Neuroendocrine regulation of the immune system as a mediator between perceived stress during pregnancy and preterm labor

Abstract

Abstract

Preterm labor is a worldwide public health problem, representing the first cause of neonatal morbimortality. Experimental and clinical evidences strongly suggest that preterm labor, as well as normal (term) labor, are the result of an inflammatory process that is mediated by maternal leukocytes. These immune cells are primed in peripheral blood and then infiltrate the maternal-fetal interface where they modulate the local mechanical and biochemical signaling that results in uterine contractions, cervical dilation and ripening and rupture of the fetal membranes.
After many decades of research, several factors have been associated with the development of preterm labor, yet current strategies aimed at its prediction and prevention have proven to be mainly ineffective, since its prevalence has not been reduced. Such research and strategies have been congruent with the dominating medical and scientific materialistic paradigm which presupposes that only material causes can produce material effects. From this view, the etiology of a phenomenon such as preterm labor must be fundamentally of biochemical nature and the pregnant woman that develops the condition has very little influence over it, if any.
However, the problem of preterm labor could be considered from a different paradigm, one centered in the person and more holistic in the sense that it considers that non-material (i.e. mental) phenomena may causally influence over material physiological processes (e.g. cellular functions, gene and protein expression). In this sense, recent evidences show an association between the psychosocial stress that is perceived by the pregnant woman and the development of preterm labor. However, the cellular and molecular mechanisms mediating such relation are yet to be elucidated.
It is well known that perceived stress can influence the immune function by way of the neuroendocrine mediators produced by the activation of the hypothalamic-pituitary-adrenal axis, including cortisol, adrenaline and corticotropin releasing hormone. These molecules have the capacity not only of activating leukocytes but also of altering the production of other hormones critical to the normal development of pregnancy, such as progesterone and prolactin.
We hypothesize that high levels of psychosocial stress in the pregnant woman would be associated with an increase in circulating neuroendocrine mediators, corresponding to an increase in their receptors in maternal peripheral leukocytes. This would lead to leukocyte activation and increased expression of inflammatory cytokines, which would correlate to an increased incidence of preterm labor.


Main text

Preterm labor, defined as labor that occurs before 37 weeks of gestation, is the main cause of neonatal morbimortality, complicating between 5 and 10% of births  worldwide⁠. Preterm labor is currently considered to be a multicausal phenomenon, with several causal elements being identified, ranging from maternal and/or fetal medical and genetic conditions, to environmental, behavioural and socioeconomic factors (Beck 2010) . However, the complexity of the pathophysiological process that leads to preterm labor has impeded the development of prevention and diagnosis strategies that have an effective impact on its prevalence.
The adequate progress of human pregnancy depends on a fine regulation of the maternal immune system throughout gestation, in order to prevent the immune rejection of the semi allogenic fetus. Therefore, any factor that alters such regulation may trigger before time the mechanisms that would normally lead to labor and potentially result in preterm birth. One such factor, widely described as an activator of the immune function during pregnancy and a trigger of preterm labor, is intrauterine infection, a pathology frequently associated with premature rupture of the fetal membranes, which is present in around 30% of preterm births.
However, most preterm births are not associated with infection and thus are considered of idiopathic etiology. In other words, we simply don’t know the causes that trigger labor in the absence of infection. What we do know is that in those cases maternal immune system is also activated; therefore, human labor, both at term and preterm, is now recognised to be an inflammatory process that is mediated by maternal leukocytes (Gomez-Lopez 2014).
In traditional biomedical research on preterm labor, both the theoretical/methodological approach aimed at seeking its causes, as well as the various strategies for its prediction, prevention and treatment, have been based on the asumption that this phenomenon's etiology is mainly biochemical, over which the pregnant woman was little or no influence. Accordingly, for more than 40 years research has focused on seeking for so-called biomarkers (either genes or proteins) as predictive causes of preterm labor, a strategy that has proven to be uneffective (Menon 2011).
Such strategy, however, is congruent with the reigning scientific and medical paradigm, one that is materialistic, mechanistic and deterministic, and assumes that only material causes can produce material effects. Thus,  the subject "suffers" her/his condition as a passive being that has no influence over it. In our case, the pregnant woman becomes a helpless victim of preterm labor, because she had no part in its causes and therefore cannot possibly influence them.
But this approach has not worked, as becomes evident by the fact that 1) we have still not delucidated the biological "mechanisms" that lead to preterm labor; 2) its worlwide prevalence is increasing rather than decreasing; 3) most cases of preterm labor are considered of idiopathic causes.
We propose seting off from a different paradigm, one holistic and centered in the subject. It is holistic in the sense that non-material (i.e. mental) phenomena are considered to have as much causal efficacy over physiological processes as material phenomena (genes, proteins, microorganisms, etc.). In other words, under this paradigm mental phenomena can be considered as causes that generate biological effects.
Thus, the subject becomes an active agent with the capactity to influence her/his condition. The pregnant woman, with her vast array of mental states (feelings, emotions, worries, expectations, etc.) becomes an active agent with the ability to completely influence her pregnancy, whether towards an adequate development or an adverse outcome such as (but not limited to) preterm labor.
In our view, one mental phenomenon that could have a major influence on pregnancy is maternal psychosocial stress. It is a multifactorial phenomenon in which the exposure to stressfull events interacts with personal psychosocial resources (coping styles, social support) to generate a perception of stress that results in a variety of  psychologic and pshysiologic efects, ranging from a mild feeling of anxiety to clinically defined cases of anxiety or depression disorders.
The main way through which psychosocial stress could alter the adequate course of pregnancy is by its influence over the immune system, particularly by altering the delicate balance between fetal tolerance and rejection. The relationship between the immune system and psychosocial stress is well known. It is mediated by neuroendocrine factors produced by the activation of the hypothalamic-pituitary-adrenal axis (HPA) characteristic of physiologic responses to perceived stress, including the corticotropin releasing hormone (CRH) and cortisol. These factors are capable of inducing the leukocyte expression and secretion of cytokines (Webster 1997)(Kin 2006)⁠, lower the placentary production of progesterone (Arck 2007)(Nakamura 2008). Moreover, maternal CRH may be considered a biological clock of gestation and a risk marker for preterm labor (Nepomnaschy 2007)(Kramer 2009).
During pregnancy, some of the traits that constitute psychosocial stress have been associated with the development of preterm labor, particularly perceived stress and pregnancy-related anxiety (Shapiro 2013). Despite this and the well known relationship between stress and immune system, the neuroendocrine and immunological mechanisms relating psychosocial stress with preterm labor have been scarcely studied (Coussons-Read 2005). In a recent study we found that pregnant single women with low social support reported greater psychosocial stress, which was associated with the incidence of preeclampsia, preterm labor and low birth weight (Laresgoiti-Servitje 2013). However, at that time we did not measure any neuroendocrine or immunologic markers and therefore were not able to determine the mechanisms mediating in the interaction between psychosocial stress and adverse perinatal outcomes.