Discussion
To our knowledge, this is the first prospective, population-based, birth-cohort study considering wheeze phenotypes during early to mid-childhood in relation to stress assessed as life events at different time points during perinatum. Prior studies rarely distinguished among longitudinal phenotypes of wheeze and typically measured stress indirectly as psychological distress. The present study documents that early exposure to stressful events is linked to wheezing. The timing of stress exposure matters for which wheeze phenotype likely develops. The likelihood of wheeze with late onset increases with stress exposure during pregnancy. Stress exposure during the first six months after birth, in contrast, predicts persistent wheeze, which manifests by age three years and persists until age seven years or longer. In prior literature, persistent wheeze showed a relationship with poor lung function and chronic asthma38, warranting better understanding of this particular wheeze phenotype.
Specifying pathways leading from maternal stress to child wheezing represents a contribution since these pathways were rarely examined in prior literature. Perhaps without surprise is the finding that women who experience more stress during pregnancy also tend to experience more stress after delivery, which accounts in part for the link between prenatal stress and wheezing. More intriguing is the finding that mediation through postnatal stress is partial only, leaving an independent effect of prenatal stress of a substantial magnitude, with the increase in relative risk ranging 44%-69%. We examined several additional mechanisms from perinatal stress to wheezing. LRTI diagnosis emerged as a mediator, suggesting that children exposed to more postnatal stress are more likely to develop LRTIs. This accounts for some, but not for all, of the increase in wheezing among children of mothers exposed to more postnatal life events. In other words, the significant association between early-life stress exposure and wheezing persists after adjusting for LRTI and covariates.
Multivariate modelling strengthens the evidence of relationships independent of confounders, but causal interpretation is not warranted with observational data. Nevertheless, using rigorous statistical controls and mediation analysis, we rule out several alternative mechanisms. This is an important contribution since mechanisms for the stress gradient in wheezing are under-explored. Maternal emotional dysregulation, for instance, is a candidate mechanism. It is commonly preceded by stress exposure. Literature suggests that maternal emotional difficulties are linked to child respiratory problems3. Other mechanisms warranting future research include neuro-endocrine-immune processes involved in airway functioning.
Childhood wheeze is commonly discussed in literature on allergic asthma. Allergic asthma bronchiale is defined by allergic eosinophil inflammation with bronchial obstruction. Wheeze is its symptom but it is also a broader nosologic unit with heterogeneous pathogenic origins. Factors triggering wheeze are not limited to allergic reaction; they also include infection, irritation, and sudden change in ambient temperature. Prior analysis of ELSPAC-CZ found that children with persistent wheeze had higher risk of allergic asthma during school age38. Surprising, our supplementary analyses indicated that allergic asthma diagnosis at ages five and fifteen years did not relate to prenatal or postnatal life events in adjusted models (five years, high vs. low prenatal life events odds ratio [OR]=2.63, 95% CI 0.74-9.34, p=0.113; five years, high vs. low postnatal life events OR=0.71, 95% CI 0.22-2.26, p=0.653; fifteen years, high vs. low prenatal life events OR=1.01, 95% CI 0.59-1.73, p=0.938; fifteen years, high vs. low postnatal life events OR=0.99, 95% CI 0.57-1.73, p=0.975). Moreover, neither prenatal nor postnatal life events were associated with physician-diagnosed allergy among children ages 0-18 months, as indicated in Figure 3. We speculate that early-life stress is important for the types of wheeze unrelated to allergic asthma. Our data did not distinguish between allergic vs. non-allergic wheeze; mothers simply reported whether their child experienced any wheezing episodes. Yet, the observation that LRTI partially mediated between life events and wheeze suggests the involvement of respiratory infections, potentially accounting for some cases of wheeze unrelated to allergy, though this explanation is tentative.
Strengths of this study include prospective design with a large sample of mother-child dyads with fully completed questionnaires (n=1,849); accounting for multiple mechanisms and confounders; using established methodology to categorize wheeze phenotypes28, and separately considering stress exposures during prenatal vs. postnatal periods. Both periods are developmentally sensitive but they differ in the types of developmental processes taking place. Assessment of life events was quite broad with 42 different types of events, yielding a more comprehensive picture of the overall stress levels compared to more narrowly-focused instruments.
Methodological limitations must be noted. The cohort included mostly young gravidas with uncomplicated pregnancies. Mean age at delivery (25.2 years) and the caesarean section rate (8.1%) roughly correspond to the demographic profile of the Czech population at the time of the study39, suggesting good generalizability except for older and complicated gravidas. Generalizability to societies outside of the Czech Republic, however, is unknown. Child wheeze was mother-reported. Maternal reports are routinely used in epidemiological surveys of child health40. They are cost-effective and capture symptoms known only to the mother, such as wheezing episodes for which healthcare was not obtained. Potential biases include under-report (child wheezed; mother reported no wheezing), over-report (child did not wheeze; mother reported wheezing), and misreport (child wheezed; mother reported another condition). Finally, biomarkers quantifying biological mechanisms between early-life stress and wheeze were not available.