Postpartum depression: Etiology, treatment and consequences for maternal
care

Susanne Brummelte, Liisa A.M. Galea

PII: S0018-506X(15)30042-8
DOI: doi: 10.1016/j.yhbeh.2015.08.008
Reference: YHBEH 3950

To appear in: Hormones and Behavior

Received date: 14 April 2015

Revised date: 18 August 2015
Accepted date: 21 August 2015

Please cite this article as: Brummelte, Susanne, Galea, Liisa A.M., Postpartum depres-
sion: Etiology, treatment and consequences for maternal care, Hormones and Behavior
(2015), doi: 10.1016/j.yhbeh.2015.08.008

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Postpartum depression: etiology, treatment and consequences for maternal care

Susanne Brummelte*1 and Liisa A.M. Galea2

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Dept. of Psychology, Wayne State University, Detroit, MI, USA 2 Dept. of Psychology,

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Graduate Program in Neuroscience, Centre for Brain Health, University of British Columbia,

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Vancouver, BC CANADA

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*Corresponding author: MA
Susanne Brummelte, Ph.D., Department of Psychology, Wayne State University,

5057 Woodward Ave., Detroit, MI, 48202, USA

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Phone 1 313 577 2834

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Fax 1 313 577 7636

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sbrummelte@wayne.edu
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Abstract

Pregnancy and the postpartum is associated with dramatic alterations in steroid and peptide

hormones which alter the mothers’ hypothalamic pituitary adrenal (HPA) and hypothalamic

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pituitary gonadal (HPG) axes. Dysregulations in these endocrine axes are related to mood

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disorders and as such it should not come as a major surprise that pregnancy and the

postpartum period can have profound effects on maternal mood. Indeed, pregnancy and the

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postpartum are associated with an increased risk for developing depressive symptoms in

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women. Postpartum depression affects approximately 10-15% of women and impairs mother-

infant interactions that in turn are important for child development. Maternal attachment,
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sensitivity and parenting style are essential for a healthy maturation of an infant’s social,

cognitive and behavioral skills and depressed mothers often display less attachment, sensitivity
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and more harsh or disrupted parenting behaviors, which may contribute to reports of adverse
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child outcomes in children of depressed mothers. Here we review, in honor of the “father of

motherhood”, Jay Rosenblatt, the literature on postnatal depression in the mother and its effect
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on mother-infant interactions. We will cover clinical and pre-clinical findings highlighting putative
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neurobiological mechanisms underlying postpartum depression and how they relate to maternal
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behaviors and infant outcome. We also review animal models that investigate the neurobiology

of maternal mood and disrupted maternal care. In particular, we discuss the implications of

endogenous and exogenous manipulations of glucocorticoids on maternal care and mood.

Lastly we discuss interventions during gestation and postpartum that may improve maternal

symptoms and behavior and thus may alter developmental outcome of the offspring.

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Keywords: maternal care, postpartum depression, antenatal depression, animal models,

maternal attachment, mother-infant interaction

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Major depressive disorder (MDD) affects 12-20% of the population and according to the

World Health Organization is the first leading cause of disability in the world (Greenberg et al.,

2003; Ustun et al., 2004). Women are twice as likely to develop depression (Gutierrez-Lobos et

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al., 2002), have more severe symptoms and present with co-morbid anxiety compared to men

(Kornstein et al., 2002; Sloan and Kornstein, 2003). The sex difference in incidence of

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depression is greatest during the reproductive years, suggesting that sex hormones and

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reproductive events play some role in the etiology of depression (Brummelte and Galea, 2010b;

Gutierrez-Lobos et al., 2002; Hammarstrom et al., 2009; Sloan and Kornstein, 2003). Indeed,

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steroid and peptide hormones (such as cortisol, estrogens, progesterone and oxytocin) fluctuate
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dramatically during these reproductive years particularly during pregnancy and the postpartum

(Brett and Baxendale, 2001). Because these periods of hormone fluctuations coincide with the

greatest risk to develop depression during a woman’s lifetime (Noble, 2005) this suggests an
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intimate association that is important to investigate in order to develop biomarkers to determine

susceptibility to depression and new treatments.

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Depression occurring after birth is referred to as postpartum depression (PPD), while

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depression occurring during pregnancy is referred to as antenatal depression. The prevalence

of antenatal depression is estimated at approximately 12%, with the highest prevalence in the
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last two trimesters (Bennett et al., 2004). The prevalence of PPD ranges from approximately 10-

15 %, but can be as high as 30% depending on the criteria used for diagnosis (Darcy et al.,

2011; Gavin et al., 2005; Vesga-Lopez et al., 2008). One of the greatest risk factors for

developing PPD is antenatal depression and/or depression prior to pregnancy (O'Hara, 2009;

Robertson et al., 2004). The trajectory of depressive symptoms can continue or even worsen

throughout the course of the pregnancy and postpartum period. Unfortunately the new

Diagnostic and Statistical Manual of Mental Disorders (DSM-5) does not consider that

depressive symptoms can develop beyond 4 weeks postpartum. Further, it does not distinguish

between a prenatal or postnatal onset of depression and collectively refers to the episodes as

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‘peripartum episodes’ (DSM-5, 2013). Thus this classification of peripartum depression cannot

distinguish between the consequences of antenatal and postpartum depression for both the

mother and child, which becomes problematic as there are differences in manifestation,

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treatment and incidence as discussed below. Furthermore it is widely recognized that 4 weeks

postpartum for perinatal depression is too limited a time frame and that the term ‘maternal

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depression’ may be a better descriptor of depression during pregnancy and the postpartum

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during the first year after giving birth (Stuart-Parrigon and Stuart, 2014).

Maternal depression is a serious mental illness that not only concerns the affected

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mother, but also impacts the fetus and child. A recent study by Dubber et al., (2014) suggests
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that both maternal-fetal bonding measured with the Maternal-Fetal Attachment scale (Cranley,

1981) and PPD are significant predictors of postpartum bonding between the mother and her

infant (Dubber et al., 2014). This implies that a disturbed mother-fetal attachment during
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pregnancy can impact the relationship between the mother and her child in the postpartum. This

underlines the importance of taking timing of depression, during pregnancy and/or the
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postpartum, into account when investigating the effects of maternal depression. Antenatal
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depression can result in re-programming of the fetus (Buss et al., 2012; Sandman et al., 2011;

Welberg and Seckl, 2001), while PPD can interfere with the child’s maturation in a way that
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includes direct interactions with caregivers. Women with PPD can have different characteristics

than women with antenatal plus postnatal depression (Cooper and Murray, 1995), arguing for

distinguishing between these two periods of depression. It should also be noted that, while prior

depression is the greatest risk factor for PPD, approximately 40% of women will have their first

episode of depression during the postpartum (Wisner et al., 2013). In addition, as mentioned

earlier, while the DSM-5 criteria also encompasses only the first 4 weeks postpartum, the

greatest incidence of new depression postpartum occurs 2-3 months after parturition (Gavin et

al., 2005; O'Hara, 2009; O'Hara and McCabe, 2013). Interestingly, untreated PPD increases the

risk for depression beyond the postpartum period with women experiencing approximately six

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times the risk for depression later in life in comparison to non-PPD women (Josefsson and

Sydsjo, 2007).

It is important to understand that while PPD has many of the same characteristics of

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major depressive disorder (MDD) it presents during a unique time physiologically and women

with PPD tend to present with greater co-morbid anxiety than women with MDD (Hendrick et al.,

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2000). Further, if symptom onset is within 1-14 days after delivery, women with PPD convert to

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bipolar disorder to a greater extent than women with MDD (Munk-Olsen et al., 2012). Thus, we

urge the research community to continue to label, classify and analyze maternal depression as

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antenatal and/or postnatal as it is clear that there are differences in incidence and trajectory of
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depression, outcome on child development and potentially different requirements for treatment.

