JOURNAL OF WOMEN’S HEALTH
Volume 17, Number 9, 2008
© Mary Ann Liebert, Inc.
The Psychoneuroimmunology of Postpartum Depression
Elizabeth J. Corwin, Ph.D., and Kathleen Pajer, M.D., M.P.H.
Postpartum depression (PPD) is a potentially debilitating disorder that develops in a significant percentage of
women during the first year after giving birth. Women afflicted with PPD experience long-term consequences,
including sadness, guilt, and despair. Offspring may be affected as well. Several investigators have tested psy-
chosocial risk factors for the development of PPD; however, substantial amounts of variance in PPD have gone
unexplained with regression on psychosocial variables alone. Likewise, interventions for PPD that have focused
on psychosocial risk factors alone have been largely unsuccessful. The unexplained variance and disappoint-
ing treatment success could well be due to investigators’ failure to address relevant biological changes occur-
ring during the postpartum period. Two biological systems that are affected significantly and remain in flux
during the postpartum period are the innate immune system and the hypothalamic-pituitary-adrenal (HPA)
axis. Bidirectional interactions between these two systems are well established, and it is generally acknowl-
edged that dysfunction in either system can lead to depression in nonpregnant, nonpostpartum populations.
To date, little research has pursued the contribution of these interacting systems to the development of PPD.
The purpose of this paper is to review the psychoneuroimmunology of PPD. The central hypothesis presented
is that dysregulation in either system individually or in their bidirectional interaction is associated with the de-
velopment of PPD.
(PPD) is a debilitating disorder
that develops in new mothers during the first year after
giving birth. Long-term sequelae, including maternal sad-
ness, guilt, and despair, may occur, as may consequences for
Despite much research, the mechanisms under-
lying PPD remain elusive. Psychosocial variables are insuf-
ficient as the sole explanatory variables, and interventions
focused on altering psychosocial risk factors alone have
yielded disappointing results.
Biological mechanisms have
also been explored, but research on the role of gonadal hor-
mone fluxes, thyroid dysregulation, and abnormal neuro-
transmitter levels likewise have been inconclusive.
The purpose of this paper is to review the psychoneu-
roimmunology of PPD, wherein the contributions of two
other, interconnected biological systems, both significantly
altered during pregnancy and childbirth, are reviewed in re-
gard to the development of PPD. Specifically, we review how
pregnancy-related changes in the innate immune system and
the hypothalamic-pituitary-adrenal (HPA) axis may contrib-
ute to the development of PPD if they do not return to nor-
mal function after delivery. This perspective is an extrapo-
lation of data indicating that overstimulation of the innate
immune system and HPA axis dysregulation are both asso-
ciated with depression in adults who are not in the post-
First, a brief overview of the epidemiological, clinical, and
physiological characteristics of PPD is presented. The next
two sections review data in support of innate immune sys-
tem dysfunction and HPA axis dysregulation as possible eti-
ological factors in the development of PPD. The paper con-
cludes with recommendations for future research to clarify
these associations. Our goal throughout is to highlight the
significance of these two systems in postpartum women in
light of their known relationships with depression, in order
to encourage future research to improve the health of post-
Overview of Postpartum Depression
The birth of a child is usually a time of great joy. For some
women, however, the stressors of the postpartum period
combine to reduce the ability of a new mother to meet her
The Ohio State University, Columbus, Ohio.
The authors deny any conflict of interest or financial arrangement with any companies or institutions that may benefit from the find-
ings presented in this paper.
role demands. Of particular concern is the development of
PPD, which occurs in 15%–20% of women during the first
year after giving birth.
PPD is a moderate to severe mood disorder comparable
to a major depressive episode in the DSM-IV-TR. PPD car-
ries significant and dangerous implications for a new
mother’s health and the health of her infant.
