Karl Mårild

Pregnancy Outcome and Risk of Celiac Disease in Offspring: A Nationwide Case-Control Study

BACKGROUND & AIMS Studies on pregnancy characteristics and mode of delivery and risk of later celiac disease in offspring are inconsistent. In recent decades rates of cesarean delivery and preterm birth survival have increased while at the same time the prevalence of celiac disease has doubled. METHODS In this population-based case-control study we examined the risk of celiac disease in individuals exposed to cesarean delivery and adverse fetal events (ie, low Apgar score, small for gestational age, low birth weight, preterm birth, and neonatal infections). Prospectively recorded pregnancy data were obtained from the Swedish Medical Birth Register between 1973 and 2008. Study participants consisted of 11,749 offspring with biopsy-verified celiac disease identified through histopathology reports from Swedens 28 pathology departments, and 53,887 age- and sex-matched controls from the general population. RESULTS We found a positive association between elective cesarean delivery and later celiac disease (adjusted odds ratio [OR], 1.15; 95% confidence interval [CI], 1.04-1.26), but no increased risk of celiac disease after emergency (adjusted OR, 1.02; 95% CI, 0.92-1.13) or any cesarean delivery (adjusted OR, 1.06; 95% CI, 0.99-1.13). Infants born small for gestational age were at a 21% increased risk of celiac disease (95% CI, 1.09-1.35), whereas other pregnancy exposures did not increase the risk of future celiac disease. CONCLUSIONS The positive association with elective, but not emergency, cesarean delivery is consistent with the hypothesis that the bacterial flora of the newborn plays a role in the development of celiac disease.

Antibiotic exposure and the development of coeliac disease : a nationwide case-control study

BackgroundThe intestinal microbiota has been proposed to play a pathogenic role in coeliac disease (CD). Although antibiotics are common environmental factors with a profound impact on intestinal microbiota, data on antibiotic use as a risk factor for subsequent CD development are scarce.MethodsIn this population-based case–control study we linked nationwide histopathology data on 2,933 individuals with CD (Marsh stage 3; villous atrophy) to the Swedish Prescribed Drug Register to examine the association between use of systemic antibiotics and subsequent CD. We also examined the association between antibiotic use in 2,118 individuals with inflammation (Marsh 1–2) and in 620 individuals with normal mucosa (Marsh 0) but positive CD serology. All individuals undergoing biopsy were matched for age and sex with 28,262 controls from the population.ResultsAntibiotic use was associated with CD (Odds ratio [OR] = 1.40; 95% confidence interval [CI] = 1.27-1.53), inflammation (OR = 1.90; 95% CI = 1.72–2.10) and normal mucosa with positive CD serology (OR = 1.58; 95% CI = 1.30–1.92). ORs for prior antibiotic use in CD were similar when we excluded antibiotic use in the last year (OR = 1.30; 95% CI = 1.08-1.56) or restricted to individuals without comorbidity (OR = 1.30; 95% CI = 1.16 – 1.46).ConclusionsThe positive association between antibiotic use and subsequent CD but also with lesions that may represent early CD suggests that intestinal dysbiosis may play a role in the pathogenesis of CD. However, non-causal explanations for this positive association cannot be excluded.

Infections and Risk of Celiac Disease in Childhood: A Prospective Nationwide Cohort Study

Objectives:Studies on early life infections and risk of later celiac disease (CD) are inconsistent but have mostly been limited to retrospective designs, inpatient data, or insufficient statistical power. We aimed to test whether early life infections are associated with increased risk of later CD using prospective population-based data.Methods:This study, based on the Norwegian Mother and Child Cohort Study, includes prospective, repeated assessments of parent-reported infectious disease data up to 18 months of age for 72,921 children born between 2000 and 2009. CD was identified through parental questionnaires and the Norwegian Patient Registry. Logistic regression was used to estimate odds ratios adjusted for child’s age and sex (aOR).Results:During a median follow-up period of 8.5 years (range, 4.5–14.5), 581 children (0.8%) were diagnosed with CD. Children with ≥10 infections (≥fourth quartile) up to age 18 months had a significantly higher risk of later CD, as compared with children with ≤4 infections (≤first quartile; aOR=1.32; 95% confidence interval (CI)=1.06–1.65; per increase in infectious episodes, aOR=1.03; 95% CI=1.02–1.05). The aORs per increase in specific types of infections were as follows: upper respiratory tract infections: 1.03 (95% CI=1.02–1.05); lower respiratory tract infections: 1.12 (95% CI=1.01–1.23); and gastroenteritis: 1.05 (95% CI=0.99–1.11). Additional adjustments for maternal CD, education level, smoking, birth weight, prematurity, infant feeding practices, birth season, and antibiotic treatment yielded largely unchanged results.Conclusions:This is the first large-scale population-based cohort study of this association. Our results are in line with immunological data suggesting that early life infections may have a role in CD development. However, non-causal explanations for this association due to surveillance bias and reverse causation cannot be excluded.

