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Psychosomatic Medicine 67:625-631 (2005)
© 2005 American Psychosomatic Society

ORIGINAL ARTICLES

Prenatal Stress Alters Cytokine Levels in a Manner That May Endanger Human Pregnancy

Mary E. Coussons-Read, PhD, Michele L. Okun, MA, Mischel P. Schmitt, BS and Scott Giese, BS

From the Department of Psychology (M.E.C-R., M.P.S., S.G.) and the Program in Health and Behavioral Science (M.E.C-R., M.L.O.), The University of Colorado at Denver, Denver, Colorado.

Address correspondence and reprint requests to Mary E. Coussons- Read, PhD, University of Colorado at Denver, Department of Psychology, CB 173, POB 173364, Denver, CO 80217. E-mail: Mary.Coussons-Read{at}cudenver.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: Recent data suggest that prenatal stress negatively affects pregnancy and infant outcome. Existing studies implicate dysregulation of the immune and endocrine systems in stress-related increases in premature labor and poor birth outcome, but no published studies have directly addressed the relationships among these variables during pregnancy. We sought to test the hypothesis that high levels of psychosocial stress and low levels of social support during pregnancy alter maternal cytokine profiles in a manner that contributes to poor birth outcomes.

Methods: Psychosocial stress and social support were measured in 24 women with overtly normal pregnancies once during each trimester of pregnancy. Levels of interleukin-10 (IL-10), IL-6, and tumor necrosis factor-{alpha} (TNF-{alpha}) were assessed concurrently with stress and support measurements.

Results: High social support was associated with low stress scores. Elevated stress scores were positively correlated with higher levels of the proinflammatory cytokines IL-6 and TNF-{alpha}, and with low levels of the antiinflammatory cytokine IL-10.

Conclusions: These findings provide initial support for our hypothesis that stress-related neural immune interactions may contribute to pregnancy complications and poor outcome, but require further study to determine the mechanism and significance of these effects.

Key Words: pregnancy • stress • cytokines • social support • neural-immune interactions

Abbreviations: NK = natural killer; DMHA = Denver Maternal Health Assessment; SRR = Social Readjustment Rating; MCSD = Marlowe-Crowne Social Desirability; MRC = multiple linear regression and correlation.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
It is clear that birth and infant development are affected by prenatal events. Recently, maternal psychosocial stress has been identified as a factor in early development, and there is growing evidence that perinatal psychological and environmental stresses are detrimental to pregnancy success and infant outcomes. Although increasing evidence suggests that stress can have a negative impact on pregnancy, the clinical importance and physiological mechanism of these effects has not been determined. The present study uses a psychoneuroimmunological framework to begin to assess how stress and other psychosocial factors may play a role in pregnancy success. At the core of this theoretical approach is the task of determining if meaningful associations exist among stress, physiology, immunity, and health, in this case, the health of the pregnant woman and her baby (1). Stress is often defined as events, situations, emotions, and interactions that are perceived as negatively affecting the well-being of the individual or that cause responses perceived as harmful. The concept of a psychosocial stressor encompasses life experiences, including changes in personal life, job status, housing, domestic violence, and family makeup, which require adaptive coping behavior on the part of the affected individual (2). Maternal stress experiences during and after pregnancy can range from severe and acute (e.g., trauma) to moderate (e.g., life event changes) to chronic (e.g., experience of daily hassles, and although some studies have shown minimal effects of prenatal stress on pregnancy (3,4); 3) the general finding is that both short- and long-term stress experienced during gestation can negatively affect pregnancy and birth outcome (i.e., (5,6)). Likewise, the state of pregnancy can affect how a woman views negative or stressful life events, which can subsequently influence how she responds to the stressors throughout the pregnancy (7). Recent data suggests that racial–ethnic disparities influence the perception of various stressful life events during pregnancy and can proportionately influence pregnancy outcomes such as preterm birth (8,9). These are important observations, because infants of stressed pregnancies have higher rates of childhood illnesses, and may experience physical and cognitive developmental delays in later years (10–13).

