Utilization of healthcare prior to endometriosis diagnosis: a Danish case-control study.

STUDY QUESTION: Do women with endometriosis have higher utilization of primary and secondary healthcare prior to diagnosis compared to women without endometriosis? SUMMARY ANSWER: Women with a hospital-based diagnosis of endometriosis had an overall higher utilization of both primary and secondary healthcare in all 10 years prior to diagnosis. WHAT IS KNOWN ALREADY: Endometriosis is associated with a diagnostic delay, but only a few studies have investigated the potential consequences of this delay with regard to the utilization of healthcare. To the best of our knowledge, no study has investigated it in a period corresponding to the estimated diagnostic delay. STUDY DESIGN, SIZE, DURATION: This national Danish registry-based case-control study included 129 696 women. Cases were women with a first-time hospital-based diagnosis of endometriosis between 1 January 2000 and 31 December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified 21 616 cases using density sampling. Each case was matched on age at the date of diagnosis (index date) to five women without diagnosed endometriosis (n = 108 080). The utilization of healthcare was assessed for the 10 years before the index. MAIN RESULTS AND THE ROLE OF CHANCE: Cases had significantly higher use of healthcare in all 10 years preceding the index. The mean number of yearly contacts with the GP was 9.99 for cases and 7.85 for controls, with an adjusted incidence rate ratio of 1.28 (1.27; 1.29). For hospital contacts, the association increased slightly in the first 9 years and was most profound in the last year preceding index when the adjusted incidence rate ratio was 2.26 (95% CI 2.28; 2.31). LIMITATIONS, REASONS FOR CAUTION: We were not able to include women with an endometriosis diagnosis from the general practitioner or private gynaecologist. Therefore, our results are only applicable to hospital-based diagnoses of endometriosis. We do not have information on the specific reasons for contacting the healthcare providers and we can therefore only speculate that the higher utilization of healthcare among cases was related to endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: This study is in agreement with the other known studies on the subject. Future studies should include specific reasons for contacting the healthcare system and thereby identify any specific contact patterns for women with endometriosis. With this knowledge, healthcare professionals could be better at relating certain healthcare seeking behaviour to endometriosis earlier and thereby reduce the time from onset of symptoms to diagnosis. STUDY FUNDING/COMPETING INTEREST(S): This study is supported by grants from the project 'Finding Endometriosis using Machine Learning' (FEMaLe/101017562), which has received funding from The European Union's Horizon 2020 research and innovation program and Helsefonden (21-B-0141). K.Z. report grants from Bayer AG, Roche Inc. and Volition, royalties from Oxford-Bayer scientific collaboration in gynaecological therapies, non-financial collaboration with the World Endometriosis Society and World Endometriosis Research Foundation and is a Wellbeing of Women research advisory committee member. All this is outside the submitted work. The other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Measures of fetal growth and preterm birth and risk of endometriosis and adenomyosis in adult life: a systematic review and meta-analysis.

INTRODUCTION: Exposures in utero are suggested to play a role in the etiology of endometriosis and adenomyosis, although the current evidence is inconclusive. Knowledge about potential prenatal programming and early life exposures that may affect this risk is of high importance, to focus potential preventive strategies for the diseases already during pregnancy. The aim of this study was to review systematically the literature of the association between measures of fetal growth and preterm birth and endometriosis and adenomyosis in adult life. MATERIAL AND METHODS: A systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines and by search on PubMed and EMBASE was carried out. We included published case-control and cohort studies. We excluded studies without a reference group, eg case series, case reports as well as commentaries, letters and editorials. The quality of the studies was assessed using the Newcastle-Ottawa Scale. Meta-analyses using a random-effect inverse variance weighted model were performed. PROSPERO registration number is CRD42021249322. RESULTS: A total of 11 studies were included. In general, the quality scores of the studies were moderate. We found that the risk of endometriosis was 26% higher in women born with a birthweight <2.5 kg (pooled odds ratio [pOR] 1.26, 95% confidence interval [CI] 1.05-1.52) and 32% higher in women born preterm (pOR 1.32, 95% CI 1.01-1.72) than in the reference groups. The studies on adenomyosis pointed towards no association, but a meta-analysis was unfeasible due to the small number of studies. CONCLUSIONS: This systematic review and meta-analysis found that low birthweight and being born preterm were associated with endometriosis in adult life, but the results must be interpreted cautiously. No solid conclusion could be made regarding adenomyosis due to a limited number of published studies, but the studies included found no association. The results support the hypothesis of a potential early programming effect of endometriosis. However, the body of evidence is sparse and this hypothesis needs to be investigated further.

