To Örebro University

Introduction: There are limited data on the relationship between eosinophilic esophagitis (EoE) and asthma. We aimed to assess the risk of asthma in EoE patients compared with matched controls and siblings.

Methods: Through the ESPRESSO study, a Swedish nationwide population-based histopathology cohort, we identified EoE patients diagnosed between 1989 and 2017 (n = 1146) and up to 5 age- and sex-matched controls (n = 5022). Cox regression generated hazard ratios (HRs) for developing asthma. We compared EoE patients with sibling controls.

Results: The median age at EoE diagnosis was 42 years. During a median follow-up of 3.8 years, 140 EoE patients (28.1/1000 person-years) and 174 controls (7.2/1000 person-years) developed asthma (HR = 3.96; 95% confidence interval [CI] = 3.16-4.96, p < 0.001). An increased risk of asthma was seen in the first 10 years after EoE diagnosis but not thereafter. EoE patients diagnosed in childhood or young adulthood were at a particularly high risk of asthma (HR = 4.74; 95% CI = 2.93-7.67, p < 0.001 and HR = 5.84; 95% CI = 3.68-9.29, p < 0.001, respectively). Compared with their non-EoE siblings, EoE patients were at a 5-fold increased risk of asthma (HR = 4.97; 95% CI = 3.13-7.92, p < 0.001).

Conclusion: EoE patients are at an increased risk of asthma compared with the general population, which is unlikely to be entirely explained through unmeasured intrafamilial factors given that the positive association remained in sibling analyses. Physicians caring for EoE should have a high awareness of concomitant asthma.

BACKGROUND: Celiac disease (CeD) is associated with several immune-mediated disorders, but it is unclear whether it is associated with eosinophilic esophagitis (EoE).

OBJECTIVE: We sought to examine the risk of EoE in patients with biopsy-verified CeD compared with matched controls and siblings.

METHODS: Using nationwide population-based histopathology data, we identified 27,338 patients with CeD diagnosed in the period 2002 to 2017 in Sweden. Patients with CeD were age- and sex-matched with up to 5 reference individuals (n = 134,987) from the general population. Cox Regression was used to estimate hazard ratios (HRs) for developing biopsy-verified EoE. In a secondary analysis, we used unaffected siblings of patients with CeD as comparators to adjust for intrafamilial confounding.

RESULTS: The median age at CeD diagnosis was 27 years, and 63.3% were female patients. During a median follow-up of 8.1 years, 17 patients with CeD and 13 matched reference individuals were diagnosed with EoE. This corresponded to incidence rates of 0.08 versus 0.01 per 1000 person-years, respectively, and an adjusted HR for EoE of 6.65 (95% CI, 3.26-13.81). Compared with their siblings without CeD, patients with CeD were however at a no increased risk of EoE (HR, 1.39; 95% CI, 0.55-3.51).

CONCLUSIONS: In this study, individuals with CeD were at a 6.6-fold increased risk of later EoE compared with the general population. This association might be explained by an altered health-seeking behavior or through shared genetic or early environmental factors because the excess risk disappeared in sibling analyses.

BACKGROUND: Owing to insufficient data, current guidelines recommend against initiating allergen-specific immunotherapy (AIT) during pregnancy but suggest that well-tolerated ongoing immunotherapy may be continued.

OBJECTIVE: To evaluate the safety of MT in pregnancy, especially the risk for congenital malformations.

METHODS: This nationwide Swedish cohort study identified pregnancies exposed to AIT, both subcutaneous and sublingual, through the Swedish Medical Birth register and the Prescribed Drug Register between 2005 and 2014. Information on congenital malformations in offspring was retrieved from the National Patient Register. Using the personal identity number, we linked data between registers. Using logistic regression, we calculated odds ratios (ORs) with 95% CIs for congenital malformations and other adverse pregnancy outcomes after adjusting for potential confounders.

RESULTS: From 2005 to 2014, we identified 924,790 singleton pregnancies. Among these, 743 pregnancies had been exposed to MT 3 months before conception up until gestational week 22. Allergen-specific immunotherapy in pregnancy was not linked to congenital malformations (OR = 0.90; 95% CI, 0.63-1.27) or other adverse pregnancy outcomes (preterm birth: OR = 0.98; 95% CI, 0.71-1.35; stillbirth: OR = 0.79; 95% CI, 0.26-2.47; or cesarean delivery: OR = 0.91; 95% CI, 0.76-1.09). Stratification by route of immunotherapy, subcutaneous or sublingual, resulted in similar ORs. Restricting the pregnancy cohort to women with asthma or pulmonary disease, nulliparous women, births in 2012 to 2014, or Swedish-born women yielded similar results.