Down Syndrome Is Associated with Elevated Risk of Celiac Disease: A Nationwide Case-Control Study

OBJECTIVE To provide risk estimates for celiac disease (CD) in Down syndrome (DS) compared with the general population. STUDY DESIGN In this nationwide Swedish case-control study, we examined the risk of CD in individuals with DS born between 1973 and 2008. Study participants consisted of 2 populations: 11,749 patients with biopsy-verified CD (villous atrophy [VA], equivalent to Marsh grade III) who were identified through histopathology reports from the 28 pathology departments in Sweden and 53,887 population-based controls matched for sex, age, calendar year of birth, and county of residence. We used prospectively recorded data from Swedish health registers to identify individuals with DS. ORs were calculated using conditional logistic regression. RESULTS Of the 11,749 individuals with CD, 165 had a diagnosis of DS (1.4%) compared with 55/53,887 controls (0.1%). This corresponded to an OR of 6.15 (95% CI = 5.09-7.43) for subsequent CD in individuals with DS compared with the general population. The association between DS and CD was not affected by maternal age at delivery, infant sex, or presence of type 1 diabetes mellitus in the child. CONCLUSIONS We found a sixfold increased risk of CD in individuals with DS. This study adds precision to the previously reported association between DS and CD.

Increased Risk of Hospital Admission for Influenza in Patients With Celiac Disease: A Nationwide Cohort Study in Sweden

OBJECTIVES:Although earlier studies suggest an increased risk of infectious disease in celiac disease (CD), data on the risk of influenza in patients with CD are limited. We examined the risk of hospital admission for influenza in CD patients, but for comparative reasons also in individuals with small-intestinal inflammation or normal mucosa but positive CD serology.METHODS:In 2006–2008, we collected duodenal/jejunal biopsy data on CD (Marsh 3: villous atrophy, VA; n=29,008 unique individuals) and inflammation (Marsh 1–2; n=13,200) from all 28 pathology departments in Sweden. A third regional cohort consisted of 3,709 individuals with positive CD serology but normal mucosa (Marsh 0). The biopsies were performed between 1969 and 2008. Through linkage with the Swedish Hospital Discharge Register, we estimated the risk of hospital admission for influenza compared with that of 224,114 age- and sex-matched controls from the general population.RESULTS:Individuals with CD were at increased risk of hospital admission for influenza (hazard ratio (HR)=2.1; 95% confidence interval (CI)=1.6–2.7; n=81). The absolute risk of influenza was 30/100,000 person-years (excess risk: 16/100,000 person-years). Furthermore, children with CD were at increased risk of influenza (HR=2.5; 95% CI=1.3–4.8). Whereas individuals with inflammation without VA were also at increased risk of influenza (HR=1.9; 95% CI=1.4–2.5), individuals with normal mucosa but positive CD serology were not (HR=1.2; 95% CI=0.5–3.0).CONCLUSIONS:This study found an increased risk of hospital admission for influenza in patients with CD.

Celiac disease and anorexia nervosa: A nationwide study

Through linkages between national histopathology and diagnostic code databases, this study provides new insights into a bidirectional association between celiac disease and anorexia nervosa. BACKGROUND AND OBJECTIVE: Previous research suggests an association of celiac disease (CD) with anorexia nervosa (AN), but data are mostly limited to case reports. We aimed to determine whether CD is associated with the diagnosis of AN. METHODS: Register-based cohort and case-control study including women with CD (n = 17 959) and sex- and age-matched population-based controls (n = 89 379). CD (villous atrophy) was identified through the histopathology records of Sweden’s 28 pathology departments. Inpatient and hospital-based outpatient records were used to identify AN. Hazard ratios for incident AN diagnosis were estimated by using stratified Cox regression with CD diagnosis as a time-dependent exposure variable. In the secondary analyses, we used conditional logistic regression to estimate odds ratios for being diagnosed with AN before CD. RESULTS: Median age of CD diagnosis was 28 years. During 1 174 401 person-years of follow-up, 54 patients with CD were diagnosed with AN (27/100 000 person-years) compared with 180 matched controls (18/100 000 person-years). The hazard ratio for later AN was 1.46 (95% confidence interval [CI], 1.08–1.98) and 1.31 beyond the first year after CD diagnosis (95% CI, 0.95–1.81). A previous AN diagnosis was also associated with CD (odds ratio, 2.18; 95% CI, 1.45–3.29). Estimates remained largely unchanged when adjusted for socioeconomic characteristics and type 1 diabetes. CONCLUSIONS: The bidirectional association between AN diagnosis and CD warrants attention in the initial assessment and follow-up of these conditions because underdiagnosis and misdiagnosis of these disorders likely cause protracted and unnecessary morbidity.