Although it is clear that prenatal stress can alter pregnancy and infant outcome, the mechanisms of these effects remain unclear. Stress-related changes in immune function have meaningful consequences for health in nonpregnant organisms, and it is likely that such interactions contribute to the deleterious effects of stress on pregnancy. For example, stress suppresses the function of lymphocytes, natural killer (NK) cells, and production of cytokines in nonpregnant animals and humans (14–16). Importantly, there is substantial evidence that the reported changes in in vitro immune cell function described here have meaningful consequences for human health. For example, stress exacerbates the common cold and influenza A infection in humans, and alters cytokine production in respiratory infection (17); major life event stress increases levels of circulating antibodies to herpes virus, indicating an alteration of immune function, and the chronic stress of caring for a spouse or relative with Alzheimer disease reduces NK cell activity and increases the frequency and duration of illness (18,19).

The immune system also plays an important supporting role in pregnancy. Cytokines, produced by cells of the immune system during stress and infection, are involved in the maintenance of pregnancy and in labor and delivery (20–23). Infections contribute to premature labor and delivery, and cytokines produced as part of inflammatory processes involved in these infections may play a role in these outcomes (24,25). Cytokines, produced by cells of the immune system during stress and infections, are involved in maintenance of pregnancy and in labor and delivery (21–23). Infections contribute to premature labor and delivery, and cytokines produced as part of inflammatory processes involved in these infections may play a role in these outcomes (24,25). For example, untreated malaria and typhoid fever predispose women to preterm labor and delivery (25,26), and undetected intrauterine and urinary tract infections contribute to preterm labor (27). These studies suggest that activation of the immune system affects maternal physiology and pregnancy, and the mechanism through which these infections induce labor appears to involve increased production of proinflammatory cytokines (25). Interestingly, the proinflammatory cytokines interleukin-6 (IL-6), IL-8, and tumor necrosis factor-{alpha} (TNF-{alpha}) are involved in the ripening of the cervix before delivery, and are associated with premature labor and delivery (28). Thus, although increased production of proinflammatory cytokines supports the immune system in its response to infection, it can also contribute to preterm labor and delivery.

We hypothesized that psychosocial stress, low social support, and low self-efficacy during pregnancy alter production of inflammatory mediators by the maternal immune system, which may in turn contribute to pregnancy complications or premature delivery. The constructs of social support and self-efficacy were incorporated in the present work as a result of previous literature indicating that social support plays a role in pregnancy success, especially in at-risk women (29–31), and that high social support and self-efficacy are related to higher levels of health-promoting behaviors, including stress reduction, in nonpregnant adults (32–35). The present study began to test this hypothesis by examining relationships among psychosocial stress, social support, and self-efficacy and circulating pro- and antiinflammatory cytokines in women throughout pregnancy.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Subjects
Thirty pregnant women, aged 18 to 34 years, were recruited through the prenatal clinic of Planned Parenthood of the Rocky Mountains during their first or early second trimester of pregnancy (gestational age range 8–20 weeks). Potential subjects were identified by examination of clinic appointments at the beginning of each week, and all women attending the clinic for their first prenatal visit. Subject recruitment was conducted over a 6-week period. A total of 45 women were approached about participation in the study, and 11 refused participation as a result of lack of interest, time, or at the advice of the individual accompanying them to the clinic (mother or partner). All subjects were informed of the goals of the study and gave informed consent according to the procedures approved by the Institutional Review Board of the University of Colorado at Denver. Recruiting and consent procedures were conducted by the principal investigator (MC-R) and a research assistant (MPS). Inclusion criteria were age >18 years, willingness and ability to participate and sign informed consent, and absence of exclusionary conditions. Both primi- and multiparous women were recruited for this study. Subjects were enrolled during their first scheduled prenatal care visit. Ideally, women were enrolled between 1 and 12 weeks of gestation, but because many women do not seek prenatal care until later in pregnancy, women beginning to attend the clinic as late as 18 to 20 weeks of gestation were recruited. Exclusion criteria were the presence of a known medical or obstetrical complication associated with increased risk for preterm birth, specifically cervical incompetence, placenta previa, preexisting vaginal or intrauterine infection, multiple fetuses, current preeclampsia, preexisting diabetes, or history of gestational diabetes in a prior pregnancy. Three women who expressed interest in the study were excluded for these reasons. Women with known psychiatric diagnoses or diagnosed drug or alcohol abuse were also excluded, and 1 subject was excluded on this basis. Subjects were compensated for their participation with a $10 grocery coupon each time they provided a blood sample and completed a survey, and received an extra $10 on completion of the study, resulting in a possible total of $50 of compensation. Loss of subjects as a result of attrition, which included women who provided data at only 1 time point, and loss of subjects as a result of early spontaneous abortion or development of gestational diabetes resulted in a final pool of 24 women. Of these, 3 provided data only at the second- and third-trimester points, and the remaining 21 provided data at all 3 time points.

