The results of our study support a positive association between maternal anxiety symptoms during pregnancy and subsequent asthma in the offspring during childhood. The strength of the associations, their consistency across different outcome measures, their robustness to adjustment for a wide range of confounding or mediating variables, and the evidence for a dose-response relationship raise the possibility that this association may be causal, although its mechanism remains speculative. Although others have reported links between maternal distress and asthma in children,11,12
we believe this is the first report of an association between antenatal exposure and subsequent asthma during childhood.
Wright et al11
first reported the association of parental stress, measured by using a 4-item scale of perceived stress by regular telephone interview, and wheezing in infancy. More recently, a study of maternal stress in early childhood in a large Canadian population-based cohort reported an association with asthma at age 7 years in their children.12
In this study, stress was defined as a combination of depression and anxiety using health care utilization data. The authors also reported a dose-response relationship between the duration of exposure and the prevalence of asthma and concluded that short-term exposure, limited to the first year after birth, was not related to the subsequent development of asthma. Consistent with our observations, there was a relationship between severity of anxiety/depression and duration of symptoms. We found a stronger relationship between maternal anxiety symptoms and asthma when anxiety symptoms had been present for longer, but this is likely to be explained by a severity effect so that mothers who reported continuing anxiety symptoms to the postnatal period had higher antenatal anxiety scores and severe prenatal anxiety is more likely to be associated with persistence of symptoms. When we adjusted postnatal associations between maternal anxiety symptoms and asthma in childhood for the prenatal measures, the effect was attenuated completely.
Another difference between our approach and previous studies was the use of anxiety symptoms alone rather than a combination of anxiety and depression as the primary exposure. This decision was reached on the basis of exploratory analyses of the relative contributions of reported anxiety and depression symptoms to the association with the primary outcome, in which we found that the inclusion of prenatal depression scores did not affect the association between anxiety symptoms and childhood asthma, and no independent association between childhood asthma and maternal reported depression symptoms was detected. In addition, others have reported associations between maternal anxiety in the prenatal period and childhood outcomes that would be consistent with an intrauterine effect of maternal stress on altered fetal physiology in this population.25-27
We believe our data to be consistent with an antenatal programming effect, although the precise mechanism of this has still to be explained. We carefully considered the possibility that this observation was confounded by adjusting for a large number of variables known to be associated with asthma and by using the anxiety symptom score of the mother's partner as a further test of confounding.28
If there was a true intrauterine effect, we would expect the observed association to be considerably stronger for the mother's than for the partner's anxiety, which is what our analyses indicated. One of the possible confounding variables considered by Kozyrskyj et al12
but not by us was the attendance of the child at day care. Although it might be supposed that mothers with higher reported levels of anxiety symptoms would be less likely to send their young children to preschool day care, the reported protective association of day care with subsequent asthma29
in children would be expected to attenuate associations between anxiety symptoms and asthma. However, there are discrepant findings that suggest day care attendance may increase the risk of asthma, at least in young children,30
and the associations between day care and asthma may be modified depending on family history of allergy.31
Therefore, we could not discount the possibility of spurious associations arising through this source of confounding. However, in post hoc
analyses, we found no evidence of a relationship between maternal anxiety scores and reported day care attendance by their children (see this article's Table E9
in the Online Repository at www.jacionline.org
Our study has several strengths, including recruitment during pregnancy, enabling the prospective ascertainment of maternal anxiety and depression symptoms, thus making the possibility of recall bias or reverse causation unlikely. The use of an objective measure of bronchial hyperresponsiveness also increased the association with anxiety at 32 weeks, presumably because of less measurement error in the outcome. However, in common with many large, population-based longitudinal surveys,32
there was a considerable loss of data, because of either incomplete ascertainment or loss to follow-up. Those with incomplete data were more likely to come from socially disadvantaged backgrounds and had evidence of higher maternal anxiety scores compared with the population with complete data. This introduces the possibility of selection bias, but one would have to postulate that the association between anxiety and asthma in subjects with missing data operated in the opposite direction (anxiety symptoms associated with reduced risk of asthma) to abolish the observed association, which seems unlikely. Furthermore, adjustment for a range of variables associated with social disadvantage produced very little attenuation of effect sizes in our primary analyses.
Another potential weakness of this study was the reliance on maternal self-report to define anxiety and depression symptoms. The scales used have been validated previously for self-completion, and these measures have been associated with a number of clinical and biochemical outcomes in a sample of our study population.17
Because recall bias is not possible, any measurement error is likely to be random and hence will make our observed associations conservative. Also, although we reported positive associations of maternal anxiety symptoms with asthma, the interpretation for these findings must be viewed with some caution. We were unable to ascertain the biological sources of anxiety in the women in our study and had no maternal or fetal biomarker data to confirm anxiety had a biological effect in this population. There is also the possibility of residual confounding through unmeasured social or lifestyle variables, although we found little evidence of attenuation with the markers that were considered in this study.
Wright et al33
identified associations between caregiver stress in early childhood and allergic responses in infants predisposed to asthma or atopy. It was suggested these were related to changes in neuroendocrine function, in particular through the HPA axis, and might influence immune development through alterations of cytokine responses.34
Another possible mechanism for a prenatal programming effect is through epigenetic regulation of the glucocorticoid receptor gene, which has been shown to occur in human beings.35
Emerging evidence suggests that environmental variables may alter methylation profiles of other genes of relevance to asthma,36
opening the possibility that maternal stress could operate through direct epigenetic effects, as well as indirect effects mediated through neuroendocrine dysregulation. Kozyrskyj et al12
reported effects of continued stress beyond the perinatal period on childhood asthma. It is possible to reconcile these results with our observations if postnatal behaviors modify the effects of prenatal anxiety,37
such as changing emotional attachments to the newborn infant, which could alter postpartum cortisol levels38
; although in primate studies, high prenatal levels were associated with more attentive infant care behaviors. Early caregiving behavior can also modify neurobiological responses, including the response of the HPA axis to stressful stimuli.39
Thus, prenatal programming and postnatal behavioral modification could operate through similar pathways to influence fetal and child development.
Our data support an independent effect of prenatal exposure to maternal anxiety on the development of asthma during childhood, although we can only speculate on the mechanisms of this association, and we hope in future studies to have biomarker data on cortisol responses in children to explore this further. We did not find evidence to suggest a stronger association in subjects reporting atopic asthma, suggesting that the association between maternal anxiety and asthma is not mediated directly through influences on allergic sensitization. There has been a continuing interest in pregnancy as a critical period in the development of asthma in children, and emerging evidence supports the possibility of programming effects of maternal stress in pregnancy on several childhood outcomes. The development of relatively straightforward interventions to reduce maternal stress in pregnancy makes it possible to test these hypothetical relationships in a controlled trial.40
Although it is too early to advocate specific interventions aimed at primary prevention of asthma, we would suggest that asthma and allergic outcomes are included if intervention studies to reduce anxiety and distress during pregnancy are considered.
These results indicate a biologically plausible risk factor for asthma that is amenable to prenatal intervention.