Professional Documents
Culture Documents
11
ª The Author 2009. Published by the Johns Hopkins Bloomberg School of Public Health. DOI: 10.1093/aje/kwp061
All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org. Advance Access publication April 10, 2009
Original Contribution
Michael S. Kramer, John Lydon, Louise Séguin, Lise Goulet, Susan R. Kahn, Helen McNamara,
Jacques Genest, Clément Dassa, Moy Fong Chen, Shakti Sharma, Michael J. Meaney,
Initially submitted October 28, 2008; accepted for publication February 18, 2009.
The authors investigated a large number of stressors and measures of psychological distress in a multicenter,
prospective cohort study of spontaneous preterm birth among 5,337 Montreal (Canada)-area women who de-
livered from October 1999 to April 2004. In addition, a nested case-control analysis (207 cases, 444 controls) was
used to explore potential biologic pathways by analyzing maternal plasma corticotrophin-releasing hormone
(CRH), placental histopathology, and (in a subset) maternal hair cortisol. Among the large number of stress and
distress measures studied, only pregnancy-related anxiety was consistently and independently associated with
spontaneous preterm birth (for values above the median, adjusted odds ratio ¼ 1.8 (95% confidence interval: 1.3,
2.4)), with a dose-response relation across quartiles. The maternal plasma CRH concentration was significantly
higher in cases than in controls in crude analyses but not after adjustment (for concentrations above the median,
adjusted odds ratio ¼ 1.1 (95% confidence interval: 0.8, 1.6)). In the subgroup (n ¼ 117) of participants with
a sufficient maternal hair sample, hair cortisol was positively associated with gestational age. Neither maternal
plasma CRH, hair cortisol, nor placental histopathologic features of infection/inflammation, infarction, or maternal
vasculopathy were significantly associated with pregnancy-related anxiety or any other stress or distress measure.
The biologic pathways underlying stress-induced preterm birth remain poorly understood.
anxiety; corticotropin-releasing hormone; hydrocortisone; premature birth; stress, physiological; stress, psychological
Abbreviations: CI, confidence interval; CRH, corticotrophin-releasing hormone; OR, odds ratio; PPROM, preterm prelabor rupture
of membranes; SD, standard deviation.
Preterm birth is the leading cause of infant mortality in measured in early pregnancy has been shown to be a risk
industrialized societies (1–3). Despite several decades of marker of subsequent preterm birth (7–9). The main source
intensive investigation, an understanding of its etiologic de- of maternal CRH, however, is the placenta, rather than the
terminants has proved elusive, and few effective preventive hypothalamus, and the relation between elevated concentra-
interventions have been identified. In fact, rates of preterm tions of CRH to stressors and psychological distress on the
birth continue to rise throughout the developed world (4). one hand and maternal CRH on the other remains unclear
Recent interest has focused on the potential etiologic (10). Hobel et al. (8) reported a significant positive associ-
roles of acute and chronic stressors, the psychological dis- ation between perceived stress and maternal plasma CRH in
tress caused by those stressors, and the hypothalamic- women who subsequently delivered preterm but a negative
pituitary-adrenal axis (5, 6). The maternal serum or plasma correlation of a similar magnitude in those who delivered at
corticotrophin-releasing hormone (CRH) concentration term. A more recent study from the same group found no
Correspondence to Dr. Michael S. Kramer, Montreal Children’s Hospital, 2300 Tupper Street (Les Tourelles), Montreal, Quebec H3H 1P3,
Canada (e-mail: michael.kramer@mcgill.ca).
correlation between maternal CRH and perceived stress but hospital at 24–26 weeks of gestation, based on an ultrasound
a small positive correlation with pregnancy-related anxiety estimate obtained prior to the visit. The clinic visit included
at 28–30 weeks (11). Other studies have found no associa- an interview, vaginal examination, and venipuncture, all
tion between psychosocial stresses and maternal CRH (12, performed by a research nurse. The interview questionnaire
13). In fact, even fetal intra-hepatic vein transfusion, which requested standard demographic data, including place of
raises fetal adrenocorticotropic hormone and cortisol, had no birth (no information was collected on race or ethnic origin)
effect on maternal or fetal CRH concentrations, suggesting and language spoken at home; detailed socioeconomic in-
that placental CRH secretion is not responsive to stressful formation, including education and occupation of the
stimuli (14). Thus, despite numerous studies with measure- mother, family income, and marital and cohabitation status;
ments of maternal CRH, few have identified ‘‘upstream’’ medical and obstetric history; height and prepregnancy
predictors of maternal CRH or ‘‘downstream’’ biologic me- weight; and cigarette, alcohol, and drug use prior to and
diators of its robust association with preterm birth. since the beginning of pregnancy.
