A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation.

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P < 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.

Maternal pre-pregnancy BMI and reproductive health in adult sons: a study in the Danish National Birth Cohort.

STUDY QUESTION: Is maternal pre-pregnancy BMI associated with semen quality, testes volume, and reproductive hormone levels in sons? SUMMARY ANSWER: Maternal pre-pregnancy BMI was associated with an altered reproductive hormone profile in young adult sons, characterized by higher levels of oestradiol, LH, and free androgen index (FAI) and lower levels of sex hormone-binding globulin (SHBG) in sons born of mothers with pre-pregnancy overweight and obesity. WHAT IS KNOWN ALREADY: Evidence suggests that maternal pre-pregnancy BMI may influence reproductive health later in life. Only one pilot study has investigated the association between maternal pre-pregnancy BMI and reproductive health outcomes in sons, suggesting that a high BMI was associated with impaired reproductive function in the adult sons. STUDY DESIGN, SIZE, DURATION: A population-based follow-up study of 1058 young men from the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998-2019, was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1058 adult sons (median age 19 years, 2 months), born 1998-2000 by mothers included in the DNBC, participated in FEPOS. At a clinical examination, they provided a semen and blood sample, measured their testes volume, and had height and weight measured. Maternal pre-pregnancy BMI was obtained by self-report in early pregnancy. Semen characteristics, testes volume, and reproductive hormone levels were analysed according to maternal pre-pregnancy BMI categories and as restricted cubic splines using negative binomial and ordinary least square regression models. Mediation analyses examined potential mediation by the sons' birthweight, pubertal timing, fat mass, and BMI. Additional analyses investigated the role of paternal BMI in the potential associations between maternal BMI and reproductive health outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: We found no consistent associations between maternal pre-pregnancy BMI and semen characteristics or testes volume. Sons of mothers with higher pre-pregnancy BMI had higher oestradiol and lower SHBG levels, both in a dose-dependent manner. Sons of mothers with pre-pregnancy obesity (≥30 kg/m2) had higher LH levels and a higher FAI than sons born by mothers with normal pre-pregnancy BMI (18.5-24.9 kg/m2). The mediation analyses suggested that the effect of maternal pre-pregnancy BMI on higher levels of oestrogen, LH, and FAI was partly mediated by the sons' birthweight, in addition to adult fat mass and BMI measured at the clinical examination, whereas most of the effect on lower levels of SHBG was primarily mediated by the sons' own fat mass and BMI. Paternal BMI was not a strong confounder of the associations in this study. LIMITATIONS, REASONS FOR CAUTION: This study was based in a population-based cohort with a low prevalence of overweight and obesity in both mothers and adult sons. Some men (10%) had blood for reproductive hormone assessment drawn in the evening. While several potential confounding factors were accounted for, this study's inherent risk of residual and unmeasured confounding precludes provision of causal estimates. Therefore, caution should be given when interpreting the causal effect of maternal BMI on sons' reproductive health. WIDER IMPLICATIONS OF THE FINDINGS: Given the widespread occurrence of overweight and obesity among pregnant women, it is imperative to thoroughly examine the potential consequences for reproductive hormone levels in adult sons. The potential effects of maternal pre-pregnancy obesity on sons' reproductive hormone profile may potentially be partly avoided by the prevention of overweight and obesity in the sons. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis's Grant, Axel Muusfeldt's Foundation (2016-491), AP Møller Foundation (16-37), the Health Foundation, Dagmar Marshall's Fond, Aarhus University, Independent Research Fund Denmark (9039-00128B), and the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Prevalence and predictors of post-COVID-19 symptoms in general practice - a registry-based nationwide study.

