Possible psychophysiologic mechanisms in premature labor

HAIM OMER, Ph.D.

Possible psychophysiologic mechanisms in premature labor ABSTRACf: The influence of psychological factors on uterine activity has been demonstrated, but the mechanism of psychophysiologic mediation is not known. Possible mediation processes are the following: (I) a rise in catecholamine secretion may bring about an increase in uterine activity directly in the case of norepinephrine and indirectly through a rebound reaction in the case of epinephrine; (2) a stress-related corticosteroid or opiate increase may lead to higher vulnerability to infectious diseases, particularly to choriamnionitis; (3) a higher degree of neuromuscular reactivity may mediate between chronic anxiety and premature labor; and (4) stress has been shown to increase secretion of oxytocin, which increases uterine motility. Oxytocin is a possible candidate as a mediator between psychological stress and premature labor. The evidence implicating social and psychological factors in premature labor and in increased uterine motility derives from epidemiologic, laboratory, and clinical studies. Epidemiologic studies have shown that single, divorced, or widowed mothers deliver prematurely more frequently than married mothers. This finding has been replicated with large samples in many countries. The social

and psychological stress of being a single mother has been shown"> to be associated with premature deliveries, independently of objective factors, such as poverty. Laboratory research'·> in which uterine activity in nonpregnant women was measured directly has demonstrated that unpleasant or frightening stimuli, such as sudden noises or the prospect of receiving an injection,

Dr. Omer is instructor of psychology at the Hebrew University of Jerusalem. Reprint requests to him in the Department of Psychology. Hebrew University. Mt. Scopus. Jerusalem 91905. Israel.

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may lead to increases in the frequency and amplitude ofcontractions or to desynchronization of uterine activity. On the other hand, the presence of a relaxing stimulus, such as having the subject concentrate on a calm, pleasant activity, could lead to quieting of the uterus.' The clinical evidence is of two kinds: (I) studies of the relationship between psychological variables (as manifested in interviews, questionnaires, and projective tests) and premature deliveries; and (2) studies of therapeutic interventions designed to reduce uterine activity or inhibit premature labor. Many studies have shown that variables such as life stresses,"'? psychopathologic tendencies,'·9 and negative attitudes toward pregnancy,•.'.9 were more pronounced in women who delivered prematurely than in those who delivered at term. However, these studies have a serious methodologic flaw, owing to their retrospective design. Their findings might have been distorted by the mothers' anxiety about their just-born premature babies or by the proximity in time to the trauma of premature delivery. NeverthePSYCHOSOMATICS

less, similar findings have also been reported in two prospective studies: Omer and associates '0 found that pregnant women who later developed premature contractions had higher anxiety scores than those who did not develop them; Herms and Gabelman" showed that women who later delivered prematurely were less well adapted socially and less attached to their families than women who later delivered at term. As for clinical interventions, Herms" demonstrated that a simple relaxation exercise reduced the frequency of spontaneous uterine contractions in the late stages of pregnancy. Omer and associates OJ developed a hypnotic relaxation procedure for women with premature contractions. The intervention, aimed chiefly at diminishing anxiety and bodily tension, was highly effective in inhibiting premature labor. A serious problem in the search for psychophysiologic mechanisms affecting uterine function lies in the lack of accepted criteria for the definition of psychological stress. Even a less broad concept than that of stress, such as that of anxiety, has been found'· to produce conflicting behavioral, cognitive, and physiologic measures. Luckily, in the field of physiologic measurements alone, considerable agreement exists as to the main characteristics of the organism's responses to environmental or psychological stress, however defined. In particular, it is widely accepted"'" that psychological stress leads to an abrupt rise in the levels of catecholamines, corticosteroids, and neuromuscular reactivity. These variables will be our main concern in what follows. Catecholamines One of the best known correlates of psychological stress is increased secretion of catecholamines.'o Persons

