Booster vaccination with SARS-CoV-2 mRNA vaccines and myocarditis in adolescents and young adults: a Nordic cohort study.

BACKGROUND AND AIMS: The SARS-CoV-2 mRNA vaccines are associated with an increased risk of myocarditis. This association appears to be strongest in male adolescents and younger males and after the second dose. The aim was to evaluate the risk of myocarditis following SARS-CoV-2 mRNA booster vaccination in 12-to-39-year-olds. METHODS: A multinational cohort study was conducted using nationwide register data in Denmark, Finland, Norway, and Sweden and comprising all 8.9 million individuals residing in each of the four countries. Participants were followed for an inpatient diagnosis of myocarditis. In each of the four countries, Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) of myocarditis comparing vaccination schedules, with associated 95% confidence intervals (CIs). Country-specific results were combined in meta-analyses. RESULTS: A total of 8.9 million residents were followed for 12 271 861 person-years and 1533 cases of myocarditis were identified. In 12-to-39-year-old males, the 28-day acute risk period following the third dose of BNT162b2 or mRNA-1273 was associated with an increased incidence rate of myocarditis compared to the post-acute risk period 28 days or more after the second dose [IRR 2.08 (95% CI 1.31-3.33) and 8.89 (2.26-35.03), respectively]. For females, the corresponding IRR was only estimable for BNT162b2, 3.99 (0.41-38.64). The corresponding absolute risks following the third dose of BNT162b2 and mRNA-1273 in males were 0.86 (95% CI 0.53-1.32) and 1.95 (0.53-4.99) myocarditis events within 28 days per 100 000 individuals vaccinated, respectively. In females, the corresponding absolute risks following the third dose of BNT162b2 were 0.15 (0.04-0.39) events per 100 000 individuals vaccinated. No deaths occurred within 30 days of vaccine-related cases. CONCLUSIONS: The results suggest that a booster dose is associated with increased myocarditis risk in adolescents and young adults. However, the absolute risk of myocarditis following booster vaccination is low.

The effect of intravenous hyoscine butylbromide on slow progress in labor (BUSCLAB): A double-blind randomized placebo-controlled trial.

BACKGROUND: Prolonged labor is a common condition associated with maternal and perinatal complications. The standard treatment with oxytocin for augmentation of labor increases the risk of adverse outcomes. Hyoscine butylbromide is a spasmolytic drug with few side effects shown to shorten labor when used in a general population of laboring women. However, research on its effect on preventing prolonged labor is lacking. We aimed to assess the effect of hyoscine butylbromide on the duration of labor in nulliparous women showing early signs of slow labor. METHODS AND FINDINGS: In this double-blind randomized placebo-controlled trial, we included 249 nulliparous women at term with 1 fetus in cephalic presentation and spontaneous start of labor, showing early signs of prolonged labor by crossing the alert line of the World Health Organization (WHO) partograph. The trial was conducted at Oslo University Hospital in Norway from May 2019 to December 2021. One hundred and twenty-five participants were randomized to receive 1 ml hyoscine butylbromide (Buscopan) (20 mg/ml), while 124 received 1 ml sodium chloride intravenously. Randomization was computer-generated, with allocation concealment by opaque sequentially numbered sealed envelopes. The primary outcome was duration of labor from administration of the investigational medicinal product (IMP) to vaginal delivery, which was analyzed by Weibull regression to estimate the cause-specific hazard ratio (HR) of vaginal delivery between the 2 treatment groups, with associated 95% confidence interval (CI). A wide range of secondary maternal and perinatal outcomes were also evaluated. Time-to-event outcomes were analyzed by Weibull regression, whereas continuous and dichotomous outcomes were analyzed by median regression and logistic regression, respectively. All main analyses were based on the modified intention-to-treat (ITT) set of eligible women with signed informed consent receiving either of the 2 treatments. The follow-up period lasted during the postpartum hospital stay. All personnel, participants, and researchers were blinded to the treatment allocation. Median (mean) labor duration from IMP administration to vaginal delivery was 401 (440.8) min in the hyoscine butylbromide group versus 432.5 (453.6) min in the placebo group. We found no statistically significant association between IMP and duration of labor from IMP administration to vaginal delivery: cause-specific HR of 1.00 (95% CI [0.77, 1.29]; p = 0.993). Among 255 randomized women having received 1 dose of IMP, 169 women (66.3%) reported a mild adverse event: 75.2% in the hyoscine butylbromide group and 57.1% in the placebo group (Pearson's chi-square test: p = 0.002). More than half of eligible women were not included in the study because they did not wish to participate or were not included upon admission. The participants might have represented a selected group of women reducing the external validity of the study. CONCLUSIONS: One intravenous dose of 20 mg hyoscine butylbromide was not found to be superior to placebo in preventing slow labor progress in a population of first-time mothers at risk of prolonged labor. Further research is warranted to answer whether increased and/or repeated doses of hyoscine butylbromide might have an effect on duration of labor. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03961165) EudraCT (2018-002338-19).