BACKGROUND: With Norwegian national registry data, we assessed the prevalence of post-COVID-19 symptoms at least 3 months after confirmed infection, and whether sociodemographic factors and pre-pandemic health problems were risk factors for these symptoms. METHODS: All persons with a positive SARS-CoV-2 PCR test from February 2020 to February 2021 (exposed) were compared to a group without a positive test (unexposed) matched on age, sex, and country of origin. We used Cox regression to estimate hazard ratios (HR) for 18 outcome symptoms commonly described as post-COVID-19 related, registered by GPs. We compared relative risks (RR) for fatigue, memory disturbance, or shortness of breath among exposed and unexposed using Poisson regression models, assessing sex, age, education, country of origin, and pre-pandemic presence of the same symptom and comorbidity as possible risk factors, with additional analyses to assess hospitalisation for COVID-19 as a risk factor among exposed. RESULTS: The exposed group (N = 53 846) had a higher prevalence of most outcome symptoms compared to the unexposed (N = 485 757), with the highest risk for shortness of breath (HR 2.75; 95%CI 2.59-2.93), fatigue (2.08; 2.00-2.16) and memory disturbance (1.41;1.26-1.59). High HRs were also found for disturbance of smell/taste and hair loss, but frequencies were low. Concerning risk factors, sociodemographic factors were at large similarly associated with outcome symptoms in both groups. Registration of the outcome symptom before the pandemic increased the risk for fatigue, memory disturbance and shortness of breath after COVID-19, but these associations were weaker among exposed. Comorbidity was not associated with fatigue and shortness of breath in the COVID-19 group. For memory disturbance, the RR was slightly increased with the higher comorbidity score both among exposed and unexposed. CONCLUSION: COVID-19 was associated with a range of symptoms lasting more than three months after the infection.

Paternal and maternal birthweight and offspring risk of macrosomia at term gestations: A nationwide population study.

BACKGROUND: There is a paucity of data on whether parents' macrosomia (birthweight ≥4500 g) status influences the risk of macrosomia in the offspring. The role of maternal overweight in the generational effect of macrosomia is not known. OBJECTIVE: To estimate the risk of macrosomia by parental birthweight at term and evaluate if this risk varied with maternal body mass index (BMI, kg/m2 ) early in pregnancy. METHODS: We used data from the Medical Birth Registry of Norway on all singleton term births (37-42 gestational weeks) during 1967-2017. The primary exposure was parental macrosomia, and the outcome was macrosomia in the second generation. The secondary exposure was maternal BMI. We used binomial regression to calculate relative risk (RR) with a 95% confidence interval. We assessed potential unmeasured confounding and selection bias using a probabilistic bias analysis and performed analyses with and without imputation for variables with missing values. RESULTS: The data included 647,957 singleton parent-offspring trios born at term. The prevalence of macrosomia was 3.2% (n = 41,396) in the parental generation and 4.0% (n = 25,673) in the offspring generation. Macrosomia in parents was associated with an increased risk of macrosomia in offspring, with the RR for both parents were born macrosomic being 6.53 (95% confidence interval [CI] 5.31, 8.05), only mother macrosomic 3.37 (95% CI 3.17, 3.57) and only father macrosomic RR 2.22 (95% CI 2.12, 2.33). These risks increased by maternal BMI in early pregnancy: if both parents were born macrosomic, 17% of infants were macrosomic among mothers with normal BMI. If both parents were macrosomic and the mothers were obese, 31% of offspring were macrosomic. Macrosomia-related adverse outcomes did not differ with parental macrosomia status. CONCLUSIONS: Parents' weight at birth and maternal BMI appear to be strongly associated with macrosomia in the offspring delivered at term gestations.

Reproductive outcomes in women and men conceived by assisted reproductive technologies in Norway: prospective registry based study.