In this paper, we use data from a case-control study nested Information was also collected on both chronic and acute
within a large, multicenter, prospectively followed cohort of stressors, with an emphasis on chronic stressors. Crowding
pregnant women who delivered from October 1999 to April was assessed by using the density ratio (number of persons
Am J Epidemiol 2009;169:1319–1326
Stress Pathways to Spontaneous Preterm Birth 1321
was assessed using a short form of the Life Orientation Test (Phoenix Pharmaceuticals, Inc., Burlingame, California)
(35). We used a single item from the scale of Taylor et al. with 125I-CRH as tracer and a human CRH (anti-rabbit)
(36) to rate the study woman’s perception of her risk of birth antibody. The assay has a range from 0 to 1,280 pg/mL,
complications (including preterm birth) on a 6-point Likert with modifications to the suggested protocol yielding a sen-
scale; responses were then dichotomized as high (somewhat sitivity of 1.25 pg/mL. The antibody is highly specific for
or much higher than average risk) or not high (average or CRH, with no cross-reactivity to urocortin, vasopressin,
lower risk). Depressed affect was assessed with the Center adrenocorticotrophin, or leutinizing hormone.
for Epidemiologic Studies Depression (CES-D) Scale (37), As previously described (40), placentas from cases (n ¼
dichotomized (as suggested by the developers of the scale 198) and controls (n ¼ 427) were placed immediately after
(37)) as depressed (score 16) or not (score 15). Commit- delivery in a double plastic bag and refrigerated. Three
ment to the pregnancy was measured by using an 8-item transmural sections of 3-mm thickness (1 each near the in-
scale (38). sertion of the umbilical cord, near a placental margin, and
The case room (delivery ward) of each of the 4 study midway in-between) were cut from the fresh placenta. All
hospitals was monitored daily (including weekends and hol- placental histopathologic features were evaluated by a single
idays) for deliveries of study subjects. Of the 5,337 women placental pathologist (M. F. C.) blind to the case versus
Am J Epidemiol 2009;169:1319–1326
1322 Kramer et al.
similar factor structures in the English and French versions Table 1. Baseline Characteristics (in Percentages) of Cases and
of all scales used to assess stressors or psychological dis- Controls in a Study of Spontaneous Preterm Birth Among 5,337
tress. All statistical analyses other than the principal com- Montreal (Canada)-Area Women Who Delivered From October 1999
ponents analysis were carried out by using SAS, version 9.1, to April 2004
software (SAS Institute, Inc., Cary, North Carolina). Term Controls Total Cases
Characteristic
(n 5 4,885) (n 5 207)
Am J Epidemiol 2009;169:1319–1326
Stress Pathways to Spontaneous Preterm Birth 1323
Table 2. Associations of Acute and Chronic Stressors, Psychological Distress, Stress Hormone Levels, and Preterm Birth Among 5,337
Montreal (Canada)-Area Women Who Delivered From October 1999 to April 2004
Term Controls Total Cases Crude 95% Confidence Adjusted 95% Confidence
(n 5 4,885) (n 5 207) Odds Ratio Interval Odds Ratioa Interval
Acute stressors, %
2 Negative life events, first 2 trimesters 22.5 19.0 0.8 0.6, 1.2 0.9 0.6, 1.3
1 Negative life event, third trimester 40.9 37.3 0.9 0.6, 1.2 0.9 0.6, 1.4
Chronic stressors
Crowding, mean (SD) 0.6 (0.3) 0.6 (0.3) 1.1 0.8, 1.4 1.0 0.7, 1.5
Unintended pregnancy, % 12.5 15.3 1.3 0.9, 1.9 1.2 0.8, 2.0
Marital Strain Scale, mean (SD) 18.5 (7.9) 18.3 (7.6) 0.9 0.7, 1.3 0.8 0.6, 1.1
Conjugal violence, % 6.8 7.7 1.2 0.7, 1.9 0.9 0.5, 1.8
Job-related stress, %b 23.6 23.6 1.0 0.7, 1.5 1.0 0.6, 1.4
Abbreviations: CES-D, Center for Epidemiologic Studies Depression [Scale]; CRH, corticotrophin-releasing hormone; SD, standard deviation.
* P < 0.05 vs. controls; **P < 0.01 vs. controls; ***P < 0.001 vs. controls.
a
Adjusted for all of the variables in Table 1.
b
Job-related stress (n ¼ 3,869).
c
Maternal plasma CRH (n ¼ 635).
d
Maternal hair cortisol (n ¼ 117).
of the acute or chronic stressors or measures of psycholog- the stressors or measures of psychological distress and
ical distress and either maternal CRH or hair cortisol levels. maternal plasma CRH or hair cortisol levels.
Nor were any of these factors significantly associated with Our finding that spontaneous preterm birth was consis-
placental histopathologic features of infection/inflammation, tently and independently associated only with pregnancy-
infarction, or maternal vasculopathy. related anxiety, among the large number of stressor and
psychological distress measures we studied, is strikingly
similar to that reported by Mancuso et al. (11), Orr et al.
