Can prenatal maternal stress increase the risk of asthma?

Abstract

Maternal stress adversely affects a mother’s well-being and health and also negatively impacts her offspring. That this relationship also holds true for maternal stress during the pregnancy period is intuitive. However, whether maternal stress increases the risk of asthma development in her offspring is less clear and will be evaluated in this review. There is evidence from murine models to suggest that maternal stress during pregnancy increases the risk of asthma in the offspring. While recent experimental research adds to the increasing body of evidence supporting a causal relationship between prenatal maternal stress and asthma risk in the offspring, the epidemiological evidence supporting this notion is insufficient. Almost all existing observational studies suffer from severe methodological limitations. Nevertheless, the results from experimental work on maternal stress during pregnancy and asthma risk in the offspring, in concert with other obvious adverse health effects in the offspring are sufficient to justify a recommendation to reduce maternal stressors, particularly during pregnancy.

Keywords:

• asthma
• in utero
• maternal stress
• offspring
• pregnancy
• prenatal maternal stress

Günter Dörner, the former head of the Institute of Experimental Endocrinology at the Charité in Berlin, was the first to highlight the role of prenatal stress on physical and mental health using results from his experimental and clinical studies conducted in the 1970s [1]. His visionary research was mirrored several years later by the epidemiological and clinical observations of David Barker, who proposed that common chronic diseases in adulthood have their origins in prenatal life – the ‘Barker’s hypothesis’. Despite this coined name, much of the pioneering research, especially that on experimentally induced prenatal stress, goes back to the almost forgotten work of Dörner and his group. This editorial summarizes population studies on prenatal maternal stress and asthma development in offspring, published during the last 5 years, and provides subjective evaluations of the current evidence and uncertainties on this relationship.

Mechanisms for prenatal stress & asthma risk

Two recent reviews comprehensively summarized the state of the art on maternal influences on allergic responses in offspring, and discussed potential biological mechanisms [2,3]. Maternal effects on Th1 and Th2 cytokines in the offspring, as well as maternal vitamins as regulators of offspring allergic responses were highlighted [2]. It may also be important to consider how those maternal stress-related markers can be transferred to the fetus via the placenta. One possible key mechanism may be the capability of glucocorticoid stress hormones to upregulate Th2 cytokine responses, as was shown in murine models and clinical studies [4]. A recent study in mice showed that low-level maternal corticosterone induced by moderate restraint was associated with increased responsiveness to a low-dose challenge with ovalbumin in the offspring [5]. A medication-induced blockade of stress-induced corticosterone removed these effects. The authors concluded that stress-induced glucocorticoids during pregnancy can increase allergy susceptibility in offspring mice [5]. Indeed, results from murine studies provide some evidence to suggest biological mechanisms for how prenatal stress and associated immunological responses in the offspring might increase the risk for (allergic) asthma. The few existing clinical studies support this notion, but the evidence is less strong.

Population studies

While prenatal exposures to environmental toxicants and microbial compounds, as well as maternal food-derived components are commonly agreed to be determinants of allergy (specifically asthma) development in offspring, the role of prenatal maternal stress is less clear. The most commonly used surrogates for maternal stress are adverse life events and maternal traits such as anxiety. Although these surrogates have the (pragmatic) advantage of a retrospective assessment and are well introduced in the literature, their validity is unknown. Nevertheless, recent articles on maternal stress during pregnancy and asthma development in offspring are reviewed here.

Adverse life events

A few previous studies reported increased risks for asthma, allergic sensitization and eczema in relation to stressful life events for the pregnant mother [6–9]. In addition to these ‘historic’ publications, further relevant papers were published in the last 5 years. While experimental work on animals has shown the effects of prenatal stress on fetal immune function, results from human studies are scarce. In a study on 557 low-income pregnant women living in cities with a high proportion of ethnic minorities, the production of IL-8, TNF-α and IL-13 was found to be increased after external stimulation of cord blood mononuclear cells in offspring in association with increased maternal stress [10]. Prenatal stress was defined using a combination of individual stressors (financial hardship, difficult life circumstances) and neighborhood characteristics (community violence, housing problems).

Prenatal adverse life events during pregnancy, such as divorce, marital problems, pregnancy problems, etc., were assessed in 1587 pregnant women in the Western Australian Rhine Study, and their offspring followed until 14 years of age [11]. The risk of asthma and eczema substantially increased with increasing numbers of negative life events during the second half of pregnancy. The results for allergic rhinitis were less strong. The risk for adverse life events was more pronounced in children born to non-asthmatic mothers.

