No association between long-chain n-3 fatty acid intake during pregnancy and risk of type 1 diabetes in offspring in two large Scandinavian pregnancy cohorts.

AIMS/HYPOTHESIS: The aim of this study was to investigate whether higher dietary intake of marine n-3 fatty acids during pregnancy is associated with a lower risk of type 1 diabetes in children. METHODS: The Danish National Birth Cohort (DNBC) and the Norwegian Mother, Father and Child Cohort Study (MoBa) together include 153,843 mother-child pairs with prospectively collected data on eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake during pregnancy from validated food frequency questionnaires. Type 1 diabetes diagnosis in children (n=634) was ascertained from national diabetes registries. RESULTS: There was no association between the sum of EPA and DHA intake during pregnancy and risk of type 1 diabetes in offspring (pooled HR per g/day of intake: 1.00, 95% CI 0.88, 1.14), with consistent results for both the MoBa and the DNBC. Robustness analyses gave very similar results. CONCLUSIONS/INTERPRETATION: Initiation of a trial of EPA and DHA during pregnancy to prevent type 1 diabetes in offspring should not be prioritised.

Genotypes predisposing for celiac disease and autoimmune diabetes and risk of infections in early childhood.

OBJECTIVES: Infections in early childhood have been associated with risk of celiac disease (CD) and type 1 diabetes (T1D). We investigated whether this is driven by susceptibility genes for autoimmune disease by comparing infection frequency by genetic susceptibility variants for CD or T1D. METHODS: We genotyped 373 controls and 384 children who developed CD or T1D in the population-based Norwegian Mother, Father and Child Cohort study (MoBa) study for human leukocyte antigen (HLA)-DQ, FUT2, SH2B3, and PTPN22, and calculated a weighted non-HLA genetic risk score (GRS) for CD and T1D based on over 40 SNPs. Parents reported infections in questionnaires when children were 6 and 18 months old. We used negative binomial regression to estimate incidence rate ratio (IRR) for infections by genotype. RESULTS: HLA genotypes for CD and T1D or non-HLA GRS for T1D were not associated with infections. The non-HLA GRS for CD was associated with a nonsignificantly lower frequency of infections (aIRR: 0.95, 95% CI: 0.87-1.03 per weighted allele score), and significantly so when restricting to healthy controls (aIRR: 0.89, 0.81-0.99). Participants homozygous for rs601338(A;A) at FUT2, often referred to as nonsecretors, had a nonsignificantly lower risk of infections (aIRR: 0.91, 95% CI: 0.83-1.01). SH2B3 and PTPN22 genotypes were not associated with infections. The association between infections and risk of CD (OR: 1.15 per five infections) was strengthened after adjustment for HLA genotype and non-HLA GRS (OR: 1.24). CONCLUSIONS: HLA variants and non-HLA GRS conferring susceptibility for CD were not associated with increased risk of infections in early childhood and is unlikely to drive the observed association between infections and risk of CD or T1D in many studies.

Frequency and risk of SARS-CoV-2 reinfections in Norway: a nation-wide study, February 2020 to January 2022.

BACKGROUND: SARS-CoV-2 reinfection rates have been shown to vary depending on the circulating variant, vaccination status and background immunity, as well as the time interval used to identify reinfections. This study describes the frequency of SARS-CoV-2 reinfections in Norway using different time intervals and assesses potential factors that could impact the risk of reinfections during the different variant waves. METHODS: We used linked individual-level data from national registries to conduct a retrospective cohort study including all cases with a positive test for SARS-CoV-2 from February 2020 to January 2022. Time intervals of 30, 60, 90 or 180 days between positive tests were used to define potential reinfections. A multivariable Cox regression model was used to assess the risk of reinfection in terms of variants adjusting for vaccination status, demographic factors, and underlying comorbidities. RESULTS: The reinfection rate varied between 0.2%, 0.6% and 5.9% during the Alpha, Delta and early Omicron waves, respectively. In the multivariable model, younger age groups were associated with a higher risk of reinfection compared to older age groups, whereas vaccination was associated with protection against reinfection. Moreover, the risk of reinfection followed a pattern similar to risk of first infection. Individuals infected early in the pandemic had higher risk of reinfection than individuals infected in more recent waves. CONCLUSIONS: Reinfections increased markedly during the Omicron wave. Younger individuals, and primary infections during earlier waves were associated with an increased reinfection risk compared to primary infections during more recent waves, whereas vaccination was a protective factor. Our results highlight the importance of age and post infection waning immunity and are relevant when evaluating vaccination polices.

