Open Journal of Depression
2013. Vol.2, No.3, 24-31
Published Online August 2013 in SciRes (http://www.scirp.org/journal/ojd) http://dx.doi.org/10.4236/ojd.2013.23006
The Relationship between Prenatal Stress, Depression,
Cortisol and Preterm Birth: A Review
Kiran Shaikh1*, Shahirose Premj i2, Khurshid Khowaja3, Suzanne Tough4, Ambreen Kazi5,
Shaneela Khowaja6
1Aga Khan University School of Nu rsing and Midwifery, Karachi, Pakistan
2University of Calgary, Alberta, Canada
3Director of Nursing Al Noor Hospital, Al Ain and Associate Professor, Aga Khan University, Karachi, Pakistan
4Department of Pediatrics an d C ommunity Health, University of Calgary, Alberta, Canada
5Department of Community Health Sciences, Aga Khan University, Karachi, Pakistan
6Aga Khan University School of Nu rsing and Midwifery, Karachi, Pakistan
Received May 20th, 2013; revised June 22nd, 2013; accepted July 3rd, 2013
Copyright © 2013 Kiran Shaikh et al. This is an open access article distributed under the Creative Commons At-
tribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Preterm birth is one of the most common adverse pregnancy outcomes. Maternal risk factors such as
stress and depression have been associated with preterm birth. Preterm infants are at a higher risk of poor
growth and neuro developmental outcomes. The objective of this paper is to examine the relationship be-
tween maternal stress, depression, cortisol level, and preterm birth. Preterm birth is one of the most com-
mon adverse pregnancy outcomes with a global prevalence of 9.6% and one of the major contributors to
infant mortality and morbidity. The association between psychosocial stress and preterm birth, although
examined for more than 25 years, has not yet been fully established. A systemic review was conducted in
which research studies and review articles from 1970 to 2012, published in English, focusing on human
subjects, and addressing the relationship between stress, depression, cortisol and preterm birth were in-
cluded in this review. The studies examining the relationship between stress, cortisol levels and preterm
birth have shown inconsis tent findings that may be explained by varied study designs, differences in defin-
ing and measuring stress, timing of stress measurement, sample characteristics, and study designs. The
relationship between stress, cortisol levels and preterm birth may be multifactorial and complex with
premature birth being the final common pathway. A longitudinal cohort study, with a large sample size
and multiple measures of stress, depression, and cortisol level, as well as a measure of anxiety and other
stress hormone biomarkers may add new knowledge and enhance our understanding about the contribu-
tion of psychosocial stress to preterm birth.
Keywords: Maternal Stress; Antenatal Stress; Maternal Depression; Preterm Delivery; Preterm Birth;
Gestational Age; Low Birth Weights; Cortisol
Introduction
Preterm birth, defined as “birth before 37 completed weeks”
(Steer, 2005: p. 1), is one of the most common adverse preg-
nancy outcomes. Preterm birth is a global issue, irrespective of
region or the level of resources (Beck et al., 2010). All resource
regions: high, middle, and low report varying degrees of pre-
term birth rates (Beck et al.). The rate of preterm delivery
ranges from 5% in developed countries to 25% in developing
countries (Goldenberg et al., 2008; Steer, 2005). Africa (11.9%),
followed by North America (10.6%) and Asia (9.1%) have the
highest rates of preterm birth. The estimated global rate of pre-
term birth is 9.6% which is close to the rate of preterm birth
rate in Asia (Beck et al.). Studies indicate that preterm birth has
an impact on the rate of infant mortality and morbidity (Ma-
thew & Mac Dorman, 2007). According to the World Bank
(2008), the global infant mortality rate was 46 per 1000 live
births. Prematurity and its complications account for almost 30
percent of neonatal deaths (Mathews & Mac Dorman). The cost
of the hospitalization of preterm birth infant is $5.8 billion rep-
resenting half of infant hospitalization cost (Russell et al.,
2007). Moreover, stress of hospitalization and fear of losing an
infant is trauma tic and a source of grief for the family. Beside s
this, the psychological distress and risk of postpartum depres-
sion increases with having a preterm baby (Hill & Aldag, 2007).
Preterm infants are also at a greater risk of serious health prob-
lems, such as cerebral palsy, blindness, breathing problems, and
cognitive learning disabilities (Green et al., 2005; Latengresse,
2009; Rafati et al., 2005). Kramer et al. (2009) stated that un-
derstanding the etiology of preterm birth will facilitate early
identification of mothers at risk for preterm birth. Imple-
mentation of early intervention strategies for these high risk
mothers will decrease preterm birth thereby reducing the
burden of preterm birth (i.e., infant mortality, morbidity,
postpartum depression, parental role stress, and financial
*Corresponding author.

K. SHAIKH ET AL.
stress).
There are many maternal factors which are associated with
preterm birth and these have been extensively highlighted in
literature, such as low socioeconomic status, maternal age, and
low level of education, anemia, inadequate prenatal care, psy-
chosocial stress, obstetric complications, smoking, and mater-
nal history of preterm delivery (Allen, 2001; Astolfi & Zonta,
1999; Hsieh et al., 2005; Ismail, Zaidi, & Maqbool, 2003; Ma-
valankar, Gray, & Trivedi, 1992). The relationship of many of
these factors to preterm birth is clear. However, the association
between psychosocial stress and preterm delivery, although
examined for more than 25 years, has not yet been fully estab-
lished (Dunkel-Schetter, 1998; Latendresee, 2009).
Stress and depression alters the hypothalamic-pituitary-ad-
renal (HPA) axis whereby corticotrophin-releasing-hormone
(CRH) is secreted by the hypothalamus which in turn stimulates
the pituitary gland to secrete adrenocorticotrophic hormone
(ACTH). ACTH stimulates the adrenal cortex to secrete cortisol
hor mo ne ( Di eg o et al., 2009; Giurgescu, 2009; Ruiz et al., 2001)
and the adrenal medulla to secrete norepinephrine and epineph-
rine (Holzman et al., 2009). Increased cortisol levels further
signal the hypothalamus and pituitary gland in a negative feed-
back loop to decrease CRH production. However, in depressed
patients the negative feedback loop malfunctions resulting in
excess production of CRH; he nce cortisol. Simultaneously , stress
alters the immune function and increases the production of cy-
tokines. A negative feedback loop exists between the HPA axis
and the immune system. Cytokines stimulate the HPA axis and
lead to excessive secretion of cortisol (Behrman & Butler,
2007). In acute stress, glucocorticoids suppress the inflamma-
tory process but in chronic stress glucocorticoids can enhance
inflammation (Behrman & Butler). The increased secretion of
CRH, ACTH, cortisol, and cytokines stimulate prostaglandin
secretion which is responsible for the contraction and dilation
of the smooth muscle, could lead to preterm labor and prema-
ture rupture of membrane. Therefore, changes in the hormonal
milieu due to stress and depression may contribute to premature
initiation of labor and preterm birth.