Objectives: To determine whether the perinatal outcomes of women or men who were conceived by assisted reproductive technologies are different compared with their peers who were naturally conceived. Design: Prospective registry based study. Setting: Medical Birth Registry of Norway. Participants: People born in Norway between 1984 and 2002 with a registered pregnancy by the end of 2021. Exposure: People who were conceived by assisted reproductive technologies and have had a registered pregnancy. Main outcome measures: Comparing pregnancies and births of people who were conceived by assisted reproductive technologies and people who were naturally conceived, we assessed mean birth weight, gestational age, and placental weight by linear regression, additionally, the odds of congenital malformations, a low 5 min Apgar score (<7), transfer to a neonatal intensive care unit, delivery by caesarean section, use of assisted reproductive technologies, hypertensive disorders of pregnancy and pre-eclampsia, preterm birth, and offspring sex, by logistic regression. The occurrence of any registered pregnancy from people aged 14 years until age at the end of follow-up was assessed using Cox proportional regression for both groups. Results: Among 1 092 151 people born in Norway from 1984 to 2002, 180 652 were registered at least once as mothers, and 137 530 as fathers. Of these, 399 men and 553 women were conceived by assisted reproductive technologies. People who were conceived by assisted reproductive technologies had little evidence of increased risk of adverse outcomes in their own pregnancies, increased use of assisted reproductive technologies, or any difference in mean birth weight, placental weight, or gestational age. The only exception was for an increased risk of the neonate having a low Apgar score at 5 min (adjusted odds ratio 1.86 (95% confidence interval 1.20 to 2.89)) among women who were conceived by assisted reproductive technologies. Odds were slightly decreased of having a boy among mothers conceived by assisted reproductive technologies (odds ratio 0.79 (95% confidence interval 0.67 to 0.93)). People conceived by assisted reproductive technologies were slightly less likely to have a registered pregnancy within the follow-up period (women, adjusted hazard ratio 0.88 (95% CI 0.81 to 0.96); men, 0.91 (0.83 to 1.01)). Conclusions: People conceived by assisted reproductive technologies were not at increased risk of obstetric or perinatal complications when becoming parents. The proportion of people conceived by assisted reproductive technologies with a registered pregnancy was lower than among people who were naturally conceived, but a longer follow-up is required to fully assess their fertility and reproductive history.

Impact of COVID-19 on pregnancy-related healthcare utilisation: a prospective nationwide registry study.

OBJECTIVE: To assess the impact of COVID-19 on pregnancy-related healthcare utilisation and differences across social groups. DESIGN: Nationwide longitudinal prospective registry-based study. SETTING: Norway. PARTICIPANTS: Female residents aged 15-50 years (n=1 244 560). MAIN OUTCOME MEASURES: Pregnancy-related inpatient, outpatient and primary care healthcare utilisation before the COVID-19 pandemic (prepandemic: 1 January to 11 March 2020), during the initial lockdown (first wave: 12 March to 3 April 2020), during the summer months of low restrictions (summer period: 4 April to 31 August 2020) and during the second wave to the end of the year (second wave: 1 September to 31 December 2020). Rates were compared with the same time periods in 2019. RESULTS: There were 130 924 inpatient specialist care admissions, 266 015 outpatient specialist care consultations and 2 309 047 primary care consultations with pregnancy-related diagnostic codes during 2019 and 2020. After adjusting for time trends and cofactors, inpatient admissions were reduced by 9% (adjusted incidence rate ratio (aIRR)=0.91, 95% CI 0.87 to 0.95), outpatient consultations by 17% (aIRR=0.83, 95% CI 0.71 to 0.86) and primary care consultations by 10% (aIRR=0.90, 95% CI 0.89 to 0.91) during the first wave. Inpatient care remained 3%-4% below prepandemic levels throughout 2020. Reductions according to education, income and immigrant background were also observed. Notably, women born in Asia, Africa or Latin America had a greater reduction in inpatient (aIRR=0.87, 95% CI 0.77 to 0.97) and outpatient (aIRR 0.90, 95% CI 0.86 to 0.95) care during the first wave, compared with Norwegian-born women. We also observed that women with low education had a greater reduction in inpatient care during summer period (aIRR=0.88, 95% CI 0.83 to 0.92), compared with women with high educational attainment. CONCLUSION: Following the introduction of COVID-19 mitigation measures in Norway in March 2020, there were substantial reductions in pregnancy-related healthcare utilisation, especially during the initial lockdown and among women with an immigrant background.

Investigating causal relations between sleep duration and risks of adverse pregnancy and perinatal outcomes: linear and nonlinear Mendelian randomization analyses.