Prepregnancy body mass index and visceral fat exhibit divergent associations with metabolic factors in pregnant women with obesity: A Norwegian cohort study.

INTRODUCTION: Pregnancy involves changes in maternal metabolism that differ between normal-weight women and women with overweight or obesity, including changes in glucose, insulin, lipids, and adipokines. These changes contribute to altered risk profiles for adverse outcomes for both mother and child during pregnancy, childbirth, and postpartum. We explored associations between visceral fat and prepregnancy body mass index (pBMI), respectively, with glucose and lipid metabolism, as well as with adipokines and C-reactive protein (CRP), measured fasting in early and late pregnancy. We hypothesized that among women with pBMI ≥35 kg/m2, visceral fat measured around gestational week 18 (visceral fat18) would show associations with greater number of metabolic variables during pregnancy, than pBMI. MATERIAL AND METHODS: This prospective longitudinal cohort study was conducted at the Department of Gynecology and Obstetrics at Drammen Hospital from 2016 to 2019. We included 166 nulliparous (47.6%) and parous pregnant women with pBMI ≥35 kg/m2 and singleton pregnancy. Women with type 1 diabetes were excluded. We evaluated associations of pBMI and visceral fat estimated with bioimpedance weight around gestational week 18 (visceral fat18) with fasting metabolic measures around gestational weeks 18 and 36 using median regression models. We used the paired t-test or the Wilcoxon signed-rank test, as appropriate, to analyze changes in metabolic measures from early to late pregnancy, and median regression to estimate crude and adjusted differences in medians of 21 maternal metabolic measures associated with one-unit changes in pBMI and visceral fat18, respectively. RESULTS: pBMI and visceral fat18 were highly correlated and showed associations with similar metabolic measures in pregnancy in crude analysis. After mutual adjustment for each other in addition to age and parity, pBMI was associated with glucose metabolism, in particular fasting insulin, whereas visceral fat18 was primarily associated with leptin. CONCLUSIONS: Among pregnant women with BMI ≥35 kg/m2, easily obtainable pBMI and the more resource-demanding estimate of visceral fat18 exhibit divergent associations with metabolic measures; pBMI was positively associated with insulin, glucose, and HbA1c, while visceral fat18 was positively associated with leptin. We did not find visceral fat18 to be associated with greater number of metabolic factors than pBMI.

Hypertensive disorders of pregnancy among women with cardiovascular disease in Norway: A historical cohort study.

INTRODUCTION: Women with cardiovascular disease may be at increased risk of hypertensive disorders of pregnancy (HDP). We aimed to: (1) Investigate the occurrence of HDP in a cohort of pregnant women with cardiovascular disease and compare it with the occurrence in the general population. (2) Assess the association between maternal cardiovascular risk and risk of HDP. MATERIAL AND METHODS: We reviewed clinical data on a cohort of 901 pregnancies among 708 women with cardiovascular disease who were followed at the National Unit for Pregnancy and Heart Disease and gave birth at Oslo University Hospital between 2003 and 2018. The exposure under study was maternal cardiovascular risk, classified as low, moderate, or high based on a modified classification by the World Health Organization. The main outcome of interest was HDP, which included pre-eclampsia and gestational hypertension. The proportion of HDP cases in the general population in the same period was extracted from the Medical Birth Registry of Norway. We used logistic regression to estimate crude and adjusted odds ratios (OR) of HDP, with associated 95% confidence intervals (CIs), for women with moderate- and high cardiovascular risk compared to women with low risk. RESULTS: The occurrence of HDP in the study cohort was 12.1% (95% CI: 10.0%-14.4%) and varied between 8.7% (95% CI: 6.5%-11.3%) in the low-risk group, 15.7% (95% CI: 11.1%-21.4%) in the moderate-risk group, and 22.2% (95% CI: 15.1%-30.8%) in the high-risk group. By contrast, the nationwide occurrence of HDP was 5.1% (95% CI: 5.1%-5.2%). In the study cohort, the proportions of pregnancies with gestational hypertension and pre-eclampsia were similar (6.3% and 5.8%, respectively). Compared to pregnancies with low cardiovascular risk, the adjusted OR of HDP was 2.04 (95% CI: 1.21-3.44) in the moderate-risk group and 2.99 (95% CI: 1.73-5.18) in the high-risk group. CONCLUSIONS: The occurrence of hypertensive disease of pregnancy in the study cohort was more than doubled compared to the general population in Norway. The risk of HDP increased with maternal cardiovascular risk group. We recommend taking into account maternal cardiovascular risk group when assessing risk and prophylaxis of HDP.