Given the high prevalence of psychological disorder in wo-
men during pregnancy (Bennett, Einarson, Taddio, Koren, &
Einarson, 2004) preterm birth may be reduced by understanding
the psychosocial risk factors associated with cortisol and pre-
term birth and developing intervention strategies to mitigate
their impact. Cortisol levels may be a more objective measure
of stress and depression thereby facilitate our understanding of
the relationship between stress, depression and preterm birth.
The purpose of this review was to critically examine the rela-
tionship between stress, depression, cortisol and preterm birth
and identify gaps in the scientific literature.
Methods
A systematic and comprehensive search was undertaken to
extract relevant articles on the relationship between maternal
stress, depression, cortisol level, and preterm birth. The litera-
ture search was carried out through several electronic databases
like Cumulative Index to Nursing and Allied Health (CINAHL),
Science Direct, MD Consult and Blackwell Synergy from 1970
to 2011. Key words used to guide the search included maternal
stress, antenatal stress, maternal depression, preterm delivery,
preterm birth, gestational age, low birth weights and cortisol.
The search was expanded to specific nursing and medical jour-
nals such as J ourna l of M idwifery and Wom en He alth , Rese arch
and Health, Journal of Obstetrics, Gynecology and Neonatal
Nursing, American Journal of Obstetrics and Gynecology, and
Lancet and American Journal of Epidemiology as they are the
most relevant sources for new knowledge in maternal and child
health. Also, the reference lists of all relevant articles were re-
viewed to identify additional articles. Articles were included if
they examined the relationship between stress or depression,
cortisol level and preterm birth.
Findings
Overview of the Included Studies
A total of 49 articles were found examining the relationship
between stress, depression, cortisol and preterm birth. Of these,
27 articles wer e excluded as the y focused on infant cor tisol level,
non-pregnant women, fetal cortisol, and birth weight of the
infant rather than examine the r elationship betwee n the variables
of interest. Therefore, a total of 22 articles were selected for the
review as given their focuses on the relationship between stress,
depression, cortisol and preterm birth (see Figure 1). Although
everal studies have attempted to understand the psychosocial
risk factors associated with preterm birth, the relationships exa-
mined have varied between studies. For instance, a number of
researches examined the relationship between stress, depression
and preterm birth without considering cortisol (Copper et al.,
1996; Dole et al., 2003; Jesse, Swanson, Newton, & Morrow,
2009; Jesse, Seaver, & Wallace, 2003; Wadhwa, Culhane, Vit-
gina, Brave et al., 2001; Khashan et al., 2009; Whitehead et al.,
2002; Zhu et al., 2010). Two studies examined the relationship
between stress and cortisol only (Harville et al., 2009; Obel et
al., 2004) while five studies only explored the relationship be-
tween cortisol and preterm birth (Campbell, Challis, DaSilva, &
Bocking, 2005; Phocas, Sarandakou, & Rizos, 1990; Mazor et
al., 1994, 1996; Sandman et al., 2006). Of the 22 articles seven
determined the relationship between stress or depression,
Figure 1.
Flow of studies from initial screening to inclusion.

K. SHAIKH ET AL.
cortisol and preterm birth together at the same time (Diego et
al., 2009; Erickson et al., 2001; Field et al., 2004, 2006; Hobel
et al., 1999; Kramer et al., 2009; Shaikh et al., 2011).
Relationsh i p be tw e en Prenatal Stress or D epres sion
and Preterm Birth
Many studies demonstrate an association between stress and
preterm birth (Copper et al., 1996; Erickson et al., 2001; Hobel
et al., 1999; Jesse et al., 2009; Ruiz et al., 2001). Copper et al.,
in a prospective study, enrolled 2593 pregnant women between
25 to 29 weeks of gestation and demonstrated that stress was
significantly associated with sp ontaneous preterm birth and low
birth weight. Similarly, Jesse et al. (2003) conducted a prospec-
tive correlation research design in which 120 Appalachian
pregnant women were recruited between 16 and 28 weeks of
gestation and showed that symptoms of depression, level of self
esteem, and perception towards pregnancy were significantly
associated with preterm delivery. Women with depressive sy mp-
toms were four times more likely to deliver preterm birth as
compared to women without depressive symptoms. In this stu-
dy the rate of preterm delivery was 27 out of 120 babies (i.e.,
23% delivered preterm). Also, a population based retrospective
cohort study conducted in Denmark between January 1979 and
December, 2002, reported that maternal exposure to severe life
events increased the risk of preterm delivery (Khashan et al.,
2009). Whitehead, Hill, Brogan, and Blackmore-Prince (2002)
explored that stress beyond a certain threshold affects the rela-
tionship between stress and preterm birth.
On the other hand, many studies have reported contradictory
findings. Jesse et al. (2009) studied the relationship between bi-
opsychosocial factors and preterm birth in different ethnic
groups. Preterm delivery was three times higher in African
American than Hispanic and Caucasian women, but there was
no significant relationship between depressive symptoms and
preterm birth in African American or Caucasian women. Many
other studies have emphasized racial disparity as one of the
causes of preterm birth and highlighted that preterm birth was
more evident in African-American women compared to non-
Hispanic white women (Kramer & Hogue, 2009; Pearl, Brave-
man, & Abrams, 2001).
Wadhwa et al. (1993) also used a prospective study and re-
cruited 90 women at 22 and 28 weeks of pregnancy and showed
no significant relationship between perceived stress and gesta-
tional age at birth. In addition, Dole et al. (2003) reported simi-
lar findings in which life events, social support and depression
were not significantly associated with preterm birth. Similarly,
Hedegaard, Henriksen, Secher, Hatch and Sabroe (1996) in a
population based study of 5873 pregnant women reported that
negatives life events during pregnancy did not increase the risk
of preterm birth.