BACKGROUND: Observational studies have reported maternal short/long sleep duration to be associated with adverse pregnancy and perinatal outcomes. However, it remains unclear whether there are nonlinear causal effects. Our aim was to use Mendelian randomization (MR) and multivariable regression to examine nonlinear effects of sleep duration on stillbirth (MR only), miscarriage (MR only), gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth and low/high offspring birthweight. METHODS: We used data from European women in UK Biobank (N=176,897), FinnGen (N=~123,579), Avon Longitudinal Study of Parents and Children (N=6826), Born in Bradford (N=2940) and Norwegian Mother, Father and Child Cohort Study (MoBa, N=14,584). We used 78 previously identified genetic variants as instruments for sleep duration and investigated its effects using two-sample, and one-sample nonlinear (UK Biobank only), MR. We compared MR findings with multivariable regression in MoBa (N=76,669), where maternal sleep duration was measured at 30 weeks. RESULTS: In UK Biobank, MR provided evidence of nonlinear effects of sleep duration on stillbirth, perinatal depression and low offspring birthweight. Shorter and longer duration increased stillbirth and low offspring birthweight; shorter duration increased perinatal depression. For example, longer sleep duration was related to lower risk of low offspring birthweight (odds ratio 0.79 per 1 h/day (95% confidence interval: 0.67, 0.93)) in the shortest duration group and higher risk (odds ratio 1.40 (95% confidence interval: 1.06, 1.84)) in the longest duration group, suggesting shorter and longer duration increased the risk. These were supported by the lack of evidence of a linear effect of sleep duration on any outcome using two-sample MR. In multivariable regression, risks of all outcomes were higher in the women reporting <5 and ≥10 h/day sleep compared with the reference category of 8-9 h/day, despite some wide confidence intervals. Nonlinear models fitted the data better than linear models for most outcomes (likelihood ratio P-value=0.02 to 3.2×10-52), except for gestational diabetes. CONCLUSIONS: Our results show shorter and longer sleep duration potentially causing higher risks of stillbirth, perinatal depression and low offspring birthweight. Larger studies with more cases are needed to detect potential nonlinear effects on hypertensive disorders of pregnancy, preterm birth and high offspring birthweight.

General practitioner visits after SARS-CoV-2 omicron compared with the delta variant in children in Norway: a prospective nationwide registry study.

BACKGROUND: SARS-CoV-2 infection in children is followed by an immediate increase in primary care utilisation. The difference in utilisation following infection with the delta and omicron virus variants is unknown. OBJECTIVES: To study whether general practitioner (GP) contacts were different in children infected with the omicron versus delta variant for up to 4 weeks after the week testing positive. SETTING: Primary care. PARTICIPANTS: All residents in Norway aged 0-10. After excluding 47 683 children with a positive test where the virus variant was not identified as delta or omicron and 474 children who were vaccinated, the primary study population consisted of 613 448 children. MAIN OUTCOME MEASURES: GP visits. METHODS: We estimated the difference in the weekly share visiting the GP after being infected with the delta or omicron variant to those in the study population who were either not tested or who tested negative using an event study design, controlling for calendar week of consultation, municipality fixed effects and sociodemographic factors in multivariate logistic regressions. RESULTS: Compared with preinfection, increased GP utilisation was found for children 1 and 2 weeks after testing positive for the omicron variant, with an OR of 6.7 (SE: 0.69) in the first week and 5.5 (0.72) in the second week. This increase was more pronounced for children with the delta variant, with an OR of 8.2 (0.52) in the first week and 7.1 (0.93) in the second week. After 2 weeks, the GP utilisation returned to preinfection levels. CONCLUSION: The omicron variant appears to have resulted in less primary healthcare interactions per infected child compared with the delta variant.

Health at age 17 in Norwegian adolescents: Mental and physical status in the national cohort born in 2001.