In this review, we will focus on the effects of PPD on the mother and interactions with her

offspring, however we will also highlight findings from antenatal depression to underscore
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different development outcomes where appropriate. We will discuss the underlying mechanisms

for PPD, focusing on hormones, existing animal models of maternal depression and how those
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can help us to study treatments and interventions for PPD. Lastly we will discuss the effects of
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PPD and antenatal depression on maternal care, mother-infant interactions as well as child

development.
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Possible underlying mechanisms of PPD

Steroid Hormones: ovarian hormones Steroid hormones play a significant role in depression

including PPD (Bloch et al., 2003; Brummelte and Galea, 2010b). During pregnancy and

postpartum, levels of steroid and peptide hormones fluctuate dramatically which could

contribute to the etiology of PPD (Bloch et al., 2003; Brummelte and Galea, 2010b). These

changes in hormone levels, such as estradiol, corticosterone, corticotropic releasing hormone

(CRH) and oxytocin, occur in rodents and humans albeit with different profiles and gestational

periods (see Figure 1). Briefly, in women, progesterone levels are approximately 20x higher

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during gestation and remain elevated throughout pregnancy, while estradiol levels are very high

(200-300x higher) throughout pregnancy in women and both these steroid hormones drop with

the expulsion of the placenta (for review see: Brett and Baxendale, 2001). In rodents,

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progesterone is elevated throughout the first two weeks of gestation but declines a few days

prior to parturition, while estradiol levels are at modest levels (approximately diestrous levels)

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during gestation until just a few days prior to parturition when they increase dramatically

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(Rosenblatt, 1980). In both rodents and women, cortisol and corticosterone levels are higher

during gestation (for review see: Brett and Baxendale, 2001).

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In women, elevated estradiol levels continue to increase during the third trimester but

drop dramatically after parturition, leading to the hypothesis that an “estradiol-withdrawal state”
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during the first few weeks after parturition contributes to PPD (Bloch et al., 2003; Hendrick et al.,

1998). Consistent with this hypothesis, women with a previous history of PPD showed increased
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negative affect in response to ovarian steroid withdrawal compared to women without a

previous history of PPD (Bloch et al., 2000), illustrating that women with a predisposition for
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depression may be more sensitive to large fluctuations in steroid hormone levels. In an elegant
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study, Frokjaer and her colleagues found that biphasic estradiol (induction and then reduction

but not progesterone) via a gonadotropin releasing hormone agonist resulted in increased HAM-
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D scores that were correlated with decreased estradiol levels and increased levels of the

serotonin transporter (SERT) in neocortex of women (Frokjaer et al., 2015). These data

illustrate that dramatically fluctuating estradiol levels from high to hypogonadal status, such as

seen during the early postpartum, is associated with reduced mood that is correlated with

increased SERT levels, likely resulting in reduced serotonin. Reduced serotonin levels have

long been implicated in the etiology of depression, however, a causal link has not been

established (Lacasse and Leo, 2005).

Interestingly, despite the prominent hypothesis of steroid involvement in PPD, not many

studies have investigated this relationship in humans. A recent study by Parizek and colleagues

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(2014) found that in a small sample of moderately depressed women increased levels of

androgens and estrogens measured 4 weeks before birth or from mixed umbilical cord blood at

birth were associated with depressive mood in the postpartum period. Furthermore other studies

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find that fetal sex may play a modest role with women pregnant with boys more likely to report

postpartum blues 5 days after parturition but fetal sex was not linked to depression 6 months

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later (Sylven et al., 2011). These findings suggest that changes in maternal and fetal

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steroidogenesis may be involved in the etiology of PPD.

Studies indicate that previous reproductive experience can significantly alter the

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mechanisms (ER or ) at play to alter anxiety and perhaps other affective behaviors in
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females. ER expression is reduced in late pregnancy (day 21) in the CA3 region of the

hippocampus of primi- or multi-gravid rats (Pawluski et al., 2010). Furthermore ER attenuates
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anxiety and depressive-like behaviors postpartum in nulliparous rats (Furuta et al., 2013) and
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while activation of ER attenuates anxiety in nulliparous females, activation of ER reduces

anxiety in primiparous rats (Byrnes et al., 2012). Thus it is important to consider when designing
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models or investigating PPD in women that parity may influence response to hormones either
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via specific ER (Byrnes et al., 2012), ovarian hormone levels across the menstrual (or estrous)
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cycle (Barrett et al., 2014), and hippocampus plasticity (for review see: Galea et al., 2014).

Lastly in examining epigenetic modifications in an effort to establish biomarkers of PPD,

Guintivano et al. (2014) found altered DNA methylation patterns in PPD vs euthymic women.

They studied women with a history of PPD and women without a history and followed both

groups prospectively throughout pregnancy and the postpartum. CpG methylation levels at two

loci within the HP1NP3 and TTC9B genes were modified in PPD. These genes are implicated in

estradiol-mediated signaling, ER in the former and tied to hippocampal plasticity in the latter.

The fact that these epigenetic modifications are associated with estradiol related plasticity gives

credence to the theory that withdrawal from estradiol is linked to PPD in vulnerable women.

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Glucocorticoids Along with fluctuations in ovarian steroids, glucocorticoids (cortisol: the main

glucocorticoid in humans and corticosterone (CORT): the main glucocorticoid in rats), are

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implicated in depression. Stress and the HPA axis are intimately linked to the etiology of

depression (Bale, 2006; Brummelte and Galea, 2010b). Depressed patients, including those

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with PPD, show abnormal HPA axis function such as hypersecretion of cortisol and abnormal

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diurnal secretion of cortisol (Glynn et al., 2013; Jolley et al., 2007). In fact, normalizing the HPA

axis is one of the major targets of recent therapies (Ising et al., 2007b). Normalization of the

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HPA axis by antidepressants is associated with improved mood scores (Ising et al., 2007a) that
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either precedes or is coincident with the alleviation of depressive symptoms in humans.

Intriguingly, men and women show differential HPA normalization in response to antidepressant

treatment, evidence for the existence of a sex difference in HPA function with depression and
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treatment (Binder et al., 2009).

As noted above, pregnancy and postpartum are associated with sustained high flattened
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levels of glucocorticoids in both humans (Glynn et al., 2013) and rodents (Lightman et al., 2001;
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Pawluski et al., 2009b), which is a similar hormonal profile observed in depressed patients,

suggesting another mechanism for increased vulnerability to depression during pregnancy and
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the postpartum. Certainly the early postpartum is associated with impaired HPA negative

feedback as dexamethasone failed to suppress cortisol levels adequately in 80% healthy non-

depressed postpartum women (Maes et al., 1992). Evidence from our laboratory shows that

corticosterone binding globulin (CBG) levels are low throughout the postpartum in rats, which

suggests that free CORT levels are higher during postpartum compared to controls, as CBG

binds with CORT (Pawluski et al., 2009b). Two studies found that in women placental CRH at

mid gestation (25-32 weeks), but not cortisol, was a significant predictor of PPD symptoms at 2-

3 months, but not 6 months, postpartum (Glynn and Sandman, 2014; Yim et al., 2009), although

other studies have failed to find associations (Meltzer-Brody et al., 2011; Rich-Edwards et al.,

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2008). Furthermore, women who previously suffered from PPD, reported more depressive

symptoms and showed greater cortisol responses during exposure to a hormone simulated

pregnancy (Bloch et al., 2005), suggesting that in vulnerable women, the HPA axis and mood

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are altered in response to pregnancy hormones. In short, it is clear that HPA axis hormones,

perhaps interacting with other pregnancy hormones, are related to PPD symptoms.

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Oxytocin - Besides steroid hormones, the nonapeptide oxytocin has recently gained attention

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for potential involvement in depression and its possible use as a biomarker for depression (for

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review see: Kim et al., 2014; McQuaid et al., 2014). Animal studies have provided evidence for

a link between the oxytocin system and depressive-like behavior (Broadbear et al., 2014;
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Kormos and Gaszner, 2013). In 1987, Arletti and Bertolini reported for the first time that oxytocin

administration in male mice reduced immobility in the forced swim test (Arletti and Bertolini,
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1987). Since then, several studies have contributed to the hypothesis that oxytocin
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administration may have antidepressant properties (Lonstein et al., 2014; Slattery and

Neumann, 2010). However, administration of oxytocin in humans does not always result in
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reduced depressive symptoms and there seems to be a complex relationship between the
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oxytocin genotype, sex, early-life experience and depression (Feng et al., 2014; McQuaid et al.,
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2014; Rilling et al., 2014). In fact, human postmortem studies found increases in the number,

size and mRNA expression of oxytocin neurons in the paraventricular nucleus (PVN) between

patients with a past diagnosis of depression compared to healthy controls (Meynen et al., 2007;

Purba et al., 1996).