Relationship between Stress and Cortisol
Harville et al. (2009) analyzed data of stress and cortisol
from 1587 North Carolina and collected one saliva sample for
cortisol measurement and blood for CRH at 14 - 19 and 24 - 29
weeks’ gestation and found no co-relation between self-report-
ed indicators of stress and hormones such as cortisol and corti-
cotrophin-releasing hormone. While Obel et al. (2005) examin-
ed the exposure to stressful life events and changes in levels of
cortisol during pregnancy in a population of 603 pregnant wo-
men and found evening cortisol to be more strongly associated
with stress markers than morning cortisol.
Relationship between Cortisol and Preterm Birth
High cortisol level in pregnancy has been associated with
adverse pregnancy outcomes like aborted fetus, delayed fetal
growth, preterm delivery, and low birth weight baby (Campbell,
Challis, DaSilva, & Bocking, 2005; Field, Diego, Hernandez-
Reif, et al., 2008). A systematic review has been done to deter-
mine the relationship between cortisol levels and preterm birth
(Giurgescu, 2009). For this review, fifteen studies were selected.
Out of these, some studies determine the relationship of cortisol
and preterm birth and the remaining studies determine the rela-
tionship of maternal stress, depression, anxiety, cortisol, and
preterm delivery. The majority of these studies suggested that
women with higher cortisol levels in pregnancy were at greater
risk of preterm birth. Phocas et al. (1990) measured maternal
cortisol levels in 204 pregnant women at different gestational
ages. The blood cortisol samples were obtained between 8:00
a.m. to 9:00 a.m. Cortisol gradually increased from 6 weeks to
40 weeks of pregnancy and a sharp rise was noted two weeks
before the onset of labor in normal pregnancy.
Mazor et al. (1994) measured the amniotic fluid and plasma
concentrations of cortisol in 38 women with preterm labor and
intact membrane between 32 and 36 weeks of gestation. Ma-
ternal plasma cortisol levels were significantly higher in women
with preterm births than in those who delivered at term, but no
significant differences were reported in amniotic fluid cortisol
concentration. Similar results were found in a study where plas-
ma and amniotic fluid cortisol were measured for 40 pregnant
women with preterm labor and intact membrane at 28 to 30
weeks of gestation (Mazor et al., 1996).
Sandman et al. (2006) studied the relationship between ma-
ternal cortisol and CRH in 203 pregnant women in a longitudi-
nal study. Cortisol at 15 weeks of gestation predicted elevated
CRH at 31 weeks. A few studies measured the blood cortisol
level in pregnant women admitted with a diagnosis of threat-
ened preterm labor (Campbell et al., 2005). Cortisol was sig-
nificantly higher in women who gave birth within 24 to 48
hours of hospitalization. A majority of results of these studies
lend support to the premise that high blood level of cortisol in-
creases the risk of preterm delivery.
Relationship between Stress or Depression, Cortisol
and Preterm Birth
The studies that examine the relationship between maternal
stress, cortisol and preterm birth together at the same time have
inconsistent findings (see Table 1) (Erickson et al., 2001; Ho-
bel et al., 1999; Kramer et al., 2009; Ruiz et al., 2001; Shaikh et
al., 2011). Few studies (Erickson et al., 2001; Hobel et al., 1999;
Kramer et al., 2009) support the hypothesis that cortisol levels
increase with maternal stress. However, the Ruiz et al. (2001)
study does not support the hypothesis that cortisol levels in-
creases with stress, but it shows a significant relationship be-
tween stress and gestational age. Moreover, Shaikh et al. (2011)
did not find any relationship between stress, cortisol and pre-
term birth.
Erickson et al. (2001) prospectively recruited 3596 women
and matched 59 women who delivered preterm with 300 wo-
men who delivered at term. Hobel (1999) also conducted a pro-
spective study in which 524 women of diverse ethnic and
26

K. SHAIKH ET AL.
Table 1.
Relationship between prenatal stress, cortisol, and preterm birth.
Study Design Participants Scales SpecimenTime Period of
measurement Result
Erickson
et al. (2001)
Prospective
cohort study
design
3596 pregnant
women
Questionnaire I : Previous
and present medical
history. Que stionnaire II:
Social and demographic
information. Q u estionnaire
III: Present u r ogential and
obstetric problems.
Blood
7 - 23 and 27 - 37
weeks of gestat ion
and at 37 - 43
weeks of gestat ion
for those who
delivered at term.
Mean cortisol levels were highe r in
women who delivered preterm at
27 - 37 wee ks of g estation.
27 - 37 weeks: Cortisol levels were
higher in the preterm group as
compared to the term gro up .
Hobel et al.
(1999) Case control study design
524 pregnant
women
18 preterm patients
were matched with
18 term patie n ts.
PSS, SSAI Blood
18 to 20 wee ks, 28
to 30 week s and 35
to 36 weeks of
gestation
Patients wh o delivered preterm had
significantly elevated cortisol levels
at 18 to 20 weeks’ gestation and 28
to 30 weeks’ gestation.
Kramer et al.
(2009)
Prospective
cohort study
nested case
control analysis
5337 pregnant
women
Demographic questionnaire,
daily hassles scale, marital
strain scale of pearlin and
schooler, abu s e assessment
screen, arizona social support
interview s chedule, per ceived
stress scale , dunkel-schetter
scale, rosenberg self esteem
scale, and CES-D
Hair 24 - 26 weeks
of gestation
Pregnancy related anxiety and
depression were associated with
preterm b ir th .
Hair cortisol was positively
associated with gestational age
but not CRH.
Maternal plasma CRH, hair
cortisol, and placental
histopathologic of infection
were not associated with stress,
anxiety, or d istress me asures.
Ruiz et al.
(2001)
Prospective
longitudinal
observational
study design
78 pregnant
women PSS Blood,
vaginal
swabs
15 - 19, 20 to 22,
23 - 26, 27 - 30,
and 31 - 35 we eks
of gestation
Cortisol conce ntration did not
correlate with gestational age at
birth. The change in PSS scores
was significantly related to
gestational age at birth.
Shaikh et al.