Down syndrome and associated atrioventricular septal defects in a nationwide Norwegian cohort: Prevalence, time trends, and outcomes.

INTRODUCTION: The prevalence of Down syndrome (DS) is approximately 1 per 1000 births and is influenced by increasing maternal age over the last few decades. DS is strongly associated with congenital heart defects (CHDs), especially atrioventricular septal defect (AVSD). Our objectives were to investigate the prevalence of live-born infants with DS having a severe CHD in the Norwegian population over the last 20 years and compare outcomes in infants with AVSD with and without DS. MATERIAL AND METHODS: Information on all births from January 1, 2000 to December 31, 2019 was obtained from the Medical Birth Registry of Norway. We also obtained data on all infants with severe CHDs in Norway registered in Oslo University Hospital's Clinical Registry for Congenital Heart Defects during 2000-2019 and accessed individual-level patient data from the electronic hospital records of selected cases. Infants with AVSD and DS were compared to infants with AVSD without chromosomal defects. Crude and adjusted odds ratios (ORs) of infant mortality and need for surgery during the first year of life, with associated 95% confidence intervals (CIs), were estimated by logistic regression. RESULTS: A total of 1 177 926 infants were live-born in Norway during the study period. Among these, 1456 (0.1%) had DS. The prevalence of infants with DS having a severe CHDs was relatively stable, with a mean of 17 cases per year. The most common CHD associated with DS was AVSD (44.4%). Infants with AVSD and DS were more likely to have cardiac intervention during their first year of life compared to infants with AVSD without chromosomal defects (adjusted OR [aOR]: 2.52; 95% CI 1.27, 4.98). However, we observed no difference in infant mortality during first year of life between the two groups (aOR: 1.08; 95% CI 0.43, 2.70). CONCLUSIONS: The prevalence of live-born infants with severe CHDs and DS has been stable in Norway across 20 years. Infants with AVSD and DS did not have higher risk of mortality during their first year of life compared to infants with AVSD without chromosomal defects, despite a higher risk of operative intervention.

Maternal metabolic profiling across body mass index groups: An exploratory longitudinal study.

INTRODUCTION: Increased BMI has been identified as a risk factor for most pregnancy complications, but the underlying metabolic factors mediating the detrimental effects of BMI are largely unknown. We aimed to compare metabolic profiles in overweight/obese women (body mass index [BMI] ≥ 25 kg/m2 ) and normal weight/underweight women (BMI < 25 kg/m2 ) across gestation. We also explored how gestational weight gain (GWG) affected maternal metabolic profiles. MATERIAL AND METHODS: Exploratory nested case-control study based on a prospective longitudinal cohort of women who were healthy prior to pregnancy and gave birth at Oslo University Hospital from 2002 to 2008. The sample consisted of 48 women who were overweight/obese and 59 normal-weight/underweight women. Plasma samples from four time points in pregnancy (weeks 14-16, 22-24, 30-32 and 36-38) were analyzed by nuclear magnetic resonance spectroscopy and 91 metabolites were measured. Linear regression models were fitted for each of the metabolites at each time point. RESULTS: Overweight or obese women had higher levels of lipids in very-low-density lipoprotein (VLDL), total triglycerides, triglycerides in VLDL, total fatty acids, monounsaturated fatty acids, saturated fatty acids, leucine, valine, and total branched-chain amino acids in pregnancy weeks 14-16 compared to underweight and normal-weight women. Docosahexaenoic acid and degree of unsaturation were significantly lower in overweight/obese women in pregnancy weeks 36-38. In addition, overweight or obese women had higher particle concentration of XXL-VLDL and glycoprotein acetyls (GlycA) at weeks 14-16 and 30-32. GWG did not seem to affect the metabolic profile, regardless of BMI group when BMI was treated as a dichotomous variable, ≥25 kg/m2 (yes/no). CONCLUSIONS: Overweight or obese women had smaller pregnancy-related metabolic alterations than normal-weight/underweight women. There was a trend toward higher triglyceride and VLDL particle concentration in overweight/obese women. As this was a hypothesis-generating study, the similarities with late-onset pre-eclampsia warrant further investigation. The unfavorable development of fatty acid composition in overweight/obese women, with possible implication for the offspring, should also be studied further in the future.

Time-varying exposure to anti-osteoporosis drugs and risk of first-time hip fracture: a population wide study within the Norwegian Epidemiologic Osteoporosis Studies (NOREPOS).

