for conventional semen characteristics and reproductive hormones, respectively, and results were related to prospectively self-reported information on maternal alcohol consumption during pregnancy. RESULTS: The sperm concentration decreased with increasing prenatal alcohol exposure. The adjusted mean sperm concentration among sons of mothers drinking >or=4.5 drinks per week during pregnancy was 40 (95% CI: 25-60) millions/ml. This concentration was approximately 32% lower compared with men exposed to <1.0 drink per week, who had a sperm concentration of 59 (95% CI: 44-77) millions/ml. The semen volume and the total sperm count were also associated with prenatal alcohol exposure; sons prenatally exposed to 1.0-1.5 drinks per week had the highest values. No associations were found for sperm motility, sperm morphology or any of the reproductive hormones, including testosterone. CONCLUSIONS: These results indicate that prenatal exposure to alcohol may have a persisting adverse effect on Sertoli cells, and thereby sperm concentration. If these associations are causal they could explain some of the reported differences between populations and long-term changes in semen quality.

Perceived stress and risk of colorectal cancer in men and women: a prospective cohort study.

OBJECTIVE: We aim to assess the relationship between stress and risk of primary colorectal cancer in men and women. DESIGN: A prospective cohort study. SETTING: The Copenhagen City Heart Study, Denmark. SUBJECTS: A total of 6488 women and 5426 men were included in the study. The participants were asked about intensity and frequency of stress at baseline in 1981-1983 and were followed until the end of 2000 in the Danish Cancer Registry. Less than 0.1% was lost to follow-up. MAIN OUTCOME MEASURES: First time incidence of primary colorectal cancer. RESULTS: During follow-up 162 women and 166 men were diagnosed with colorectal cancer. Women with moderate and high stress intensity had a hazard ratio of 0.60 (95% CI: 0.37-0.98) and 0.52 (0.23-1.14) for colorectal cancer, respectively, compared to women with no stress. For colon cancer, a one-unit increase on a seven-point stress-score was associated with an 11% lower incidence of the disease (HR = 0.89, 95% CI: 0.81-0.99) amongst women. There was no consistent evidence of an association between stress and colorectal cancer in men. CONCLUSION: Perceived stress was associated with lower risk of particularly colon cancer in women, whilst there was no clear relationship between stress and colorectal cancer in men.

Use of nicotine replacement therapy during pregnancy and stillbirth: a cohort study.

OBJECTIVE: The objective of this study was to examine whether the use of nicotine replacement therapy (NRT) during pregnancy increases the risk of stillbirth. DESIGN: Cohort study with prospective data. SETTING: Denmark 1996-2002. POPULATION: A total of 87,032 singleton pregnancies enrolled in the Danish National Birth Cohort for which information on NRT use as well as smoking was available. METHODS: Outcome of pregnancy was identified by register linkage, with <1% loss to follow up. We conducted Cox regression analyses to estimate the hazard ratio (HR) and 95% CI of stillbirth according to the use of NRT, type of NRT use and a combination of NRT use and smoking. MAIN OUTCOME MEASURES: Stillbirth, defined as delivery of a dead fetus after 20 completed weeks of gestation. RESULTS: A total of 495 pregnancies (5.7 in 1000 births) ended in stillbirth, 8 of which were among NRT users (4.2 in 1000 births). After adjustment for confounders, women who used NRT during pregnancy had a HR of 0.57 (95% CI 0.28-1.16) for stillbirth compared with those who did not use NRT. Smoking during pregnancy was associated with an increased risk of stillbirth (HR 1.46, 95% CI 1.17-1.82), while women who both smoked and used NRT had a HR of 0.83 (95% CI 0.34-2.00) compared with nonsmoking women who did not use NRT. CONCLUSION: Our study does not indicate that use of NRT during pregnancy increases the risk of stillbirth.

Comparison of assessment methods for self-reported alcohol consumption in health interview surveys.

OBJECTIVE: To select a simple method for assessing alcohol consumption and to compare how different reference periods and response categories influence the self-reported frequency of binge drinking. DESIGN: Four random samples of 1000 adult Danes. Data were collected via personal interview at the respondents' home. SETTING: Denmark, nationwide. PARTICIPANTS: The total number of interviewed was 2593 individuals. MEASUREMENTS: The assessment methods in the four samples were (1) the 7-day recall method, (2) intake each day in a typical week, (3) intake last weekend, and (4) intake in a typical week. Furthermore, binge drinking was assessed in the samples using different reference periods and response formats. FINDINGS: The sex- and age-adjusted mean number of drinks in the last week (the 7-day recall method) was 10.6 drinks compared to 10.4 drinks among respondents reporting their intake for each day in a typical week and 8.7 drinks among subjects reporting the average intake in a typical week. Furthermore, subjects that reported their typical intake for each day were as likely as subjects that had the 7-day recall method to report a high weekly alcohol intake. Respondents who had close-ended questions were more likely to report binge drinking compared to respondents that had open-ended questions. CONCLUSIONS: Questions concerning typical alcohol intake for each day of the week are feasible to use in epidemiological studies. Furthermore, it is more appropriate to use close-ended questions compared to open-ended questions in measuring binge-drinking when the reference period is long.

Do women give the same information on binge drinking during pregnancy when asked repeatedly?

OBJECTIVE: To study if pregnant women give the same answers to questions on frequency and timing of binge drinking when asked more than once during and after pregnancy. DESIGN: Cohort study. SETTING: The Danish National Birth Cohort. SUBJECTS: The study is based on 76 307 pregnant women with repeated information on binge drinking during the early part of pregnancy and 8933 pregnant women with information on binge drinking during pregnancy weeks 30-36, obtained while pregnant and 6 months after delivery. RESULTS: More women reported binge drinking, if the interview took place close to the period in question. As the report of binge drinking was highest in the first of two interviews referring to the same period, as well as women who participated in the first interview in pregnancy week 12 or earlier reported more binge drinking compared to women who participated in the interview later in pregnancy. CONCLUSIONS: Self-reported information on binge drinking is more frequently under-reported when the recall period is long. To improve the validity of data on binge drinking, future birth cohorts should obtain information several times during pregnancy.

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.

Influence of the recall period on a beverage-specific weekly drinking measure for alcohol intake.

BACKGROUND/OBJECTIVES: Our knowledge of the association between alcohol intake and alcohol-related health outcomes depends, to a large extent, on the validity and reliability of self-reported alcohol intake. Weekly drinking measures are frequently used in epidemiological surveys, but it has been shown that respondents have problems in correctly reporting intake for a full week. The aim of this study is to investigate whether a beverage-specific question implies better recall and, thereby, eliminates or diminishes the previously reported association between the recall period and the self-reported weekly alcohol intake. SUBJECTS/METHODS: The data is derived from the Danish Health Interview Survey 2005, which is based on a region-stratified random sample of 21,832 Danish citizens aged ≥16 years (response rate: 67%). The data were collected via face-to-face interviews. RESULTS: A beverage-specific question on alcohol intake on each day during the last week did not alter the strong association between the recall period and self-reported alcohol intake. However, the overall self-reported alcohol intake increased substantially when using the beverage-specific question instead of asking for the overall alcohol intake on each day. Moreover, the analyses indicated that interviews on Sundays should be avoided if the purpose is to assess alcohol intake for the previous day (Saturdays). CONCLUSIONS: It seems problematic to recall alcohol intake even when the recall period is as short as 1 week. Weekly drinking measures should primarily be used when the main aim of the study is to assess the average volume of alcohol intake in a specific population.