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with chronic anxiety have high catecholamine blood levels. ,. Treatments for anxiety, such as relaxation training, may lead to a decrease in catecholamine levels in these patients. 20 The influence of catecholamines on uterine activity is a function of the adrenergic receptors stimulated by them. Stimulation of a-receptors is known to increase uterine motility, whereas stimulation of (3-receptors inhibits it." Norepinephrine stimulates a-receptors, and epinephrine stimulates both a- and (3-receptors." Ac-

A decrease in immune defenses in women under chronic stress might indirectly increase their risk for premature labor. cordingly, these agents have different effects on the uterus: epinephrine has an immediate inhibiting effect and norepinephrine has a stimulating one. By itself norepinephrine might possibly lead to premature contractions as a function of psychological stress. However, this effect is initially countered by a steep rise in epinephrine. This rise in epinephrine produced by psychological stress is deemed to be the main reason for prolongation of labor in anxious women. Lederman and associates" measured epinephrine blood levels and self-reported anxiety of women during labor. The two were found to be positively correlated (Spearman correlation of 0.60). The duration of labor was directly related to epinephrine secretion (the duration oflabor at from 3 to 10 cm dilatation had a correlation of 0.60 with epinephrine levels). High levels of anxiety and blood epinephrine led to a pronounced decrease in uterine activity, particularly in the

second stage of labor. However, epinephrine's inhibiting influence on uterine motility is timelimited. After a while (the length of time varies from woman to woman) uterine contractions return to their initiallevel and a rebound effect usually takes place, leading to a pronounced increase in uterine motility. The usual explanation for the rebound effect is based on epinephrine's stimulation of both a- and (3-receptors. As labor progresses, the amount of a-receptor stimulation rises as compared with (3receptor stimulation (probably because of proliferation or increased sensitivity of a-receptors, caused by estrogen) so that epinephrine's inhibiting action is changed into a stimulating one." An alternative mechanism for the rebound reaction is possible: Ishikawa and Fuchs'" have shown that epinephrine causes a steep rise in the level of F prostaglandins in the uterus of pregnant rats. Tothill and associates" have shown that the same is true for E prostaglandins. Those authors hold this to be the cause of the epinephrine rebound effect, since prostaglandins (particularly from the E and F groups) are very powerful uterine stimulators. To sum it up, the causal mechanism hypothesized would be as follows: Stress leads to an increase in both norepinephrine and epinephrine. In the first few hours the rise in epinephrine is greater," and this leads to reduced uterine activity. A rebound reaction to epinephrine later develops, perhaps through mediation by prostaglandins, and both catecholamines begin acting in concert in stimulating uterine activity. Corticosteroids or other immunosuppressive substances The influence of stress and anxiety on the secretion of corticosteroids is well known. The rich literature in this field

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makes the stress-corticosteroids connection one of the central facts of psychoendocrinology. ,. Although corticosteroids may bring about premature labor in many nonhuman species. there is no evidence that they do so in humans. 27 Corticosteroids do not increase uterine activity when injected into pregnant women. nor do these hormones manifest a spontaneous rise in late pregnancy or in the days preceding delivery. ,. It is thus improbable that they have a direct role in causing premature labor. However. an indirect role is possible. Corticosteroids are known for their immunosuppressive influence. Not too long ago. they were considered to be the main mediator between stress and immunodeficiency." The relationship between chronic stress and increased vulnerability to infectious diseases has been generally supported by research JO ; these and other studies" have shown that corticosteroids may have an important role in this relationship but certainly not a unique one. The opiates. for instance, also seem to playa role in the suppression of immunologic defenses by stress. J2 Infectious diseases in general are known to increase the risk for premature labor." In particular, chorioamnionitis may be one of the important antecedents of premature labor and delivery. Naye. in one" of his various studies on this subject. examined the causes for premature rupture of fetal membranes in 10,460 pregnancies. Chorioamnionitis was deemed present when acute inflammatory cells were spread diffusely along the surface of the chorion in the extraplacental membranes. Rupture of fetal membranes increased threefold when chorioamnionitis was present. A decrease in immune defenses might predispose women under chronic stress to chorioamnionitis or to other infectious dis511

eases. thus increasing their risk for premature labor. Neuromuscular overreactivity Persons under psychological stress are known"'" to suffer from high muscle tone and from a tendency to overreact. Such a tendency has also been found in some German studies"·J6 to characterize women who tend to develop premature labor. Those studies have shown that a patient's level of neuromuscular reactivity. as measured by the rheobase in