Psychosocial Stress, Support, and Self-Efficacy Assessments
Once during each trimester of pregnancy (a maximum of 3 times depending on when the subject was enrolled in the study), women completed the Denver Maternal Health Assessment (DMHA), which quantifies self-reported levels of stress, social support, and self-efficacy as well as demographic information and information on overall health. The DMHA was adapted from a validated questionnaire developed by Meikle et al and is a valid and reliable instrument for assessing maternal stress, social support, and self-efficacy among Latinas, blacks, and whites (36,37). Although the Meikle et al instrument is validated for use in Hispanic and white pregnant women, it could not be used in its full form in the present studies because it takes 45 to 55 minutes to administer. In our early pilot studies, this lengthy administration time was disruptive to the flow of patient care in busy prenatal clinics, resulted in very little subject compliance and virtually no complete datasets from subjects who did remain in the study (data not included). Thus, to facilitate collection of the data included in the second preliminary study and that to be collected in the proposed work, we developed the DMHA from the original measure by shortening it and adding a set of stress items. The DMHA includes 2 parts. The first portion collects education, demographic, and other stable subject characteristic data, and was administered to subjects only at study enrollment. The second part includes the psychosocial measures of interest, and was administered to women at each prenatal visit and at the designated postnatal times. A primary component of the DMHA is to assess the participants’ levels of stress using a life stress subscale. This subscale of the DMHA was added to the original Meikle et al instrument and includes items that focus on personal habits, time constraints, work, money, and relationships with partner and family. Items on the life stresses subscale use a 5-point Likert scale with responses ranging from not a stress at all to major stress. Participants can also mark the does not apply response, which would exclude the item from the analysis. Thus, the DMHA differs from the original measure because it includes stress factors, and is shorter and therefore more easily used in outpatient medical settings.

Because the DMHA differs in some ways from the original measure, we included groups of items to assess the discriminant and convergent validity of our measure. The Social Readjustment Rating Scale (SRR scale) has been used to measure the convergent validity of the DMHA’s ability to assess life stress and life stresses subscale. The SRR scale has been used for over 30 years, and has been shown to be a valid and reliable instrument, and has good cross-cultural validity. The SRR scale has exhibited consistent convergent validity for assessing life stresses and coping (38). The Marlowe-Crowne Social Desirability Scale (MCSD scale) was included to determine the discriminant validity of the DMS life stresses subscale, and to investigate whether a social desirability response set exists among participants. The MCSD scale is composed of various questions regarding personal attitudes and behavior. The MCSD scale is a well-established instrument that has been reported to be a reliable and valid assessment measure (39). Our preliminary studies (based on 68 administrations of the DMHA in pilot studies) showed that the DMHA has good reliability for assessing stress (initial average alpha = 0.87), reasonable convergent validity with the SRR (Spearman’s rho = 0.66), and adequate discriminant validity with the MCSD (Spearman’s rho = –0.58). More recent analyses in which the pilot administrations of the DMHA were combined with the data from the present study demonstrated that the subscales of the DMHA retained their reliability for assessing different categories of stress (major stress alpha = 0.72; minor stress alpha = 0.77; overall stress score alpha = 0.75), further supporting the fact that the DMHA is a good instrument for assessing life stresses in pregnancy.