Antibiotic exposure in pregnancy and risk of coeliac disease in offspring: a cohort study

BackgroundThe infant microbiota may play a pathogenic role in coeliac disease (CD). Antibiotic treatment in pregnancy is common and could significantly impact the infant microbiota. In this study, we aimed to investigate the association between antibiotic exposure during pregnancy and CD in offspring.MethodsProspective questionnaire data on antibiotic exposure in pregnancy were available in 8729 children participating in the All Babies in Southeast Sweden (ABIS) cohort study, and of these 46 developed CD until December 2006. Cox regression estimated hazard ratios (HRs) for CD in the offspring among mothers exposed to antibiotics during pregnancy, with adjustment for parent-reported diary data on breastfeeding, age at gluten introduction and number of infections in the child’s first year of life.ResultsOf the 1836 children exposed to antibiotics during pregnancy, 12 (0.7%) children developed CD as compared with 34/6893 (0.5%) unexposed children (HR = 1.33; 95% CI = 0.69-2.56). Risk estimates remained unchanged after adjustment for breastfeeding, age at gluten introduction and infection load in the child’s first year of life (HR = 1.28; 95% CI = 0.66-2.48).ConclusionsWe found no statistically significant association between antibiotic exposure during pregnancy and CD in offspring. This lack of association may either be true or the result of limited statistical power.

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

Abstract 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.

Current evidence on whether perinatal risk factors influence coeliac disease is circumstantial

Coeliac disease is triggered by an interplay of environmental and genetic factors and is one of the most prevalent autoimmune diseases in children, occurring in about 1% of Europeans. Over the last few decades, there has been a growing interest in the role of the perinatal environment in coeliac disease and this review discusses the growing body of literature on coeliac disease and perinatal risk factors.

Increased use of hypnotics in individuals with celiac disease: a nationwide case-control study

BackgroundAlthough poor sleep is common in numerous gastrointestinal diseases, data are scarce on the risk of poor sleep in celiac disease. The objective of this study was to estimate the risk of repeated use of hypnotics among individuals with celiac disease as a proxy measure for poor sleep.MethodsThis is a nationwide case–control study including 2933 individuals with celiac disease and 14,571 matched controls from the general Swedish population. Poor sleep was defined as ≥2 prescriptions of hypnotics using prospective data from the National Prescribed Drug Register (data capture: July 2005-January 2008). We estimated odds ratios and hazard ratios for poor sleep before and after celiac disease diagnosis respectively.ResultsIn this study, poor sleep was seen in 129/2933 individuals (4.4%) with celiac disease, as compared with 487/14,571 controls (3.3%) (odds ratio = 1.33; 95% CI = 1.08-1.62). Data restricted to sleep complaints starting ≥1 year before celiac disease diagnosis revealed largely unchanged risk estimates (odds ratio = 1.23; 95% CI = 0.88-1.71) as compared with the overall risk (odds ratio 1.33). The risk of poor sleep in celiac disease was essentially not influenced by adjustment for concomitant psychiatric comorbidity (n = 1744, adjusted odds ratio =1.26; 95% CI = 1.02-1.54) or restless legs syndrome (n = 108, adjusted odds ratio = 1.33; 95% CI = 1.08-1.63). Poor sleep was also more common after celiac disease diagnosis as compared with matched controls (hazard ratio = 1.36; 95% CI = 1.30-1.41).ConclusionsIn conclusion, individuals with celiac disease suffer an increased risk of poor sleep, both before and after diagnosis. Although we cannot rule out that surveillance bias has contributed to our findings, our results are consistent with previous data suggesting that sleep complaints may be a manifestation of celiac disease.