It may in-
terfere with maternal role development and mother-infant
bonding and may cause physical risk to mother and child
alike. The effects on children may include behavioral, de-
velopmental, and cognitive delay and may last years beyond
The development of PPD is often insidious, with symptoms
including sadness, an inability to take pleasure in most ac-
tivities, anxiety, irritability, fatigue, poor sleep, and recurrent
thoughts of suicide or death, beginning as early as 2 weeks
to as late as several months after delivery.
PPD is diag-
nosed by careful history and physical examination followed
by application of one of many screening tools; women who
score at high risk may receive a follow-up interview to con-
firm the diagnosis.
Major psychosocial risk factors for PPD
include prenatal depression, previous history of depression,
low self-esteem, inadequate social support, child care stress,
a fussy infant, and life stressors.
Financial hardship more
than triples the risk of PPD, partially explaining the higher
prevalence of PPD in black and Hispanic mothers.
Physiological risk factors for PPD have been proposed as
well, including hypothyroidism and acute change in repro-
ductive hormone levels.
Although depressed mood is
common in those suffering a thyroid abnormality, most
women with PPD have thyroid hormone levels in the nor-
mal range. Similarly, although acute changes in estrogen lev-
els may precipitate PPD, this appears to affect only a sub-
population of women with a history of depression.
A possible biological mechanism that has received little
attention to date is the bidirectional innate immune system-
HPA axis association. This is surprising, given the profound
changes that occur within these systems during pregnancy
and delivery and their associations with depression in other
Innate Immune System
The innate immune response is stimulated by infection,
injury, malignancy, autoimmune disease, and stress. It is
rapid in onset and serves to acutely limit tissue damage and
the spread of infection. It is orchestrated by the synthesis and
release of proinflammatory and anti-inflammatory cyto-
kines. Proinflammatory cytokines, including interleukin-1-
beta (IL-1), IL-2, IL-6, tumor necrosis factor-alpha (TNF-),
interferon-alpha (IFN-), and interferon-gamma (IFN-), are
proteins released from activated white blood cells in re-
sponse to the conditions noted.
Release of proinflamma-
tory cytokines initiates a systemic inflammatory response
characterized by fever, increased sleep, reduction in activity,
increased fatigue, decreased food intake, decreased explo-
ration, diminished sexual activity, and, in humans, de-
Because of the potential for unabated inflammation to
cause undesirable side effects in the host, the proinflamma-
tory response normally is kept in check through the recip-
rocal production of anti-inflammatory cytokines, including
IL-4 and IL-10, which inhibit the production of proinflam-
Occasionally, the balance between
proinflammatory and anti-inflammatory cytokines shifts,
impacting an individual’s mental health.
Inflammation and depression
Research suggests that prolonged or excessive activation
of the proinflammatory immune response may be a mecha-
nism for depression.
Administration of even nanomolar
concentrations of proinflammatory cytokines to patients
with cancer, hepatitis C, or other diseases induces symptoms
In individuals already suffering from de-
pression, proinflammatory cytokines, including IL-1, IL-6,
and TNF-, are elevated.
The HPA axis has far-reaching effects on immunity, me-
tabolism, and reproduction. These are accomplished through
frequent pulsatile secretion of cortisol, accompanied by large
surges of the same hormone in response to changes or threats
in the environment. The secretion of cortisol is the final prod-
uct in a secretory pathway initiated by the release of corti-
cotrophin-releasing hormone (CRH) from the hypothalamus.
CRH stimulates the secretion of adrenocorticotrophic hor-
mone (ACTH) from the anterior pituitary, which serves as
the stimulus for adrenal cortisol secretion. HPA axis func-
tion is predominantly regulated by a negative feedback loop.
Control of HPA axis activity is essential in protecting the or-
ganism from the catabolic, lipogenic, antireproductive, and
immunosuppressive effects of prolonged exposure to gluco-
When exposed to changes in the environment perceived
to be threatening or those which are physically stressful, the
HPA axis secretes a larger amount of cortisol than the fre-
quent pulses that comprise the basal circadian rhythm.
stress response produces an increase in alertness and pro-
vides additional energy through gluconeogenesis, accompa-
nied by suppression of nearly all components of the immune
response, including all the key steps of proinflammatory cy-
tokine production and secretion.