CONCLUSIONS: This nationwide study found no evidence of congenital malformations or other adverse pregnancy outcomes in women treated with MT in pregnancy.

Allergic diseases are very common in children and young adults, while there is an ongoing interest worldwide in exploring the early origins of these conditions. The perinatal period is considered crucial as it encompasses the maturation of gut microbiota and the establishment of an efficient immunoregulation. Early-life factors might be the key drivers of an altered immune response, sometimes leading to sensitization and allergic disease. Preterm birth is believed to affect the risk of immune-mediated diseases, while a delayed and altered gut microbiota composition and diversity following caesarean delivery might influence the induction of tolerance.

In the first paper, using a large population database, we found that caesarean delivery increased the risk of allergic rhinitis (AR) in offspring, while moderately preterm birth (≥32–36 weeks of gestation) was associated with a slightly elevated risk. No association was observed between post-term birth (≥42 weeks) and AR. There also seems to be a positive association between large for gestational age, low 5-minute Apgar score (<7) and AR. 

In the second paper, we used data from the BAMSE population-based birth cohort to assess the impact of gestational age at birth on future IgE sensitization. The study concluded that preterm birth (<37 weeks of gestation) was inversely associated with IgE sensitization to common food and/or inhalant allergens up to the age 24 years, while no association was found between postterm birth and IgE sensitization.

Uncontrolled asthma and allergic disease in pregnancy are associated with poor pregnancy outcome. Current guidelines recommend against the initiation of allergen-specific immunotherapy (AIT) in pregnant patients, while welltolerated ongoing AIT might be continued. In the third paper, using national health-care registers, we found no association between AIT during pregnancy and risk of congenital malformations, preterm birth, caesarean delivery, stillbirth, or other adverse pregnancy outcomes. 

Background: Immunoglobulin E (IgE) sensitization is associated with asthma and allergic diseases. Gestational age influences early immune system development, thereby potentially affecting the process of tolerance induction to allergens.

Objective: To study IgE sensitization to common allergens by gestational age from childhood up to early adulthood.

Methods: Population-based birth cohort, data from the Swedish BAMSE study were used. Allergen-specific IgE antibodies to a mix of common food (fx5) and inhalant (Phadiatop) allergens were analysed at 4, 8, 16 and 24 years. Sensitization was defined as allergen-specific IgE >= 0.35 kU(A)/L to fx5 and/or Phadiatop at each time point. Using logistic regression and generalized estimated equations, adjusted odds ratios (aORs) for sensitization in relation to gestational age were calculated. Replication was sought within the Swedish twin study STOPPA.

Results: In BAMSE, 3522 participants were screened for IgE antibodies during follow-up; of these, 197 (5.6%) were born preterm (<37 gestational weeks) and 330 (9.4%) post-term (>= 42 weeks). Preterm birth reduced the risk of sensitization to common food and/or inhalant allergens up to early adulthood by 29% (overall aOR = 0.71; 95% CI: 0.52-0.98), and to food allergens specifically by 40% (overall aOR = 0.60; 95% CI: 0.38-0.93). No relation was found between post-term birth and IgE sensitization at any time point. Replication analyses in STOPPA (N = 675) showed similar risk estimates for sensitization to food and/or inhalant allergens (aOR = 0.72; 95% CI: 0.42-1.21), which resulted in a combined meta-analysis aOR = 0.71 (95% CI: 0.54-0.94).

Conclusions: Our study suggests an inverse association between preterm birth and long-term IgE sensitization.

Background: Immunoglobulin E (IgE) sensitization is associated with asthma and allergic diseases. Gestational age influences early immune system development, thereby potentially affecting the process of tolerance induction to allergens. We aimed to study IgE sensitization to common allergens by gestational age from childhood up to early adulthood.  

Method: Population-based birth cohort, data from the Swedish BAMSE study was used. Allergen-specific IgE to a mix of common food (fx5) and inhalant (Phadiatop) allergens were analysed at 4, 8, 16 and 24 years. Sensitization was defined as allergen-specific IgE ≥0.35 kU A /l to fx5 and/or Phadiatop at each time-point. Using logistic regression and generalized estimated equations, adjusted odds ratios (aORs) for sensitization in relation to gestational age were calculated. Replication was sought within the Swedish twin study STOPPA.