Temporal and regional differences in the incidence of hospital-diagnosed endometriosis: a Danish population-based study.

INTRODUCTION: Due to diagnostic challenges, normalization of symptoms and an overall lack of awareness among both patients and physicians, endometriosis is an underdiagnosed disease. This can result in delayed treatment and potentially worsening of the disease. Despite initiatives, such as patients' support organizations and specialized endometriosis referral centers, differences in awareness, socioeconomic factors and lifestyle, combined with varying distances to specialized referral centers, could result in regional differences in the degree of underdiagnosing. This study aims to explore temporal and regional variations in the incidence of endometriosis based on the Danish hospital discharge register, and shed light on the degree of underdiagnosing of endometriosis in Denmark. MATERIAL AND METHODS: This registry-based cohort study included all women aged 15-55 living in Denmark from 1990-2017. Participants were identified through the Danish Civil Registration system and endometriosis diagnoses received at a hospital were obtained from the Danish National Patient Registry. Incidence rates of diagnosed endometriosis were calculated for each year of the study period and for each municipality in Denmark. A Cox regression analysis, stratified by calendar time and adjusted for ethnic origin, household composition, highest educational level and family socioeconomic status, was performed to estimate the association between residence and likelihood of receiving a hospital-based diagnosis of endometriosis. RESULTS: The nationwide incidence rate of hospital-diagnosed endometriosis was 7.89 (95% confidence interval [CI] 7.80-7.99) per 10 000 person-years and the prevalence in 2017 was 1.63%. The results showed an overall increase in the incidence of diagnosed endometriosis of 46.8% (95% CI 32.9-62.2) during the study period and also displayed significant regional differences. After adjustments, women living in northern Jutland had the highest probability of receiving a hospital-based diagnosis of endometriosis (hazard ratio 1.13, 95% CI 1.09-1.18), whereas women living in northern Zealand had the lowest probability (hazard ratio 0.63, 95% CI 0.60-0.67) compared with eastern Jutland. These regional differences have become more evident over time. CONCLUSIONS: Our results reveal significant regional differences in the incidence of hospital-diagnosed endometriosis, suggesting that a significant number of women may be left behind without a diagnosis. Further studies are needed to assess the underlying reasons for the significant regional differences.

Pre-adolescents with multiple health complaints redeem more prescriptions: A follow-up study in the Danish National Birth Cohort.

Aims: This study aimed to examine the association between multiple health complaints (MHC) in pre-adolescence and prescription redemption in adolescence. Methods: This was a nationwide population-based study based on the Danish National Birth Cohort for an average of 6.9 years (2010-2018). A total of 96,382 children were invited at the age of 11. A modified version of the Health Behaviour in School Children Symptom Checklist was dichotomised into the World Health Organization's definition of MHC (⩾2 complaints, each with a frequency of at least weekly, yes/no). The number of prescriptions was retrieved from Danish registries. Negative binomial regression estimated incidence rate ratios (IRRs) comparing children with MHC to children without. Prescription redemption was further stratified by psychiatric/somatic medication and into subtypes of prescriptions. Results: A total of 47,365 (49.1%) children participated (Mage=11.2 years, 52% girls). MHC were reported by 10.3%. The unadjusted IRR (MHC vs. no MHC) of all types of redemptions was 1.57 (95% confidence interval (CI) 1.49-1.64). Results were robust to adjustment for socio-demographic variables and somatic/psychiatric morbidity at baseline (IRR=1.47; 95% CI 1.40-1.54). Associations were especially strong for psychiatric medication (adjusted IRR=3.88; 95% CI 3.43-4.40) and were modified by neither sex nor maternal education. Conclusions: MHC in pre-adolescents predict prescription redemption. This implies that changes in MHC might be indicative of changes in public health. This requires further study, as the cause of a change in reporting of symptoms might also cause a change in treatment response. The latter determines whether prescriptions are treating ill-being or needlessly medicalising subjective symptoms.

Infections in temporal proximity to HPV vaccination and adverse effects following vaccination in Denmark: A nationwide register-based cohort study and case-crossover analysis.

BACKGROUND: Public trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination. METHODS AND FINDINGS: The study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period ± 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination. Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test ± 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010). Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results. CONCLUSIONS: Treated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies.