The system usually re-
turns to baseline within a few hours after stress exposure,
but if chronic exposure continues, the system can become
dysregulated, manifest by various patterns of hyperactivity
HPA axis dysfunction and depression
Chrousos and Gold
originally hypothesized that dys-
regulation in HPA axis function is best characterized by a U-
shaped curve. With HPA axis function on either end of the
curve, depression, dysphoria, suicidal ideation, and all the
neurovegetative symptoms of depression are possible.
Clinically, hyperactivation of the stress response is associ-
ated with melancholic depression, anorexia nervosa, attach-
ment disorder of infancy, and childhood maltreatment.
Hypoactivation of the HPA, in turn, has been linked to sea-
sonal and atypical depression, rheumatoid arthritis, fi-
bromyalgia, and chronic fatigue syndrome.
cluded in this group depression that develops during the
postpartum period, as described later.
CORWIN AND PAJER1530
Innate System and HPA Axis Function
There is a well-documented bidirectional association be-
tween the innate immune response and the HPA axis.
IL-1, IL-2, IL-6, and TNF-stimulate cortisol secretion, di-
rectly by acting on the cells of the adrenal cortex and indi-
rectly via stimulation of CRH from the hypothalamus and
ACTH from the anterior pituitary.
IL-2 is a more potent
known stimulator of ACTH release than CRH on a molar-
to-molar basis. Chronically elevated proinflammatory cyto-
kines appear to induce a decrease in central nervous system
(CNS) glucocorticoid receptor function, decreasing the sen-
sitivity of hypothalamic CRH-secreting cells to rising corti-
sol and blunting the normal negative feedback response of
the hypothalamus to cortisol.
HPA activation, in turn, has profound inhibitory effects
on the immune/inflammatory response, acting to block vir-
tually each step of the proinflammatory process.
cocorticoids, of which cortisol is the primary type in humans,
inhibit the production of proinflammatory cytokines at the
level of the DNA by blocking the genes responsible for their
production and by inducing the production of NFkB, a pro-
tein that binds to and neutralizes important cytokine tran-
scription factors. Cytokines known to be downregulated by
cortisol and other glucocorticoids include IL-1, IL-2, TNF-,
and IFN-. Moreover, glucocorticoids favor the production
of the anti-inflammatory cytokines,
especially at low con-
centrations of glucocorticoids.
Innate Immune System, HPA Axis Function, and PPD
The implication that dysregulation in the immune system
or the HPA axis or both may contribute to the development
of PPD is conceptually based on the psychoneuroimmunol-
ogy model originally suggested by Chrousos and Gold as
early as 1992
and expanded upon more recently.
impact of the innate immune response and HPA axis function
on postpartum emotional regulation is depicted as occurring
both independently and via their bidirectional relationships.
In Figure 1, normal immune and HPA axis responses are pro-
posed, which individually and together contribute to post-
partum emotional regulation. In Figure 2, dysfunction in ei-
ther system alone or in their bidirectional interactions is shown
to destabilize emotional regulation and contribute to PPD.
Innate Immunity, HPA Axis Function, and Pregnancy
Pregnancy presents a unique immunological challenge to
the body. To carry a pregnancy to term, a woman must not
reject her developing fetus despite its antigenic incompati-
bility. At the same time, she must maintain her own im-
munocompetence. Studies suggest that maternal anti-in-
flammatory cytokines favorable for immunosuppression and
pregnancy maintenance are elevated during pregnancy
and proinflammatory cytokines are downregulated.
With the cessation of pregnancy and delivery of the in-
fant and placenta, the anti-inflammatory mileu abruptly,
that is, within hours, shifts to a proinflammatory state.
