The rate of preterm birth, defined as birth before 37 weeks’ gestation, is rising worldwide. It accounts for 75.0% of perinatal mortality and more than half the longterm morbidity. The frequency and severity of adverse outcomes are rising with decreasing gestational age and decreasing quality of care. The preterm birth rate has also risen in most industrialized countries, despite increasing knowledge of risk factors and mechanisms related to preterm birth, and the introduction of many public health and medical interventions designed to reduce preterm birth [1]. The frequency of preterm birth is about 12.0-13.0% in the USA and 5.0-9.0% in many other developed countries [2].
Spontaneous preterm birth accounts for at least 50.0% of all preterm birth. A previous spontaneous preterm birth is the greatest risk factor for spontaneous preterm birth [2]. Chronic maternal stress is increasingly recognized as one of the contributing risk factors for spontaneous preterm birth [3, 4, 5]. Thus, preterm birth and chronic maternal stress load during pregnancy are closely connected. We have not, as yet, found the biological mechanisms of stress that relate to the triggering of preterm births, but we can identify several risk factors and behaviors that are connected to spontaneous preterm birth and chronic maternal stress. For example, these are previous trauma in childhood, anxiety and depression, experiences with previous labor, low socioeconomic status, low education, and nutrition.
Measures of stressful life events, the perception of stress, depressive symptoms, and levels of pregnancy-related anxiety are commonly used to indicate maternal adversity. Chronic maternal stress load has been a sum of adverse mother’s life events since her birth. Epigenetic biomarkers of several specific genetic loci could be a reliable measure of this chronic maternal stress load. These epigenetic biomarkers may reveal mother’s stress bioprofile or stress diathesis. Studies showed that there is no strong scientific proof for either the role of abnormal response of corticotropin-releasing hormone (CRH), cytokines or for the role of catecholamines in the pathogenesis of preterm birth [6,7]. Epigenetic modifications interacting with genetic variation to precipitate disease [8] can provide a hypothetical explanation for stress-related disorders such as preterm birth.
DNA methylation changes are tissue-specific. Evidence show that blood/leucocytes might be a possible surrogate through which to investigate stress related conditions that act through the central nervous system (CNS). We suggest that methylation changes of DNA isolated from blood leucocytes are a reliable enough measure of stress related changes that occur in the brain.
Understanding the molecular physiology of chronic maternal stress load in preterm birth has important implications for the development of preventive and treatment measures for preterm birth and for decreasing mortality and morbidity in preterm newborns. Additionally, such understanding could also enable us to develop simple assays based on epigenetic changes, thus providing us with a process that also enables the measurement of chronic stress load in expectant mothers.
Early life experiences appear to increase human susceptibility for anxiety and depression that are known risk factors for preterm birth [12, 13, 14]. Chronic stressors are recognized for being particularly salient among poor and minority women, that is, women who also correspondingly experience the highest rates of adverse birth outcomes. Expectant mothers from lower socio-economic groups are often exposed to a higher incidence of incomplete families, poor housing, low educational level, high mobility, dysfunctional families and social pathology [10]. We know that for individual subjects within this group, such factors often represent an accumulation of psychological stresses. Evaluating relationship between chronic maternal stress load and spontaneous preterm birth, Manuck
Influence of specific risk factors on chronic maternal stress that has effect on HPA hypersensitivity and can lead to preterm birth.
Existing studies have primarily investigated the role of glucocorticoid receptor expression and sensibility, which is related to the promoter
In animals, however, maternal licking/grooming (LG) behavior has effect on offspring stress responses by increasing HPA axis responses to stress. This kind of mother’s behavior increases glucocorticoid receptor expression and negative feedback. These changes in the offspring result from epigenetic alterations, including DNA demethylation and increased histone acetylation [2]. Subsequent studies in humans expanded on the findings in rats. Turecki and Meaney [27] systematically reviewed the effects of the social environment and stress on
Nevertheless, these processes are related to the placenta physiology and to the role of
Paquette
Epigenetic changes of several specific genetic loci may comprise parts of the larger metabolic network, where hypersensibility of the HPA axis is just one side of the story (Figure 2). Hypersensibility of the HPA axis is not necessarily manifested by increased cortisol concentration in the blood, but may be related to receptor changes in the hormones and neurotransmitters related to human stress response. Preterm birth may, therefore, be identifiable as a clinical symptom of chronic maternal stress load that has accumulated since mother’s birth and is part of mother’s stress bioprofile. Studies involving preterm birth and DNA methylation changes in specific genetic loci can, therefore, provide us with new opportunities and research challenges.
Suggested epigenetic mechanisms that can lead to HPA hypersensitivity and preterm birth.
Three studies have investigated CpG sites connected to preterm birth using neonatal blood [35, 36, 37]. Parets
There have been few studies examining DNA methylation differences in mothers who deliver preterm. Parets
Many other studies examined other types of biomarkers for preterm birth such as cytokines and other metabolites in maternal serum, but biomarkers that examine DNA methylation changes may allow for earlier identification of those at increased risk for preterm birth. DNA methylation changes are also more suitable to screening with next-generation sequencing panels that utilize standardized chemistry, and are able for more rapid and reproducible assessment of multiple biomarkers. However, evidence of preterm birth’s epigenetic signature is still scarce and studies are so far inconclusive.
Measuring DNA methylation changes in single genes, as in promoter I and IV of
Researchers mostly studied the whole methylome across various tissues. Fan and Zhang [43] reported strong positive correlations in CpG-island methylation status across all somatic tissues but they did not included brain tissue in the study. Davies
Recent studies also suggest that certain blood cells such as lymphocytes and monocytes are a reliable source of DNA methylation changes in the blood. And these changes are correlated with DNA methylation changes in the brain. An increasing body of evidence suggests that there is a close relationship between the CNS and the immune system. Lymphocytes appear to play a central role in this communication. Numerous studies have shown similarities between receptor expression and mechanisms of the transduction processes of cells in the nervous system and lymphocytes. In several neuropsychiatric disorders such as depression, stress, Alzheimer’s disease and schizophrenia, researchers found alterations of metabolism and cellular functions in the CNS as well as main neurotransmitter and hormonal systems that are similar to altered function and metabolism of blood lymphocytes [47, 48, 49]. The presence of sympathetic fibers in lymphoid tissues suggests that direct contact occurs for neural signaling cascades with the immune system [50].
An important limitation in all of these studies was that brain DNA methylation changes were studied in postmortem tissue. Because taking a blood sample is a minimally invasive procedure, it is typically considered as a practical surrogate. For the present, however, such a practice affords a reliable enough procedure for the examination of DNA methylation changes in peripheral blood for evaluating the risk of preterm birth as one kind of various stress-related disorder.
Finding epigenetic biomarkers of increased stress susceptibility for preterm birth or mother’s stress bioprofile would be a first step in characterizing that group of women with preterm births. Based on the results of a blood sample, we could begin preventive and therapeutic measures to decrease chronic maternal stress load in this group of women. Preventive measures could involve cognitive behavior therapy support, social assistance for underprivileged groups of women, and mind-body therapies for stress reduction. Therapeutic measures such as drugs that change DNA methylation patterns are also underway. Nutrition, too, might play a role as a preventive measure against chronic stress accumulation.
Investigating chronic maternal stress load and risk for preterm birth is also important in identifying epigenetic mechanisms of human stress response, and fetal programing. Again, in doing so, we may then be able to develop simple assays based on epigenetic changes in order to measure chronic stress load in expectant mothers.