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 smoking during pregnancy and offspring utilisation of health care services: A population-based cohort study.

BACKGROUND: Maternal smoking during pregnancy (MSDP) has been associated with a wide range of adverse effects on offspring health, such as low birthweight, behavioural disorders, and asthma. The number of women that smoke during pregnancy in Denmark is still high, making it relevant to study the long-term health outcomes in offspring exposed to maternal smoking in utero. OBJECTIVE: We investigated whether exposure to MSDP is associated with more frequent use of health care services during the first 10 years of life. METHODS: This population-based cohort study included participants enrolled in the Danish National Birth Cohort between 1996 and 2003. Data on MSDP were obtained from two telephone interviews during pregnancy and one interview after pregnancy. The primary outcome was contacts to the health care system. From Danish national registries, we obtained information on number and type of contacts to the general practitioner (GP), and information on the specific types of services provided. Further, we obtained information on hospital admissions, and redemption of prescribed medicine. We fitted negative binomial regression models and Cox proportional hazards regression models to estimate associations. All analyses were adjusted for socio-economic status, birth year, and various maternal factors. RESULTS: We studied 83,905 liveborn singletons and found that offspring exposed to maternal smoking in utero had more contacts to the GP in the first 10 years of life with an incidence rate ratio of 1.05, 95% confidence interval [CI] 1.04, 1.06. A higher rate of admission to hospital in 9 out of 20 categories was found, as was a higher rate of being prescribed psychoanaleptics (hazard ratio [HR] 1.41, 95% CI 1.25, 1.60), drugs for obstructive pulmonary disease (HR 1.14, 95% CI 1.14, 1.20), and antibiotics (HR 1.03, 95% CI 1.01, 1.05). CONCLUSIONS: We found that offspring exposed to MSDP had a higher use of health care services than unexposed offspring.

Use of primary healthcare for persons with epilepsy.

INTRODUCTION: In Denmark, care and treatment related to epilepsy primarily takes place at specialized hospital departments (neurology and pediatrics). The general practitioner (GP) in contrast is the primary contact and acts as a gatekeeper to the healthcare system for other disorders. The aim of the present study was to describe the utilization of services provided by the GP for children with epilepsy before and after diagnosis of epilepsy and to compare it with that of children without epilepsy. METHODS: All live born children born in Denmark between 1st of January 1996 and 1st of December 2013 were identified in the Danish National Patient Registry. Information about number and type of contact to the general practitioner was obtained from the Health Insurance Service Register. Information about epilepsy was obtained from the Danish National Patient Registry (n=10,062). For each child with epilepsy, we sampled 10 children without an epilepsy diagnosis matched on sex and age at the time of diagnosis (n=100,620). Children were followed up until 31st of December 2013. Multiple negative binomial regression analysis adjusting for relevant confounders was used to estimate the association between epilepsy and the use of GPs both before and after the time of epilepsy diagnosis. RESULTS: Children with epilepsy had a higher utilization of services provided by the GP after the diagnosis of epilepsy compared with children without epilepsy (incidence rate ratio (IRR): 1.64 (1.61-1.67)). The IRR for any contacts stayed relatively stable during the follow-up period, whereas the IRR for face-to-face contacts tended to decline and phone contacts tended to increase. The more frequent GP contacts in children with epilepsy were also evident before the time of diagnosis and for both sexes and in all age groups. For the specific services provided, children with epilepsy more often had a blood sample taken and more urine stix and CRP tests performed during the first years following diagnosis. CONCLUSION: Children with epilepsy have a higher use of services provided by the GP both before and after the epilepsy diagnosis compared with children without epilepsy. This is likely due to a higher prevalence of comorbid conditions in children with epilepsy as well as consequences of the underlying condition.

Socioeconomic predictors of referral to a diagnostic centre on suspected adverse events following HPV vaccination.