Studies of oxytocin in PPD women found that women at risk for PPD (EDPS scores >

10) had lower plasma oxytocin concentration in their last trimester (Skrundz et al., 2011; Stuebe

et al., 2013). However, administering oxytocin to women suffering from PPD resulted in lowered

mood, albeit in a small sample study (Mah et al., 2013). Finally, oxytocin is a strong inhibitor of

the HPA axis response to stress in nulliparous, but not pregnant or lactating, female rats

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(Neumann et al., 2000). Furthermore, stressed dams did not show the typical rise in oxytocin

mRNA in the PVN of the hypothalamus in the peripartum period (Hillerer et al., 2011). These

findings suggest that oxytocin and glucocorticoids may interact during pregnancy and the

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postpartum to increase vulnerability to depressive mood and that chronic stress during

pregnancy may prevent some of the neurobiological adaptations in the oxytocin system needed

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in the rewarding aspects of motherhood. These findings highlight again that the physiology of

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the pregnant and postpartum female is very different than in the nulliparous female. More

research is needed to better understand the complex relationship between adverse early-life

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experience, oxytocin genotypes, oxytocin levels, chronic stress, maternal depression and

mother-infant interactions.
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Neurobiology of MDD
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The hippocampus, prefrontal cortex (PFC) and amygdala are implicated in the
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neurobiology of depression (McKinnon et al., 2009). A meta-analysis determined that depressed

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patients have a smaller hippocampus volume after 2 years with depression and that smaller

hippocampal volume was seen in children and middle-aged or older adults (McKinnon et al.,
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2009), suggesting that gonadal hormones may buffer changes in hippocampal volume in young

adults. Antidepressant use protects against hippocampal volume loss primarily in women

(Lorenzetti et al., 2009). Sex differences in the neural manifestations of depression exist as

depressed women are more likely to present with a smaller amygdala but depressed men are

more likely to present with a smaller medial orbitofrontal cortex and hippocampus compared to

healthy controls (Lorenzetti et al., 2009). Reduced volume may be due to reductions in

neurogenesis, synaptic density, neuropil and/or increased cell death. Interestingly, research

suggests that neuronal loss during depression may be partly attributed to activation of

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neuroinflammatory pathways (Wager-Smith and Markou, 2011). A recent study confirmed

neuroinflammatory markers were increased during depression (Setiawan et al., 2015).

Reduced hippocampal neurogenesis is seen in all animal models of depression (for

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review see: Wainwright and Galea, 2013), and treatment with antidepressants in these models

restores neurogenesis (Bessa et al., 2009) including in a model of PPD (Green and Galea,

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2008). Chronic, but not acute, antidepressant treatment increases neurogenesis (Malberg et al.,

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2000) in a timeline that coincides with the behavioral alleviation of depressive symptoms.

Furthermore, reduction of adult neurogenesis prevents the behavioral benefit of antidepressants

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on novelty suppressed feeding (Santarelli et al., 2003) and dysregulates HPA negative feedback
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(Snyder et al., 2011). It is important to note that a reduction in neurogenesis in the hippocampus

does not result in a depressive state (Bessa et al., 2009), nor does a reduction in neurogenesis

prevent the behavioral impact of antidepressants on sucrose anhedonia or immobility in the

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forced swim test (Bessa et al., 2009; David et al., 2009). While most studies show that

antidepressant treatment increases hippocampal neurogenesis postmortem in depressed

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patients (Boldrini et al., 2009; Epp et al., 2013), one study did not (Reif et al., 2006). However
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this latter study did not consider sex, age or duration of illness as contributing factors and these

factors likely played important roles, as both age (Lucassen et al., 2010) and sex (Epp et al.,
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2013) of patient influence the effects of antidepressants to increase neurogenesis in

postmortem tissue. Furthermore the duration of illness profoundly affects hippocampal volume

(McKinnon et al., 2009) and this has yet to be considered in studies on hippocampal

neurogenesis levels in depressed patients. For example prescription to antidepressants

increased doublecortin (immature neurons) expression, in the hippocampus of depressed

women but not depressed men (Epp et al., 2013). Furthermore antidepressant exposure did not

increase neurogenesis in postmortem tissue of older patients (Epp et al., 2013). Indeed, both

older patients and rodents do not show the antidepressant-induced increase in neurogenesis,

an effect which may be linked to low gonadal hormone levels (Epp et al., 2013; Lucassen et al.,

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2010). Taken together this suggests that depression is associated with changes in

hippocampus, amygdala and PFC with women showing greater changes in the amygdala and

hippocampal neuroplasticity. Intriguingly lower brain derived neurotrophic factor (BDNF) levels

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have been implicated in depression particularly in women with severe depression (de Azevedo

Cardoso et al., 2014; Kreinin et al., 2015). It bears repeating that studies need to not only

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include both sexes in their results but also to analyze the effects of sex on neural outcomes in

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depression, considering the evidence that there are often profound sex differences in structures

compromised with depression (Lorenzetti et al., 2009), antidepressant efficacy (Binder et al.,

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2009; Kornstein et al., 2002; Thase et al., 2005), HPA negative feedback (Binder et al., 2009)
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and neurogenesis levels (Epp et al., 2013).

Neurobiology of PPD
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There are relatively few studies examining the neurobiology of PPD. It is important to

remember that the postpartum period is associated with neuroplastic changes in the
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hippocampus and PFC, irrespective of mood. For example total brain volume decreases during
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pregnancy and increases to normal levels within 6 months postpartum (Oatridge et al., 2002). In
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rodents, primiparity is associated with reduced dendritic branching in the CA1 and CA3 regions

(Pawluski and Galea, 2006), reduced cell proliferation in the early postpartum (Darnaudery et

al., 2007; Leuner et al., 2007; Pawluski and Galea, 2007) and reduced survival of new neurons

produced in the early and late postpartum (Pawluski and Galea, 2007; Workman et al., 2015).

Indeed even at the point of weaning, when cell proliferation levels have normalized, the density

of immature neurons remains low in primiparous rats (Workman et al., 2015). Thus it is

important to keep in mind that the postpartum in ‘healthy’ females is associated with reductions

in plasticity in the hippocampus and perhaps other regions (Roes and Galea, 2015), which may

also contribute to the vulnerability for certain women to PPD.

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While fewer studies have examined healthy euthymic women in the postpartum one

study showed elevated brain monoamine oxidase (MAO-A) binding in postpartum of healthy

euthymic mothers 5 days postpartum (Sacher et al., 2010). Within 18 months postpartum in

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PPD mothers and mothers who ‘cry due to sad mood’ there was elevated MAO-A distribution

volume in the PFC and anterior cingulate cortex (ACC) compared to healthy postpartum and

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non-postpartum controls (Sacher et al., 2015). The increased MAO-A distribution volume in

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association with PPD was also seen in the hippocampus and ventral striatum, although this did

not reach significance. Furthermore within 3 months postpartum increased glutamate levels

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were seen in the mPFC of PPD patients (McEwen et al., 2012), which is in contrast to studies
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showing decreased levels of glutamix (glutamate and glutamine) in major depression (Auer et

al., 2000; Hasler et al., 2007; Merkl et al., 2011). However, those latter studies had a mix of men

and women with major depression and the studies did not control for menstrual cycle.
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Glutamate levels are decreased during the luteal phase (high estradiol and progesterone)

compared the follicular phase (low estradiol and progesterone; Batra et al., 2008). Finally,
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BDNF levels are lower in women with PPD (Gazal et al., 2012) and in rat dams stressed during
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pregnancy (Maghsoudi et al., 2014) suggesting multiple neurotransmitters and neurotrophic

factors are altered with PPD as with MDD. These data further point to the necessity of
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examining neurobiology of PPD in comparison with healthy euthymic postpartum women and

the realization that the neurobiology of depression may manifest differently in men versus

women and in women in different reproductive states.

Animal models of PPD based on steroid hormones

Most animal models of PPD have been created on the basis of ovarian hormone

withdrawal, chronic stress during pregnancy or glucocorticoid exposure during the postpartum

(Brummelte and Galea, 2010b). Galea and her colleagues found that withdrawal from a

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hormone-simulated pregnancy induced depressive-like behaviors including increased immobility

in the forced swim test (FST) and sucrose anhedonia (Galea et al., 2001; Green et al., 2009).