AIMS: We present self-reported data on physical and mental health at age 17 years from 82% of Norwegians born in 2001. METHODS: In Norway, the Armed Forces require that each resident who reaches the age of 17 years completes a self-administered declaration of health that is used for military selection. The declaration collects information on height and weight, various clinically diagnosed diseases, mental and behavioural disorders, and other health conditions where clinical diagnosis is not required. In 2018, there were 65,913 adolescents born in 2001 living in Norway, of whom 10,223 were exempt from completing the declaration; declarations were therefore sent to 55,690 participants. We included 54,132 participants who completed the declaration (response rate 97.2%): 27,220 male and 26,912 female respondents. RESULTS: We found that 18% of male and 28% of female respondents reported at least one clinically diagnosed disease, mental disorder or behavioural disorder. Among health condition where clinical diagnosis was not required, 19% of male and 37% of female respondents reported anxiety/depression affecting daily life and 10 versus 18% reported migraines/recurring headaches. The respondents probably represent the healthiest part of the total cohort of 17-year-old Norwegians because those who are exempt from completing the declaration are already considered unfit for military service. CONCLUSIONS: These data represent a rich resource for further research. Similar data exist for the birth cohorts in 1993-2003. We encourage further research that can help decision-makers identify areas of concern that should be targeted for interventions.

Antipsychotic use in pregnancy and risk of attention/deficit-hyperactivity disorder and autism spectrum disorder: a Nordic cohort study.

BACKGROUND: Antipsychotics are increasingly used among women of childbearing age and during pregnancy. OBJECTIVE: To determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders. Design Population-based cohort study, including a sibling analysis. Setting Nationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016). Participants 4 324 086 children were eligible for inclusion to the study cohort. Intervention Antipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use. Main outcome measures Non-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors. FINDINGS: Among 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD. DISCUSSION: Our findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics. CLINICAL IMPLICATIONS: Results regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.

The international Perinatal Outcomes in the Pandemic (iPOP) study: protocol.

Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread "natural experiment" of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide critical new information to shape prenatal care strategies throughout (and well beyond) the pandemic.

Social and life skills in adolescents who have self-harmed: analysis of survey responses from a national sample of adolescents in Norway.

OBJECTIVE: Social and life skills (SLS) may be important in the prevention and treatment of self-harm, but few studies have described this relationship. We examined three components of SLS in adolescents who reported self-harm that was, according to themselves, diagnosed by a clinician. DESIGN: Cross-sectional. SETTING: National screening prior to military service. PARTICIPANTS: 176 284 residents of Norway born in 1999-2001 received a declaration of health. We included 171 486 individuals (84 153 (49%) women and 87 333 (51%) men) who were 17 (n=1 67 855) or 18 years of age (n=3631) when they completed the declaration. OUTCOME MEASURE: The main outcome was clinically diagnosed self-harm, defined as self-harm that the adolescents themselves stated had been diagnosed by a clinician. Components of SLS were social interactions; coping strategies; and emotional regulation/aggression. The association between SLS and self-reported clinically diagnosed self-harm was assessed in hierarchical multiple regression models controlling for sex; school absence; and feelings of emotional pain. RESULTS: Three percent (n=5507) of the adolescents reported clinically diagnosed self-harm. The three components of SLS together added little to the prediction of clinically diagnosed self-harm (∆R2=0.02). After controlling for school absence and emotional pain, emotional regulation/aggression was the only SLS-component that was independently associated with clinically diagnosed self-harm (OR 1.33, 95% CI 1.31 to 1.36). The young men who said they had been clinically diagnosed for self-harm scored slightly worse on social interactions (Hedge's g (g) = -0.13, p<0.001) and emotional regulation/aggression (g = -0.18, p<0.001) than the young women in this group. CONCLUSION: Young women and young men who reported clinically diagnosed self-harm had more problems with emotional regulation/aggression than other adolescents, but did not have worse social interactions or coping strategies.

Severe acute respiratory syndrome coronavirus 2 prevalence in 1170 asymptomatic Norwegian conscripts.