Background: In Denmark, the human papillomavirus (HPV) vaccines have been suspected of adverse events since 2014. However, as no causal associations between the HPV vaccines and numerous diseases have been demonstrated, factors prior to vaccination may influence the risk of suspecting the HPV vaccines of causing symptoms. We studied the associations between individual and parental socioeconomic characteristics and the risk of referral to a diagnostic centre in a female population aged 11-29 years with a first HPV vaccination in January 2008 to June 2015. Methods: Individual and parental data from national registries were linked using the unique personal identification number. Logistic regression analyses were used to estimate crude and adjusted odds ratio's according to each individual and parental socioeconomic factor with two-sided 95% 95% CI. Results: The cohort consisted of 453 216 individuals of which 1316 (0.29%) were referred to a diagnostic centre in 2015. Having a mother outside the workforce or an unemployed mother was associated with an increased risk of referral, while girls and women who had fathers with a higher educational level were less likely to be referred. In addition, women aged 20-29 years who were unemployed or outside the workforce prior to vaccination had increased odds of being referred to a diagnostic centre. Conclusion: We found social inequality in the referral to a diagnostic centre following HPV vaccination. This might be explained by an increased morbidity in girls and women of lower socioeconomic status.

Fish oil supplementation during pregnancy and allergic respiratory disease in the adult offspring.

BACKGROUND: Maternal supplementation with long-chain n-3 polyunsaturated fatty acids can have immunologic effects on the developing fetus through several anti-inflammatory pathways. However, there is limited knowledge of the long-term programming effects. OBJECTIVE: In a randomized controlled trial from 1990 with 24 years of follow-up, our aim was to determine whether supplementation with 2.7 g of long-chain n-3 polyunsaturated fatty acids in pregnancy can reduce the risk of asthma in offspring and allergic respiratory disease. METHODS: The randomized controlled trial included 533 women who were randomly assigned to receive fish oil during the third trimester of pregnancy, olive oil, or no oil in the ratio 2:1:1. The offspring were followed in a mandatory national prescription register, with complete follow-up for prescriptions related to the treatment of asthma and allergic rhinitis as primary outcomes. Furthermore, the offspring were invited to complete a questionnaire (74% participated) and attend a clinical examination (47% participated) at age 18 to 19 years. RESULTS: In intention-to-treat analyses the probability of having had asthma medication prescribed was significantly reduced in the fish oil group compared with the olive oil group (hazard ratio, 0.54, 95% CI, 0.32-0.90; P = .02). The probability of having had allergic rhinitis medication prescribed was also reduced in the fish oil group compared with the olive oil group (hazard ratio, 0.70, 95% CI, 0.47-1.05; P = .09), but the difference was not statistically significant. Self-reported information collected at age 18 to 19 years supported these findings. No associations were detected with respect to lung function outcomes or allergic sensitization at 18 to 19 years of age. CONCLUSION: Maternal supplementation with fish oil might have prophylactic potential for long-term prevention of asthma in offspring.

Maternal thyroid function in pregnancy may program offspring blood pressure, but not adiposity at 20 y of age.

BACKGROUND: Experimental evidence exists indicating that maternal thyroid hormones during pregnancy may affect the metabolic set point and cardio-vascular function in the offspring. The objective of this study was to investigate the association between maternal thyroid function in week 30 of gestation and offspring adiposity and blood pressure at 20 y. METHODS: The study was based on the follow up of a Danish birth cohort from 1988 to 1989 (n = 965). A blood sample was drawn from the pregnant women in week 30 of gestation (N = 877). In 2008-2009, the offspring were followed up with self-reported anthropometrics (N = 645) and a clinically measured blood pressure (N = 425). Multiple linear regressions were used to estimate the association between maternal thyroid function and offspring BMI, waist circumference, and blood pressure. RESULTS: Offspring of subclinical hypothyroid women had higher systolic blood pressure (adjusted difference = 3.6, 95% confidence interval: 0.2, 7.0 mmHg) and a tendency toward higher diastolic blood pressure (adjusted difference = 2.3, 95% confidence interval: -0.2, 4.9 mmHg) compared to offspring of euthyroid women. No association was found with offspring BMI and waist circumference. CONCLUSION: Maternal thyroid function during third trimester of pregnancy may affect long-term blood pressure in the offspring.

Examining confounding by diet in the association between perfluoroalkyl acids and serum cholesterol in pregnancy.