Furthermore hippocampal plasticity was affected with reduced hippocampal neurogenesis that

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was alleviated by an estrogen receptor (ER) β agonist or the tricyclic antidepressant, imipramine

(Green and Galea, 2008). Others have shown similar effects using withdrawal from a hormone-

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simulated pregnancy that modelled human pregnancy (Suda et al., 2008). Suda et al (2008)

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found increased learned helplessness, anxiety-like behavior and increased aggression (using

the resident intruder test) in females following a hormone-simulated pregnancy. Furthermore

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they found increased mRNA levels of SERT, Ca2/calmodulin-dependent protein kinase II,
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Gamma-aminobutyric acid type A receptor 4 (GABAARA4) and aquaporin 4 (AQP4) in the

hippocampus of female rodents after withdrawal that quickly returned to normal levels

approximately 4 days after withdrawal. Aquaporin is located on astrocytes and is implicated in

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secretion of proinflammatory cytokines, which are increased during depression (Xiao and Hu,

2014). Thus these are important findings as increased serotonin turnover, GABA A receptors
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and inflammation have been implicated in the etiology of depression (for review see: Dale et al.,
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2015; Young et al., 2014) and are furthermore sensitive to fluctuations in ovarian hormones

(Frokjaer et al., 2015; Habib and Beyer, 2015; Mody, 2008; Suda et al., 2008).
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Brummelte and Galea created a model of PPD or stress by administering high CORT

postpartum to dams (Brummelte et al., 2006; Brummelte and Galea, 2010a). We found that

dams given high CORT postpartum exhibited depressive-like behavior (increased immobility

and decreased struggling in the forced swim test) compared to oil-treated rats. CORT dams

spent less time nursing and more time away from the nest (Brummelte et al., 2006; Brummelte

and Galea, 2010a). High CORT postpartum also resulted in reduced cell proliferation in the

dentate gyrus (Brummelte and Galea, 2010a) and reduced dendritic branching in the CA3

region of the hippocampus of the dam (Workman et al., 2013). More recent data shows that

doublecortin (an endogenous marker of immature neurons) is reduced in healthy postpartum

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rodents but further reduced in CORT-treated postpartum rodents (Workman et al., submitted).

These data collectively suggest that the neurochemistry and neuroplasticity of both

hippocampus and PFC is compromised in dams of animal models of PPD. Although the

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offspring of the CORT-treated dams showed no depressive-like behavior in the forced swim test

as adults, they did show increased hyperactivity, anxiety-like behaviors and ‘impulsivity’, which

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were more pronounced in male than in female offspring (Brummelte et al., 2006; Brummelte et

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al., 2012). Furthermore, we found that male, but not female, offspring of CORT-treated dams

had a decrease in cell proliferation in the dentate gyrus prior to adolescence, indicating altered

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hippocampal plasticity during development (Brummelte et al., 2006). Intriguingly, these findings
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parallel the human literature in which boys of PPD mothers are more likely to be affected and

show antisocial behavior, hyperactivity and poorer academic performance than girls of PPD

mothers (Hay et al., 2008; Korhonen et al., 2012; Murray et al., 2010a). Furthermore we found
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that high CORT in the dam resulted in higher levels of CORT in stomach milk, serum and brain

of the offspring (Brummelte et al., 2010). These findings point to the fact that the mother’s
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hormonal state can influence emotional and neural outcomes in her offspring, and potentially
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influence their vulnerability to subsequent neuropsychiatric disorders.

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PPD and maternal care

The neurobiological changes due to motherhood and contributing to maternal behaviors

are described in detail elsewhere (Bridges, 2015; Brunton and Russell, 2008). However, not

much is known about whether these alterations are affected by PPD. Rodent models suggest

that chronic stress prevents some of the peripartum induced adaptations in the brain and

behavior (Hillerer et al., 2012). Further, chronic treatment with CORT in the postpartum reduced

neurogenesis in the hippocampus as well as reduced maternal care (Brummelte and Galea,

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2010b; Workman et al., submitted), suggesting that some of the neurobiological changes

observed in PPD or animal models of PPD may contribute to the altered maternal care (see

below).

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Reduced mother-child interactions are associated with PPD as meta-analyses suggest

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that PPD has a mild to moderate effect on maternal–infant interaction (Beck, 1995; Lovejoy et

al., 2000). In particular, Lovejoy et al., (2000) found that depressed mothers exhibited

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significantly more negative and disengaged behavior towards children of varying ages

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compared to non-depressed mothers. This is evidenced by the fact, that depressed mothers

touch their infants less and in a less affectionate manner (Ferber et al., 2008) and engage in
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fewer vocal and visual communication such as smiling, face to face interactions and infant-

directed speech or storytelling (Field et al., 2006; Field, 2010; Herrera et al., 2004; Kaplan et al.,
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1999; Paulson et al., 2006; Righetti-Veltema et al., 2002). However some studies have found
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that the effect of maternal depression is accounted for by mothers with comorbid diagnosis for

other mental illnesses such as anxiety or personality disorder (Carter et al., 2001; Conroy et al.,
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2010; Conroy et al., 2012; Dietz et al., 2009), which highlights the importance of investigating
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the context of the maternal depression and including clinical diagnostic tools.
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One meta-analysis showed a significant effect for a reduced likelihood of infants of

depressed mothers to be securely attached (Martins and Gaffan, 2000). Mother-infant

attachment is defined as the infant using the mother as a source of safety, security and

protection (Benoit, 2004). However, the length of the depressive episode and co-morbidities

may contribute to positive associations between maternal depression and attachment (Wan and

Green, 2009). For instance, in a large NICHD study chronic maternal depression was

associated with insecure and disorganized attachment at 3 years (Campbell et al., 2004). But

Tharner et al., (2012) did not find an increased risk of attachment insecurity or disorganization at

14 months with lifetime, pre-or postnatal depression, regardless of severity and comorbidity in a

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large Dutch population-based cohort. The heterogeneity of findings highlights that there is a

crucial need to better understand: 1) how negative outcomes in children of depressed mothers

are mediated; 2) which features of the depressive episodes or the maternal behavior contribute

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to the adverse effects; 3) what factors pre or post-natally may be protective for child

development and 4) consequences for treated or untreated depression on attachment.

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However, some meta-analyses have failed to prove a strong link between maternal

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depression and infant attachment (Atkinson et al., 2000; Martins and Gaffan, 2000; van

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Ijzendoorn et al., 1999). It has been frequently suggested that depressed mothers display

altered behavior when interacting with their children compared to non-depressed mothers and
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that this could explain some of the children’s developmental delays and problems (Field, 2010).

Mother-infant interaction is usually described as the behavior the mother and infant are
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displaying in response to each other and is for instance measured by the mother’s sensitivity
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and responsivity in reacting to infant cues and behaviors (Halle et al., 2011). As illustrated in

Figure 2, PPD may lead to impaired mother-infant interactions, which in turn can affect the
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neurobiological, social and cognitive development of the infant. However, similar to the
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discrepancies among studies on maternal depression and infant attachment (see below), there
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is a vast heterogeneity in reported effects on mother–infant interaction (Murray et al., 2014),

which may partly be due to the variability in tests and observations used to study these

interactions.

One simple explanation for some of the variance in the literature on PPD and maternal

care are different methodologies in measuring mother-infant interaction as well as in diagnosing

or defining postpartum depression. The Edinburgh Postpartum Depression Scale (EPDS) (Cox

et al., 1987) is a 10-item questionnaire that is widely used for identifying women who suffer from

postpartum depression. The maximum score is 30 with cut-off scores for identifying a

depressive illness ranging from 9-14 points. It is recommended that a careful clinical

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assessment should confirm the diagnosis of this self-report questionnaire, however this is not

routinely done in all studies reporting the use of the EPDS. The Beck Depression Inventory

(BDI, BDI-1A, BDI-II), is a 21-item self-report questionnaire, that is also widely used to measure

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depressive symptoms during pregnancy or the postpartum period (Beck, 1961; Beck et al.,

1996). The maximum score on the BDI-II is 63 with a range of 14-19 being considered ‘mild

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depression’. An advantage of the Beck inventory compared to the EPSD is that this test can

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give an indication of the severity of the depression not just if it is present or not. Other

questionnaires may be used to measure depression, such as the Hamilton Depression Rating

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Scale (HAM-D), which has also been shown to be effective in identifying depressive symptoms
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particularly during pregnancy and the postpartum period (Ji et al., 2011). Many studies reporting

an association between depressive symptoms and mother-infant interaction are based solely on

self-report questionnaires such as the Beck Depression Inventory without a clinical diagnosis
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and self-report measure have been shown to yield higher estimates of postpartum depression

than clinician-administered assessments (Ji et al., 2011). Furthermore studies differ on their
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methods of depression classification with differing cut-off scores for depression (Matthey et al.,
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2006), depression scores or cut-off scores are not provided (e.g. Forman et al., 2007), or

depression scores are used as continuous measure in the analysis (e.g. Britton, 2011). For
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example, a study by Boyd et al., (2006) using a cut off score of 14 on the BD-II (self-report) for

mild depression did not find a difference in maternal behaviors or mother-infant interaction

during a lab visit at 3 months postpartum, while Britton and colleagues (2011) used the scale as

a continuous measure in correlation and hierarchical regression analyses that revealed an

association between depression scores and infant temperament, but did not distinguish

between depressed and non-depressed mothers. Thus each of these methodological issues on

depression scores may explain the inconsistences for reported depression prevalence as well

as outcome measures on infant attachment.

