Maternal stress: a cause of childhood asthma?

Childhood wheeze is common, with a reported prevalence of 1 in 4 among a nationwide sample of 2to 3-year-olds in the United States (1). While “all that wheezes is not asthma,” the most common cause of recurrent wheezing in children is asthma. The prevalence rate of asthma among young children is reported to be rising (2). Although genetic predisposition is clearly evident (3), environmental and social factors might be contributing to the childhood asthma epidemic. In this issue of the Journal, Chiu and coworkers (pp. 147–154) report the results of their careful prospective cohort study to assess the role of one potential key factor, that of maternal stress, on childhood wheeze (4). Unraveling the complex role that the environment plays in the development of childhood asthma remains an intense area of research. Tobacco-smoke exposure, traffic-related air pollution, allergic sensitization to aeroallergens, and viral infections of the lower respiratory tract have all been associated with early childhood asthma (5). In the United States, inner city children from families of low socioeconomic position appear to be disproportionately impacted in terms of asthma prevalence and severity (6). Whether this is a result of independent biologic factors, reduced access to health care, or an increase in environmental exposures related to living in low socioeconomic conditions remains controversial (7). The potential role of social conditions in contributing to the childhood asthma epidemic has received less attention. Environmental, social, and economic factors can converge to influence health status. Stress, through its influence on immune function, has been proposed to play an important role in infection susceptibility (8) and allergy (9). A growing number of animal and human studies have focused on the role of maternal stress as a contributor to early-onset asthma. A previous prospective birth-cohort study identified parental stress as a predictor of wheezing in infancy (10), and another key study noted that parental stress increased the impact of ambient air pollution on the incidence of childhood asthma (11). There are a few postulated mechanisms by which maternal stress in the prenatal period may influence childhood asthma risk. At birth, infants with asthma already demonstrate maladaptive T-helper 2 immune responses (12). Immune development is epigenetically regulated in utero, and therefore maternal stress (13) in the prenatal period may alter neonatal immunity and asthma risk (12). Prenatal maternal stress has been associated with elevated cord blood IgE and altered innate and adaptive cytokine responses (14, 15). Although complex and incompletely understood, maternal stress may also modulate interactions between the central nervous system and the immune system in utero through the hypothalamic–pituitary–adrenal axis (16). Chiu and coworkers contribute important insights into the role that maternal stress might play in the development of recurrent wheeze in early childhood. The authors’ research goals were to evaluate the relationship between maternal stress (as measured by a negative life events score generated by the Crisis in Family Systems-Revised survey) experienced during pregnancy and in the postnatal period (12–18 mo postpartum) and the risk of recurrent childhood wheeze by the age of 2 years. They found that both preand postnatal stress were independently associated with recurrent childhood wheeze in separate multivariable adjusted regression models. In a model evaluating both preand postnatal stress in the same model, only mothers that experienced stress in both periods had offspring with increased odds of wheeze. Interestingly, the effect was present only in those mothers who were not sensitized to specific aeroallergens during pregnancy (as reflected by elevated allergen-specific IgE), suggesting that maternal stress may only exert its influence on the offspring of nonatopic mothers. One of the major strengths of this study is its prospective design as the study authors followed 653 families as part of the AsthmaCoalition on Community, Environment, and Social Stress (ACCESS) project. Their study cohort consisted of subjects representing diverse ethnic and sociodemographic backgrounds. The study authors also carefully controlled for important potential confounders such as preand postnatal traffic-related air pollution (e.g., black carbon) exposure, prenatal cockroach allergen exposure, and neighborhood-level socioeconomic disadvantage. Potential mediators in the association between maternal stress and childhood wheeze were also adjusted for, including preand postnatal maternal smoking habit. The association remained significant following adjustment for mediators, suggesting a direct link between stress and recurrent childhood wheeze. A major limitation of epidemiologic research in general is that associations may not be indicative of a cause-and-effect relationship. Several factors can aid in determining whether causal inferences can be drawn from observational data, including biological plausibility, appropriate temporal sequence (the exposure [in this case, maternal stress] precedes the outcome [recurrent childhood wheeze]), strength of the association including biologic gradient (i.e., dose–response), and robustness of the association to sensitivity analysis. This study meets most of these criteria, including biologic plausibility, a strong association between exposure and outcome with a positive dose–response relationship, and findings that were robust to sensitivity analyses, including alternate ways of categorizing negative life events. Precisely quantifying exposures and their timing is a major challenge in epidemiologic research. Although prenatal maternal stress clearly precedes the outcome of childhood wheeze, postnatal maternal stress was measured on just one occasion (12–18 mo postpartum), whereas childhood wheeze was reported every 3 months postpartum. This means that recurrent childhood wheeze may have predated exposure ascertainment, thus resulting in reverse causation. Although the overall study findings seem compelling, there are two limitations that deserve further attention prior to accepting these results at face value. The outcome of early childhood wheeze was based on maternal report. Parental misclassification of wheeze has certainly been reported when formally evaluated using a gold standard (videos of physician-adjudicated wheeze), as just over half of parents correctly identified wheeze based on C.H. G. was supported by National Institutes of Health grants 1R01HL103965, 1R41HL098985, P30DK089507, and P30ES0070333, U.S. Food and Drug Administration grant 1R01FD003704, and a Cystic Fibrosis Foundation grant. B.S.Q. ’s training was supported by the University of British Columbia Clinical Investigator Program and a British Columbia Lung Association Fellowship Award. The supporting agencies played no role in the preparation or approval of this manuscript.