BACKGROUND: Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) have consistently been associated with higher cholesterol levels in cross sectional studies. Concerns have, however, been raised about potential confounding by diet and clinical relevance. OBJECTIVE: To examine the association between concentrations of PFOS and PFOA and total cholesterol in serum during pregnancy taking into considerations confounding by diet. METHODS: 854 Danish women who gave birth in 1988-89 and provided a blood sample and reported their diet in week 30 of gestation. RESULTS: Mean serum PFOS, PFOA and total cholesterol concentrations were 22.3 ng/mL, 4.1 ng/mL and 7.3 mmol/L, respectively. Maternal diet was a significant predictor of serum PFOS and PFOA concentrations. In particular intake of meat and meat products was positively associated while intake of vegetables was inversely associated (P for trend <0.01) with relative difference between the highest and lowest quartile in PFOS and PFOA concentrations ranging between 6% and 25% of mean values. After adjustment for dietary factors both PFOA and PFOS were positively and similarly associated with serum cholesterol (P for trend ≤0.01). For example, the mean increase in serum cholesterol was 0.39 mmol/L (95%CI: 0.09, 0.68) when comparing women in the highest to lowest quintile of PFOA concentrations. In comparison the mean increase in serum cholesterol was 0.61 mmol/L (95%CI: 0.17, 1.05) when comparing women in the highest to lowest quintile of saturated fat intake. CONCLUSION: In this study associations between PFOS and PFOA with serum cholesterol appeared unrelated to dietary intake and were similar in magnitude as the associations between saturated fat intake and serum cholesterol.

Fetal growth and cardio-metabolic risk factors in the 20-year-old offspring.

OBJECTIVE: To investigate the association between prenatal growth patterns as estimated by biparietal diameter and cardio-metabolic risk at 20 years. DESIGN: Follow-up study. SETTING: Denmark 1988-2009. POPULATION: Two cohorts of children born between 1988 and 1990 (n=707) and followed up in 2008-2009 (n=333-509). METHODS: We have access to biparietal diameter from early ultrasound scan and birthweight. For each gender, biparietal diameter and birthweight, gestational age-specific growth-z-scores were calculated. A change in growth trajectory was depicted as a shift in z-score for the two growth measures. Multiple linear regression modeling was used to estimate associations between biparietal diameter and birthweight z-scores and later cardio-metabolic risk factors as well as estimating whether changing growth trajectory was associated with later cardio-metabolic risk. MAIN OUTCOME MEASURES: Self-reported anthropometrics and clinically measured blood pressure, heart rate and biochemical measures associated with cardio-metabolic health. RESULTS: After adjustments, biparietal diameter was not associated with any of the outcomes. Birthweight was positively associated with both adult height and weight and inversely associated with insulin, triglyceride and insulin resistance. Also, the data indicated a U-shaped association between growth in the second half of pregnancy and adult body mass index among individuals with a low biparietal diameter in mid-pregnancy. CONCLUSION: Different patterns of intrauterine growth may be associated with later risk of cardio-metabolic disease.

Capillary refill time is a predictor of short-term mortality for adult patients admitted to a medical department: an observational cohort study.

BACKGROUND: Capillary refill time (CRT) has been advocated as a tool for rapid assessment of circulatory status. The correlation between neither CRT and mortality nor CRT and markers of circulatory status has been assessed. We performed a prospective observational cohort study to assess the relationship between CRT (using two existing definitions and as a continuous variable) and short-term mortality. METHODS: We included all acutely admitted adult patients to a medical admission unit. We measured CRT, blood pressure, pulse, temperature and peripheral oxygen saturation. We presented the data descriptively. Difference between continuous data was analysed using Wilcoxon Rank Sum Test and categorical data using χ(2) test. The primary endpoint was 1-day all-cause mortality. RESULTS: 3046 patients were enrolled and CRT was measured on 1935. In univariate analyses, we found increasing all-cause 1-day mortality with all definitions of CRT. Performing multivariable analysis, controlling for age, sex, mean blood pressure, pulse, temperature and peripheral oxygen saturation, we found increasing CRT as a continuous variable and according to the Schriger and Baraff definition to be associated with increased mortality. Both the Trauma score and Schriger and Baraff definitions had high negative predictive values. The calculations on the Schriger and Baraff definition were based on limited power. CONCLUSIONS: We found a significant association between CRT measured as a continuous variable and short-term mortality. Using the definition of Schriger and Baraff also seems appropriate, but this is based on calculations of limited power.

Where Birth Month, Sex and Age Matters: The Burden of Severe Respiratory Disease in Danish Children <5 Years, 2016-2022.