Stroke After SARS-CoV-2 mRNA Vaccine: A Nationwide Registry Study.

BACKGROUND: Whether the SARS-CoV-2 mRNA vaccines may cause a transient increased stroke risk is uncertain. METHODS: In a registry-based cohort of all adult residents at December 27, 2020, in Norway, we linked individual-level data on COVID-19 vaccination, positive SARS-CoV-2 test, hospital admissions, cause of death, health care worker status, and nursing home resident status extracted from the Emergency Preparedness Register for COVID-19 in Norway. The cohort was followed for incident intracerebral bleeding, ischemic stroke, and subarachnoid hemorrhage within the first 28 days after the first/second or third dose of mRNA vaccination until January 24, 2022. Stroke risk after vaccination relative to time not exposed to vaccination was assessed by Cox proportional hazard ratio, adjusted for age, sex, risk groups, health care personnel, and nursing home resident. RESULTS: The cohort included 4 139 888 people, 49.8% women, and 6.7% were ≥80 years of age. During the first 28 days after an mRNA vaccine, 2104 people experienced a stroke (82% ischemic stroke, 13% intracerebral hemorrhage, and 5% subarachnoid hemorrhage). Adjusted hazard ratios (95% CI) after the first/second and after the third mRNA vaccine doses were 0.92 (0.85-1.00) and 0.89 (0.73-1.08) for ischemic stroke, 0.81 (0.67-0.98) and 1.05 (0.64-1.71) for intracerebral hemorrhage, and 0.64 (0.46-0.87) and 1.12 (0.57-2.19) for subarachnoid hemorrhage, respectively. CONCLUSIONS: We did not find increased risk of stroke during the first 28 days after an mRNA SARS-CoV-2 vaccine.

Nine-fold higher risk of acute myocardial infarction in subjects with type 1 diabetes compared to controls in Norway 1973-2017.

BACKGROUND: We aimed to study the cumulative incidence and risk factors (sex, age, calendar year of diabetes onset, country of origin and educational level) of acute myocardial infarction (AMI) in subjects with type 1 diabetes and matched controls. METHODS: A nationwide cohort of subjects with type 1 diabetes diagnosed at age < 15 years in Norway during 1973-2000 was followed until the first AMI event, emigration, death or 31st of December 2017. The Norwegian Childhood Diabetes Registry was linked to five nationwide registries, and up to ten sex- and age-matched controls per case were included. RESULTS: Among 7086 subjects with type 1 diabetes, 170 (2.4%) were identified with incident AMI, compared to 193 (0.3%) of 69,356 controls. Mean age and diabetes duration at first AMI was 40.8 years and 30.6 years, respectively. The probability of AMI after 40 years of follow-up was 8.0% in subjects with type 1 diabetes and 1.1% in controls, aHR 9.05 (95% CI 7.18-11.41). In type 1 diabetes, male sex (aHR 1.45), higher age at onset of diabetes and lower education (higher compared to lower, aHR 0.38) were significantly associated with higher risk of AMI. There was no significant time trend in AMI by calendar year of diabetes onset. CONCLUSIONS: We found nine-fold excess risk of AMI in subjects with type 1 diabetes, and three-fold higher risk in subjects with low versus high education. These results highlight a strengthened focus on prevention of cardiovascular disease, and diabetes education tailored to the subjects' educational background.

Maternal antibiotic use and infections during pregnancy and offspring asthma: the Norwegian Mother, Father and Child Cohort Study and a nationwide register cohort.