Women’s responses to each item on the DHMA were entered into a spreadsheet (Excel), and each item response was assigned a numerical value. Higher scores are indicative of more of the construct being tested. Thus, whereas a score of 4 on items relating to quality of relationships indicates more social support that a score of 1 on these items, scores of 4 on the stress items indicates more stress caused by given events than a score of 1. The sum of scores for all items in each section is computed to provide a support score, a stress score, and a self-efficacy score for each woman. Thus, 3 DHMA scores were generated for each woman each time she took the survey. Higher total scores of the support portion of the DHMA indicate more social support, higher scores on the stress portion indicate more psychosocial stress, and higher scores on the self-efficacy portion represent higher self-efficacy and better coping skills.

Sample Collection
Blood was collected after completion of the DMHA through routine venipuncture at 16, 24, and 36 weeks of gestation. Blood collections were performed between 8 and 10 am for all subjects. Two 10-mL venous samples were drawn into a nonheparinzed Vacutainer collection tube and allowed to clot for 30 minutes. Samples were then centrifuged and 0.5-m aliquots of serum were frozen at –70°C until analysis.

Cytokine Assessments
Levels of TNF-{alpha}, IL-6, and IL-10 in serum were determined using commercially available enzyme-linked immunosorbent assay (ELISA) kits (Ultra-sensitive Cytoscreen; Biosource Europe) as previously described (40–42). Undiluted serum samples were tested in duplicate and according to the directions provided by the manufacturer. Optical density at 450 nm was assessed using an automatic microplate reader (Biotek 310), and the amount of cytokine in each sample was determined using the standard curve generated with each assay according to the manufacturer’s instructions. Samples were frozen until the study was completed, and all samples were run together to avoid problems with assay drift and interassay variability. Cytokine kits from the same manufacturer’s lot were used for all assays for given measures. There was minimal variability between the standard curves (less than 8% variability). The mean of the duplicates was used as the unit of analysis for statistical evaluation of these data. To facilitate statistical analysis, cytokine values for the small number of assay determinations in which the duplicates varied by more than 50% (4 determinations) and samples, which were beyond the high detection limit for the assays, were replaced using a computerized program for replacement of missing values based on the mean of other values in that group using a single regression approach.

Data Disposition and Statistical Analyses
All statistical assessments were made using a computerized program for data analysis (SPSS; SPSS Inc.). A multiple linear regression and correlation (MRC) approach was used to examine the relative contributions of the psychosocial and demographic variables under study to the immune variables. The first step in the MRC analyses was the generation of a bivariate correlation matrix, which included all the variables of interest. The results of these tests were used to guide the ensuing regression analyses. These analyses did not indicate significant variations in any of the outcome measures as a function of trimester of pregnancy (r values less than 0.2 when correlating trimester status with outcome measures), so subsequent analyses collapsed across trimester of pregnancy to address relationships between the psychosocial factors of interest and the cytokine assessments. These analyses were accomplished by computing mean scores (across trimester) for each woman for each of the variables of interest.

A hierarchical linear regression analysis was conducted to examine the relations between the psychosocial variables hypothesized to affect circulating levels of IL-6, TNF-{alpha}, and IL-10 while controlling for the demographic variables of maternal age, ethnicity, and education. Separate analyses were conducted for IL-6, TNF-{alpha}, and IL-10. For each analysis, maternal age, then ethnicity, and then education were entered into the equation in steps 1 to 3. Then the maternal DMHA stress, support, and self-efficacy scores were entered in steps 4 to 6. This order of entry of the variables into the regression analyses was based on previous data that age can alter inflammatory cytokines levels (43,44) as well as on a priori hypotheses that ethnicity and education might affect health (45,46) and thus inflammatory markers. This strategy was designed to account for the potential effects of these intervening variables on the inflammatory markers before testing the influence of the psychosocial variables. The order of entry of the psychosocial variables was based on a priori hypotheses that the overall stress score would have the largest influence on inflammatory markers, followed by social support and self-efficacy.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Table 1 illustrates significant correlational relationships among the demographic and psychosocial variables assessed in the present study. Mean DMHA stress score was a linearly decreasing function of both maternal social support and maternal self-efficacy. Interestingly, DMHA stress was negatively correlated with maternal age (r = –0.282, p < .05), suggesting that the older women in the sample reported less stress overall during their pregnancies.