DISCUSSION (32), and Lobel and Cannella (29) and suggests that this
association is unlikely to have arisen by chance. Moreover,
Psychological stress is a notoriously complicated con- the fact that the association persisted after adjustment for
struct. We have prospectively assessed a large number of medical and obstetric risk, as well as for perception of preg-
acute and chronic stressors in a large cohort of pregnant nancy risk (including perceived risk of preterm birth) and
women, along with measures of psychological distress and depression, suggests that it does not merely reflect reverse
social support. Except for pregnancy-related anxiety, we did causality (i.e., anxiety caused by early signs or symptoms of
not find any significant relations between any of the stres- preterm delivery). Reverse causality cannot be completely
sors or psychological distress measures and spontaneous excluded, however, because our measures of medical and
preterm birth. Nor did we observe any associations between obstetric risk and the woman’s perception of her own risk
Am J Epidemiol 2009;169:1319–1326
1324 Kramer et al.
may not have captured subtle signs and symptoms that could CRH may also be limited by the fact that we measured CRH
be precursors of subsequent preterm delivery. at a single point in time, rather than repeated measures to
To our knowledge, ours is the first study to examine ma- observe the pattern of CRH rise (46). In addition, we collected
ternal hair cortisol as a cumulative measure of this key no information on salivary cortisol, urinary catecholamines,
adrenal stress hormone over the course of pregnancy. placental metabolism of cortisol, or other biomarkers of
Contrary to our hypothesis, maternal hair cortisol levels stress.
obtained at delivery were not elevated in women who had The role of stressors, psychological distress, and stress
spontaneous preterm birth. In fact, we observed a positive hormones in causing preterm birth remains elusive. Future
correlation between maternal hair cortisol and the duration research should attempt to identify what ‘‘upstream’’ factors
of gestation, paralleling previously observed observations influence placental CRH release and whether trajectories of
that maternal plasma cortisol levels rise during pregnancy the rise in CRH concentration are associated with exposure
(42, 43). Because of this rise, a disproportionate amount of to stressors and/or psychological distress. Other stress hor-
the cortisol deposited in maternal hair will reflect levels mone pathways or biologic pathways that may mediate the
from the latter part of pregnancy, thus obscuring potential effect of stressors are also worthy of further attention. In our
relations involving increased stress, cortisol levels earlier in view, an informed assessment of stress and stress pathways
Am J Epidemiol 2009;169:1319–1326
Stress Pathways to Spontaneous Preterm Birth 1325
4. Ananth CV, Joseph KS, Oyelese Y, et al. Trends in preterm 24. Miller WB. Relationships between the intendedness of con-
birth and perinatal mortality among singletons: United States, ception and the wantedness of pregnancy. J Nerv Mental Dis.
1989 through 2000. Obstet Gynecol. 2005;105(5 pt 1):1084–1091. 1974;159(6):396–406.
5. Hoffman S, Hatch MC. Stress, social support and pregnancy 25. Health and social survey. (In French). Quebec, Canada:
outcome: a reassessment based on recent research. Paediatr Ministry of Health and Social Services; 1998.
Perinat Epidemiol. 1996;10(4):380–405. 26. Barrera M. Social support in the adjustment of pregnant ado-
6. Borders AE, Grobman WA, Amsden LB, et al. Chronic stress lescents: assessment issues. In: Gottieb BH, ed. Social Net-
and low birth weight neonates in a low-income population of work and Social Support. Beverly Hills, CA: Sage Publishing;
women. Obstet Gynecol. 2007;109(2 pt 1):331–338. 1981:69–96.
7. Sandman CA, Wadhwa PD, Chicz-DeMet A, et al. Maternal 27. Lobel M, Dunkel-Schetter C, Scrimshaw SC. Prenatal mater-
stress, HPA activity, and fetal/infant outcome. Ann N Y nal stress and prematurity: a prospective study of socioeco-
Acad Sci. 1997;814:266–275. nomically disadvantaged women. Health Psychol. 1992;
8. Hobel CJ, Dunkel-Schetter C, Roesch SC, et al. Maternal 11(1):32–40.
plasma corticotropin-releasing hormone associated with stress 28. Lobel M, DeVincent CJ, Kaminer A, et al. The impact of
at 20 weeks’ gestation in pregnancies ending in preterm de- prenatal maternal stress and optimistic disposition on birth
livery. Am J Obstet Gynecol. 1999;180(1 pt 3):S257–S263. outcomes in medically high-risk women. Health Psychol.
Am J Epidemiol 2009;169:1319–1326
1326 Kramer et al.
44. Obel C, Hedegaard M, Henriksen TB, et al. Stress and salivary stress in human pregnancy. J Clin Endocrinol Metab. 2006;
cortisol during pregnancy. Psychoneuroendocrinology. 2005; 91(14):1329–1335.
30(7):647–656. 46. McGrath S, McLean M, Smith D, et al. Maternal plasma
45. Nierop A, Bratsikas A, Klinkenberg A, et al. Prolonged sali- corticotropin-releasing hormone trajectories vary depending
vary cortisol recovery in second trimester pregnant women and on the cause of preterm delivery. Am J Obstet Gynecol. 2002;
attenuated salivary alpha-amylase responses to psychosocial 186(2):257–260.
Am J Epidemiol 2009;169:1319–1326