BACKGROUND: Accurate estimates of SARS-CoV-2 infection in different population groups are important for the health authorities. In Norway, public infection control measures have successfully curbed the pandemic. However, military training and service are incompatible with these measures; therefore extended infection control measures were implemented in the Norwegian Armed Forces. We aimed to describe these measures, discuss their value, and investigate the polymerase chain reaction (PCR) prevalence and seroprevalence of SARS-CoV-2, as well as changes in antibody titer levels over the 6-week military training period in a young, asymptomatic population of conscripts. METHODS: In April 2020, 1170 healthy conscripts (median age 20 years) enrolled in military training. Extended infection control measures included a pre-enrollment telephone interview, self-imposed quarantine, questionnaires, and serial SARS-CoV-2 testing. At enrollment, questionnaires were used to collect information on symptoms, and SARS-CoV-2 rapid antibody testing was conducted. Serial SARS-CoV-2 PCR and serology testing were used to estimate the prevalence of confirmed SARS-CoV-2 and monitor titer levels at enrollment, and 3 and 6 weeks thereafter. RESULTS: At enrollment, only 0.2% of conscripts were SARS-CoV-2 PCR-positive, and seroprevalence was 0.6%. Serological titer levels increased nearly 5-fold over the 6-week observation period. Eighteen conscripts reported mild respiratory symptoms during the 2 weeks prior to enrollment (all were PCR-negative; one was serology-positive), whereas 17 conscripts reported respiratory symptoms and nine had fever at enrollment (all were PCR- and serology-negative). CONCLUSIONS: The prevalence of SARS-CoV-2 was less than 1% in our sample of healthy Norwegian conscripts. Testing of asymptomatic conscripts seems of no value in times of low COVID-19 prevalence. SARS-CoV-2 antibody titer levels increased substantially over time in conscripts with mild symptoms.

Influenza vaccination and risk for cardiovascular events: a nationwide self-controlled case series study.

BACKGROUND: US and European guidelines diverge on whether to vaccinate adults who are not at high risk for cardiovascular events against influenza. Here, we investigated the associations between influenza vaccination and risk for acute myocardial infarction, stroke and pulmonary embolism during the 2009 pandemic in Norway, when vaccination was recommended to all adults. METHODS: Using national registers, we studied all vaccinated Norwegian individuals who suffered AMI, stroke, or pulmonary embolism from May 1, 2009 through September 30, 2010. We defined higher-risk individuals as those using anti-diabetic, anti-obesity, anti-thrombotic, pulmonary or cardiovascular medications (i.e. individuals to whom vaccination was routinely recommended); all other individuals were regarded as having lower-risk. We estimated incidence rate ratios with 95% CI using conditional Poisson regression in the pre-defined risk periods up to 180 days following vaccination compared to an unexposed time-period, with adjustment for season or daily temperature. RESULTS: Overall, we observed lower risk for cardiovascular events following influenza vaccination. When stratified by baseline risk, we observed lower risk across all three outcomes in association with vaccination among higher-risk individuals. In this subgroup, relative risks were 0.72 (0.59-0.88) for AMI, 0.77 (0.59-0.99) for stroke, and 0.73 (0.45-1.19) for pulmonary embolism in the period 1-14 days following vaccination when compared to the background period. These associations remained essentially the same up to 180 days after vaccination. In contrast, the corresponding relative risks among subjects not using medications were 4.19 (2.69-6.52), 1.73 (0.91-3.31) and 2.35 (0.78-7.06). CONCLUSION: In this nationwide study, influenza vaccination was associated with overall cardiovascular benefit. This benefit was concentrated among those at higher cardiovascular risk as defined by medication use. In contrast, our results demonstrate no comparable inverse association with thrombosis-related cardiovascular events following vaccination among those free of cardiovascular medications at baseline. These results may inform the risk-benefit balance for universal influenza vaccination.

Yersinia enterocolitica: A Follow-up of the Outbreak in the Norwegian Armed Forces in 2014.