We investigated the association between bisphosphonate and denosumab use and risk of hip fracture in Norway. These drugs protect against fractures in clinical trials, but their population-level effect is unknown. Our results showed lowered risk of hip fracture for treated women. Treatment of high-risk individuals could prevent future hip fractures. PURPOSE: To investigate whether bisphosphonates and denosumab reduced the risk of first-time hip fracture in Norwegian women when adjusting for a medication-based comorbidity index. METHODS: Norwegian women aged 50-89 in 2005-2016 were included. The Norwegian prescription database (NorPD) supplied data on exposures to bisphosphonates, denosumab, and other drugs for the calculation of the Rx-Risk Comorbidity Index. Information on all hip fractures treated in hospitals in Norway was available. Flexible parametric survival analysis was used with age as time scale and with time-varying exposure to bisphosphonates and denosumab. Individuals were followed until hip fracture or censoring (death, emigration, age 90 years), or 31 December 2016, whichever occurred first. Rx-Risk score was included as a time-varying covariate. Other covariates were marital status, education, and time-varying use of bisphosphonates or denosumab with other indications than osteoporosis. RESULTS: Of 1,044,661 women 77,755 (7.2%) were ever-exposed to bisphosphonate and 4483 (0.4%) to denosumab. The fully adjusted hazard ratios (HR) were 0.95 (95% confidence interval (CI): 0.91-0.99) for bisphosphonate use and 0.60 (95% CI: 0.47-0.76) for denosumab use. Bisphosphonate treatment gave a significantly reduced risk of hip fracture compared with the population after 3 years and denosumab after 6 months. Fracture risk was lowest in denosumab users who had previously used bisphosphonate: HR 0.42 (95% CI: 0.29-0.61) compared with the unexposed population. CONCLUSIONS: In population-wide real-world data, women exposed to bisphosphonates and denosumab had a lower hip fracture risk than the unexposed population after adjusting for comorbidity. Treatment duration and treatment history impacted fracture risk.

Neonatal outcomes associated with time from a high fetal blood lactate concentration to operative delivery.

INTRODUCTION: Adjunctive technologies to cardiotocography intend to increase the specificity of the diagnosis of fetal hypoxia. If correctly diagnosed, time to delivery could affect neonatal outcome. In the present study, we aimed to investigate the effect of time from when fetal distress is indicated by a high fetal blood sample (FBS) lactate concentration to operative delivery on the risk of adverse neonatal outcomes. MATERIAL AND METHODS: We conducted a prospective observational study. Deliveries with a singleton fetus in cephalic presentation at 36+0 weeks of gestation or later were included. Adverse neonatal outcomes, related to decision-to-delivery interval (DDI), were investigated in operative deliveries indicated by an FBS lactate concentration of at least 4.8 mmol/L. We applied logistic regression to estimate crude and adjusted odds ratios (aOR) of various adverse neonatal outcomes, with associated 95% confidence intervals (CI), for a DDI exceeding 20 minutes, compared with a DDI of 20 minutes or less. CLINICALTRIALS: gov Identifier: NCT04779294. RESULTS: The main analysis included 228 women with an operative delivery indicated by an FBS lactate concentration of 4.8 mmol/L or greater. The risk of all adverse neonatal outcomes was significantly increased for both DDI groups compared with the reference group (deliveries with an FBS lactate below 4.2 mmol/L within 60 minutes before delivery). In operative deliveries indicated by an FBS lactate concentration of 4.8 mmol/L or more, there was a significantly increased risk of a 5-minute Apgar score less than 7 if the DDI exceeded 20 minutes, compared with a DDI of 20 minutes or less (aOR 8.1, 95% CI 1.1-60.9). We found no statistically significant effect on other short-term outcomes for deliveries with DDI longer than 20 minutes, compared with those with DDI of 20 minutes or less (pH ≤7.10: aOR 2.0, 95% CI 0.5-8.4; transfer to the neonatal intensive care unit: aOR 1.1, 95% CI 0.4-3.5). CONCLUSIONS: After a high FBS lactate measurement, the increased risk of adverse neonatal outcome is further augmented if the DDI exceeds 20 minutes. These findings give support to current Norwegian guidelines for intervention in cases of fetal distress.

Metabolic profiling of pregnancies complicated by preeclampsia: A longitudinal study.

