Asthma diagnosis is commonly preceded by childhood wheezing. In the U.S., 48.5% of children experience one or more wheezing episodes before age six years1. There is growing interest in perinatal factors related to wheeze/asthma since better understanding can suggest opportunities for early prevention. In-utero exposure to psychosocial stress has recently been advanced as a potential risk2. In a meta-analysis of ten studies, perceived stress, depression, anxiety, and adverse life events during pregnancy were significant predictors of paediatric wheeze/asthma3. Stress hormones cross placenta, influencing foetal development of diverse organs and systems including the respiratory tract. Based on animal and human studies, biological mechanisms triggered by foetal stress exposure involve hypothalamic-pituitary-adrenal axis, autonomic nervous system, and immune system, affecting the development of immune and respiratory structure-function4,5, maternal-foetal immune interactions6, pro-inflammatory states4, glucocorticoid action and sympathovagal balance7, elevated IgE levels in cord blood8, and Th2-biased cell differentiation9.
Psychosocial stress during postpartum is important as well. Stressful life circumstances may compromise mother-infant interaction, disrupt childcare routines, and worsen healthcare access. Some types of stressful events, such as job loss or chronic illness/disability, can reduce family income, require accepting poorer-quality housing, and leading to exposure to environmental pollutants and allergens, such as mold10. Breastfeeding benefits immune development and lowers the risk of allergic diseases11, but women who report more stress in their lives are less likely to breastfeed12.
Caution is needed when interpreting correlations between perinatal stress and wheeze/asthma. First, experimental evidence substantiating causal interpretation is generally limited to animal models. Pregnant mice stressed by sound, for instance, are more likely to have offspring with allergen-induced airway inflammation13. Human studies of stress during pregnancy typically rely on observation, making it less clear whether the observed relationships are causal or result from residual confounding9. Second, the quality of data varies. In a meta-analysis focusing on prenatal stress and allergic/atopic conditions9, only 15% of qualifying studies were deemed high-quality. Third, few investigations assess stress using instruments designed and validated for pregnant women. Research on psychosocial stress in humans more generally is fraught with methodological weaknesses14. A conceptual definition of stress is often lacking, making it difficult to evaluate concept-measure fit. Instead of direct stress measurement, studies often use proxy measures originally designed for other concepts, e.g., psychological distress, anxiety, and depression. In a meta-analysis3, 60% of studies assessed stress during pregnancy using measures of depression, psychological distress, and self-reported or physician-diagnosed anxiety. This approach is problematic because of conceptual conflation14. Six prospective studies15–20 and one retrospective study21 of asthma/wheeze in children used a more direct approach, measuring stress through exposure to life events.
A notable limitation is the lack of a theoretical framework in most research on perinatal stress and wheezing. To address this gap, we build on recent scholarship to propose a conceptual model displayed in Figure 1. Life events during pregnancy are conceptualized as psychosocial stressors that lead to maternal stress response. Maternal stress hormones crossing placenta contribute to immune, endocrine, and respiratory dysregulation in the foetus4,5, especially when stress is severe and long-lasting. Some types of psychosocial stressors tend to persist long-term and proliferate across life domains, generating yet new stressful circumstances for the mother and child22. Job loss in the family, for instance, can lead to a cascade of stressful events, e.g., job search, residential move, and changes in lifestyle to accommodate income loss. Consequently, we expect higher stress among postpartum women who had experienced high stress when pregnant. Postnatal stress adversely influences maternal health behaviour and mother-infant interaction. Hence, postnatal stress is conceptualized as a mediator between prenatal stress and wheeze. Additional mediators include lower respiratory tract infections (LRTI)23, allergies, lack of breastfeeding11, and secondary smoke exposure (SSE)24. These mediators are selected since in past literature, they relate both to wheeze and to perinatal stress. Higher perceived stress, for instance, contributes to tobacco smoking25 and prenatal stress is linked to allergic rhinitis, atopic eczema/dermatitis, and infectious diseases in offspring26.
Figure 1
The following testable hypotheses are derived from the proposed model:
H1: Higher exposure to prenatal life events relates to higher risk of childhood wheeze.
H2: Higher exposure to postnatal life events relates to higher risk of childhood wheeze.
H3: The relationship between prenatal life events and wheeze is mediated by postnatal life events (H3a), smoking in pregnancy (H3b), SSE (H3c), lack/short duration of breastfeeding (H3d), LRTI (H3e), and allergy (H3f).
H4: The relationship between postnatal life events and wheeze is mediated by SSE (H4a), lack/short duration of breastfeeding (H4b), LRTI (H4c), and allergy (H3d).
These hypotheses are tested using prospective population-based data. Addressing limitations of prior research, stress assessment is based on exposure to life events using an instrument specifically designed for pregnancy/postpartum. A range of life events is covered for comprehensive assessment of psychosocial stress, including events with unique relevance for pregnancy/postpartum, e.g., learning about pregnancy complications. The size of the analytical sample (n=1,849) ensures an adequate number of cases of child wheeze, facilitating multivariate modelling and mediation analysis.