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In addition to inconsistences in coding for depression, there are a wide array of tests to

examine mother-infant interaction which provides more variability to explain the equivocal

effects of depression on mother-infant interactions. Mother-infant interaction tests can differ

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dramatically in their approach or experimental settings (for an overview and review of available

tests see: Lotzin et al., 2015; Munson and Odom, 1996). Most approaches include a session of

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uninterrupted play between the mother and the infant at home or in the lab that is video

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recorded and later scored and coded by a trained experimenter. However, some studies limit

their mother-infant interaction assessments to maternal questionnaires. A frequently used test is

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the Nursing Child Assessment Teaching Scale (NCATS; Sumner and Spietz, 1994) that
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contains 76 items and behaviors are observed and binary items are scored as either present or

absent. Many studies observe the mother-infant interaction only once for a limited amount of

time (as short as 3-5 min). Despite the clear advantages of these independent observations by
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an experimenter compared to mother-filled questionnaires, certain limitations for the

generalizability of the obtained observations remain. Mothers may not engage in playing
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behaviors if they know they are being filmed or observed and may feel, and subsequently act,
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uncomfortably. Further, the short time period limits the interpretability of the results for everyday

mother-infant interactions. In fact, the meta-analysis by Lovejoy et al., (2000) revealed that
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length of observation as well as type of observation played a role in the strength of the

association between maternal depression and mother-infant interaction. Studies using

observations of 10 min or less exhibited stronger associations of depression on maternal

behaviors and unstructured observations in the laboratory were more likely to have significant

associations compared to structured or home visit observations (Lovejoy et al., 2000). This

suggests that short observations may over-interpret negative maternal behaviors in depressed

women compared to those that are not observed if given more time or a more natural

environment. Alternatively, it is possible that when stress is placed on the depressed mother

(such as when they know there is a limited observation time) this may bring out more negative

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maternal behaviors. Taken together, there is moderate evidence that mother-infant interaction

patterns are affected by PPD.

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Maternal Depression and Child Development

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PPD is negatively associated with child outcome (for reviews see: Beck, 1998;

Grigoriadis et al., 2013; Suri et al., 2014). In particular, children of mothers suffering from PPD

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are at risk for emotional, behavioral and psychological problems as well as cognitive and

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language development delays that are evident beyond early infancy (Murray et al., 2003; Murray

et al., 2010b). Further, boys of mothers with PPD may have a greater risk of antisocial disorders
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and impaired cognitive and motor development than girls of mothers with PPD (Deave et al.,

2008; Murray and Cooper, 1997; Nomura et al., 2002; Pilowsky et al., 2006). Interestingly, a
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recent systematic review suggests that the timing of maternal distress (which includes anxiety,
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stress or depression) is related to different consequences for children (Kingston et al., 2012).In

particular, Kingston et al. (2012) found that prenatal distress adversely affects cognitive,
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behavioral and psychomotor development while maternal postpartum distress affects cognitive
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and socio-emotional development (Kingston et al., 2012). This emphasizes that it is important to
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differentiate between the impact of prenatal and postnatal influences on the developing child.

Studies that report associations between maternal postpartum depression and infant

general health outcomes beyond the first weeks of life are of particular concern. For instance,

some studies found a higher incidence of gastrointestinal symptoms or infant diarrhea among

children of mothers with depressive symptoms (Darcy et al., 2011; Rahman et al., 2004). Also,

in a large cohort study, depressed mothers reported more Emergency room visits and

hospitalizations for their infants in the last year and they attended fewer of the well-child visits

within the first 2 years after birth (Minkovitz et al., 2005). Another reason for concern is that

mothers suffering from postpartum depression may be at increased risk for negative-infant

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feeding outcomes including reduced odds for continued breastfeeding and breast feeding

difficulties (for review see: Dennis and McQueen, 2009). Depressed mothers were also more

likely to breastfeed at low intensity, add cereal to formula feeds and start solid foods earlier

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which may explain a greater weight gain at 6 months postpartum among infants of mothers with

PPD (Gaffney et al., 2014). Thus, infants of depressed mothers may receive less of the benefits

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of breast feeding such as immune protection. These findings may further play a role in the

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reported higher incidence of hospital and emergency room visits.

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Impairments in mother-infant interactions are associated with the adverse child
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outcomes (Murray et al., 2014). In particular, insecure attachment is related to maternal

insensitivity, while hostile parenting is associated with externalizing problems in the children;
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and finally difficulties in noticing infant signs of interest and supporting their engagement with
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the environment is associated with poor cognitive development (Murray et al., 2014). Although

direct evidence is lacking, it is assumed that the adverse child outcomes that are observed in
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children of depressed mothers such as externalizing problems and poor cognitive skills, are
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largely due to the effects of depression on mother-infant interactions. However, it remains

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difficult to entangle the effect of parenting from potential direct effects of depression on the

development. Exposed children may already have different maturational trajectories due to the

exposure to maternal depression during pregnancy or due to altered hormonal milieus in

maternal breast milk. Animal studies may help shed some light on the underlying mechanisms

and the contribution of maternal care to poor development outcome.

Maternal care in animal models of depression

In line with human reports, studies using animal models of maternal depression have

also reported altered maternal care in rodents (Brummelte et al., 2006; Perani and Slattery,

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2014; Smith et al., 2004; Zhou et al., 2014). The most common models of PPD include

gestational stress and high maternal corticosterone (CORT) postpartum (Brummelte et al.,

2006; Brummelte and Galea, 2010b; Leuner et al., 2014). Disruptions in maternal care with

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exogenous glucocorticoids is seen across a variety of species including primates (Saltzman and

Abbott, 2009), rodents (Brummelte et al) and birds (Angelier et al., 2009). Administering high

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levels of corticosterone induces depressive-like behavior in rodents (Brummelte et al., 2006;

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Kalynchuk et al., 2004). If given to dams during pregnancy or the postpartum period, it results in

reduced maternal care with dams spending less time on the nest (more time away from their

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pups) and reduced total nursing compared to control dams (Brummelte et al., 2006; Brummelte
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and Galea, 2010a). Chronic gestational stress leads to postpartum depressive-like behavior and

altered maternal care (Leuner et al., 2014; O'Mahony et al., 2006; Smith et al., 2004). For

instance, Leuner et al., (2014), showed that stress exposure to a pregnant dam between
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gestational day 7-20 led to increased depressive-like behavior (immobility in forced swim test,

decreased sucrose anhedonia) and decreased maternal care (decreased time spent on the nest
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or arched back nursing). Treatments with antidepressants can influence stress and CORT
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effects on maternal care dependent on when treatment was given. While chronic gestational

stress resulted in reduced maternal care, this was not be prevented by antidepressant
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(escitalopram) treatment throughout pregnancy (Bourke et al. (2013). However, treatment with

the SSRI, fluoxetine, reversed the maternal care deficits seen with chronic CORT given

postpartum (Workman et al., submitted).

Interestingly, most studies report a reduction in maternal care as reduced time spent

with the pups but no significant alteration in the time the dams spent licking their pups. This is

important as the amount a dam spends licking and grooming her pups is associated with

epigenetic changes in the glucocorticoid receptor pathway and subsequent alterations in the

behavioral outcome of the offspring (Champagne and Meaney, 2001; Szyf et al., 2005).

However, less is known about the mechanisms in which time spent nursing or in contact with

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pups can modulate the outcome of the offspring. It is noteworthy that a study by Hillerer et al.,

(2011) failed to reveal increased depressive-like behavior or reduced maternal care after

chronic gestational stress. In this study, gestational stress decreased basal corticosterone levels

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in lactating rats and increased the amount of arched back nursing compared to unstressed

controls. This study contradicts the previous studies mentioned (Leuner et al., 2014; Smith et

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al., 2004) and may be due to the type or time of the stressor used (gestational day 4-16, twice

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daily 1h of restraint stress or caging conditions (4 rats per cage) and highlights the complexity of

prenatal stress effects.