Maternal antibiotic use during pregnancy has been linked to asthma risk in children, but the role of underlying infections remains unclear. We investigated the association of maternal antibiotic use and infections during pregnancy with offspring risk of asthma. We used two population-based cohorts: the Norwegian Mother, Father and Child Cohort Study (MoBa) (n = 53 417) and a register-based cohort (n = 417 548). Asthma was defined based on dispensed asthma medications at 7 and 13 years from the Norwegian Prescription Database. Self-reported information on antibiotic use and infections during pregnancy was available in MoBa, while registrations of dispensed prescriptions were used to classify use of antibiotics in the register-based cohort. Maternal antibiotic use during pregnancy was associated with asthma at 7 in both cohorts (adjusted risk ratio (aRR) 1.23, 95% CI 1.11-1.37 in MoBa and 1.21, 1.16-1.25 in the register cohort) and asthma at 13 in the register cohort (1.13, 1.03-1.23) after adjusting for maternal characteristics. In MoBa, the estimate was attenuated after adjusting for infections during pregnancy. Maternal lower and upper respiratory tract infections (aRR 1.30, 95% CI 1.07-1.57 and 1.19, 1.09-1.30, respectively) and urinary tract infections (1.26, 1.11-1.42) showed associations with asthma at 7. Register cohort also showed an increased risk of asthma in relation to maternal antibiotics before and after pregnancy. Our findings suggest that both maternal antibiotics and infections during pregnancy have a role in the risk of offspring asthma. However, results from the register cohort suggest that the effect of antibiotics may reflect the shared underlying susceptibility.

Effects of eccentric vs concentric cycling training on patients with moderate COPD.

PURPOSE: The present study compared the effects of eccentric cycling (ECC) and conventional concentric cycling (CONC) training on muscle function, body composition, functional performance, and quality of life (QOL) of patients with moderate chronic obstructive pulmonary disease (COPD). METHODS: Twenty patients (age: 69.6 ± 10.1 years, forced expiratory volume in 1-s: 73.2 ± 11.4% of predicted) were randomly allocated to ECC (n = 10) or CONC (n = 10) group. They performed 12 weeks of ECC or CONC training at similar perceived exertion. The workload, heart rate (HR), blood oxygen saturation (SpO2), and dyspnea were monitored during cycling. Outcomes measures included maximal voluntary isometric contraction (MVC) strength of the knee extensors, rate of force development (RFD), lower limb fat-free (LLFFM) and fat (LLFM) mass, 6-min walking test (6MWT), timed up-and-go test (TUG), stairs ascending (SAWT) and descending walking time (SDWT), and QOL assessed by the Saint George's respiratory questionnaire. RESULTS: ECC produced on average threefold greater (P < 0.001) workload (211.8 ± 106.0 kJ) than CONC (78.1 ± 62.6 kJ) over 34 training sessions. ECC showed 1.5 ± 2.1% greater SpO2, 24.7 ± 4.1% lower HR, and 64.4 ± 29.6% lower dyspnea in average than CONC (P < 0.001). ECC increased LLFFM (4.5 ± 6.2%; P = 0.03), while CONC decreased LLFM (3.3 ± 6.4%; P = 0.04) after training. Both ECC and CONC reduced (P < 0.05) SAWT (- 16.1 ± 9.3% vs - 10.1 ± 14.4%) and SDWT (- 12.2 ± 12.6% vs - 14.4 ± 14.7%), and improved (P < 0.05) QOL (33.4 ± 38.8 vs 26.1 ± 36.6%) similarly, but only ECC improved (P < 0.05) RFD (69-199%), TUG (13.6 ± 13.6%), and 6MWT (25.3 ± 27.7%). CONCLUSION: These results suggest that ECC training with less cardio-pulmonary demands was more effective in increasing functional performance and muscle mass for COPD patients than CONC training.

Parechovirus Infection in Early Childhood and Association With Subsequent Celiac Disease.