BACKGROUND: In light of the substantial impact that respiratory diseases in young children poses on healthcare systems globally, and in the wake of the recent COVID-19 pandemic, there is a growing urgency to obtain reliable estimates on the burden of respiratory disease. OBJECTIVES: The aim of this study is to quantify the overall burden of respiratory disease requiring hospitalizations and explore the trends in these admissions in Danish children <5 years, January 1, 2016-October 31, 2022. METHODS: The number of hospitalizations attributed to respiratory infections in children <5 years, was extracted from the Danish National Patient Register, and stratified into subgroups based on age, gender and birth month, and presented on a month-to-month basis. RESULTS: A total of 48,194 children under the age of 5, were hospitalized due to respiratory infections within the study period and the annual hospitalization incidence exhibited a noteworthy variation. Risk factors associated with the highest hospitalization incidence were young age, male gender and in children under 1-year-old, birth months falling in the period of November to January. Younger age and admission during the winter months were linked to longer hospital stays. The seasonal pattern of hospitalizations and the distribution of hospitalizations across various subgroups were greatly influenced by the COVID-19 pandemic. CONCLUSION: This study describes and quantifies the importance of factoring in specific child demographics and seasonal variations in hospitalizations when devising preventive healthcare strategies such as the use of monoclonal antibody therapy and vaccines.

COVID-19 vaccination and involuntary movements: A longitudinal panel study.

OBJECTIVE: Despite high COVID-19 vaccination rates in many populations, concerns persist about potential adverse events, including concerns about involuntary movements. While case studies have shown occurrences of involuntary movements following COVID-19 vaccination, no systematic studies have explored this association. Our study aims to investigate the relationship between COVID-19 vaccination and involuntary movements. METHODS: This study employs a longitudinal panel design. The study population consists of 165,834 responses from a total of 97,537 unique individuals sourced from the BiCoVac cohort, which is a randomly sampled cohort of Danish individuals aged 16 to 65. Data were collected through a combination of questionnaires and national registers, and analyses were conducted using mixed effects logistic regression. RESULTS: Vaccinated individuals had lower odds of reporting involuntary movements compared to non-vaccinated individuals. Although adjustments attenuated the results, a consistent pattern of lower odds was observed among the vaccinated individuals. The strongest association for the first dose was observed in individuals who received the vaccine within the last 4 weeks before reporting symptoms (OR = 0.72 (0.60; 0.85)). For the second dose, the strongest association was found in individuals who received the second vaccine dose more than 4 weeks before reporting symptoms (OR = 0.77 (0.65; 0.91)). CONCLUSION: The results of the study do not indicate involuntary movements as an adverse reaction to the COVID-19 vaccine. These findings support the safety profile of the COVID-19 vaccine concerning involuntary movements and contribute to enhancing public trust in vaccination programs.

No association between the intake of marine n-3 PUFA during the second trimester of pregnancy and factors associated with cardiometabolic risk in the 20-year-old offspring.

The intake of marine n-3 PUFA has been shown to decrease the risk of CVD in a number of studies. Since the development of CVD is often a lifelong process, marine n-3 PUFA intake early in life may also affect the development of later CVD. The aim of the present study was to investigate the association between maternal intake of marine n-3 PUFA during the second trimester of pregnancy and factors associated with cardiometabolic risk in the 20-year-old offspring. The study was based on the follow-up of the offspring of a Danish pregnancy cohort who participated in a study conducted from 1988 to 1989. A total of 965 pregnant women were originally included in the cohort and detailed information about the intake of marine n-3 PUFA during the second trimester was collected. In 2008-9, the offspring were invited to participate in a clinical examination including anthropometric, blood pressure (BP) and short-term heart rate variability measurements. Also, a fasting venous blood sample was drawn from them. Multiple linear regression modelling, using the lowest quintile of marine n-3 PUFA intake as the reference, was used to estimate the association with all outcomes. A total of 443 offspring participated in the clinical examination. No association between the intake of marine n-3 PUFA during the second trimester of pregnancy and offspring adiposity, glucose metabolism, BP or lipid profile was found. In conclusion, no association between the intake of marine n-3 PUFA during the second trimester of pregnancy and the factors associated with cardiometabolic risk in the 20-year-old offspring could be detected.

The effect of maternal fish oil supplementation during the last trimester of pregnancy on blood pressure, heart rate and heart rate variability in the 19-year-old offspring.

