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.
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.