INTRODUCTION: To test whether parechovirus and anellovirus, frequent enteric viruses, were associated with subsequent celiac disease (CD). We hypothesized that children who later developed CD would have increased frequency of parechovirus infections before transglutaminase 2 (TG2) antibody development. Anellovirus testing was exploratory, as a potential marker of immune status. METHODS: Matched case-control design nested within a longitudinal birth cohort (the MIDIA study) of children at genetic risk of CD (carrying the human leukocyte antigen genotype DR4-DQ8/DR3-DQ2, recruited throughout Norway during 2001-2007). We retrospectively tested blood samples taken at age 3, 6, 9, and 12 months, and then annually, to determine when TG2 antibodies developed. Of 220 genetically at-risk children tested, 25 were diagnosed with CD (cases; ESPGHAN 2012 criteria) and matched for follow-up time, birthdate, and county of residence with 2 randomly selected children free from CD (controls) from the cohort. Viruses were quantified in monthly stool samples (collected from 3 through 35 months of age) using real-time polymerase chain reaction methods. RESULTS: Parechovirus was detected in 222 of 2,005 stool samples (11.1%) and was more frequent in samples from cases before developing TG2 antibodies (adjusted odds ratio 1.67, 95% confidence interval 1.14-2.45, P = 0.01). The odds ratio was higher when a sample was positive for both parechovirus and enterovirus (adjusted odds ratio 4.73, 95% confidence interval 1.26-17.67, P = 0.02). Anellovirus was detected in 1,540 of 1,829 samples (84.2%), but did not differ significantly between case and control subjects. DISCUSSION: Early-life parechovirus infections were associated with development of CD in genetically at-risk children.

Relative lipid oxidation associates directly with mitochondrial fusion phenotype and mitochondria-sarcoplasmic reticulum interactions in human skeletal muscle.

Disturbances in skeletal muscle lipid oxidation might induce ectopic fat deposition and lipotoxicity. Nevertheless, the cellular mechanisms that regulate skeletal muscle lipid oxidation have not been fully determined. We aimed to determine whether there was an association between relative whole body lipid oxidation and mitochondrial size or mitochondria-sarcoplasmic reticulum interactions in the skeletal muscle. Twelve healthy men were included [mean (standard deviation), 24.7 (1.5) yr old, 24.4 (2.6) kg/m2]. The respiratory quotient (RQ) was used to estimate relative lipid oxidation at rest and during exercise (50% maximal oxygen consumption, 600 kcal expended). A skeletal muscle biopsy was obtained from the vastus lateralis at rest. Transmission electron microscopy was used to determine mitochondrial size and mitochondria-sarcoplasmic reticulum interactions (≤50 nm of distance between organelles). Protein levels of fusion/fission regulators were measured in skeletal muscle by Western blot. Resting RQ and exercise RQ associated inversely with intermyofibrillar mitochondrial size (r = -0.66 and r = -0.60, respectively, P < 0.05). Resting RQ also associated inversely with the percentage of intermyofibrillar mitochondria-sarcoplasmic reticulum interactions (r = -0.62, P = 0.03). Finally, intermyofibrillar mitochondrial size associated inversely with lipid droplet density (r = -0.66, P = 0.01) but directly with mitochondria fusion-to-fission ratio (r = 0.61, P = 0.03). Our results show that whole body lipid oxidation is associated with skeletal muscle intermyofibrillar mitochondrial size, fusion phenotype, and mitochondria-sarcoplasmic-reticulum interactions in nondiabetic humans.

Maternal and child gluten intake and association with type 1 diabetes: The Norwegian Mother and Child Cohort Study.