INTRODUCTION: Preeclampsia is associated with maternal metabolic disturbances, but longitudinal studies with comprehensive metabolic profiling are lacking. We aimed to determine metabolic profiles across gestation in women who developed preeclampsia compared with women with healthy pregnancies. We also explored the respective effects of body mass index (BMI) and preeclampsia on various metabolic measures. MATERIAL AND METHODS: We measured 91 metabolites by high-throughput nuclear magnetic resonance spectroscopy at four time points (visits) during pregnancy (weeks 14-16, 22-24, 30-32 and 36-38). Samples were taken from a Norwegian pregnancy cohort. We fitted a linear regression model for each metabolic measure to compare women who developed preeclampsia (n = 38) and healthy controls (n = 70). RESULTS: Among women who developed preeclampsia, 92% gave birth after 34 weeks of gestation. Compared to women with healthy pregnancies, women who developed preeclampsia had higher levels of several lipid-related metabolites at visit 1, whereas fewer differences were observed at visit 2. At visit 3, the pattern from visit 1 reappeared. At visit 4 the differences were larger in most subgroups of very-low-density lipoprotein particles, the smallest high-density lipoprotein, total lipids and triglycerides. Total fatty acids were also increased, of which monounsaturated fatty acids and saturated fatty acids showed more pronounced differences. Concentration of glycine tended to be lower in pregnancies with preeclampsia until visit 3, although this was not significant after correction for multiple testing. After adjustment for age, BMI, parity and gestational weight gain, all significant differences were attenuated at visits 1 and 2. The estimates were less affected by adjustment at visits 3 and 4. CONCLUSIONS: In early pregnancy, the metabolic differences between preeclamptic and healthy pregnancies were primarily driven by maternal BMI, probably representing the women's pre-pregnancy metabolic status. In early third trimester, several weeks before clinical manifestation, the differences were less influenced by BMI, indicating preeclampsia-specific changes. Near term, women with preeclampsia developed an atherogenic metabolic profile, including elevated total lipids, very-low-density lipoprotein, triglycerides, and total fatty acids.

Maternal body mass index and risk of obstetric, maternal and neonatal outcomes: A cohort study of nulliparous women with spontaneous onset of labor.

INTRODUCTION: This study investigates associations between maternal body mass index (BMI) early in pregnancy and obstetric interventions, maternal and neonatal outcomes. MATERIAL AND METHODS: This is a cohort study of nulliparous women originally included in a cluster randomized controlled trial carried out at 14 Norwegian obstetric units between 2014 and 2017. The sample included 7189 nulliparous women with a singleton fetus, cephalic presentation and spontaneous onset of labor at term, denoted as group 1 in the Ten-Group Classification System. The women were grouped according to the World Health Organization BMI classifications: underweight (BMI <18.5), normal weight (BMI 18.5-24.9), pre-obesity (BMI 25.0-29.9), obesity class I (BMI 30.0-34.9), and obesity classes II and III (BMI ≥35.0). We used binary logistic regression to estimate crude and adjusted odds ratios (ORs) of the interventions and outcomes, with associated 95% confidence intervals (CIs), comparing women in different BMI groups with women of normal weight. RESULTS: We found an increased risk of intrapartum cesarean section in women of obesity class I and obesity classes II and III, with adjusted OR of 1.70 (95% CI 1.21-2.38) and 2.31 (95% CI 1.41-3.77), respectively. Women in obesity groups had a gradient of risk of epidural analgesia and use of continuous CTG (including STAN), with adjusted OR of 2.39 (95% CI 1.69-3.38) and 3.28 (95% CI 1.97-5.48), respectively. Women in obesity classes II and III had higher risk of amniotomy (adjusted OR = 1.42, 95% CI 1.02-1.96), oxytocin augmentation (adjusted OR = 1.54, 95% CI 1.11-2.15), obstetric anal sphincter injuries (adjusted OR = 2.21, 95% CI 1.01-4.85) and postpartum hemorrhage ≥1000 mL (adjusted OR = 2.20, 95% CI 1.29-3.78). We found a reduced likelihood of spontaneous vaginal delivery for pre-obese women (adjusted OR = 0.85, 95% CI 0.74-0.97) and no associations between maternal BMI and neonatal outcomes. CONCLUSIONS: Obese women in Ten-Group Classification System group 1 had increased risks of obstetric interventions and maternal complications. There was a gradient of risk for intrapartum cesarean section, with the highest risk for women in obesity classes II and III. No associations between maternal BMI and neonatal outcomes were observed.

Seasonal and pandemic influenza during pregnancy and risk of fetal death: A Norwegian registry-based cohort study.

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.

Influenza and risk of later celiac disease: a cohort study of 2.6 million people.

