Pre-eclampsia and risk of early-childhood asthma: A register study with sibling comparison and an exploration of intermediate variables

Background: We aimed to study whether pre-eclampsia is associated with childhood asthma, allergic and non-Allergic asthma, accounting for family factors and intermediate variables. Methods: The study population comprised 779 711 children born in 2005-2012, identified from Swedish national health registers (n = 14 823/7410 exposed to mild/moderate and severe pre-eclampsia, respectively). We used Cox regression to estimate the associations of mild/moderate and severe pre-eclampsia with incident asthma, before and after age 2 years. Cox regressions were controlled for familial factors using sibling comparisons, then stratified on high and low risk for intermediate variables: caesarean section, prematurity and small for gestational age. We used logistic regression for allergic and non-Allergic prevalent asthma at 6 years as a measure of more established asthma. Results: The incidence of asthma in children was 7.7% (n = 60 239). The associations varied from adjusted hazard ratio (adjHR) 1.11, 95% confidence interval (CI): 1.00, 1.24 for mild/moderate pre-eclampsia and asthma at >2 years age, to adjHR 1.78, 95% CI: 1.64, 1.95 for severe pre-eclampsia and asthma at <2 years age. Sibling comparisons attenuated most estimates except for the association between severe pre-eclampsia and asthma at <2 years age (adjHR 1.45, 95% CI: 1.10, 1.90), which also remained when stratifying for the risk of intermediates. Mild/moderate and severe pre-eclampsia were associated with prevalent non-Allergic (but not allergic) asthma at 6 years, with adjusted odds ratio (adjOR) 1.17, 95% CI: 1.00, 1.36 and adjOR 1.51, 95% CI: 1.23, 1.84, respectively. Conclusions: We found evidence that severe, but not mild/moderate, pre-eclampsia is associated with asthma regardless of familial factors and confounders

Double jeopardy-pregnancy and birth during a catastrophic bushfire event followed by a pandemic lockdown, a natural experiment

Background: From November 2019 to January 2020, eastern Australia experienced the worst bushfires in recorded history. Two months later, Sydney and surrounds were placed into lockdown for six weeks due to the COVID-19 pandemic, followed by ongoing restrictions. Many pregnant women at this time were exposed to both the bushfires and COVID-19 restrictions. Objective: To assess the impact of exposure to bushfires and pandemic restrictions on perinatal outcomes. Methods: The study included 60 054 pregnant women who gave birth between November 2017 and December 2020 in South Sydney. Exposure cohorts were based on conception and birthing dates: 1) bushfire late pregnancy, born before lockdown; 2) bushfires in early-mid pregnancy, born during lockdown or soon after; 3) conceived during bushfires, lockdown in second trimester; 4) conceived after bushfires, pregnancy during restrictions. Exposure cohorts were compared with pregnancies in the matching periods in the two years prior. Associations between exposure cohorts and gestational diabetes, preeclampsia, hypertension, stillbirth, mode of birth, birthweight, preterm birth and small for gestational age were assessed using generalised estimating equations, adjusting for covariates. Results: A decrease in low birth weight was observed for cohort 1 (aOR 0.81, 95%CI 0.69, 0.95). Conversely, cohort 2 showed an increase in low birth weight, and increases in prelabour rupture of membranes, and caesarean sections (aOR 1.18, 95%CI 1.03, 1.37; aOR 1.21, 95%CI 1.07, 1.37; aOR 1.10 (1.02, 1.18) respectively). Cohort 3 showed an increase in unplanned caesarean sections and high birth weight babies (aOR 1.15, 95%CI 1.04, 1.27 and aOR 1.16, 95%CI 1.02, 1.31 respectively), and a decrease in gestational diabetes mellitus was observed for both cohorts 3 and 4. Conclusion: Pregnancies exposed to both severe climate events and pandemic disruptions appear to have increased risk of adverse perinatal outcomes beyond only experiencing one event, but further research is needed

Early-Life Adversity Due to Bereavement and Inflammatory Diseases in the Next Generation: A Population Study in Transgenerational Stress Exposure

