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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.

Patients with multiple sclerosis (MS) are at increased risk of infections and related worsening of neurological function. Influenza infection has been associated with increased risk of various neurological complications. We conducted a population-based registry study to investigate the risk of acute hospitalization of MS patients in relation to influenza infection or pandemic vaccination in Norway. The entire Norwegian population in the years 2008–2014 was defined as our study population (N = 5,219,296). Information on MS diagnosis, influenza infection and vaccination were provided by Norwegian national registries. The self-controlled case series method was used to estimate incidence rate ratios (IRRs) with 95% confidence intervals (95% CI) in defined risk periods. 6755 MS patients were identified during the study period. Average age at first registration of an MS diagnosis was 51.8 years among men and 49.9 years among females (66.9%). The IRR for emergency hospitalization among MS patients the first week after an influenza diagnosis was 3.4 (95% CI 2.4–4.8). The IRR was 5.6 (95% CI 2.7–11.3) after pandemic influenza, and 4.8 (95% CI 3.1–7.4) after seasonal influenza. Pandemic vaccination did not influence risk of hospitalization [IRR within the first week: 0.7 (95% CI 0.5–1.0)]. Among MS patients, influenza infection was associated with increased risk for acute hospitalization while no increased risk was observed after pandemic vaccination. Influenza vaccination could prevent worsening of MS-related symptoms as well as risk of hospitalization.

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.

Previous studies of fetal death with maternal influenza have been inconsistent. We explored the effect of maternal influenza-like illness (ILI) in pregnancy on the risk of fetal death, distinguishing between diagnoses during regular influenza seasons and the 2009/2010 pandemic and between trimesters of ILI. We used birth records from the Medical Birth Registry of Norway to identify fetal deaths after the first trimester in singleton pregnancies (2006–2013). The Norwegian Directorate of Health provided dates of clinical influenza diagnoses by primary-health-care providers, whereas dates of laboratory-confirmed influenza A (H1N1) diagnoses were provided by the Norwegian Surveillance System for Communicable Diseases. We obtained dates and types of influenza vaccinations from the Norwegian Immunisation Registry. Cox proportional-hazards regression models were fitted to estimate hazard ratios (HRs) of fetal death, with associated 95% confidence intervals (CIs), comparing women with and without an ILI diagnosis in pregnancy. There were 2510 fetal deaths among 417,406 eligible pregnancies. ILI during regular seasons was not associated with increased risk of fetal death: adjusted HR = 0.90 (95% CI 0.64–1.27). In contrast, ILI during the pandemic was associated with substantially increased risk of fetal death, with an adjusted HR of 1.75 (95% CI 1.21–2.54). The risk was highest following first-trimester ILI (adjusted HR = 2.28 [95% CI 1.45–3.59]). ILI during the pandemic—but not during regular seasons—was associated with increased risk of fetal death in the second and third trimester. The estimated effect was strongest with ILI in first trimester.

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.

BackgroundIt remains unclear what underlies the greater risk of asthma reported among children conceived by assisted reproductive technologies (ART).ObjectiveOur aim was to clarify the role of parental subfertility and unmeasured confounding on the association between ART and childhood asthma, and to examine the possibility for common mechanisms underlying parental subfertility and miscarriages influencing asthma pathogenesis.MethodsWe used data from national Norwegian health registries (n=474 402) and the Norwegian Mother and Child Cohort Study (MoBa) (n=75 797). We used log-linear regression to estimate overall associations, and fixed-effects logistic regression to estimate associations within siblings.ResultsART offspring had greater asthma risk, the adjusted relative risk (aRR) was 1.20 (95% CI 1.09 to 1.32) in the registry-based cohort, and 1.42 (95% CI 1.14 to 1.76) in MoBa. The sibling analysis yielded similar associations, although the CI included the null value. The elevated asthma risk among ART offspring was attenuated when they were compared with spontaneously conceived offspring with time to conception >12 months, aRR 1.22 (95% CI 0.95 to 1.57). Asthma risk also increased with maternal history of early miscarriages (≤12 weeks), with an aRR of 1.07 (95% CI 1.03 to 1.11) for one, aRR 1.18 (95% CI 1.10 to 1.26) for two and aRR 1.24 (95% CI 1.12 to 1.37) for three or more.ConclusionOur findings indicate that both parental subfertility and characteristics related to the ART procedure itself might increase offspring asthma risk, although this needs to be confirmed in future studies, and further suggest that common mechanisms underlying parental subfertility and recurrent miscarriages might influence offspring asthma pathogenesis.

Background Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero , when global redistribution of DNA methylation occurs driving tissue differentiation. Methods Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations. Results The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues ( n =5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression ( n =2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation. Conclusion This study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy. Key points • Precursors of pediatric acute lymphoblastic leukemia may be of epigenetic origin, detectable since birth and affecting patient prognosis. • These epigenetic precursors can be robust over several years and across several populations, ethnicities and surrogate and target tissues.

Objectives Air pollution exposure may contribute to the development of preeclampsia and hypertension during pregnancy. However, the evidence for such a relation is still limited. We investigated the associations between exposure for moderate to low levels of air pollution during pregnancy and preeclampsia and gestational hypertension in selected urban and county areas of Norway. Methods This study used a sub-group of 17,533 women in the Norwegian Mother and Child Cohort Study. Air pollution levels at residential addresses were estimated using land use regression models and back-extrapolated to the period of each pregnancy. Information on preeclampsia and gestational hypertension were obtained from the Medical Birth Registry of Norway and information on lifestyle factors was collected from questionnaires completed by the women during pregnancy. Results Moderate mean levels of NO2 (13.6 ± 6.9 µg/m3) at residential address during pregnancy were not associated with preeclampsia and pregnancy hypertension. We found no statistically significant associations per 10 µg/m3 change in NO2 exposure and preeclampsia (adjusted OR 0.89, 95% CI 0.74, 1.08) or hypertension during pregnancy (adjusted OR 0.91, 95% CI 0.78, 1.06). Conclusions for Practice In this large Norwegian pregnancy cohort, we found no statistically significant associations for moderate to low levels of pregnancy NO2 exposure and preeclampsia or hypertension during pregnancy.

ObjectiveTo assess the impact of COVID-19 on pregnancy-related healthcare utilisation and differences across social groups.DesignNationwide longitudinal prospective registry-based study.SettingNorway.ParticipantsFemale residents aged 15–50 years (n=1 244 560).Main outcome measuresPregnancy-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.ResultsThere 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.ConclusionFollowing 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.

BackgroundAntipsychotics are increasingly used among women of childbearing age and during pregnancy.ObjectiveTo 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.DesignPopulation-based cohort study, including a sibling analysis.SettingNationwide 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).Participants4 324 086 children were eligible for inclusion to the study cohort.InterventionAntipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use.Main outcome measuresNon-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.FindingsAmong 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.DiscussionOur findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics.Clinical implicationsResults regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.