Stress in Pregnancy Increases Susceptibility to Asthma In Offspring

Stress in Pregnancy Asthma Offspring
Stress in Pregnancy – Asthma In Offspring

A recent study published in the American Journal of Physiology – Lung Cellular and Molecular Physiology provides new evidence that release of glucocorticoids (GCs) as the result of stress in pregnancy can induce asthma susceptibility in offspring.

We now know that asthma risk begins in utero during rapid lung morphogenesis, when the developing fetus is particularly vulnerable to toxic insults due to immature immune, neuroendocrine and antioxidant defences.

References specifically linking psychological processes to asthma date back at least to the 12th century. As recently as the first half of the 20th century, Western medicine considered asthma to be psychogenic and treatment primarily involved psychoanalysis and other “talking cures”.

As science informed our understanding of the pathophysiological basis of airway inflammation and bronchial hyperresponsiveness, beginning in the 1960s, the psychiatric theory of asthma was largely set aside by the biomedical community, which then recognised asthma as a physical (i.e. inflammatory or allergic) condition.

Yet, it is known that psychological stress contributes to the pathogenesis and exacerbations of asthma. One mechanism may be the capacity of stress hormones and GCs to skew the balance of T helper (Th)1/Th2 immune responses towards the Th2-type ‘proallergic’ responses (Elenkov IJ & Chrousos GP, Trends Endocrinol Metab 1999, 10:359).

Thus, the maternal stress and the excessive cortisol secretion during pregnancy could affect the developing immune system and the Th1/Th2 cell differentiation and further increase the susceptibility to asthma in genetically predisposed children (von Hertzen LC, J Allergy Clin Immunol. 2002, 109:923).

A growing number of prospective epidemiological studies over the past decade have demonstrated significant associations between stress in pregnancy and early asthma phenotypes in the next generation.

The magnitude of the association varies across these studies, probably due to differences in populations, study design, the stress measure used, characterisation of the outcome (e.g. wheeze or asthma), timing of exposure, etc.

Of note, a recent study indicates that girls before the age of 12 who had mothers with high levels of stress were more likely to have experienced wheezing and to have been diagnosed with asthma (Turcotte-Tremblay AM et al, Biomed Res Int, 2014:201717. Epub 2014 May 8).

In the American Journal of Physiology study R Lim, AV Fedulov and L Kobzik from the Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts have used an experimental model to expose a mild restraint stress (RS) on pregnant mice.

The authors’ hypothesis was that glucocorticoids (GCs) generated by stress in pregnancy can induce asthma susceptibility in offspring. To test this hypothesis, they stressed mice on day 15 of pregnancy, allowed them to give birth, and assessed offspring for asthma susceptibility. Among the experimentally-induced stress models in mice (i.e., sound, cold, social conditions, restraint stress), for these experiments, the authors chose restraint stress (RS) because it was found effective in prior murine asthma studies.

The investigators demonstrate that a relatively short episode of restraint stress significantly elevated maternal corticosterone (CORT) levels and only the offspring of stressed mothers demonstrated increased asthma susceptibility and the development of an asthma-like phenotype (airway hyper-reactivity and allergic airway inflammation).

Importantly, injection of non-stressed pregnant mice with dexamethasone, an analog of GCs, also resulted in increased asthma susceptibility in offspring, whereas the effect of maternal RS was prevented by pretreatment with metyrapone, a drug that blocks CORT synthesis.

In conclusion, this study demonstrates that a relatively short-lived physical restraint stress of pregnant mice can indeed promote initiation of an asthma-like phenotype in offspring. Furthermore, the stress effect can be recapitulated with a single injection of dexamethasone, a stress hormone analog, in a nonstressed pregnant female and blocked by inhibiting the endogenous production of a surge in CORT that follows restraint stress.

An update

As per a recent review by Konstantinos Douros, Maria Moustaki, […], and Kostas N. Priftis the link of the maternal prenatal stress with the development of childhood asthma is complex.

prenatal stress and factorsMechanism of maternal prenatal stress in asthma predisposition in the offspring. From Konstantinos Douros, Maria Moustaki, […], and Kostas N. Priftis, Front. Pediatr., 2017. Public domain.

This may include placental deregulated metabolism of maternal steroids, impaired maturation of fetal Hypothalamic-Pituitary-Adrenal (HPA) axis, imbalanced efflux of commensal bacteria across the placenta, and skewed immune development toward T cell helper (Th2) phenotypes and responses.

According to these authors, during stress in pregnancy, the the maternal glucocorticoids (GCs), along with the improper activation of placental–fetal HPA axis, are considered the main mediators of this predisposition.

A 2018 meta-analysis by Flanigan et al., found an association between any prenatal stress (composite of stress indicators) in pregnancy and increased ORs for both current or ever wheeze and current or ever asthma in children. Maternal stress was associated with increased risk of early-onset, late-onset, and persistent wheeze.

Brew and colleagues used Swedish register data to examine the association between maternal and paternal distress, defined as having a diagnosis of or receiving medication for an anxiety or depressive disorder during the mother’s pregnancy, and the development of asthma by age 5–6 years among all children born in Sweden. Notably, only maternal distress was significantly associated with higher odds of asthma diagnosis in children.

More recently, Magnus and colleagues examined child asthma development by age 7 years in the Norwegian Mother and Child Cohort Study in relation to maternal psychosocial stress during pregnancy and at 6 months after delivery (n=63,626) and in a subset with data on fathers, paternal and maternal psychosocial stress during pregnancy was also considered (n=47,619).

In this large-scale birth cohort in Norway, maternal symptoms of anxiety/depression and negative life events both during pregnancy and the first 6 months after delivery were positively associated with asthma in children followed to 7 years.

In conclusion, the evidence establishing that there is an increased risk of asthma with exposure to psychosocial stress, particularly during the prenatal and early postnatal period, continues to mount.

Mechanisms central to the pathophysiology of wheeze/asthma and lung growth and development overlap and involve a cascade of events that include disrupted immune, neuroendocrine and autonomic function as well as oxidative stress.

Homeostatic functions of these integrated systems are disrupted in response to chronic stress. Altered stress-response functioning carried into pregnancy as a result of the mother’s own stress history can disrupt optimal programming of these integrated systems in the fetus leading to enhanced vulnerability to asthma and altered lung development.

Source: Am J Physiol Lung Cell Mol Physiol. 2014, 307:L141-8. doi: 10.1152/ajplung.00250.2013. Epub 2014 May Read more: Am J Physiol Lung Cell Mol Physiol

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