BACKGROUND: The relationship between maternal gluten intake in pregnancy, offspring intake in childhood, and offspring risk of type 1 diabetes has not been examined jointly in any studies. Our aim was to study the relationship between maternal and child intake of gluten and risk of type 1 diabetes in children. METHODS AND FINDINGS: We included 86,306 children in an observational nationwide cohort study, the Norwegian Mother and Child Cohort Study (MoBa), with recruitment from 1999 to 2008 and with follow-up time to April 15, 2018. We used registration of type 1 diabetes in the Norwegian childhood diabetes registry as the outcome. We used Cox proportional hazard regression to estimate hazard ratios (HRs) for the mother's intake of gluten up to week 22 of pregnancy and offspring gluten intake when the child was 18 months old. The average time followed was 12.3 years (0.70-16.0). A total of 346 children (0.4%) children were diagnosed with type 1 diabetes, resulting in an incidence rate of 32.6/100,000 person-years. Mean gluten intake per day was 13.6 g for mothers and 8.8 g for children. There was no association between the mother's intake of gluten in pregnancy and offspring type 1 diabetes, with an adjusted HR (aHR) of 1.02 (95% confidence interval [CI] 0.73-1.43, p = 0.91) for each 10-g-per-day increment. There was an association between offspring intake of gluten and a higher risk of type 1 diabetes, with an aHR of 1.46 (95% CI 1.06-2.01, p = 0.02) for each 10-g-per-day increment. Among the limitations are the likely imprecision in estimation of gluten intake and that we only had information regarding gluten intake at 2 time points in early life. CONCLUSIONS: Our results show that, while the mother's intake of gluten in pregnancy was not associated with type 1 diabetes, a higher intake of gluten by the child at an early age may give a higher risk of type 1 diabetes.

Maternal Microchimerism in Cord Blood and Risk of Celiac Disease in Childhood.

OBJECTIVES: During pregnancy, small quantities of maternal cells are naturally transmitted to the fetus. This transmission, termed maternal microchimerism (MMc), has been implicated in autoimmune diseases but its potential role is unclear. We aimed to investigate if MMc at birth predicted childhood celiac disease (CD) risk, a common immune-mediated enteropathy often presenting in childhood. METHODS: We designed a case-control study, nested in the Norwegian Mother, Father and Child Cohort. Participants were HLA class II typed to determine noninherited, nonshared maternal alleles (NIMA). Droplet digital (dd) PCR assays specific for common HLA class II NIMAs (HLA-DQB103:01, 04:02 and 06:02/03) were used to estimate the quantity of maternal DNA, as a marker of maternal cells, in cord blood DNA from 124 children who later developed clinically diagnosed CD (median age at end of study 7.4 years, range 3.6-12.9) and 124 random controls. We tested whether presence of MMc was associated with CD using logistic regression, and compared ranks between cases and controls. RESULTS: MMc, for example, maternal HLA antigens not inherited by the child, was found in 42% of cases and 43% of controls, and not associated with CD (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.58-1.60). The ranks of MMc quantities in cases and controls were also similar (Mann-Whitney U-test, P = 0.71). The subgroup with HLA-DQB1:03*01 as their NIMA had a potential association with MMc, where levels greater than median was associated with CD (OR 3.78, 95% CI 1.28-11.18). CONCLUSION: MMc measured in cord blood was not associated with later risk of CD.

Gluten Intake in Early Childhood and Risk of Celiac Disease in Childhood: A Nationwide Cohort Study.

OBJECTIVES: Celiac disease (CD) may occur in genetically predisposed individuals exposed to gluten, but it is unclear whether the amount of gluten influences the risk of disease. We aimed at determining whether the amount of gluten intake at age 18 months predicted later risk of CD. METHODS: In an observational nationwide cohort study, the Norwegian Mother and Child Cohort Study (MoBa), we included 67,608 children born during 2000-2009 and followed up for a mean of 11.5 years (range 7.5-15.5) after exclusions for missing data. Information regarding CD diagnosis was obtained from the Norwegian Patient Register 2008-2016 and from parental questionnaires at child age 7 and 8 years. We estimated gluten intake at age 18 months from a prospectively collected parental questionnaire. RESULTS: CD was diagnosed in 738 children (1.1%, 62% girls). The mean estimated amount of gluten in the diet at 18 months was 8.8 g/d (SD 3.6). The adjusted relative risk of CD was 1.10 (95% confidence interval 1.03-1.18) per SD increase in daily gluten amount at age 18 months. Children in the upper quartile of gluten intake compared with the lower quartile had an increased risk of CD (adjusted relative risk 1.29, 95% confidence interval 1.06-1.58). The association with gluten amount was independent of the age at introduction of gluten. Gluten introduction ≥6 months was also an independent risk factor for CD. DISCUSSION: In this nationwide study, increased gluten intake at 18 months was associated with a modestly increased risk of CD later in childhood.