OBJECTIVES: Influenza has been linked to autoimmune conditions, but its relationship to subsequent celiac disease (CD) is unknown. Our primary aim was to determine the risk of CD after influenza. A secondary analysis examined the risk of CD following pandemic influenza vaccination. METHODS: This nationwide register-based cohort study included 2,637,746 Norwegians (born between 1967-2013) followed during 2006-2014 with information on influenza diagnosed in primary or non-primary care, pandemic vaccination (Pandemrix), and subsequent CD. Cox regression yielded hazard ratios adjusted (HR) for socio-demographic characteristics and earlier healthcare use. RESULTS: During 13,011,323 person-years of follow-up 7321 individuals were diagnosed with CD (56/100,000 person-years). There were 351,666 individuals diagnosed with influenza, including 82,980 during the 2009-2010 pandemic, and 969,968 individuals were vaccinated. Compared with participants without influenza, who had a CD incidence of 55/100,000 person-years, those diagnosed with seasonal and pandemic influenza had a rate of 68 and 78, per 100,000 person-years, respectively. The HR for CD was 1.29 (95%CI, 1.21-1.38) after seasonal influenza and 1.29 (95%CI, 1.15-1.44) after pandemic influenza; HRs remained significantly increased one year after exposure, when restricted to laboratory-confirmed influenza, and after multivariate adjustments. The reverse association, i.e., risk of influenza after CD, was not significant (HR 1.05; 95%CI, 0.98-1.12). The HR for CD after pandemic vaccination was 1.08 (95%CI, 1.03-1.14). CONCLUSION: A positive association with influenza diagnosis is consistent with the hypothesis that infections may play a role in CD development. We could neither confirm a causal association with pandemic vaccination, nor refute entirely a small excess risk.

Risk of fetal death after pandemic influenza virus infection or vaccination.

BACKGROUND: During the 2009 influenza A (H1N1) pandemic, pregnant women were at risk for severe influenza illness. This concern was complicated by questions about vaccine safety in pregnant women that were raised by anecdotal reports of fetal deaths after vaccination. METHODS: We explored the safety of influenza vaccination of pregnant women by linking Norwegian national registries and medical consultation data to determine influenza diagnosis, vaccination status, birth outcomes, and background information for pregnant women before, during, and after the pandemic. We used Cox regression models to estimate hazard ratios for fetal death, with the gestational day as the time metric and vaccination and pandemic exposure as time-dependent exposure variables. RESULTS: There were 117,347 eligible pregnancies in Norway from 2009 through 2010. Fetal mortality was 4.9 deaths per 1000 births. During the pandemic, 54% of pregnant women in their second or third trimester were vaccinated. Vaccination during pregnancy substantially reduced the risk of an influenza diagnosis (adjusted hazard ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34). Among pregnant women with a clinical diagnosis of influenza, the risk of fetal death was increased (adjusted hazard ratio, 1.91; 95% CI, 1.07 to 3.41). The risk of fetal death was reduced with vaccination during pregnancy, although this reduction was not significant (adjusted hazard ratio, 0.88; 95% CI, 0.66 to 1.17). CONCLUSIONS: Pandemic influenza virus infection in pregnancy was associated with an increased risk of fetal death. Vaccination during pregnancy reduced the risk of an influenza diagnosis. Vaccination itself was not associated with increased fetal mortality and may have reduced the risk of influenza-related fetal death during the pandemic. (Funded by the Norwegian Institute of Public Health.).

Risk of Guillain-Barré syndrome after exposure to pandemic influenza A(H1N1)pdm09 vaccination or infection: a Norwegian population-based cohort study.

Vaccinations and infections are possible triggers of Guillain-Barré syndrome (GBS). However, studies on GBS after vaccinations during the influenza A(H1N1)pmd09 pandemic in 2009, show inconsistent results. Only few studies have addressed the role of influenza infection. We used information from national health data-bases with information on the total Norwegian population (N = 4,832,211). Cox regression analyses with time-varying covariates and self-controlled case series was applied. The risk of being hospitalized with GBS during the pandemic period, within 42 days after an influenza diagnosis or pandemic vaccination was estimated. There were 490 GBS cases during 2009-2012 of which 410 cases occurred after October 1, 2009 of which 46 new cases occurred during the peak period of the influenza pandemic. An influenza diagnosis was registered for 2.47% of the population and the vaccination coverage was 39.25%. The incidence rate ratio of GBS during the pandemic peak relative to other periods was 1.46 [95% confidence interval (CI) 1.08-1.98]. The adjusted hazard ratio (HR) of GBS within 42 days after a diagnosis of pandemic influenza was 4.89 (95% CI 1.17-20.36). After pandemic vaccination the adjusted HR was 1.11 (95% CI 0.51-2.43). Our results indicated that there was a significantly increased risk of GBS during the pandemic season and after pandemic influenza infection. However, vaccination did not increase the risk of GBS. The small number of GBS cases in this study warrants caution in the interpretation of the findings.

Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway.