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  		TABLE 1. Zero-Order Correlations for Maternal Demographic and Psychosocial Variables

 

No significant relationships between maternal age and social support or self-efficacy were evident. Maternal age was also significantly correlated with maternal education, (r = 0.387, p < .05), indicating that older women, not surprisingly, were more highly educated. Maternal ethnic minority group membership was negatively related to maternal age, (r = –0.553, p < .05), as well as to maternal level of education, (r = –0.569, p < .05), illustrating Hispanic and black mothers in the sample were both younger and not as highly educated as the white women in the sample. No significant relationships were observed between maternal age, education, or ethnicity and any of the immune variables.

Table 2 shows significant correlational relationships among the psychosocial variables and the serum cytokines assessed in the present study. Mean TNF-{alpha} and IL-6 levels in maternal circulation were linearly increasing functions of maternal stress during pregnancy, (r = 0.704, p < .01) for TNF-{alpha} and (r = 0.349, p < .01) for IL-6, and IL-10 decreased reliably as a function of higher maternal stress, (r = –0.519, p < .01).


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  		TABLE 2. Zero-Order Correlations for Maternal Psychosocial Variables and Serum Cytokines

 

Table 3 illustrates the changes in the adjusted R2 for each of the 6 steps entered into the regression equations for TNF-{alpha}, IL-6, and IL-10, respectively. As a result of the small sample size relative to the number of predictor variables of interest, the adjusted R2 (aR2) value is reported here to account for possible overestimation of R2. As predicted, none of the demographic variables produced significant increments in adjusted R2 for any of the cytokines. In all cases, DMHA stress score was the only variable that accounted for a significant proportion of the variance. For TNF-{alpha}, addition of stress into the equation in step 4 accounted for a large proportion of the variance in this measure (aR2 = 0.394, F[1, 19] = 15.745, p < .001). The same was true for both IL-6 and for IL-10, in which addition of stress into the equation in step 4 resulted in significant increments in adjusted R2 for IL-6 (aR2 = 0.261, F[1, 19] = 5.028, p < .038) and for IL-10 (aR2 = 0.161, F[1, 19] = 7.514, p < .013). None of the other steps included in the regression equations accounted for significant aspects of the variance observed in circulating levels of TNF-{alpha}, IL-6, or IL-10 during pregnancy.


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  		TABLE 3. Regression Analysis of Psychosocial and Demographic Effects on Serum Cytokines

 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
The present study investigated the influence of psychosocial stress and social support on circulating cytokines during pregnancy. The data indicate significant relationships between high levels of stress and elevated serum proinflammatory cytokines, providing initial support for our hypothesis that high levels of psychosocial are associated with immune system alterations that may contribute to suboptimal pregnancy outcomes. Although the present findings provide initial support for the hypothesis that psychosocial stress and low social support during pregnancy may alter maternal endocrine and immune function in a manner that could endanger pregnancy, it is clear that additional work is necessary to fully characterize these relationships and determine their clinical significance.

Increased levels of IL-6 and TNF-{alpha} were observed in women reporting high stress during pregnancy, and these proinflammatory cytokines are implicated in the development of preeclampsia and premature labor and delivery (47,48). Previous research shows that significantly more proinflammatory cytokines are produced by lymphocytes from preeclamptic women than those produced by lymphocytes from women with normal pregnancies, and proinflammatory cytokine-producing cells are more numerous in preeclampsia (49,50). Interestingly, infection during pregnancy, which stimulates production of these cytokines, has been shown to increase the risk of developing preeclampsia (49,51,52). Additionally, diminished levels of IL-10 in placental tissue as well as serum have been observed in women with preeclampsia compared with normal pregnancy (53). IL-10 is important to normal pregnancy because it is involved in maintenance of pregnancy and progesterone production (53). These findings and the present data suggest that stress exposure during pregnancy might indirectly increase the risk of pregnancy complications by either predisposing the immune system to infection or directly by increasing production of proinflammatory cytokines.

Pregnant women experiencing high stress had lower levels of IL-10, a Th-2 anti-inflammatory cytokine, than pregnant women reporting less stress. Some have suggested that switching away from Th1-type immune responses in favor of Th-2 responses during pregnancy is 1 way the maternal immune system adjusts to support the pregnancy (20,54,55), and it may be that psychosocial stress prevents or impairs this transition in pregnancy. Given the evidence that successful pregnancy is supported by both reduction in inflammatory mediators and a tendency toward Th2 over Th1 immune responses (6,48,56), the observed decrease in IL-10 in the presence of high maternal stress may indicate more Th1 immune responsiveness during pregnancy in these women.