Gluten Intake and Risk of Celiac Disease: Long-Term Follow-up of an At-Risk Birth Cohort.

OBJECTIVES: To determine the association between the amount of gluten intake in childhood and later celiac disease (CD), for which data are currently scarce. METHODS: The prospective Diabetes Autoimmunity Study in the Young cohort includes 1875 at-risk children with annual estimates of gluten intake (grams/d) from age 1 year. From 1993 through January 2017, 161 children, using repeated tissue transglutaminase (tTGA) screening, were identified with CD autoimmunity (CDA) and persistent tTGA positivity; of these children, 85 fulfilled CD criteria of biopsy-verified histopathology or persistently high tTGA levels. Cox regression, modeling gluten intake between ages 1 and 2 years (i.e., in 1-year-olds), and joint modeling of cumulative gluten intake throughout childhood were used to estimate hazard ratios adjusted for confounders (aHR). RESULTS: Children in the highest third of gluten intake between the ages of 1 and 2 years had a 2-fold greater hazard of CDA (aHR 2.17; 95% confidence interval [CI], 1.22-3.88; P value = 0.01) and CD (aHR 1.96; 95% CI, 0.90-4.24; P value = 0.09) than those in the lowest third. The risk of developing CDA increased by 5% per daily gram increase in gluten intake (aHR 1.05; 95% CI, 1.00-1.09; P value = 0.04) in 1-year-olds. The association between gluten intake in 1-year-olds and later CDA or CD did not differ by the child's human leukocyte antigen genotype. The incidence of CD increased with increased cumulative gluten intake throughout childhood (e.g., aHR 1.15 per SD increase in cumulative gluten intake at age 6; 95% CI, 1.00-1.32; P value = 0.04). DISCUSSION: Gluten intake in 1-year-olds is associated with the future onset of CDA and CD in children at risk for the disease.

Virus genotyping by massive parallel amplicon sequencing: adenovirus and enterovirus in the Norwegian MIDIA study.

OBJECTIVES: Direct genotyping of adenovirus or enterovirus from clinical material using polymerase chain reaction (PCR) followed by Sanger sequencing is often difficult due to the presence of multiple virus types in a sample, or due to varying efficacy of PCR amplifying the capsid gene on the background of foreign nucleic acids. Here we present a simple protocol for virus genotyping using massive parallel amplicon sequencing. METHODS: The protocol utilized a set of 16 tailed degenerate primers flanking the seventh hypervariable region of the adenovirus hexon gene and 9 tailed degenerate primers targeted to the proximal portion of the enterovirus VP1 gene. Subsequent addition of dual indices enabled simultaneous sequencing of 384 different samples on an Illumina MiSeq instrument. Downstream bioinformatic analysis was based on remapping to a set of references representative of the presently known repertoire of virus types. RESULTS: After validation with known virus types, the sequencing method was applied on 301 adenovirus-positive samples and 350 enterovirus-positive samples from a longitudinally collected series of stools from 83 children aged 3 to 36 months. We detected 7 different adenovirus types and 27 different enterovirus types. There were 37 (6.2%) samples containing more than one genotype of the same viral genus. At least one dual infection was experienced by 23 of 83 (28%) of the children observed over the 3 years' observation period. CONCLUSIONS: Amplicon sequencing with a multiplex set of degenerate primers seems to be a rapid and reliable technical solution for genotyping of large collections of samples where simultaneous infections with multiple strains can be expected.

Maternal microchimerism in cord blood and risk of childhood-onset type 1 diabetes.