(2010)
Prospective
cohort study
design
143 pregnant
women A-Z stress scale, CES-D scale Blood 28 weeks of gestation
There were no significant
relationship found between
stress, depression, cortisol
and preterm birth.
socioeconomic background were followed till delivery but only
18 women who delivered preterm were matched with 18 wo-
men who delivered at term. Moreover, Kramer, Lydon, et al.
(2009) prospectively recruited 5337 pregnant women of Mont-
real and conducted a nested case-control study. But, Ruiz et al.
(2001) conducted a prospective, longitudinal, observational stu-
dy in which 78 women were recruited and followed till delivery
and divided into three groups: normal term (n = 53), preterm
labor (n = 17), and preterm birth groups (n = 6). Shaikh (2011)
conducted a prospective cohort study in which 132 women
were recruited between 28 - 30 weeks of pregnancy and fol-
lowed till delivery.
Erickson et al. (2001) reported women with preterm birth had
higher cortisol levels at 27 - 37 weeks of gestation, but no in-
crease was reported at 7 - 23 weeks. Education level and work
related variables (walking more than 6 hours a day, working
more than 42 hours a week) were strongly associated with pre-
term delivery. Moreover, Hobel et al. (1999) concluded that the
preterm group had higher cortisol levels at 18 to 20 weeks and
28 to 30 weeks, but not at 35 to 36 weeks. In addition, Kramer
et al. (2009) concluded that among multiple stress measure-
ments, pregnancy related anxiety, perception of high pregnancy
risk, and depression were associated with preterm birth. Hair
cortisol was positively associated with gestational age but CRH
was not. In contrast, Ruiz et al.’s (2001) study does not support
the hypothesis that cortisol levels increases with stress, but it
shows a significant relationship between stress and gestational
age. Also, Shaikh (2011) study showed no significant relation-
ship between stress, cortisol, and preterm birth.
A few studies have been carried out to identify the relation-
ship between maternal depression, cortisol levels, and preterm
delivery and these show a significant relationship between the
three variables (see Table 2) (Diego et al., 2009; Field et al.,
2004, 2006; Field, Diego, Hernanzer-Rief et al., 2008). Field et
al. (2004) compared 70 pregnant women with and without de-
pression at 20 weeks of gestation by using the CES-D. The
study findings showed a significantly greater number of prema-
ture births in depressed women as compared to non-depressed
women (25% versus 7%, P < 0.01).
Field et al. (2006) recruited 300 pregnant women at 20 weeks
of gestation and their urinary cortisol levels were collected at
mid morning. The incidence of preterm was significantly higher
in the group with high cortisol level. Diego et al. (2009) con-
ducted a study in which 40 depressed and 40 non-depressed
women were recruited on the basis of their CES-D score, which
was measured in 18 and 20 weeks of gestation. The findings
suggested that depressed mothers had a 13% higher incidence
of preterm birth. Also, depressed women had more elevated pre-
natal cortisol levels than non-depressed women.
A study of 430 pregnant women, chronic prenatal depression
and cortisol levels were assessed longitudinally at 22 and 32
weeks of gestation (Field, Diego, Hernandez-Reif et al., 2008).

K. SHAIKH ET AL.
Table 2.
Relationship between prenatal depression, cortisol, and preterm birth.
Study Design Participants Scales Specimen
Time period of
measurement Results
Field et al.
(2004)
Prospective
longitudinal
study design
70 pregnant
women with
depression and
70 without
depression
CES-D scale, STAI, profile
mood states, anger scale,
vagal tone, EEG
asymmetry and neonata l
behavior during sleep and
during the brazelton neon atal
behavior assessment sca l e
Maternal and
neonatal urine for
cortisol,
dopamine, and
serotonin
20 weeks of
gestation and
within 24 hours of
delivery
The study findi ngs showed
significantly greater number of
prematur e births in depressed
women as compared to non-depressed
women (25% v ersus 7%, P < 0.01).
Cortisol was a significant predictor
of preterm birth.
Field et al.
(2006) Prospective cohort 300 pregnant women
CES-D, structured clinical
interview of diagnosis,
STAI and STAXI, behaviour
inhibition, and behaviour
approach system
questionnaire,
neonatal assessments
Urine cortisol 20 weeks of
gestation
The high cor ti sol group had higher
CES-D scores. The fetus was more
active an d had a smaller he ad
circumference, abdominal
circumference, biparietal diameter,
less fetal we i g ht and a shorter
gestational age.
Diego et al.
(2009) Prospective cohort study
40 depressed
and 40
non-depressed
pregnant w omen
Schedule of recent life
events, daily hassles,
perceived stress scale,
hopkins symptom checklist,
and pregna n cy-related
anxiety
Urine cortisol 18 - 20 weeks of gestation ( i.e .,
mid gestation)
Depressed women had a 13%
greater incidence of premature
delivery than non-depressed women.
Depressed women also had elevated
prenatal cortisol levels than
non-depressed women.
Field, Diego,
Hernandez-
Reif et al.
(2008)
Prospective
longitudinal
study design
430 pregnant
women
SCID, CE S -D, STAI and
STAXI, Daily hassles and
urine cortisol 22 weeks and 32
weeks of gestation
The depre ssed group had a higher
cortisol levels as compared to the
non-depre ss ed group on t he first
prenatal visit but no difference in
cortisol level wa s noted on the
second visit.
The depre ssed group had a higher
rate of preterm birth than the
non-depressed group.
ACTH Adrenocorticotrophic Ho rmones, CBC Complete Blood Count , CRH Corticotrophin-releasing-hormones, ACTH Adrenocorticotrophic Hormones, PSS Perceived
Stress Scale, SSAI The Spielberger State Anxiety Inventory, CES-D Centre for Epidemiology Studies Depression Scale, CRH Corticotrophin-releasing -hormon es, STAI
State Anxiety Inventory , EEG Electroencephalography, STAXI State Anger Inventory, SCID Structured Clinical Interview for DSM IV Disorder.
After delivery, postnatal depression was assessed and the rela-
tionship with neonatal outcomes was assessed.The depressed
group had higher cortisol levels as compared to the non-de-
pressed group on the first prenatal visit but no difference in
cortisol levels was noted on the second visit in the two groups.
The depressed group had more incidences of preterm birth than
the non-depressed group. Hence, all these studies highlight the
significance of maternal cortisol as an important predictor for
preterm delivery and an indicator of depression.