INTRODUCTION: In the spring of 2014, there was an outbreak of Yersinia enterocolitica (YE) gastroenteritis in four Norwegian military camps-the largest outbreak ever reported in Norway. YE is usually transmitted via food, and the gastrointestinal disease caused by the bacterium is considered a public health problem in several countries. Common symptoms of YE gastroenteritis are abdominal pain, diarrhea, fever, nausea, and vomiting. Post-infectious complications can occur after YE gastroenteritis, the most common of which are erythema nodosum and reactive arthritis. Based on self-reported data, we describe the duration of illness, the duration of any absence from service, and the incidence of symptoms of post-infectious complications in two groups of servicepeople: one diagnosed with YE gastroenteritis and the other with an unspecified acute infectious gastroenteritis. MATERIALS AND METHODS: The Norwegian Armed Forces Health Register (NAFHR) is a central health register that contains data from conscripts and from military and civilian personnel in the Norwegian Armed Forces. In this study, we identified all individuals with a diagnosis of YE gastroenteritis in the NAFHR in the period from January 1 to June 30, 2014 (n = 128) as well as all those with a diagnosis of an unspecified acute infectious gastroenteritis in the same period (n = 323) to participate as controls. In October 2018, a link to an internet-based questionnaire was distributed by e-mail to all identified individuals. The questionnaires collected data on the duration of illness, the duration of absence from service, and the incidence of symptoms of post-infectious complications. RESULTS: Of all those who received the questionnaire, 72 (59%) were included in the YE group and 117 people (36%) were included in the control group. Half of those in the YE group were ill for more than 13 days, while almost all (90%) of those in the control group recovered after 1 week. There were no differences between the groups in the incidence of symptoms of post-infectious complications during the 6 weeks after recovery. There was a significantly larger proportion of officers than conscripts in the YE group who reported symptoms of post-infectious complications. None of the respondents reported symptoms of post-infectious complications in the 6 months after the termination of military service. CONCLUSION: One strength of this study is that we were able to investigate a large outbreak of YE gastroenteritis in a group of individuals with good underlying health. Weaknesses are the low response rate, especially in the control group, and the fact that we sent out the questionnaire >4 years after the acute gastroenteritis occurred. YE gastroenteritis among personnel in the Norwegian Armed Forces was associated with a significantly longer duration of illness and a longer duration of absence from service than that resulting from an unspecified acute infectious gastroenteritis. However, YE gastroenteritis was not associated with more symptoms of post-infectious complications.

Deaths after confirmed SARS-CoV-2 in Norway. / Dødsfall etter påvist SARS-CoV-2 i Norge.

BACKGROUND: Advanced age is the most important risk factor for death as a result of COVID-19, but there is a dearth of knowledge regarding the impact of chronic diseases. Using health registry data, we describe the disease profiles of persons who died after a confirmed infection with SARS-CoV-2 during the first three months of the pandemic in Norway. MATERIAL AND METHOD: Data from the specialist health service (Norwegian Patient Registry, NPR) and the primary health service (Norwegian Registry for Primary Health Care, NRPHC) were linked to information on positive tests for SARS-CoV-2 from the Norwegian Surveillance System for Communicable Diseases (MSIS) and on deaths from the National Population Register. The data retrieval included the Norwegian population as of 1 March 2020 with data for confirmed infections, hospitalisations and deaths until 31 May 2020. RESULTS: Of 8 412 persons with a confirmed SARS-CoV-2 infection, altogether 244 (2.9 %) died, whereof 133 (55 %) were men. Among those with a confirmed infection, the proportion who died varied from 0.2 % (age < 60 years) to 52 % (age ≥ 90 years). Altogether 92 (38 %) patients died in hospital. 25 (16 %) of those who died elsewhere had previously been hospitalised for COVID-19. The proportion with no registered chronic disease was 39 % in the age group < 70 years and 26 % in the age group ≥ 70 years. The disease distribution varied between those patients who had died in and outside of hospital, especially for diagnoses of diabetes, renal failure and dementia. INTERPRETATION: Among those who had a SARS-CoV-2 infection confirmed during the first three months of the pandemic in Norway, only a small proportion died. The majority of those who died were 70 years or older and had at least one chronic disease, but the disease profile varied between patients who died in and outside of hospital. Health registry data can help provide a better overview of and advice to risk groups in the population during an ongoing pandemic.

Risk conditions in children hospitalized with influenza in Norway, 2017-2019.