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It should be noted that the dose of corticosterone during the postpartum modulates the
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effects on offspring, with low doses of corticosterone proving beneficial to offspring. Exposure of

postpartum rats to a low dose of corticosterone via drinking water result in improved spatial

learning and reduced anxiety-like behavior in the adult offspring (Casolini et al., 1997; Catalani
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et al., 2002; Catalani et al., 2011). Furthermore these exposed offspring were less vulnerable to

the damaging effects of global brain ischemia (Casolini et al., 2007) or inflammatory
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experimental colitis (Petrella et al., 2014). Collectively these data suggest that manipulating
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corticosterone levels in dams has a curvilinear outcome on offspring with low levels improving

outcome but high levels, perhaps via disrupted maternal care, detrimental to offspring outcome.
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A model of postpartum anxiety was described by Tallie Baram’s group using insufficient

bedding material in the home cage (Ivy et al., 2008). Insufficient bedding does not allow for the

dam to build a nest and results in increased frequency in leaving the nest and reduced nursing

behaviors in the dams (reviewed by Molet et al., 2014). Both pups and dams in the limited

bedding groups show increased plasma corticosterone on postpartum day 9 that was reversed

when sufficient bedding is supplied (Ivy et al., 2008; Molet et al., 2014). A modified version of

this model is used as a model of early life adversity but has potential to model of deficits in

maternal care that are coupled with increased maternal anxiety-like behavior. For an excellent

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review on the consequences for adult offspring of limited bedding the reader is directed to Molet

et al., 2014.

There are also studies that did not rely on the association between stress and

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depression for modelling postpartum depression. For instance, mice deficient in the δ subunit of

the GABAA receptor show increased depressive-like behavior specifically in the postpartum

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period and exhibit reduced maternal behavior (Maguire and Mody, 2008). Interestingly, these

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GABAA-deficient mice exhibit increased HPA axis responsiveness (Lonstein et al., 2014),

suggesting an involvement of glucocorticoids in mediating the depressive and/or maternal care

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effects in this model. Thus, animal models of PPD or postpartum anxiety, regardless of whether
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the model used stress exposure, high corticosterone, limited bedding or genetic approaches,

find reductions in maternal behavior, consistent with the human literature.

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Possible Underlying Mechanisms of Maternal Care Alterations with Maternal Depression

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Ovarian hormones: Estrogens and progesterone levels during gestation also play a role in
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maternal care in women (Fleming et al., 1997; Glynn et al., submitted) and in rodents

(Rosenblatt, 1980). A study by Fleming and colleagues (1997) showed that a high estradiol to
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progesterone ratio was associated with depression in postpartum women. Furthermore women

with a low estradiol lo progesterone ratio during gestation reported higher feelings of attachment

in the early postpartum. These findings were recently extended by Glynn et al. (submitted) who

showed that more sensitive mothers at 1 year postpartum had lower estradiol/progesterone

ratios during gestation weeks 20-33) and lower levels of estradiol in the third trimester (Glynn et

al., submitted). Animal studies confirm the involvement of steroid hormones in the induction of

maternal care behaviors and manipulating estrogens and progesterone levels can interfere with

mothering behavior in a variety of species, including non-human primates (for recent review

see: Bridges, 2015; Siegel and Rosenblatt, 1975; Terkel and Rosenblatt, 1972). Thus, while

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more data is needed, higher levels of estrogens and progesterone during the late gestational

period and perhaps androgens, in women with PPD likely contribute to disruptions in mother-

infant interactions and attachment.

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Glucocorticoids: Though some animal studies failed to confirm a central involvement of

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glucocorticoids in maternal care (Bridges, 2015), it is clear from the above studies that high

levels of maternal corticosterone can interfere with the display of proper maternal behaviors.

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Considering that women with PPD show abnormal HPA axis function and hypersecretion of

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cortisol (Glynn et al., 2013; Lightman et al., 2001), it is conceivable that the increased cortisol

levels may also play a role in the observed reduced maternal care in humans. Interestingly,
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human studies investigating the relationship between cortisol and maternal behaviors in healthy

postpartum women reported the opposite. For example, mothers who had higher plasma
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cortisol levels engaged in more affectionate approach responses with their infants (Fleming et
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al., 1987). Further, first-time mothers with higher cortisol levels were more attracted to their own

baby’s body odor and able to recognize their own infants’ odors compared to foreign infant
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odors and showed more affectionate contact with their baby in a mother-infant interaction
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session (Fleming et al., 1997). But it is important to remember that these levels are in healthy
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mothers, and that there may be a dose-dependent effect of glucocorticoids on maternal care

and that women with a history of PPD have increased cortisol responses in response to

stimulated release (by oCRH) during a hormone-simulated pregnancy, suggesting that the HPA

axis is overactive in women with PPD in response to high ovarian hormones (Bloch et al., 2005).

Some studies investigating cortisol levels during pregnancy found associations between

higher maternal cortisol levels during pregnancy and altered behavioral or cognitive outcome

and cortisol reactivity infants or children (Bergman et al., 2010; Davis et al., 2007; Davis and

Sandman, 2010; de Weerth et al., 2003). For instance, Davis and colleagues (2007) found that

maternal cortisol levels during the third trimester predicted maternal report of increased negative

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reactivity and fear in 2 months old infants. Because the infant outcome was based solely on

maternal report in this study, it is possible that the maternal psychological state can impact the

association between prenatal maternal cortisol and infant temperament. In fact, ratings of infant

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behaviors were positively associated with depressive symptoms in the mothers (Davis et al.,

2007). Furthermore, Bergman et al., (2010) reported that increased maternal cortisol during

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gestation is associated with impaired cognitive development, but only in insecurely attached

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infants, suggesting that there is a complex relationship between prenatal cortisol and mother-

infant interactions in regards to the outcome of the child. Taken together, the studies on prenatal

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cortisol elevations suggests that increases in gestational cortisol can re-program infants’ HPA
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axis and change developmental trajectories. Evidence for this hypothesis is provided by a study

by Oberlander et al., (2008) that showed that exposure to prenatal maternal depression

increased the methylation of the glucocorticoid receptor gene NR3C1, which in turn was
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associated with increased cortisol stress responses in 3 months old infants.

As mentioned above, less is known about the relationship between postnatal maternal
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cortisol levels and maternal behaviors, especially in women suffering from PPD. Several studies
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have reported negative consequences of elevated maternal cortisol levels on infant outcome.

For example, higher maternal cortisol levels are associated with increased fear behavior,
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temperament and infant cortisol levels (Clearfield et al., 2014; Glynn et al., 2007; Hinde et al.,

2015). Some of these effects may be attributed to the direct exposure of infants to maternal

cortisol through the breast milk, as formula-fed infants did show increased fear behavior or

temperament and maternal depressive symptoms were not correlated with these infant’s

outcome (Glynn et al., 2007; Grey et al., 2013). Interestingly, another study failed to show a

relationship between postpartum maternal cortisol levels and infant temperament (Davis et al.,

2007).

Studies have also investigated the effect of maternal depression on infant cortisol levels.

Infants of mothers who had an indication of lifetime depression, but not postpartum depression,

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had lower baseline cortisol levels but an increased cortisol response to a restraint stressor (Azar

et al., 2007). However, Brennan et al., (2008) found that peripartum (prepartum and/or

postpartum) maternal depression, but not a lifetime history of the disease, was associated with

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higher infant cortisol reactivity. Further, in a small sample of women, depression at 9 months

postpartum was associated with increased cortisol reactivity in infants (Feldman et al., 2009).

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However, another study found no association between maternal depression and infant’s cortisol

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levels after a heel lance procedure (Castral et al., 2014). Moreover, one study found that only

infants from mothers with comorbid depression and anxiety, but not depression alone had

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altered cortisol levels throughout the day at 6 and 12 months of age (Azak et al., 2013). These
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discrepancies suggest that there is no simple relationship between maternal depressive-

symptoms and infant HPA axis reactivity. There are likely many other contributing factors to

infant HPA axis reactivity such as prenatal maternal cortisol levels, time since last breastfed or
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maternal/paternal behaviors that mediate infant HPA axis. In fact, one study found that maternal

sensitivity (reflecting the quality of the mother-infant emotional connection) modulated the
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effects of maternal psychiatric status (depression and/or anxiety) on infant cortisol (Kaplan et
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al., 2008). Infants of healthy women had consistently low levels of cortisol regardless of whether

they received high or low sensitivity parenting, while infants of mothers with an antenatal
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diagnosis of anxiety or depression had significantly higher cortisol levels if their mothers

displayed low maternal sensitivity during a 10min free play session (Kaplan et al., 2008). As

mentioned above, animal studies have shown that very high maternal corticosterone in the

postpartum can affect corticosterone levels in the serum and brain of the exposed pups

(Brummelte et al., 2010) and decreases maternal care (Brummelte et al., 2006; Brummelte and

Galea, 2010a). Thus, it likely that elevated maternal cortisol levels in depressed women can

directly or indirectly affect child HPA outcome either by being transferred through the breast milk

and/or by affecting maternal behaviors.