Emerging evidence suggests that trauma experienced in childhood has negative transgenerational implications for offspring mental and physical health. We aimed to investigate whether early-life adversity experienced as bereavement is associated with chronic inflammatory health in offspring. The study population included 3 generations of Swedish families with a base population of 453,516 children (generation 3) born in 2001-2012. Exposure was defined as the middle generation's (generation 2) experiencing bereavement in childhood due to the death of a parent (generation 1). Outcomes in generation 3 included 2 diagnoses of inflammatory diseases, including asthma, allergic diseases, eczema, and autoimmune diseases. Survival analysis was used to identify causal pathways, including investigation of mediation by generation 2 mood disorders and socioeconomic status (SES). We found that early-life bereavement experienced by women was associated with early-onset offspring asthma (hazard ratio = 1.15, 95% confidence interval: 1.08, 1.23); mediation analysis revealed that 28%-33% of the association may be mediated by SES and 9%-20% by mood disorders. Early-life bereavement experienced by men was associated with autoimmune diseases in offspring (hazard ratio = 1.31, 95% confidence interval: 1.06, 1.62), with no evidence of mediation. In conclusion, adversity experienced early in life may contribute to an increased risk of inflammatory diseases which is partly mediated by mood disorders and SES

Asthma and affective traits in adults: A genetically informative study

Depression, anxiety and high neuroticism (affective traits) are often comorbid with asthma. A causal direction between the affective traits and asthma is difficult to determine; however, there may be a common underlying pathway attributable to shared genetic factors. Our aim was to determine whether a common genetic susceptibility exists for asthma and each of the affective traits. An adult cohort from the Swedish Twin Registry underwent questionnaire-based health assessments (n=23693) and genotyping (n=15908). Firstly, questionnaire-based associations between asthma and affective traits were explored. This was followed by genetic analyses: 1) polygenic risk scores (PRS) for affective traits were used as predictors of asthma in the cohort, and 2) genome-wide association results from UK Biobank were used in linkage-disequilibrium score regression (LDSC) to quantify genetic correlations between asthma and affective traits. Analyses found associations between questionnaire-based asthma and affective traits (OR 1.67, 95% CI 1.50-1.86 major depression; OR 1.45, 95% CI 1.30-1.61 anxiety; and OR 1.60, 95% CI 1.40-1.82 high neuroticism). Genetic susceptibility for neuroticism explained the variance in asthma with a dose-response effect; that is, study participants in the highest neuroticism PRS quartile were more likely to have asthma than those in the lowest quartile (OR 1.37, 95% CI 1.17-1.61). Genetic correlations were found between depression and asthma (rg=0.17), but not for anxiety or neuroticism. We conclude that the observed comorbidity between asthma and the affective traits may in part be due to shared genetic influences between asthma and depression (LDSC) and neuroticism (PRS), but not anxiety

Risk factors for multisystem inflammatory syndrome in children – A population-based cohort study of over 2 million children

Background: Although severe acute COVID-19 is rare in children, SARS-CoV-2 infection can trigger the novel post-infectious condition multisystem inflammatory syndrome in children (MIS-C). Increased knowledge on risk factors for MIS-C could improve our understanding of the pathogenesis of the condition and better guide targeted public health interventions. The aim of the study was to assess risk factors for MIS-C with the aim to identify vulnerable children. Methods: A register-based cohort study including all children and adolescents <19 years born in Sweden between March 1, 2001- December 31, 2020 was performed. Data on sociodemographic risk factors and comorbidities (sex, age, parental region of birth, parental education, asthma, autoimmune disease, chromosomal anomalies, chronic heart disease, chronic lung disease, obesity, life-limiting condition) were retrieved from national health and population registers. The outcome was MIS-C diagnosis according to the Swedish Pediatric Rheumatology Quality Register during March 1, 2020 – December 8, 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression analysis. Incidence rates per 100 000 person-years were calculated assuming a Poisson distribution. Findings: Among 2 117 443 children included in the study, 253 children developed MIS-C, corresponding to an incidence rate of 6·8 (95% CI: 6·0-7·6) per 100 000 person-years. Male sex (HR 1·65, 95% CI: 1·28-2·14), age 5-11 years (adjusted HR 1·44, 95% CI: 1·06-1·95 using children 0-4 years as reference), foreign-born parents (HR 2·53, 95% CI: 1·93-3·34), asthma (aHR 1·49, 95% CI: 1·00-2·20), obesity (aHR 2·15, 95% CI: 1·09-4·25) and life-limiting conditions (aHR 3·10, 95% CI: 1·80-5·33) were associated with MIS-C. Children 16-18 years had a reduced risk for MIS-C (aHR 0·45, 95% CI: 0·24-0·85). Interpretation: We report increased risks for MIS-C in children with male sex, age 5-11 years, foreign-born parents, asthma, obesity, and life-limiting condition. Knowing these risk populations might facilitate identification of children with MIS-C and potentially guide targeted public health interventions. Nevertheless, the absolute risks for MIS-C were very low. Funding: Financial support was provided from the Swedish Research Council (grant no 2018-02640), the Swedish Heart-Lung Foundation (grant no 20210416), the Asthma and Allergy Association, Ake Wiberg foundation, the Samariten Foundation, the Society of Child Care, and Region Stockholm