BACKGROUND: Norwegian children are more frequently hospitalized with influenza than adults. Little is known about the characteristics of these children. Our aim was to investigate the presence of pre-existing risk conditions and to determine the duration of influenza hospitalizations in children during two influenza seasons. METHODS: The Norwegian Patient Registry holds data on all hospitalized patients in Norway. We included all patients younger than 18 years hospitalized with a diagnosis of influenza during the influenza seasons 2017-18 and 2018-19. Pre-existing risk conditions for influenza were identified by ICD-10 diagnoses in the Norwegian Patient Registry. In addition, information on asthma diagnoses were also retrieved from the Norwegian Registry for Primary Health Care. To estimate the prevalence of risk conditions in the child population, we obtained diagnoses on all Norwegian children in a two-year period prior to each influenza season. We calculated age-specific rates for hospitalization and risk for being hospitalized with influenza in children with risk conditions. RESULTS: In total, 1013 children were hospitalized with influenza during the two influenza seasons. Children younger than 6 months had the highest rate of hospitalization, accounting for 13.5% of all admissions (137 children). Hospitalization rates decreased with increasing age. Among children hospitalized with influenza, 25% had one or more pre-existing risk conditions for severe influenza, compared to 5% in the general population under 18 years. Having one or more risk conditions significantly increased the risk of hospitalization, (Odds Ratio (OR) 6.1, 95% confidence interval (CI) 5.0-7.4 in the 2017-18 season, and OR 6.8, 95% CI 5.4-8.4 in the 2018-19 season). Immunocompromised children and children with epilepsy had the highest risk of hospitalization with influenza, followed by children with heart disease and lung disease. The average length of stay in hospital were 4.6 days, and this did not differ with age. CONCLUSION: Children with pre-existing risk conditions for influenza had a higher risk of hospitalization for influenza. However, most children (75%) admitted to hospital with influenza in Norway during 2017-2019 did not have pre-existing risk conditions. Influenza vaccination should be promoted in particular for children with risk conditions and pregnant women to protect new-borns.

The demographics of assisted reproductive technology births in a Nordic country.

STUDY QUESTION: What are the socio-demographic characteristics of families in Norway who have children after assisted reproductive technology (ART), and have these characteristics changed over time? SUMMARY ANSWER: Parents who conceive through ART in Norway tend to be advantaged families, and their socio-demographic profile has not changed considerably over the period 1985-2014. WHAT IS KNOWN ALREADY: A small number of studies show that couples who conceive through ART tend to be socio-economically advantaged. STUDY DESIGN, SIZE, DURATION: Norwegian Population Register, the Medical Birth Register and the national data bases were linked to study all live births in Norway between 1985 and 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: The sample consisted of 1 757 768 live births. Simple bivariate analyses were performed to describe the socio-demographic characteristics of parents who conceived through ART and changes in these characteristics over the time period 1985-2014. We used linear probability models to estimate the association between parental income and giving birth after ART from 2000 to 2014, before and after adjustment for maternal age at delivery, education and area of residence. MAIN RESULTS AND THE ROLE OF CHANCE: Parents conceiving through ART were more likely to be older, with the highest levels of income and education, and married. Their socio-demographic profiles did not change considerably during the period 1985-2014. In the unadjusted model, parents belonging to the top income quartile were 4.2 percentage points more likely (95% CI: 4.1 to 4.3) to have conceived through ART than parents who belonged to the bottom income quartile. Adjustment for maternal age only partially reduced the income disparities (for the top income quartile by 35% (ß = 2.7 with 95% CI: 2.5 to 2.8)). Additional adjustment for maternal education, marital status and area of residence did not further attenuate the associations. LIMITATIONS, REASONS FOR CAUTION: The data does not enable us to tell whether the lower numbers of children conceived through ART amongst more disadvantaged individuals is caused by lower success rates with ART treatment, lower demand of ART services or barriers faced in access to ART. The study focuses on Norway, a context characterised by high subsidisation of ART services. WIDER IMPLICATIONS OF THE FINDINGS: Even though in Norway access to ART services is highly subsidised, the results highlight important and persisting social inequities in use of ART. The results also indicate that children born after ART grow up in resourceful environments, which will benefit their development and well-being. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by European Research Council agreement n. 803959 (to A.G.), by Economic and Social Research Council grant ES/M001660/1 and by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. The authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.