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a complex condition. Causal factors are not established, although underlying psychological or immunological susceptibility has been proposed. We studied primary care diagnoses for children with CFS/ME, with children with another hospital diagnosis (type 1 diabetes mellitus [T1DM]) and the general child population as comparison groups. METHODS: All Norwegian children born 1992-2012 constituted the study sample. Children with CFS/ME (n = 1670) or T1DM (n = 4937) were identified in the Norwegian Patient Register (NPR) (2008-2014). Children without either diagnosis constituted the general child population comparison group (n = 1337508). We obtained information on primary care diagnoses from the Norwegian Directorate of Health. For each primary care diagnosis, the proportion and 99 % confidence interval (CI) within the three groups was calculated, adjusted for sex and age by direct standardization. RESULTS: Children with CFS/ME were more often registered with a primary care diagnosis of weakness/general tiredness (89.9 % [99 % CI 88.0 to 91.8 %]) than children in either comparison group (T1DM: 14.5 % [99 % CI: 13.1 to 16.0 %], general child population: 11.1 % [99 % CI: 11.0 to 11.2 %]). Also, depressive disorder and anxiety disorder were more common in the CFS/ME group, as were migraine, muscle pain, and infections. In the 2 year period prior to the diagnoses, infectious mononucleosis was registered for 11.1 % (99 % CI 9.1 to 13.1 %) of children with CFS/ME and for 0.5 % (99 % CI (0.2 to 0.8 %) of children with T1DM. Of children with CFS/ME, 74.6 % (1292/1670) were registered with a prior primary care diagnosis of weakness / general tiredness. The time span from the first primary care diagnosis of weakness / general tiredness to the specialist health care diagnosis of CFS/ME was 1 year or longer for 47.8 %. CONCLUSIONS: This large nationwide registry linkage study confirms that the clinical picture in CFS/ME is complex. Children with CFS/ME were frequently diagnosed with infections, supporting the hypothesis that infections may be involved in the causal pathway. The long time span often observed from the first diagnosis of weakness / general tiredness to the diagnosis of CFS/ME might indicate that the treatment of these patients is sometimes not optimal.

Febrile seizures after 2009 influenza A (H1N1) vaccination and infection: a nationwide registry-based study.

BACKGROUND: During the 2009 influenza A (H1N1) pandemic, a monovalent pandemic strain vaccine containing the oil-in-water adjuvant AS03 (Pandemrix®) was offered to the Norwegian population. The coverage among children reached 54%. Our aim was to estimate the risk of febrile seizure in children after exposure to pandemic influenza vaccination or infection. METHODS: The study population comprised 226,889 children born 2006-2009 resident in Norway per October 1st, 2009. Febrile seizure episodes were defined by emergency hospital admissions / emergency outpatient hospital care with International Classification of Diseases, Version 10, codes R56.0 or R56.8. The self-controlled case series method was applied to estimate incidence rate ratios (IRRs) in pre-defined risk periods compared to the background period. The total observation window was ± 180 days from exposure day. Among 113,068 vaccinated children, 656 (0.6%) had at least one febrile seizure episode. RESULTS: The IRR of febrile seizures 1-3 days after vaccination was 2.00 (95% confidence interval [CI]: 1.15-3.51). In the period 4-7 days after vaccination, no increased risk was observed. Among the 8172 children diagnosed with pandemic influenza, 84 (1.0%) had at least one febrile seizure episode. The IRR of febrile seizures on the same day as a diagnosis of influenza was 116.70 (95% CI: 62.81-216.90). In the period 1-3 days after a diagnosis of influenza, a tenfold increased risk was observed (IRR 10.12, 95% CI: 3.82 - 26.82). CONCLUSIONS: In this large population-based study with precise timing of exposures and outcomes, we found a twofold increased risk of febrile seizures 1-3 days after pandemic influenza vaccination. However, we found that pandemic influenza infection was associated with a much stronger increase in risk of febrile seizures.

Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012.

BACKGROUND: The aim of the current study was to estimate sex- and age-specific incidence rates of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) using population-based registry data. CFS/ME is a debilitating condition with large impact on patients and their families. The etiology is unknown, and the distribution of the disease in the general population has not been well described. METHODS: Cases of CFS/ME were identified in the Norwegian Patient Register (NPR) for the years 2008 to 2012. The NPR is nationwide and contains diagnoses assigned by specialist health care services (hospitals and outpatient clinics). We estimated sex- and age-specific incidence rates by dividing the number of new cases of CFS/ME in each category by the number of person years at risk. Incidence rate ratios were estimated by Poisson regression with sex, age categories, and year of diagnosis as covariates. RESULTS: A total of 5,809 patients were registered with CFS/ME during 2008 to 2012. The overall incidence rate was 25.8 per 100,000 person years (95% confidence interval (CI): 25.2 to 26.5). The female to male incidence rate ratio of CFS/ME was 3.2 (95% CI: 3.0 to 3.4). The incidence rate varied strongly with age for both sexes, with a first peak in the age group 10 to 19 years and a second peak in the age group 30 to 39 years. CONCLUSIONS: Early etiological clues can sometimes be gained from examination of disease patterns. The strong female preponderance and the two age peaks suggest that sex- and age-specific factors may modulate the risk of CFS/ME.