Discussion
The existing literature on the relationship between stress, de-
pression, cortisol and preterm does not have a common, clear,
and consistent definition of the concept of stress, as evident
from the different measures of stress (i.e., the various scales)
used. The researchers have used a variety of scales to measure
stress which makes it difficult to compare the results. For in-
stance, Whitehead et al. (2002) measured stress by negative life
events, which included family illness, death, finances, job loss,
relationships, physical injury, and legal matters, whereas Hobel
et al. (1999) measured the perception of stress by using the PSS
and Spielberger State Anxiety Inventory (STAI). Erickson et al.
(2001) study included previous and present medical history,
stressful life situations, and questions on behaviors, and present
urogenital and obstetric history. Ruiz et al. (2001) used only the
PSS. In addition, Wadhwa et al. (1993) assessed stress using
multiple scales, such as Schedule of Recent Life Events, Daily
Hassles Questionnaire, PSS, Hopkins Symptoms Checklist for
measuring psychological and physical symptoms and Pregnan-
cy Related Anxiety Scale. Obel et al. (2005) and Zhu et al.
(2010) used Life Events Checklist. Shaikh et al. (2011) used
A-Z stress scale. Moreover CES-D was use d to assess depress-
ion (Diego et al., 2009; Fi el d et a l. , 2004, 2006; Shaikh et al.,
2011). The varied variables for instance live events, daily
hassles, social support used in different studies to assess stress
during pregnancy makes it dif ficult to compar e the outco mes
as varied measures are used. There has been no universal stan-
dard method to measure stress in pregnant women. The lack of
use of a standardized scale to measure stress contributes to the
inability to confirm the association between maternal stress,
cortisol level and preterm birth (Lantendresse, 2009; Paarlberg
et al., 1995).
The different inclusion and exclusion criteria used in studies
may also explain the inconsistent findings. Erickson et al.
(2001); Harville et al. (2009); Hobel et al. (1999); Kramer et al.
(2009); Obel et al. (2003); Shaikh et al. (2011) and Zhu et al.
(2010) enrolled primiparous and multiparous women, while Ruiz
et al. (2001) enrolled only primiparous women. In addition, a
few studies excluded women who received betamethasone (Eri-
ckson et al.; Hobel et al.; Mazor et al., 1994, 1996; Shaikh et al.)
whereas Harville et al.; Kramer et al.; Obel et al. (2003) and
28

K. SHAIKH ET AL.
Ruiz et al. (2001) did not mention betamethasone treatment.
Betamethasone affects the cortisol level and therefore may not
highlight the relationship between stress, cortisol, and preterm
delivery. Moreover, a few studies excluded women with diabe-
tes mellitus, thyroid disorder, and chronic renal or heart disease
and uterine and cervical abnormalitywhich are the risk factors
for preterm birth and can impact the result (Diego et al., 2009;
Kramer et al.; Ruiz et al.; Shaikh et al.; Zhu et al.).
Cortisol undergoes diurnal variation. It is at its highest prior
to awakening and decreases during the day and is at its lowest
in the evening (Levine et al., 2007; Ruiz et al., 2001). Therefore,
cortisol should be drawn in the morning or the afternoon, con-
sistently, for each subject. Hobel et al. (1999) collected plasma
cortisol level between 9 a.m. to 1 p.m. Harville et al. (2009)
collected between 8 a.m. and 10 a.m. while Ruiz et al. (2001)
collected plasma cortisol either in the morning or the afternoon,
consistently, for each subject. Obel et al. (2005) collected morn-
ing and evening sample. A number of studies collected first
morning urine cortisol sample (Diego et al., 2009; Field, 2004,
2006). The different time period s in which stress and depressi on
were measured may explain the variation in findings regarding
the lin k be tw een st r ess, de p re ssi on, an d pr ete r m bir t h. Paa r lb e rg,
Vingerhoets, Passchier, Dekker, and Geijn (1995) observed that
an identical stressful condition led to different effects depend-
ing on when during the pregnancy (i.e., which trimester) the
stressful condition occurred whereas in late pregnancy the same
stimuli can lead to preterm delivery. In their view stress in early
pregnancy affects the developing fetus. The use of a longitudi-
nal design, where multiple measurements are taken, will give a
better understanding of the relationship between stress and pre-
term delivery (Giurgescu, 2009).
On the other hand, the Erickson et al. (2001) study collected
serum cortisol but did not mention the time the sample was
collected. The varied times of data collections may also explain
the inconsistent findings. Some studies used blood (Erickson et
al., 2001; Phocas et al., 1990; Hobel et al., 1999; Mazor et al.,
1994, 1996; Ruiz et al., 2001) to measure the cortisol level
whereas a few studies measured cortisol in urine (Diego et al.,
2009; Field et al., 2004, 2006) and one study used hair to mea-
sure cortisol (Kramer, et al., 2009) and two studies used sa-
liva (Harville et al.; Obel et al.). Cortisol levels can be de-
tected in blood, urine, and saliva. Urinary cortisol is a non-
invasive procedure and a better way to measure cortisol than
other measures for frequent and rapid sampling. Levine et al.
(2007) explained the reason for preferring 24 hours urine
sample for cortisol as “Urinary cortisol excretion results from
glomerular filtration and is a useful index of integrated 24
hours plasma free cortisol” (p. 46). Therefore, urinary corti-
sol may be a more accurate measure of maternal cortisol le-
vels when a 24 hours urine collection for cortisol is taken
rather than a single measure of urine for cortisol (Levine et
al.).
The studies examining the relationship between stress, corti-
sol levels and preterm birth, shows inconsistent results. Some
studies (Hobel et al., 1999; Erickson et al., 2001; Kramer et al.,
2009) support the relationship between stress, cortisol, and pre-
term births, whereas others (Ruiz et al., 2001; Harville et al.,
2009) found cortisol to be a poor biomarker. In normal preg-
nancy, the cortisol level increases throughout pregnancy and at
mid pregnancy the level increases by 50% due to the production
of CRH via placenta (Ruiz et al., 2001). Measuring stress once
in a pregnancy may not provide an adequate appraisal of the
psychosocial health of the women throughout the pregnancy.