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Oxytocin: Oxytocin plays a vital role in maternal-infant relationships, including attachment,

bonding and breastfeeding (Galbally et al., 2011). For example, oxytocin levels during the

postpartum period and oxytocin receptor genotype are associated with infant-directed behaviors

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and maternal sensitivity (Bakermans-Kranenburg and van Ijzendoorn, 2008; Feldman et al.,

2010; Feldman et al., 2012; Gordon et al., 2010). Further, polymorphisms in the oxytocin gene

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have been associated with infant-directed vocalizing and maternal instrumental care, an effect

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that was influenced by early life-experience (Mileva-Seitz et al., 2013). Moreover, Jonas et al.,

(2013) found that a polymorphism in the oxytocin gene interacted with early life adversity to

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predict variations in breastfeeding. This suggests that oxytocin levels and genotype for the
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nonapeptide and its receptor may play a role in mediating the effects of maternal behaviors and

attachment and may interact with PPD.

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In PPD women treated with oxytocin their perception of their relationship with their baby
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improved (Mah et al., 2013) and they showed improved protective behaviors towards their

infants in the presence of a socially intrusive stranger (Mah et al., 2015). However, interestingly,
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mood did not improve in these oxytocin-treated PPD mothers (Mah et al., 2013). This suggests
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that oxytocin may have the potential to improve the mother-infant relationship, but not
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necessarily the depressive symptoms of the depressed mother.

Oxytocin, as well as GABA, are thought to be major players in the change during late

pregnancy that shifts prior pup aversion towards pups being rewarding (Lonstein et al., 2014). A

dysregulation in the oxytocin system could thus underlie the problems in maternal bonding and

interactions seen in women with PPD. It may also play a role in reduced breastfeeding in

depressive women, as oxytocin is released in response to sucking stimulation and activates

areas of the reward circuitry. A reduction in the rewarding experience of nursing may in turn

contribute to an earlier discontinuation of breast feeding in PPD mothers (Lonstein et al., 2014).

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Neurobiology: Interestingly, increased neurogenesis in the subventricular zone (SVZ) and the

dentate gyrus, is associated with the induction of maternal behaviors in nulliparous rats or foster

dams (Furuta and Bridges, 2009; Pawluski and Galea, 2007). However, neurogenesis is

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paradoxically upregulated in the SVZ of suicide (mostly men) victims (Maheu et al., 2015). Both,

mating and pregnancy can stimulate the production of progenitor cells in the SVZ, which has

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been attributed to a rise in prolactin levels during those times (Furuta and Bridges, 2005; Mak et

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al., 2007; Shingo et al., 2003). The new cells migrate to the olfactory bulb where they may play

an important role in pup olfactory recognition (Shingo et al., 2003). In the dentate gyrus,

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however, new neurons are not stimulated during pregnancy (Pawluski et al., 2010) but are
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stimulated in nulliparous rats sensitized to pups within 24 h of exposure (Pawluski and Galea,

2007). This suggests that while new neurons are not involved in the induction of maternal

behavior in pregnant rats, but they are coincident with changes in maternal behaviors in
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nulliparous rats. This further highlights neurobiological differences between parous and non-

parous rats.
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Importantly, the quality or amount of maternal care received in early life, has a large
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impact on hippocampal development including neurogenesis levels, glucocorticoid receptor

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expression, dendritic complexity and synaptic function and plasticity (Bredy et al., 2003;

Brummelte et al., 2006; Nguyen et al., 2015). In humans, the amount of early maternal support

is linked to increased hippocampal volume in school-age children (Luby et al., 2012). However,

only few studies have investigated potential neurobiological changes in depressed women in

regards to maternal care or sensitivity. fMRI studies have revealed abnormalities in the

executive network and default mode connectivity in PPD women, however even fewer studies

have investigated brain activation in regards to maternal care behaviors in these women (for

review see: Moses-Kolko et al., 2014). A recent study by Laurent and Ablow (2013) revealed

that women with a history of depression during pregnancy or the postpartum had blunted

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responses to their own infant’s distress faces in the dorsal anterior cingulate cortex (ACC).

Further, current depressive symptoms were associated with reduced activation in the orbital-

frontal cortex, insula, and striatal and PFC regions in response to their own infant’s joyful faces

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(Laurent and Ablow, 2013). These results are in line with earlier work by Swain et al., (2008)

that showed that maternal mood was related to specific brain activation in response to their own

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infant’s cry. The review by Moses-Kolko et al. (2014) summarizes fMRI findings in women with

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PPD in response to varying stimuli such as negative emotional words, infant faces or cries from

own or stranger distressed infants. PPD women have lower activity in the amygdala, striatum,

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dorso-medial PFC, dorsal ACC, but increased activity in the insular region compared to healthy
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women to these stimuli. Further, there seems to be a change in the default mode network

between depressed and healthy postpartum women, with lower connectivity within corticolimbic

circuits including cingulate-amygdala connectivity (Chase et al., 2014; Deligiannidis et al.,

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2013). In particular, less amygdala activation in response to negative emotional stimuli and

infant distress was found among mothers with less secure attachment, lower oxytocin/prolactin
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levels due to cesarean section and more depressive and anxious symptoms (Moses-Kolko et
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al., 2014). Taken together these results suggest that there are a number of neurobiological

changes in PPD that are specifically related to maternal behaviors that may further help to
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illuminate the unique etiology of PPD compared to general depression.

Antidepressant use and Child Development

Certainly some depressed mothers who are taking antidepressant medication may be

advised by their doctors not to breast-feed their infants depending on the type and dose of the

medication (Bellissima et al., 2012). However, it is essential to distinguish between the effects of

treated and untreated depression on the mother on the child. Many studies report the

consequences of maternal depression without taking treatment or the mother’s feeding choices

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(breastfeeding or not) into consideration. Both are important for the infant’s HPA axis function,

as stressed-induced cortisol levels differed between selective serotonin reuptake inhibitors

(SSRI) exposed and unexposed infants if mode of feeding is taken into account (Oberlander et

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al., 2008). A recent systematic review examined the effects of antenatal depression and its

treatment with SSRIs during pregnancy (Suri et al., 2014). Untreated antenatal depression was

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associated with disrupted social and emotional behavior and language maturation patterns in

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the child, while SSRI exposure in utero was associated with disrupted motor and language

development in the child (Suri et al., 2014). However, less is known about postpartum treatment

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of depression compared to untreated PPD on child development and maternal care. Non-
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pharmacological interventions aimed at improving the mother-infant relationship in the

postpartum period are moderately effective in improving certain aspects of child outcome (e.g.

Poobalan et al., 2007), but not much is known about any long-term harm or benefit for the
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cognitive and behavioral outcome of children after pharmacological treatments of PPD.

Gestational antidepressant use has been associated with increased risk for attention
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deficit hyperactivity disorder (Clements et al., 2014), congenital heart defects and pulmonary
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hypertension (Hanley and Oberlander, 2014; Myles et al., 2013) in the exposed children and
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shorter gestational length (Andrade, 2013; Brummelte et al., 2013). There is also an association

between prenatal antidepressant exposure and higher risk for autism spectrum disorders in

SSRI-exposed children has been reported (Clements et al., 2014; Croen et al., 2011; Man et al.,

2015; Rai et al., 2013; Sorensen et al., 2013). Though some studies suggest that this

association was no longer significant when controlling for the maternal depression status

(Clements et al., 2014; Sorensen et al., 2013) and/or may be linked to whether the fathers were

taking an SSRI (Sorensen et al., 2013). Collectively these studies suggest a complex

relationship between parental depression, SSRI treatment and the risk for autism. Although

current research supports the notion that antidepressants cannot be considered major

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teratogens (Yonkers et al., 2014), it is clear that more research is needed to investigate the risk

factors associated with antidepressant treatments during pregnancy and the postpartum in the

short and long-term on exposed children (McDonagh et al., 2014).