A very big Swedish study linked asthma cases during childhood, obtained from the Swedish Patient Register and Drug Prescription Register, with registry data on maternal loss of close relatives shortly before child birth. This prenatal maternal stress surrogate was associated with a slightly increased asthma risk in boys only (adjusted hazard ratio: 1.09; 95% CI: 0.98–1.22). Prenatal maternal stress during the second trimester showed a statistically significant increased risk [12].

A small Canadian study explored whether objective facts and perceived stress during pregnancy during the disaster ice storm in 1998 in Quebec was related to asthma development in offspring 12 years later, using data from 68 children. The retrospective assessment of perceived stress (11 years after the ice storm) was associated with an increased risk for asthma characteristics in girls only [13]. Due to the small number of subjects included and the retrospective assessment of perceived stress, the study results should be replicated before conclusions can be drawn.

Psychological traits

There is some indication that maternal anxiety during pregnancy predicts the risk for asthma in offspring [14]. However, even a prospective study design cannot conclusively establish causality, as anxiety remains relatively stable throughout life and prenatal anxiety effects cannot be disentangled from postnatal anxiety effects. Findings from cross-sectional studies may always suffer from potential reverse causality, as asthma onset in children might induce increased anxiety in their mothers [15]. However, even a prospective study cannot completely exclude the potential for reverse causality if familial aggregation of asthma and subsequent maternal stress induction due to asthma in an elder sibling are considered. A further critical aspect is related to shared genetic and familial environments between the mothers and their offspring. Heritability of a stress-prone behavior or psychological traits and of asthma should be considered when reporting observed associations between maternal stress and asthma in the offspring. In addition, the limitations of cross-sectional study designs and potential biases due to self-reporting of stress surrogates and asthma-related symptoms and physician’s diagnoses need to be cautiously evaluated. Some of these limitations were nicely addressed using an elegant study design and the data from the Twin and Offspring Study in Sweden [16]. Maternal self-reported anxiety was assessed in 1691 mothers and was associated with several asthma indicators in their offspring. Maternal anxiety was significantly associated with self-reported asthma characteristics, but not with the registry-based asthma diagnoses or medication. The authors concluded that the observed associations of self-reported stress with self-reported asthma indicators are likely due to familial confounding by heritable personality traits for both anxiety and subjective asthma data.

Two more maternal aspects need also be considered. First, a meta-analysis of several studies showed stronger effects of maternal factors compared to paternal effects on asthma risk in the offspring [17]. Second, the role of maternal factors prenatally versus postpartum is not sufficiently clarified. While it is generally agreed that in utero challenges affect the risk of allergies occurring later in life [18,19], specific studies on maternal stress factors are difficult to perform and were rarely investigated. A recent study showed that maternal asthma present before birth did not increase the risk of asthma in the offspring to a greater extent than maternal asthma that developed only after the birth of the offspring [20]. This result is consistent with the concept of similar risks of asthma determinants assessed pre- and postnatally, and demonstrates that the effects of these two periods are hard to disentangle.

Synthesis of recent publications & outlook

While recent experimental research adds to the increasing body of evidence for a causal relationship between prenatal maternal stress and asthma risk in the offspring, the epidemiological evidence supporting this notion is insufficient. Several reasons may be responsible for these weakly consistent findings. The current epidemiological evidence is restricted to observational studies, which are influenced by known uncertainties and potential biases. Randomized clinical trials in which maternal stress is induced during pregnancy have so far not been performed and are unlikely to be performed in the future because of ethical constraints. In addition, a study with interventional stress reduction in comparison to a non-interventional group would also be ethically questionable. Observational studies are in general hindered by residual confounding, which can be particularly problematic for complex factors such as maternal stress. A further reason may be related to how maternal stress is defined and measured in population studies. Epidemiological studies commonly use adverse life events as a surrogate for stress. This approach has several methodological advantages, but does not include the perception of a potential stress-induced event. Self-perceived stress might be an even more relevant marker as individuals differ in how they respond to the same life events. However, a personality trait, such as anxiety, is also a poor surrogate for stress on its own. Thus, improved assessments of stress in population studies might increase our understanding of the complex association between maternal stress and asthma risk in the offspring. Stress throughout life (life-course epidemiology), and not only during the pregnancy period, needs also to be considered in future studies and is presumably a major limitation of the previously published epidemiological studies on this topic. Finally, the inclusion of intermediate phenotypes, such as metabolic profiles and gene expression characteristics during the life-course, would help further our understanding of potential causal mechanisms.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.