Folic acid supplementation and interpregnancy interval.

BACKGROUND: Maternal folic acid supplementation between subsequent pregnancies may be important to reduce the risk of low folate status associated with short interpregnancy intervals. We examined how the prevalence of preconception folic acid use for a given pregnancy in Norwegian women varied according to the time interval from the previous pregnancy. METHODS: Analysis was based on 48 855 pairs of pregnancies with the second pregnancy included in the Norwegian Mother and Child Cohort Study (birth years 1999-2009). Interpregnancy interval was defined as the time from birth of a child to the conception of the subsequent sibling. Preconception folic acid use was defined as any use of folic acid-containing supplements within the last 4 weeks before the second pregnancy. RESULTS: The prevalence of preconception folic acid use was 31%. Among women with a term birth (≥37 weeks) in the previous pregnancy (92%), those with interpregnancy intervals ≤12 and ≥49 months were associated with up to 35% lower prevalence of preconception folic acid use for the second pregnancy, relative to the reference group (13-24 months). The low use in short intervals was mainly attributable to lower proportion of planned pregnancies and fewer women with higher education. Among women with a preterm birth (<37 weeks) in the previous pregnancy (8%), preconception folic acid use significantly decreased with increasing pregnancy spacing. CONCLUSIONS: Our finding of a lower preconception folic acid use in women with both short and long interpregnancy intervals might help identifying those with higher risk of folate deficiency and preventing unwanted pregnancy outcomes.

Identifying children with autism spectrum disorder at 18 months in a general population sample.

BACKGROUND: Previous research on clinical and high-risk samples suggests that signs of autism spectrum disorder (ASD) can be detected between 1 and 2 years of age. We investigated signs of ASD at 18 months in a population-based sample and the association with later ASD diagnosis. METHODS: The study sample includes 52,026 children born 2003 through 2008 and is a subset of children that participated in the Norwegian Mother and Child Cohort (MoBa), a population-based longitudinal study, and the Autism Birth Cohort (ABC), a sub-study on ASD. Parents completed all 23 items from the Modified Checklist for Autism in Toddlers (M-CHAT) at 18 months. RESULTS: The M-CHAT 6-critical-item criterion and the 23-item criterion had a specificity of 97.9% and 92.7% and a sensitivity of 20.8% and 34.1%, respectively. In the 173 children diagnosed with ASD to date, 60 children (34.7%) scored above the cut-off on either of the screening criteria. The items with the highest likelihood ratios were 'interest in other children', 'show objects to others' and 'response to name'. CONCLUSION: Even though one-third of the children who later received an ASD diagnosis were identified through M-CHAT items, the majority scored below cut-off on the screening criteria at 18 months. The results imply that it might not be possible to detect all children with ASD at this age.

Risk of first hip fracture under treatment with zoledronic acid versus alendronate: a NOREPOS cohort study of 88,000 Norwegian men and women in outpatient care.

We aimed to investigate the risk of hip fracture associated with zoledronic acid treatment compared to alendronate on a population level. The risk of hip fracture was lower in women using zoledronic acid and higher in women who had discontinued treatment. The findings support the effectiveness of intravenous bisphosphonate. PURPOSE: To investigate whether zoledronic acid (ZOL) was associated with a lower risk of the first hip fracture than alendronate (ALN) in Norway using real-world data. METHODS: Nationwide data on drugs dispensed in outpatient pharmacies were individually linked with all hospital-treated hip fractures. Individuals aged 50-89 years without previous hip fracture were included at their first filling of a prescription for ALN or ZOL during 2005-2016. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) for first hip fracture by time-varying exposure to ZOL versus ALN were estimated in sex-stratified flexible parametric survival analyses. Covariates included time-varying accumulated ALN exposure and comorbidity level expressed by the prescription-based Rx-Risk Comorbidity Index, marital status, education, and residential urbanity. RESULTS: Of 75,250 women who initiated treatment, 72,614 (96.5%) were exposed to ALN and 6366 (8.5%) to ZOL. Of 12,739 men who initiated treatment, 12,311 (96.6%) were exposed to ALN and 784 (6.2%) to ZOL. In women, the HR for first hip fracture was 0.75 (95% CI: 0.61-0.91) for ZOL versus ALN. In men, the corresponding HR was 0.59 (95% CI: 0.32-1.07). Discontinued treatment was associated with increased risk compared with current ALN treatment in women (HR: 1.33; 95% CI: 1.24-1.42, men: HR 1.13 (95% CI: 0.95-1.35)). CONCLUSIONS: In women, the risk of first hip fracture when treated with ZOL was 25% lower than when treated with ALN. Discontinued treatment was associated with a 33% increase in hip fracture risk. Similar, albeit statistically non-significant, results were observed in men.