This occurs for several reasons: (1) a woman who has given
birth often has experienced significant perineal tissue in-
(2) uterine involution occurs in all postpartum
women and is characterized by ischemia, autolysis, and
phagocytosis, processes that in animal and human studies
are shown to involve significant inflammation and cytokine
and (3) pain, physical exertion, and emo-
tional stress—all hallmarks of childbirth—stimulate the
Several studies have described an increase in proinflam-
matory cytokines in healthy women with the onset of labor
and lasting at least for the first 72 hours after delivery.
There are, however, only a few reports, often conflicting, that
follow cytokine changes beyond the first few days after par-
turition. In our laboratory, we found that IL-1levels are el-
evated within 24 hours after giving birth and remain signif-
icantly elevated throughout the first month postpartum
compared with levels measured in control, nonpregnant,
Other authors variously report a
decrease in anti-inflammatory cytokines in the first several
an increase in proinflammatory cyto-
kines from 2 to 11 months postpartum with an overlapping
increase in IL-4 after 6 months,
and an increase in both anti-
inflammatory and proinflammatory cytokines at 3 months
postpartum compared with levels immediately after infant
The conflicting nature of these results may be at
least partially explained by the fact that two of the studies
fail to exclude or identify women with such pregnancy-as-
sociated complications as hemorrhage, surgery, and infec-
Moreover, none collected data on immunizations or
antibiotic use, both of which affect cytokines.
Significant changes in HPA axis function also occur dur-
ing pregnancy and delivery. Maternal levels of CRH, ACTH,
and cortisol increase dramatically during parturition, at-
taining peak levels in the third trimester.
HPA axis hormones drop within the first 3 days, with cen-
PNI AND POSTPARTUM DEPRESSION 1531
FIG. 1. Conceptual framework depicting normal relation-
ship between the inflammatory response and the HPA axis.
HPA Axis Activity
in Innate Immune
FIG. 2. Conceptual framework for the proposed study, de-
picting dysregulated relationships among the HPA axis, the
inflammatory response, and PPD.
tral axis suppression similar to that occurring after abrupt
discontinuation of exogenous steroids.
The fetal adrenal gland is critical in understanding HPA
axis physiology during pregnancy and the perinatal period.
It secretes significant amounts of cortisol, which under the
influence of progesterone, stimulates cells of the trophoblast
and placenta to increase (not decrease) their production of
Placental CRH is required for successful implanta-
tion and maintenance of early pregnancy and may play a
role in initiating parturition.
Production of CRH by the pla-
centa leads to a self-propagating cycle wherein elevated CRH
stimulates further fetal cortisol production, causing contin-
ued CRH secretion. Importantly, although fetal cortisol stim-
ulates placental CRH secretion, it suppresses maternal CRH
secretion. Maternal CRH suppression continues after deliv-
ery of the infant.
Maternal HPA axis suppression may last
for several weeks in healthy postpartum women.
In synthesizing these two lines of research, we propose
that for some women, PPD might be a psychoneuroim-
munological disorder. In healthy postpartum women, the in-
nate immune response is stimulated by labor and delivery
and causes an increase in the production of proinflamma-
tory cytokines. Over the next weeks to months, a woman re-
covers from childbirth, and inflammation regresses. HPA
axis function, although elevated early on, is suppressed, and
the cytokines do not stimulate the secretion of HPA axis hor-
mones. Focusing on the HPA axis, following delivery of an
infant and the placenta, a woman’s levels of CRH, ACTH,
and cortisol drop from pregnancy levels, and the axis be-
comes hyporesponsive, normalizing by about 12 weeks.
With recovery, the HPA axis hormones return and assist in
limiting inflammation. Together, these steps assure normal
postpartum emotional regulation.
For women who develop PPD, however, we suggest that
the inflammatory response after labor and delivery is exag-
gerated, the HPA axis function is not adequately suppressed,
or both conditions occur. With an exaggerated proinflam-
matory response, the systemic inflammatory response syn-
drome would occur, characterized by fatigue, poor sleep,
poor appetite, and depressed mood. HPA axis hyperactivity
would be associated with agitation, dysphoria, insomnia,
and anorexia. One would expect an exaggerated inflamma-
tory or stress response after prolonged or difficult labor, ex-
cessive blood loss, perineal damage, clinical or subclinical in-
fection, surgery, or a negative emotional delivery.