Hence, multiple measurements of stress variables are likely to
provide a more in-depth understanding of the relationship be-
tween stress and preterm birth. Even though there are inconsis-
tencies in th e fin di ngs of th e stud ies th at ad dress t he r el ationsh ip
between stress, depression, cortisol, and preterm birth, high
levels of cortisol may be one of the strong biomarkers for pre-
term delivery (Giurgescu, 2009). In other words, higher stress
and depression scores and higher levels of cortisol when occur-
ring together, may predict preterm birth. The relationship be-
tween stress, depression, cortisol levels and preterm birth may
be multifactorial and complex with premature birth being the
final common pathway.
Implications for Research
Studies (Field et al., 2004, 2006; Field, Diego, Hernandez, et
al., 2008) suggest that among pregnant women cortisol gets
elevated with co-occurring anxiety and depression. Hence, add-
ing an anxiety measure would enhance the psychological mea-
sures and allow for more sophisticated data analyses, such as
comparing women with elevated scores on both anxiety and de-
pression. Furthermore, a recent study by Holzman et al. (2009)
proposed other biomarkers, such as catecholamine level (e.g.,
epinephrine, norepinephrine, and dopamine) for preterm deliv-
ery. Therefore, adding this biomarker in future studies may
contribute to our understanding of the mechanism responsible
for preterm birth. Moreover, such studies should be done using
non-invasive methods to check cortisol hormone like saliva
because it is easier and painless if multiple measures are going
Finally, a longitudinal cohort study design should be under-
taken in which stress, depression and cortisol are measured in
each trimester.
Implications for Practice
Mental health of pregnant women is often not given priority.
Medical and Nursing clinicians (e.g., community health nurses)
and lady health visitors should integrate assessment of psycho-
social factors as standard of care provided to pregnant women.
Early identification of stress and depression will permit the
medical and nursing clinicians to implement measures to reduce
stress and depression caused by psychological factors and its
potential negative consequences such as preterm birth (Laten-
dresse, 2009). Decreasing the incidence of preterm birth may
reduce infant which is an important fourth millennium devel-
opment goal. In addition, nurses should be educated about the
importance of the psychological aspect of care. Group prenatal
care may be one of the strategies nurses can employ to reduce
stress (Field & Diego, 2008). Ickovics et al. (2007) demonstrated
that group prenatal care which includes physical assessment,
education and skills building, and support through facilitated
group discussion, reduced the incidence of preterm birth when
compared to women who received individual prenatal care.
Group prenatal care reduced the stress and the effects on ma-
ternal and fetal endocrine stress response, minimizing the inci-
dence of preterm birth.
Health professionals (e.g., physicians, nurses and psycholo-
gist) who have skills need to intervene in a timely way in order
to lower the stress of pregnant women and to monitor the im-
pact of their interventions to ensure that appropriate outcomes
are attained. A number of interventions have been shown to re-
duce stress, anxiety and depression or its negative consequen-

K. SHAIKH ET AL.
ces including music therapy (Chang, Chen, & Feng, 2007),
yoga (Narendran, Nagarathna, Narendran, Gunasheela, & Na-
gendra, 2005) and massage (Field et al., 2005).
The impact of interventions directed at reducing or managing
stress thereby reducing the rate of preterm births needs to be
evaluated. Those health providers who do not have expertise
should make appropriate referrals to the psychologist.
Conclusion
Preterm birth is one of the most common adverse pregnancy
outcomes and it is associated with infant mortality. Stress and
depression stimulate HPA axis which enhance cortisol secretion
increasing the risk of preterm birth. The relationship between
stress, depression, cortisol level and preterm birth remains un-
clear. The studies discussed in this paper are in partial agree-
ment that stress, depression and cortisol levels may contribute
to preterm birth. Therefore, health care provider should assess
psychological indicators more closely to provide appropriate
treatment. A longitudinal cohort study, with multiple measures
of stress, depression, and cortisol level, as well as a measure of
anxiety and other stress hormone biomarkers may add new
knowledge and enhance our understanding about the relation-
ship between stress, depression, anxiety, cortisol level and pre-
term birth.
REFERENCES
Bruce, V., & Allen, L. H. (2001). Biological mechanisms that might
underlie iron’s effects on fetal growth and preterm birth. Journal of
Nutrition, 13, 581S-589S.
Astolfi, P., & Zonta, L. A. (1999). Risks of preterm delivery and asso-
ciation with maternal age, birth order, and fetal gender. Human Re-
production, 14, 2891-2894. doi:10.1093/humrep/14.11.2891
Beck, S., Wojdyl a, D., Say, L., Betran, A. P ., Merialdi, M., Requejo, J.
H., et al. (2010). The world wide incidence of preterm birth: A sys-
tematic review on maternal mortality and morbidity. The Bulletin of
the World Health Organization, 88, 31-38.
Behrman, R. E., & Butler, A. S. (2007). Preterm birth, cause, conse-
quence and prevention. Washington DC: Nat ional Academic Press.
Bennett, H. A., Einarson, A., Taddio, A., Koren, G., & Einarson, T. R.
(2004). Prevalence of depression during pregnancy: Systematic re-
view. Obstetrics and Gynecology, 103, 698-709.
Campbell, M. K., Challis, J. R., DaSilva, O., & Bocking, A. D. (2005).
A cohort study found that white blood cell count and endocrine mar-
kers predicted preterm birth in symptomatic women. Journal of Cli-
nical Epidemiology, 58, 304-310. doi:10.1016/j.jclinepi.2004.06.015
Chang, M. Y., Chen, C. H., & Feng Huang, K. (2008). Randomized ex-
perimental study of women during pregnancy. Journal of Clinical
Nursing, 17, 2580-2587.
Copper, R. L., Goldenberg, R. L., Das, A., Elder, N., Swain, M., Nor-
man, G., et al. (1996). The preterm prediction study: Maternal stress
is associated with spontaneous preterm birth at less than thirty-five
weeks’ gestation. American Journal of Obstetrics and Gynecology,
175, 1286-1292. doi:10.1016/S0002-9378(96)70042-X
Diego, M. A., Field, T., Hernandez-Reif, M., Schanberg, S., Kuhn, C.,
& Gonzalez-Quintero, V. H. (2009). Prenatal depression restricts fe-
tal growth. Early Human Development, 85, 65-70.
doi:10.1016/j.earlhumdev.2008.07.002
Dole, N., Savitz, D. A., Hertz-Picciotto, I., Siega-Riz, A. M., McMahon,
M. J., & Buekens, P. (2003). Maternal stress and preterm birth. Ame-
rican Journal of Epidemiology, 157, 14-24. doi:10.1093/aje/kwf176
Dunkel-Schetter, C. (1998). Maternal stress and preterm delivery. Pre-
natal and Neonatal Medici ne , 3, 39-42.