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Interventions for PPD

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As noted above, children may be affected by pharmacological interventions in women

with PPD. Women may be reluctant to take pharmacological antidepressants during pregnancy

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and/or the postpartum as only 18% of depressed mothers seek treatment (Marcus, 2009). This

reluctance may be partly explained by the fact that antidepressants, such as SSRIs, remain
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active in breast milk and can potentially affect child development (Wisner et al., 1996). Although

clinical evidence suggests that low levels of SSRIs enter breast milk (Wisner et al., 1996),
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maternal antidepressant use remains controversial (Ornoy and Koren, 2014). Maternal
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antidepressant use may benefit (via therapeutic effect to the mother) or harm (via
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pharmacological effects in the milk) child development. Moreover, systematic reviews of clinical
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trials indicate that current pharmacological antidepressants are not as efficacious to the mother

during the postpartum period (De Crescenzo et al., 2014; Molyneaux et al., 2014; Sharma and
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Sommerdyk, 2013). A recent randomized placebo-controlled double-blind trials suggests some

efficacy with Sertraline in women with PPD that occurred within the first 4 weeks after childbirth

(Hantsoo et al., 2014). However, unfortunately in this study, women differed in their Hamilton

Depression Rating (HAM-D) scores at baseline, with the group randomized to Sertraline

exhibiting lower HAM-D scores from the onset and there was not a time by group effect in the

full cohort of PPD women across the 6 weeks of treatment. It should be noted that often PPD

remits on its own within 12 months after giving birth (Horowitz et al., 2013; Klier et al., 2008).

Intriguingly, non-pharmacological interventions such as intensive individualized home visits by

midwives or prenatal nurses during the postpartum, peer-based telephone support and

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psychotherapy were each seen as promising and effective in reducing incidence of PPD in a

recent review (Dennis and Dowswell, 2013a).

Outcomes with antidepressants treatment differ in women with PPD than in non-

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postpartum MDD women, as women with PPD take longer to recover and require more

pharmacological therapies than non-postpartum women (Hendrick et al., 2000). As mentioned

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earlier, in the postpartum, women are hypogonadal for many months (Bloch et al., 2003; Brett

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and Baxendale, 2001). This can be a challenge for finding effective antidepressant treatment.

Antidepressant efficacy is modulated by gonadal hormone levels in non-perinatal depression in

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both men and women (Pae et al., 2009; Soares et al., 2003; Zarrouf et al., 2009). In
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postmenopausal women SSRI antidepressant efficacy improved when women were on

hormone therapy compared to women not taking hormone therapy (Pae et al., 2009; Thase et

al., 2005). A similar relationship exists in men, as a meta-analysis showed alleviation of

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depressive symptoms when men were given antidepressants in conjunction with testosterone

(Zarrouf et al., 2009). Thus androgen and estradiol therapy is efficacious in the treatment of
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depression as an adjunct therapy in hypogonadal men and women (Kornstein et al., 2010;
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Zarrouf et al., 2009). With this in mind, coupled with the fact that women are hypogonadal

postpartum, there has been some success in the literature reported with improving
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antidepressant efficacy in the postpartum with treatment with estradiol (Ahokas et al., 2001;

Moses-Kolko et al., 2009).

Interventions for maternal behaviors

As indicated above, it is not always clear what the long-term effects of maternal

antidepressant use are on child development (though for some recent reviews see: Grigoriadis,

2014; Hanley and Oberlander, 2014; Suri et al., 2014). Considering that some of the negative

outcomes in children of depressed mothers are attributed to the disturbed mother-infant

interaction, it is important to investigate the effects of depression treatment on maternal

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depressive symptoms as well as on maternal behaviors. Unfortunately, many studies

investigating the effect of PPD on mother-infant interaction do not distinguish between, or

account for, treated versus untreated mothers (van Doesum et al., 2008). In particular, there is a

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dearth of knowledge about the effects of SSRI treatment and its effects on maternal care,

including mother-infant bonding, attachment or interaction. Interestingly, one study suggested a

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negative impact of SSRI use during pregnancy on the mother-infant attachment (Troutman and

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Momany, 2012). Another group reported that antidepressants were effective in decreasing the

depressive symptoms and enhancing maternal role gratification in depressed mothers, but not

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maternal self-efficacy or mother-infant interactions (Logsdon et al., 2009). Psychological
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interventions have been similarly ineffective in improving mother-infant relationships in the long-

term (Cooper et al., 2014; Forman et al., 2007; Goodman et al., 2014). Therapies directly

incorporating mother-infant relationship training have also yielded some improvements (Clark et
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al., 2003; O'Hara and McCabe, 2013; Poobalan et al., 2007), but often neglected the maternal

depressive symptoms. Furthermore, positive effects of the mother-infant relationship were

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usually not sustained at long term follow up (Forman et al., 2007; Murray et al., 2003) and did
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not extend to other domains such as cognitive or behavioral outcomes of the children. Thus,

there is a critical need for the development of better therapies that involve the improvement of
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maternal depressive symptoms as well as maternal-infant interactions that can be sustained

beyond the early postpartum period.

Future outlook

There is little agreement supporting the efficaciousness of pharmacological antidepressants

during the postpartum (De Crescenzo et al., 2014; Hantsoo et al., 2014; Molyneaux et al., 2014;

Sharma and Sommerdyk, 2013). However, some studies do show efficacy and it is important to

establish when and why pharmacological treatments work in the postpartum. In this endeavor it

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will be particularly important to clarify whether it is the postpartum environment that lends itself

to inefficacy such as differences in HPA and HPG regulation, inflammatory status, plasticity of

the brain or nutritional demands that make it more difficult for antidepressants to exert their

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effects. Future research should investigate whether non-pharmacological interventions are

efficacious for PPD without disrupting child development. For example exercise, acupuncture,

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massage, light therapy, and dietary supplements have been used with various degrees of

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success to treat antenatal and postpartum depression (Corral et al., 2007; Daley et al., 2007;

Dennis and Dowswell, 2013b; Miller et al., 2013; Rechenberg and Humphries, 2013; Wirz-

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Justice et al., 2011). Indeed, low levels of omega-3 index during pregnancy (Markhus et al.,
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2013) have been linked to greater incidence of depression postpartum. Furthermore low levels

of folate during pregnancy (week 26-28 of gestation) were associated with probable antenatal

but not probable postnatal depression (Chong et al., 2014). Nutritional supplements during
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pregnancy or the postpartum, including omega-3 and folic acid, have been touted as a possible

therapeutic for PPD and antenatal depression with some success with folate (Rechenberg and
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Humphries, 2013) but less so for omega-3 supplementation (Miller et al., 2013) unless it was
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given during gestation (Dennis and Dowswell, 2013b). Indeed omega-3 supplementation was

also effective in eliminating depressive-like behavior in the hormone simulated pregnancy

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animal model of PPD (Arbabi et al., 2014). However it is conceivable that changes in diet may

show good efficacy in the postpartum.

In conclusion it is important to recognize that the prenatal and postnatal periods are

times of risk to develop depression in women but are also characterized by dramatic changes in

body weight, fluid retention, nutritional demands and hormones. Thus the physical demands of

pregnancy and the postpartum are a delicate time for women that may require different

treatment regimens due to the differing physiological demands than in MDD. Given the profound

importance of early upbringing on child development and mother-infant interactions it is

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imperative that we pay more attention to maternal health, not just during pregnancy but across

the postpartum as well.

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Conflict of Interest

All authors declare that they have no conflict of interest.

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Acknowledgements

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SB is supported by a start-up fund by Wayne State University and LAMG is supported

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by operating grants from Canadian Institutes for Health Research (CIHR MOP102568)

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and Natural Sciences and Engineering Research Council of Canada (NSERC).
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Figure legends

Figure 1 Hormonal changes during pregnancy and the postpartum. The relative hormone

levels of progesterone (ng/ml), corticosterone (ng/mL) and estradiol (pg/mL) over the course of

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pregnancy and parturition. Figure reprinted with permission from (Pawluski et al., 2009a).

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Figure 2. Potential relationship between postpartum depression, maternal-infant

interaction and child outcome. Postpartum depression impacts mother-infant interaction

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which in turn may contribute to a disturbed neurobiological development of the child. Improving
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both, maternal depressive symptoms and mother-infant interaction (blue arrows) may be

important to enable a healthy development of the child (blue dotted arrow). However,

pharmacological treatment of the maternal depression may contribute to an adverse child

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development and outcome (red dotted arrow).

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Highlights

1) Maternal depression includes depression during gestation, early and late postpartum
2) Onset of timing of maternal depression influences maternal care and symptoms
3) Adrenal, placental, sex and peptide hormones are implicated in maternal depression

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4) Maternal depression can negatively impact mother-infant interactions
5) Interventions should seek to improve both, depressive symptoms and maternal care

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