There are some data to support this hypothesis. Increased
IL-6 levels have been reported in women with PPD early in
the perinatal period and in women with past histories of de-
In addition, one study has examined both cyto-
kines and cortisol, although the authors did not address this
This study was cross-sectional, involving women vis-
ited in their homes once between postpartum weeks 4 and 6.
Serum IFN-, IL-10, and cortisol were measured and evalu-
ated in light of perceived stress and dysphoric mood. Find-
ings suggested that depressed mothers had significantly lower
salivary but not serum cortisol concentrations and a lower
serum ratio of IFN-/IL-10. IL-6 levels, in contrast, were non-
significantly higher by 3-fold in depressed women. This study
suggests that hypoactivation rather than hyperactivation of
the HPA axis might contribute to PPD and supports a mixed
role for the proinflammatory immune response. It should be
noted, however, that depression was determined using a non-
specific measure (the Profile of Mood States) and was not val-
idated clinically. Also, women who delivered vaginally or sur-
gically were included, perhaps impacting cytokine and stress
hormone levels, and the women scoring as depressed were
significantly more likely to smoke, again potentially impact-
ing cytokine levels
and postpartum depression.
Hyperactivity of the HPA axis has been reported in
women with PPD by some researchers,
have failed to replicate these findings.
Still others have
found a correlation between low cortisol levels and PPD.
It is important to note that few of the studies of either sys-
tem controlled for demographic factors, breastfeeding status,
hormonal contraception, resumption of menses, vaginal vs.
surgical delivery, or season, all of which will affect cytokine
levels and HPA axis function. Very few collected data on past
psychiatric history, which may be an indicator of chronic dys-
regulation of the immune system, the HPA axis, or both.
Additional research controlling for a number of external
variables needs to be performed to clarify the psychoneu-
roimmunology of PPD. These studies should involve, at first,
only women delivering vaginally, without complications,
and without antibiotic or antidepressant therapy. Circadian
function will need to be evaluated, as it may be that very
subtle derangements in cytokines or HPA axis hormones are
at play. Both proinflammatory and antiinflammatory cyto-
kines will need to be measured, as the balance between these
is the variable of most significance. Likewise, measuring cor-
tisol alone tells less about the HPA axis feedback than in-
cluding CRH and ACTH in analysis, as well as diurnal vari-
ation. And finally, women screened as depressed must be
clinically diagnosed as well.
If dysregulation of the bidirectional interactions between
the innate immune system and the HPA axis does play a role
in the development of PPD, we would expect that studies such
as those outlined here would demonstrate that women clini-
cally diagnosed with PPD have a higher ratio of proinflam-
matory cytokines/anti-inflammatory cytokines prior to and
during their episodes of depression compared with women
who do not develop PPD. We would also expect that women
diagnosed with PPD have higher levels of CRH, ACTH, and
cortisol prior to and during their episodes of depression com-
pared with women who do not develop PPD. Finally, we
would expect that women diagnosed with PPD will demon-
strate a cytokine-driven hyperactivity of the HPA axis com-
pared with women who do not develop PPD, as indicated by
significant differences in the slopes of the relationships be-
tween cytokines and HPA axis hormones in nondepressed
women compared with women diagnosed with PPD.
PPD is a significant problem for a substantial number of
women and families. By investigating reciprocal changes in
cytokine and HPA axis functioning over time in nonde-
pressed and depressed postpartum women, researchers will
have the opportunity to address an etiology for PPD not pre-
viously studied. Insights gained from such research will sig-
nificantly influence the prevention, diagnosis, and treatment
of depression afflicting women during this vulnerable and
important time of their lives.
CORWIN AND PAJER1532
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