Erickson, K., Thorsen, P., Chrousos, G., Grigoriadis, D. E., Khongsaly,
O. N., McGregor, J., et al. (2001). Preterm birth: Associated neuro-
endocrine, medical, and behavioral risk factors. Journal of Clinical
Endocrinology and Metabolism, 86, 2544-2552.
doi:10.1210/jc.86.6.2544
Field, T., & Diego, M. (2008). Cortisol: The culprit prenatal stress va-
riable. International Journal of Neuroscience, 118, 118 1-1205.
doi:10.1080/00207450701820944
Field, T., Diego, M., Dieter, J., Hernandez-Reif, M., Schanberg, S.,
Kuhn, C., et al. (2004). Prenatal depression effects on the fetus and
newborn. Infant Behavior and D ev el o pm en t, 27 , 216-229.
Field, T., Diego, M., Hernandez-Reif, M., Figueiredo, B., Schanberg, S.,
& Kuhn, C. (2008). Chronic prenatal depression and neonatal out-
come. International Journal of Neuroscience, 118, 95- 103.
doi:10.1080/00207450601042144
Field, T., Hernand ez-Reif , M., Diego, M., Figueiredo, B., Schanberg, S.,
& Kuhn, C. (2006). Prenatal cortisol, prematurity and low birth
weight. Infant Behavior and Developm e n t , 2 9 , 268-275.
doi:10.1016/j.infbeh.2005.12.010
Giurgescu, C. (2009). Are maternal cortisol levels related to preterm
birth? Journal of Obstetric, Gynecologic, & Neonatal Nursing, 38,
377-390.
Goldenberg, R. L., Culhane, J. F., Iams, J. D., & Romero, R. (2008).
Epidemiology and causes of pr eterm birth. The Lancet, 37, 75-84.
doi:10.1016/S0140-6736(08)60074-4
Green, N. S., Damu s, K., Simpson, J. L., Iams, J., Reec e, E. A., Hobel,
C. J., et al. (2005). Research agenda for preterm birth: Recommenda-
tions from the march of dimes. American Journal of Obstetrics and
Gynecology, 19, 626-635. doi:10.1016/j.ajog.2005.02.106
Harvaline, E. W, Savitz, D. A., Dole, N., Herring, A. H, & Trop, J. M.
(2009). Stress questionnaires and stress biomarkers during pregnancy.
Journal of Women’s Health, 18, 1425-1433.
doi:10.1089/jwh.2008.1102
Hedegaard, M., Henriksen, T. B., Secher, N. J., Hatch, M. C., & Sab roe,
S. (1996). Do stressful life events affect duration of gestation and
risk of preterm delivery? Epidemiology, 7, 339-345.
Hill, P. D., & Aldag, J. C. (2007). Maternal perceived quality of life
following childbirth. Journal of Obstetric, Gynecologic, & Neonatal
Nursing, 36, 328-334. doi:10.1111/j.1552-6909.2007.00164.x
Hobel, C. J., Dunkel-Schetter, C., Roesch, S. C., Castro, L. C., & Arora,
C. P. (1999). Maternal plasma corticotropin-releasing hormone asso-
ciated with stress at 20 weeks’ gestation in pregnancies ending in
preterm delivery. American Journal of Obstetrics and Gynecology,
180, S257-S263. doi:10.1016/S0002-9378(99)70712-X
Holzman, C., Patricia, S., Tian, Y., Bullen, B., DeVos, E., Leece, C., et
al. (2009). Maternal catecholamine in midprenancy and risk of pre-
term. American Journal of Epidemiology, 170, 1014-1024.
Hsieh, T. T., Chen, S. F., Shau, W. Y., Hsieh, C. C., Hsu, J. J., & Hung,
T. H. (2005). The impact of inter pregnancy interval and previous
preterm birth on the subsequent risk of preterm birth. Journal of the
Society for Gynecologic Investigation, 12, 202-207.
doi:10.1016/j.jsgi.2004.12.004
Ickovics, J. R., Kershaw, T. S., Westdahl, C., Magriples, U., Massey, Z.,
Reynolds, H., et al. (2007). Group prenatal care and perinatal out-
comes: A randomized controlled trial. Obstetrics and Gynecology,
110, 330-339. doi:10.1097/01.AOG.0000275284.24298.23
Ismail, M., Zaidi, K., & Maqbool, S. (2003). Premature and low birth
weight neonates and their management at the neonatology unit of
Shaikh Zayed Hospital Lahore. Pakistan Journal of Medical Re-
search, 42, 54-57.
Jesse, D. E., Seaver, W., & Wallace, D. C. (2003). Maternal psychoso-
cial risks predict preterm birth in a group of women from Appalachia.
Midwifery, 19, 191-202. doi:10.1016/S0266-6138(03)00031-7
Jesse, D. E., Swanson, M. S., Newton, E. R., & Morrow, J. (2009). Ra-
cial disparities in biopsychosocial factors and spontaneous preterm
birth among rural low-income women. Journal of Midwifery and
Women’s Health, 54, 35- 42. doi:10.1016/j.jmwh.2008.08.009
Khashan, A. S., McNamee, R., Abel, K. M., Mortensen , P. B., Kenny,
L. C., Pedersen, M. G., et al. (2009). Rates of preterm birth following
antenatal maternal exposure to severe life events: A population-based
cohort study. Human Re production, 24, 429-437.
doi:10.1093/humrep/den418
Kramer, M. S., Lydon, J., Seguin, L., Goulet, L., Kahn, S. R., McNa-
mara, H. et al. (2009). Stress pathways to spontaneous preterm birth:
30

K. SHAIKH ET AL.
The role of stressors, psychological distress, and stress hormones.