BACKGROUND: Maternal microchimerism (MMc), the transmission of small quantities of maternal cells to the fetus, is relatively common and persistent. MMc has been detected with increased frequency in the circulation and pancreas of type 1 diabetes (T1D) patients. We investigated for the first time whether MMc levels at birth predict future T1D risk. We also tested whether cord blood MMc predicted MMc in samples taken at T1D diagnosis. METHODS: Participants in the Norwegian Mother and Child Cohort study were human leukocyte antigen (HLA) class II typed to determine non-inherited, non-shared maternal alleles (NIMA). Droplet digital (dd) polymerase chain reaction (PCR) assays specific for common HLA class II NIMA (HLADQB1*03:01, *04:02, and *06:02/03) were developed and validated. MMc was estimated as maternal DNA quantity in the fetal circulation, by NIMA specific ddPCR, measured in cord blood DNA from 71 children who later developed T1D and 126 controls within the cohort. RESULTS: We found detectable quantities of MMc in 34/71 future T1D cases (48%) and 53/126 controls (42%) (adjusted odds ratio [aOR] 1.27, 95% confidence interval (CI) 0.68-2.36), and no significant difference in ranks of MMc quantities between cases and controls (Mann-Whitney P = .46). There was a possible association in the NIMA HLA-DQB1*03:01 subgroup with later T1D (aOR 3.89, 95%CI 1.05-14.4). MMc in cord blood was not significantly associated with MMc at T1D diagnosis. CONCLUSIONS: Our findings did not support the hypothesis that the degree of MMc in cord blood predict T1D risk. The potential subgroup association with T1D risk should be replicated in a larger cohort.

Smoking in pregnancy, cord blood cotinine and risk of celiac disease diagnosis in offspring.

Ecological observations suggest an inverse relationship between smoking in pregnancy and celiac disease (CD) in offspring. While individual-level analyses have been inconsistent, they have mostly lacked statistical power or refined assessments of exposure. To examine the association between pregnancy-related smoking and CD in the offspring, as well as its consistency across data sets, we analyzed: (1) The Norwegian Mother and Child Cohort (MoBa) of 94,019 children, followed from birth (2000-2009) through 2016, with 1035 developing CD; (2) a subsample from MoBa (381 with CD and 529 controls) with biomarkers; and (3) a register-based cohort of 536,861 Norwegian children, followed from birth (2004-2012) through 2014, with 1919 developing CD. Smoking behaviors were obtained from pregnancy questionnaires and antenatal visits, or, in the MoBa-subsample, defined by measurement of cord blood cotinine. CD and potential confounders were identified through nationwide registers and comprehensive parental questionnaires. Sustained smoking during pregnancy, both self-reported and cotinine-determined, was inversely associated with CD in MoBa (multivariable-adjusted [a] OR = 0.61 [95%CI, 0.46-0.82] and aOR = 0.55 [95%CI, 0.31-0.98], respectively); an inverse association was also found with the intensity of smoking. These findings differed from those of our register-based cohort, which revealed no association with sustained smoking during pregnancy (aOR = 0.97 [95%CI, 0.80-1.18]). In MoBa, neither maternal smoking before or after pregnancy, nor maternal or paternal smoking in only early pregnancy predicted CD. In a carefully followed pregnancy cohort, a more-detailed smoking assessment than oft-used register-based data, revealed that sustained smoking during pregnancy, rather than any smoking exposure, predicts decreased likelihood of childhood-diagnosed CD.

Pandemic influenza and subsequent risk of type 1 diabetes: a nationwide cohort study.