Results: In BAMSE, 3523 participants were screened for IgE anti-bodies during follow-up; of these, 197 (5.6%) were born preterm (<37 gestational weeks), and 330 (9.4%) post-term (≥42 weeks). Preterm birth was inversely associated with sensitization to common food and/or inhalant allergens up to early adulthood; overall aOR = 0.71 (95% CI = 0.51- 0.98). An inverse association was also observed between preterm birth and sensitization to food allergens specifically; overall aOR = 0.59 (95% CI = 0.38- 0.95). No relation was found between post-term birth and IgE sensitization at any time-point. Replication analyses in STOPPA ( N  = 675) showed similar risk estimates for sensitization to food and/or inhalant allergens (aOR = 0.76; 95% CI: 0.45- 1.26), which resulted in a combined meta-analysis aOR = 0.72 (95% CI: 0.55- 0.95).  

Conclusion: Our study suggests an inverse association between preterm birth and later IgE sensitization.

Background: Perinatal conditions may be associated with future allergic disease; however, data are conflicting and incomplete for childhood allergic rhinitis (AR). The aim of this study was to examine pregnancy outcome (cesarean delivery, preterm birth, low birthweight) and offspring AR as defined by national registers.

Methods: Nationwide longitudinal cohort study using prospectively recorded register data from 1 059 600 singleton livebirths born in Sweden in 2001-2012. Cox regression adjusted for infant sex and maternal factors (age at delivery, country of birth, parity, smoking, body mass index, and asthma/pulmonary disease) estimated hazard ratios (HRs) for AR during childhood.

Results: During the study period 2001-2013, 22 386 (2.11%) children were diagnosed with AR. AR was more common in infants born through cesarean delivery (2.34%) than in those born vaginally (2.10%) (HR = 1.12; 95% confidence interval [95% CI] = 1.08-1.16). This was equivalent to one extra case of AR in 383 children followed up in our study. AR was also associated with moderately preterm birth (>= 32-36 weeks of gestation: HR = 1.12, 95% CI = 1.04-1.20), large for gestational age (HR = 1.05, 95% CI = 1.01-1.10), and low (<7) 5-minute Apgar score (HR = 1.15, 95% CI = 1.02-1.30). Similar risk estimates were obtained when we restricted the outcome to >= 2 hospital-based records of AR. No association was observed between very preterm birth, post-term birth, low birthweight, or small for gestational age and AR. Conclusion Our study indicates an association between pregnancy outcomes and childhood AR, although observed effect sizes were generally modest.

Background: Little is known about early-life risk factors for food allergy in children.

Objectives: We examined the association between perinatal characteristics and future risk of food allergy in offspring.

Methods: This nationwide Swedish cohort study of 1,086,378 children born in Sweden in 2001-2012 used prospectively recorded data from health care registers. Using Cox regression, we estimated hazard ratios (HRs) with 95% CIs for the association between perinatal characteristics (eg, cesarean delivery and preterm birth) and food allergy as defined by diagnoses in the National Patient Register, adjusting for infant sex and maternal factors (age at delivery, country of birth, parity, smoking, body mass index, and asthma/pulmonary disease).

Results: During the 13-year follow-up, 26,732 (2.5%) children were given a diagnosis of food allergy. Food allergy was positively associated with cesarean delivery (HR, 1.21; 95% CI, 1.18-1.25), large for gestational age (HR, 1.15; 95% CI, 1.10-1.19), and low 5-minute Apgar score (HR, 1.22; 95% CI, 1.10-1.36) but negatively associated with very preterm birth (<32 weeks of gestation: HR, 0.74; 95% CI, 0.56-0.98). No association was found between food allergy and moderately preterm birth, low birth weight, or small for gestational age. Risk estimates were similar when the outcome was restricted to 2 records of diagnosed food allergy. In 1,000 children undergoing cesarean delivery, an extra 5 developed food allergy compared with the reference group, suggesting that 17% of food allergy in children born by means of cesarean delivery can be explained by this exposure (attributable fraction).

Conclusions: Cesarean delivery was associated with increased risk of food allergy, whereas very preterm birth decreased risk.