Women who later develop premature labor may have a higher level of autonomic reactivity. her anterior tibial muscle, is a good predictor of premature delivery. The lower the rheobase. the higher the risk for premature delivery. The outcome of tocolytic treatment has also been successfully predicted from changes in rheobase in the desired direction as a result of treatment. " Konig and Seidenschnu~ hypothesized that these findings point to a higher level of autonomic reactivity in women who later develop premature labor. They hold this overreactivity to be one of the chief causes of premature labor. These women have a lower reaction threshold to stimuli of many kinds. both internal and external in nature. Increased muscle tone and autonomic overreactivity are perhaps the common denominator between anxious individuals and premature deliverers. and this may explain the effectiveness of relaxation exercises in quieting the uterus and inhibiting premature labor."·13 Herms" has shown that a relaxation exercise led to an increase in rheobase as well as a de-

crease in spontaneous uterine contractions in women in the later stages of pregnancy. thus further supporting this hypothesis. Kochenstein.\7 has criticized the methodology and the conclusions of the rheobase studies. He showed that some of the results could be explained by experimental bias. owing to the researcher's placing the rheobase-measuring electrode more carefully in cases of premature labor than in cases pertaining to the control group. This bias. however. cannot explain all of the findings connecting a lowered rheobase to premature deliveries. In at least one study'S the rheobase proved successful in predicting outcome of tocolytic treatments in a manner that was not influenced by experimental effect, since the necessary information was not available to the researchers (ie. the investigators did not know beforehand in which cases treatment would prove successful or fail. and thus differential placement of the electrodes was not possible). Oxytocin Oxytocin. unlike the other physiologic variables considered above. is not usually seen as playing a part in the organism's reaction to stress. However. recent animal research is beginning to change this view. Selye18 reviewed this literature and reported general agreement that stress raises oxytocin secretion. More recently Lang and associates" have replicated these findings with modem measuring techniques: stressful procedures such as immobilization and forced swimming brought about large increases in secretion of the hormone in rats. The authors proposed that oxytocin should be considered as one of the "stress hormones, " ie. hormones that participate in the organism's defensive response to stress. Oxytocin used to be considered'"

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one of the central factors in the initiation of labor. We know" that uterine sensitivity to oxytocin increases toward the end of pregnancy. Takahashi and associates" performed oxytocin challenge tests on 37 women who later developed premature labor and delivered before term. When compared with women who delivered at term or after term, the preterm group was found to show a significantly higher level of uterine contractility following oxytocin administration. This turns oxytocin into a possible candidate as a mediator between psychological stress and premature labor. This hypothesis is still highly speculative, and it awaits confirmation that oxytocin secretion actually does increase under psychological stress in humans as well.

Conclusion and directions for research The various possible psychophysiologic mechanisms reviewed are not necessarily mutually exclusive. Psychological stress may influence uterine activity in more than one way. Evidence for this has been adduced by Frohlich, > who demonstrated the existence of at least two time patterns of uterine reaction to psychological stimuli: one of immediate reaction, which Frohlich hypothesized might be mediated by neural pathways, and one of delayed reaction, which might be mediated by hormonal pathways. A multifactor view of psychophysiologic mechanisms would also fit with present views of premature labor as a phenomenon with multiple causes.)) It is important to emphasize that

none of the above possible mechanisms have been shown to be involved in the development of premature labor. Such a demonstration would call for research on the following: (I) psychological factors that can be assessed with psychodiagnostic instruments, such as anxiety questionnaires, or that can be brought about through experimental manipulations (such as relaxation exercises or antianxiety therapy); (2) uterine or clinical parameters, such as frequency or amplitude ofcootractions or development of premature labor; and (3) measurements of activity in the hypothesized physiologic mediator (for instance, levels of the hormone in question or rheobase values). This research will require an effort involving psychologists, physiologists, and clinicians. 0

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