AIMS/HYPOTHESIS: Case reports have linked influenza infections to the development of type 1 diabetes. We investigated whether pandemic and seasonal influenza infections were associated with subsequent increased risk of type 1 diabetes. METHODS: In this population-based registry study, we linked individual-level data from national health registries for the entire Norwegian population under the age of 30 years for the years 2006-2014 (2.5 million individuals). Data were obtained from the National Registry (population data), the Norwegian Patient Registry (data on inpatient and outpatient specialist care), the Primary Care Database, the Norwegian Prescription Database and the Norwegian Surveillance System for Communicable Diseases. Pandemic influenza was defined as either a clinical influenza diagnosis during the main pandemic period or a laboratory-confirmed test. Seasonal influenza was defined by a clinical diagnosis of influenza between 2006 and 2014. We used Cox regression to estimate HRs for new-onset type 1 diabetes after an influenza infection, adjusted for year of birth, sex, place of birth and education. RESULTS: The adjusted HR for type 1 diabetes after pandemic influenza infection was 1.19 (95% CI 0.97, 1.46). In the subgroup with laboratory-confirmed influenza A (H1N1), influenza was associated with a twofold higher risk of subsequent type 1 diabetes before age 30 years (adjusted HR: 2.26, 95% CI 1.51, 3.38). CONCLUSIONS/INTERPRETATION: Overall, we could not demonstrate a clear association between clinically reported pandemic influenza infection and incident type 1 diabetes. However, we found a twofold excess of incident diabetes in the subgroup with laboratory-confirmed pandemic influenza A (H1N1).

Lack of Association Between Maternal or Neonatal Vitamin D Status and Risk of Childhood Type 1 Diabetes: A Scandinavian Case-Cohort Study.

Studies on vitamin D status during pregnancy and risk of type 1 diabetes mellitus (T1D) lack consistency and are limited by small sample sizes or single measures of 25-hydroxyvitamin D (25(OH)D). We investigated whether average maternal 25(OH)D plasma concentrations during pregnancy are associated with risk of childhood T1D. In a case-cohort design, we identified 459 children with T1D and a random sample (n = 1,561) from the Danish National Birth Cohort (n = 97,127) and Norwegian Mother and Child Cohort Study (n = 113,053). Participants were born between 1996 and 2009. The primary exposure was the estimated average 25(OH)D concentration, based on serial samples from the first trimester until delivery and on umbilical cord plasma. We estimated hazard ratios using weighted Cox regression adjusting for multiple confounders. The adjusted hazard ratio for T1D per 10-nmol/L increase in the estimated average 25(OH)D concentration was 1.00 (95% confidence interval: 0.90, 1.10). Results were consistent in both cohorts, in multiple sensitivity analyses, and when we analyzed mid-pregnancy or cord blood separately. In conclusion, our large study demonstrated that normal variation in maternal or neonatal 25(OH)D is unlikely to have a clinically important effect on risk of childhood T1D.

Parental Smoking and Risk of Childhood-onset Type 1 Diabetes.

BACKGROUND: A few prospective studies suggest an association between maternal smoking during pregnancy and lower risk of type 1 diabetes. However, the role of unmeasured confounding and misclassification remains unclear. METHODS: We comprehensively evaluated whether maternal smoking in pregnancy predicts lower risk of childhood-onset type 1 diabetes in two Scandinavian pregnancy cohorts (185,076 children; 689 cases) and a Norwegian register-based cohort (434,627 children; 692 cases). We measured cord blood cotinine as an objective marker of nicotine exposure during late pregnancy in 154 cases and 476 controls. We also examined paternal smoking during pregnancy, in addition to environmental tobacco smoke exposure the first 6 months of life, to clarify the role of characteristics of smokers in general. RESULTS: In the pregnancy cohorts, maternal smoking beyond gestational week 12 was inversely associated with type 1 diabetes, pooled adjusted hazard ratio (aHR) 0.66 (95% CI = 0.51, 0.85). Similarly, in the Norwegian register-based cohort, children of mothers who still smoked at the end of pregnancy had lower risk of type 1 diabetes, aHR 0.65 (95% CI = 0.47, 0.89). Cord blood cotinine ≥30 nmol/L was also associated with reduced risk of type 1 diabetes, adjusted odds ratio 0.42 (95% CI = 0.17, 1.0). We observed no associations of paternal smoking during pregnancy, or environmental tobacco smoke exposure, with childhood-onset type 1 diabetes. CONCLUSION: Maternal sustained smoking during pregnancy is associated with lower risk of type 1 diabetes in children. This sheds new light on the potential intrauterine environmental origins of the disease.

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.