Although the present data indicate that prenatal psychosocial stress can affect cytokine levels in pregnancy, additional work is necessary to better characterize these effects and understand their potential significance for infant development. Animal studies indicate that exposure to stress or stress hormones prenatally alters development of brain areas associated with stress responsiveness such as the hypothalamus, and that these changes can have longlasting effects on behavior, stress reactivity, and development (57,58). Human studies suggest similar relationships. For example, infants from stressed pregnancies are harder to soothe and are characterized as being more temperamental than infants from pregnancies in which the mothers did not report significant stress (58,59). Other investigators link prenatal stress to dysregulation of the infant HPA axis and autonomic nervous system, manifested in altered stress reactivity (60,61), and animal research shows that prenatal stress impairs immune system development in infant monkeys, rats, and cows (5,62,63). Clearly, additional work is needed to characterize the impact of maternal prenatal stress on human infant immune function to ultimately improve pregnancy outcome and support healthy early development.

The present data have a number of interesting implications. For example, although the women in the present study were free of diagnosed infections, undetected infections are not uncommon in pregnancy and contribute to preterm labor by increasing production of proinflammatory cytokines, presumably in response to the illness (25,27). For example, the proinflammatory cytokine TNF-{alpha} is released in response to viral and bacterial infection. High levels of TNF-{alpha} are associated with premature labor in women with infections during late pregnancy, and administration of TNF-{alpha} to animals produces preterm labor (24,64,65). Proinflammatory cytokines contribute to other aspects of suboptimal pregnancy outcome besides premature labor. Elevated levels of proinflammatory cytokines during pregnancy are associated with the development of preeclampsia, a serious vascular disease characterized by maternal hypertension, organ system dysfunction, fetal distress, and premature birth (50). Unfortunately, although several investigators have described relationships between cytokines and pregnancy complications, these studies have yet to delineate the mechanisms and full significance of these effects. Interestingly, several controlled studies show that both stress and infection elevate proinflammatory cytokines in nonpregnant laboratory animals and humans (12,66). These data suggest that increased levels of proinflammatory cytokines, certainly in response to infection and possibly in response to stress, may be related to the development of serious pregnancy complications.

Although the present data are intriguing, a few limitations must be taken into account in interpreting them. It is unclear in the current dataset what cells and tissues are responsible for the concentrations of cytokines that accumulate in serum during pregnancy and the extent to which alterations in degradatory processes may play a role in the elevations or decreases reported. For example, it is clear that IL-6 is produced by immune cells activated by stress or infection and by adipose tissue (50,51). Moreover, the placenta produces significant amounts of cytokines and chemokines, and the present data are unable to address the placental versus nonplacental sources of these materials (25,67). Thus, although the present data clearly indicate that there are pregnancy-related changes in cytokine concentrations in the blood of pregnant women, and that these are altered by maternal stress, the origin of these changes cannot be determined. Future studies should include in vitro analysis of the production of cytokines from cells in maternal peripheral blood, and from the term placenta as a function of prenatal stress to better understand and interpret the present data.

Our understanding of the importance of neural-immune interactions during pregnancy is in the early stages, and ongoing studies in our laboratory and others will undoubtedly begin to clarify the importance of stress-induced immune suppression in pregnancy in the coming years. This field of study is well-supported by existing literature that provides strong converging evidence on which to form the hypothesis that stress-induced immunosuppression negatively affects pregnancy, and by our initial studies demonstrating that these connections exist and may have meaningful consequences for health and pregnancy outcome. Describing the connections between stress, maternal health, and immunity and pregnancy will provide new information about the causes of poor birth outcomes and related challenges to infant development, and ultimately, this line of inquiry will provide new strategies for medical and clinical practitioners and their patients to use to circumvent the effects of prenatal stress on maternal and infant well-being.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 

Received for publication September 1, 2004; revision received February 25, 2005.

DOI:10.1097/01.psy.0000170331.74960.ad


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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