Studies in experimental animals and human subjects have suggested that intake of n-3 fatty acids in early life can affect cardiovascular risk factors in adult life. Therefore, the aim of the present study was to investigate the effect of fish oil (FO) supplementation during the third trimester of pregnancy on blood pressure (BP), heart rate (HR) and HR variability (HRV) in the 19-year-old offspring. The study was based on follow-up of a randomised, controlled trial from 1990, in which 533 pregnant women were randomised to FO, olive oil (OO) or no oil (NO) during the last trimester of pregnancy. The offspring was invited to a physical examination including BP, HR and HRV measurements. A subgroup consisting of the offspring of mothers with a low baseline fish intake also had 24 h HRV determined. The OO group was used as reference and multiple linear regression modelling was used to compare the FO and OO groups. A total of 180 of the offspring from the FO and OO groups agreed to participate in the study (45%). The adjusted difference between the FO and OO groups was 2 (95% CI -1, 4) mmHg in systolic and 1 (95% CI 0, 3) mmHg in diastolic BP. The difference in HR was 1 (95% CI -2, 4). Also, HRV indices did not differ significantly between groups. Hence, FO supplementation during late pregnancy was not associated with offspring BP, HR and HRV during adolescence.

Multiple health complaints in preadolescence and hospital contacts during adolescence: a prospective cohort study.

Multiple health complaints (MHC) is increasing among preadolescents in many countries, but their prognostic effect for individual thriving or societal resource use is scarcely studied. This makes interpreting the significance of this increase challenging. We contribute by examining whether MHC in preadolescence predicts hospital contacts in adolescence by doing a nation-wide population-based cohort-study following preadolescents from the Danish National Birth-Cohort from 2010 to 2018. 96,382 children were invited at age 11. Responses to a modified version of the Health Behaviour in School Children Symptom Checklist (headache, dizziness, stomachache, irritability, feeling nervous, difficulty in getting to sleep and feeling low) was dichotomized into MHC (≥ 2 concurrent symptoms, each with a frequency of at least weekly, yes/no). Hospital contacts were derived from Danish registers from the date of answering the questionnaire to December 31st 2018. Negative binomial regression estimated incidence rate ratios (IRRs) comparing children with MHC to children without. Analyses were further broken down by hospital sector (psychiatric/somatic) and contact type (in-patient/out-patient/emergency room). 47,365 (49.1%) responded. Mean age was 11.2 years, 52% girls. 10.3% of responders reported MHC. For hospital contacts, the unadjusted IRR was 1.74 [95% CI 1.65, 1.83]. Results were robust to adjustment for sociodemographic variables and somatic/psychiatric morbidity diagnosed before baseline, IRR 1.62 [95% CI 1.54-1.71]. In conclusion, MHC in preadolescents are prognostic of hospital contacts. This shows that we cannot ignore MHC, and to prevent potentially unhelpful healthcare use, we must act. Future research should focus on the underlying causes of MHC to understand which changes will be most helpful and thus how to act.

Healthcare Use in the Five Years Before a First Infertility Diagnosis: A Danish Register-Based Case-Control Study in the CROSS-TRACKS Cohort.

Purpose: Infertility may affect somatic and mental health later in life. Nevertheless, health status before diagnosed infertility is sparsely studied in women. We aimed to describe healthcare use in primary and secondary care before a first infertility diagnosis and compare use between cases and controls. Materials and Methods: The case-control study was based on register data and used incidence density sampling. From the CROSS-TRACKS Cohort, we included women residing in the Horsens area in Denmark in 2012-2018 (n = 54,175). Eligible women were aged 18-40 years, nulliparous, and living in heterosexual relationships. Cases were women with a first infertility diagnosis in the Danish National Patient Registry (index date). Five controls were matched on age, birth year, and calendar time. Through linkage to Danish national health registries, we identified general practitioner (GP) attendance, paraclinical examinations, hospital contacts, diagnoses, and redeemed prescriptions. Healthcare use from one year to five years before index date was compared with conditional logistic regression. Results: We identified 711 cases and 3555 controls. At one year before index date, cases consulted their GP (odds ratio (OR) = 5.2, 95% confidence interval (CI): 3.2, 8.3) and visited hospital (OR = 1.2, 95% CI: 1.0, 1.4) and redeemed prescriptions (OR = 2.3 95% CI: 1.9, 2.7) more often compared to controls. Cases more often had blood and hemoglobin tests performed, redeemed more drugs related to genitourinary and hormonal diseases, and were more often diagnosed with endocrine and genitourinary diseases in the year before a first infertility diagnosis compared to controls. Cases and controls had comparable healthcare use from five years to one year before a first infertility diagnosis. Conclusion: Cases and controls had similar healthcare use from five years to one year before a first infertility diagnosis. However, cases had a higher healthcare use in the year preceding a first infertility diagnosis compared to controls.