American Journal of Epidemiology, 169, 1319-1326.
doi:10.1093/aje/kwp061
Latendresse, G. (2009). The interaction between chronic stress and
pregnancy: Preterm birth from a biobehavioral perspective. Journal
of Midwifery and Women's Health, 54, 8-17.
doi:10.1016/j.jmwh.2008.08.001
Levine, A., Zagoory-Sharon, O., Feldman, R., Lewis, J. G., & Weller,
A. (2007). Measuring cortisol in human psychobiological studies.
Physiology and Behavior, 90, 43-53.
doi:10.1016/j.physbeh.2006.08.025
Mathews, T. J., & MacDorman, M. F. (2007). Infant mortality statistics
from the 2004 period linked birth/infant death data set. National vital
statistics reports, 55.
http://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_02.pdf
Mavalankar, D. V., Gray, R. H., & Trivedi, C. R. (1992). Risk factors
for preterm and term low birthweight in Ahmedabad, India. Interna-
tional Journal of Epidemiology, 21, 2 63-272.
doi:10.1093/ije/21.2.263
Mazor, M., Chaim, W., Hershkowitz, R., Levy, J., Leiberman, J. R., &
Glezerman, M. (1994). Association between preterm birth and in-
creased maternal plasma cortisol concentrations. Obstetrics and Gy-
necology, 84, 521-524.
Mazor, M., Hershkowitz, R., Ghezzi, F., Cohen, J., Silber, A., Levy, J.
et al. (1996). Maternal plasma and amniotic fluid 17 beta-estradiol,
progesterone and cortisol concentrations in women with successfully
and unsuccessfully treated preterm labor. Archives of Gynecology
and Obstetrics, 258, 89-96. doi:10.1007/BF00626029
Narendran, S., Nagrathna, R., Narendran, V., Gunasheela, S., & Rao, N.
H. R. (2005). Efficacy of yoga on pregnancy outcome. The Journal
of Alternative and Complementary Medicine , 11, 237-244.
doi:10.1089/acm.2005.11.237
Obel, C., Hedegaard, M., Henriksen, T. B., Secher. N. J., Olsen, J., &
Levine, S. (2005). Stress and salivary cortisol during pregnancy.
Psychoneuroendrocrinology, 30, 647-656.
doi:10.1016/j.psyneuen.2004.11.006
Paarlberg, K. M., Vingerhoets, A. D., Passchier, J., Dekker, G. A., &
Van Geijn, H. P. (1995). Psychosocial factors and pregnancy out-
come: A review with emphasis on methodological issues. Journal of
Psychosomatic Research, 39, 563-595.
doi:10.1016/0022-3999(95)00018-6
Pearl, M., Braveman, P., & Abrams, B. (2001). Relationship of socio-
economic characteristics to birthweight among 5 ethnic groups in
California. American Journ al of P ublic Health, 91, 1808-1814.
doi:10.2105/AJPH.91.11.1808
Phocas, I., Sarandakou, A., & Rizos, D. (1990). Maternal serum total
cortisol levels in normal and pathologic pregnancies. International
Journal of Gynecology and Obstetrics, 31, 3-8.
doi:10.1016/0020-7292(90)90173-I
Rafati, S., Borna, H., Akhavirad, M. B., & Fallah, N. (2005). Maternal
determinants of giving birth to low-birth-weight neonates. Archives
of Iranian Medicine, 8, 277-281.
Russell, R. B., Green, N. S., Meikle, S., Meikle, S., Howse, S., Posch-
man, K. et al. (2007). Cost of hospitalization for preterm and low
birth weight infants in the United States. Pediatric, 120, e1-e9.
doi:10.1542/peds.2006-2386
Ruiz, R. J., & Avant, K. C. (2005). Effects of maternal prenatal stress
on infant outcomes: A synthesis of the literature. Advances in Nurs-
ing Science, 28, 345-355.
Ruiz, R. J., Fullerton, J., Brown, C. E. L., & Schoolfield, J. (2001).
Relationships of cortisol, perceived stress, genitourinary infections,
and fetal fibronectin to gestational age at birth. Biological Research
for Nursing, 3, 39-47. doi:10.1177/109980040100300106
Sandman, C. A., Glynn, L., Schetter, C. D., Wadhwa, P., Garite, T.,
Chicz-DeMet, A. et al. (2006). Elevated maternal cortisol early in
pregnancy predicts third trimester levels of placental corticotropin
releasing hormone (CRH): Priming the placental clock. Peptides, 27,
1457-1463. doi:10.1016/j.peptides.2005.10.002
Shaikh, K., Premji, S. S., Rose, M. R., Kazi, A., Khowaja, S., & Tough,
S. (2011). The association between parity, infant gender, high level
of paternal education and preterm birth in Pakistan: A cohot study.
BMC Pregnancy Childbirth, 11, 1-10. doi:10.1186/1471-2393-11-88
Steer, P. (2005). The epidemiology of preterm labor. International
Journal of Obstetrics and Gynecology-Supplements, 112, 1-3.
The World Bank (2008). Mor tality rate, infant (per 1,000 live births).
http://data.worldbank.org/indicator/SP.DYN.IMRT.IN/countries/latest?
display=default.
Wadhwa, P. D., Culhane, J. F., Virginia, R., & Brave, S. (2001). Stress
and preterm birth: Neuroendocrine, immune/inflamattory, and vas-
cular mechanisms. Maternal and Child Health Journal, 5, 119-125.
doi:10.1023/A:1011353216619
Wadhwa, P. D., Sandman, C. A., Porto, M., Dunkel-Schetter, C., &
Garite, T. J. (1993). The association between prenatal stress and in-
fant birth weight and gestational age at birth: A prospective investi-
gation. American Journal of Obstetrics and Gynecology, 169, 858-
865. doi:10.1016/0002-9378(93)90016-C
Whitehead, N., Hill, H. A., Brogan, D. J., & Blackmore-Prince, C.
(2002). Exploration of threshold analysis in the relation between
stressful life events and preterm delivery. American Journal of Epi-
demiology, 15, 117-124. doi:10.1093/aje/155.2.117
Zhu, P., Tao, F., Hao, J. H., Sun, Y., Jiang, S., Jiang, X. (2010). Prena-
tal life events stress: Implications for preterm birth and infant birth
weight. American Journal o f O bs t et rics and Gynecology, 204 , e1-e8.
doi:10.1016/j.ajog.2010.02.023