Archival Report Biological

Psychiatry

Prepartum and Postpartum Maternal Depressive

Symptoms Are Related to Childrens Brain
Structure in Preschool
Catherine Lebel, Matthew Walton, Nicole Letourneau, Gerald F. Giesbrecht, Bonnie J. Kaplan,
and Deborah Dewey

ABSTRACT
BACKGROUND: Perinatal maternal depression is a serious health concern with potential lasting negative
consequences for children. Prenatal depression is associated with altered brain gray matter in children, though
relations between postpartum depression and childrens brains and the role of white matter are unclear.
METHODS: We studied 52 women who provided Edinburgh Postnatal Depression Scale (EPDS) scores during each
trimester of pregnancy and at 3 months postpartum and their children who underwent magnetic resonance imaging
at age 2.6 to 5.1 years. Associations between maternal depressive symptoms and magnetic resonance imaging
measures of cortical thickness and white matter structure in the children were investigated.
RESULTS: Womens second trimester EPDS scores negatively correlated with childrens cortical thickness in right
inferior frontal and middle temporal regions and with radial and mean diffusivity in white matter emanating from the
inferior frontal area. Cortical thickness, but not diffusivity, correlations survived correction for postpartum EPDS.
Postpartum EPDS scores negatively correlated with childrens right superior frontal cortical thickness and with
diffusivity in white matter originating from that region, even after correcting for prenatal EPDS.
CONCLUSIONS: Higher maternal depressive symptoms prenatally and postpartum are associated with altered gray
matter structure in children; the observed white matter correlations appear to be uniquely related to the postpartum
period. The reduced thickness and diffusivity suggest premature brain development in children exposed to higher
maternal perinatal depressive symptoms. These results highlight the importance of ensuring optimal womens mental
health throughout the perinatal period, because maternal depressive symptoms appear to increase childrens
vulnerability to nonoptimal brain development.
Keywords: Brain development, Diffusion imaging, Magnetic resonance imaging, Maternal depression, Postpartum,
Pregnancy
http://dx.doi.org/10.1016/j.biopsych.2015.12.004

Depression is common during the perinatal period, with approx-
imately 18% of women experiencing depression sometime
during pregnancy (7% to 13% per trimester), and 13% reporting
postpartum depression (15). Exposure to prenatal and/or
postnatal maternal depression is associated with negative child
outcomes, including increased risk for poor emotional regula-
tion, mental health problems, and cognitive, behavior, or motor
delays (611). Though many effects of prenatal depression are
attenuated after controlling for postpartum depression (12),
prenatal depressive symptoms are independently associated
with lower intelligence (13) and behavioral problems (1416) in
children. Relations between perinatal depression and many child
outcomes are moderated by socioeconomic status and sex;
male and female children of mothers who experience stress
during pregnancy exhibit different outcomes (1719), and chil-
dren from families of high socioeconomic status tend to show
less severe effects of maternal depression than children from
low socioeconomic status families (20,21).
Understanding the brain abnormalities associated with
perinatal depressive symptoms can highlight brain regions
sensitive to such effects and provide information about
potential mechanisms linking maternal depression with neg-
ative behavioral and cognitive outcomes. Volumetric and
diffusion magnetic resonance imaging (MRI) are common
ways of assessing gray and white matter structure. Gray and
white matter change signicantly during the preschool period
as part of normal brain maturation (22,23), and abnormalities
are often associated with negative childhood outcomes,
including learning disabilities (24) and externalizing and inter-
nalizing disorders (25,26). Despite the importance of under-
standing brain abnormalities, few studies have examined
associations between maternal depression and childrens
brain structure. One study demonstrated lower anisotropy
and axial diffusivity in the amygdala of neonates (517 days
old) born to mothers with higher prenatal maternal depressive
symptoms compared with lower depressive symptoms (27).

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Biological
Psychiatry Maternal Depression and Childrens Brain Structure

The same infants showed associations between prenatal postpartum (11 6 2.3 weeks, n = 52); scores are reported in
maternal depressive symptoms and white matter microstruc- Table 1. Due to the timing of their enrollment in the study, 29
ture in right frontal connections including the inferior fronto- women did not complete the EPDS in their rst trimester. Five
occipital and uncinate fasciculi (28). Another study showed women were missing second trimester scores, and one
correlations between increased maternal prenatal depression woman was missing a third trimester score. Depressive
and reduced cortical thickness in the right prefrontal lobe of symptom scores across time points were highly correlated
school-aged children; cortical thickness also mediated corre- (r 5 .48.68, all p , .006). Breastfeeding status was not
lations between maternal depressive symptoms and childrens related to depressive symptoms at any time point.
externalizing behaviors (29). To our knowledge, no studies The EPDS is a screening tool for perinatal depression rather
have investigated the effects of postpartum maternal depres- than a diagnostic instrument, though scores .12 are usually
sive symptoms on childrens brain structure, despite the consistent with a physician diagnosis of major depressive disorder
strong associations between postpartum depression and (33). Screening cutoffs range from 10 to 14 and are typically 1 to 2
childrens outcomes (6). Furthermore, the few studies linking points higher in pregnancy than postpartum (35). In our sample in
prenatal maternal depression and childrens brain structure to the rst trimester, only one woman scored $10 on the EPDS (she
date are limited to infants or school-aged children, leaving a scored 16). In the second trimester, eight women scored $10,
critical gap in knowledge of brain abnormalities during early four women scored $12, and three women scored $14 on the
childhood, a period of rapid structural brain development (30) EPDS. In the third trimester, three women scored $10, two
and a time when many of the behavior problems associated women scored $12, and one woman scored $14. In the
with perinatal depression become apparent (31). postpartum period, four women scored $10, three women scored
The goal of this study was to investigate the associations $12, and one woman scored $14. Therefore, depending on the
between perinatal depressive symptoms and brain structure in cutoff used, 4% of women met criteria for further follow-up during
preschool-aged children. Specically, we used multimodal the rst trimester, 6% to 17% met criteria for further follow-up
MRI to investigate gray and white matter structure in children during the second trimester, 2% to 6% met criteria for further
born to mothers with a range of perinatal depressive symp- follow-up during their third trimester, and 2% to 8% met screening
toms. Given previous reports of cortical thickness alterations, criteria for postpartum depression. One woman was taking an
we began with a whole-brain analysis of associations between antidepressant during pregnancy.
cortical thickness in children and maternal perinatal depressive
symptoms. We then followed up with a targeted investigation Imaging
of white matter tracts emanating from affected cortical regions Brain imaging occurred at the Alberta Childrens Hospital on a
to determine whether white matter structure in underlying GE 3T MR750w (General Electric, Waukesha, Wisconsin)
areas is also associated with maternal depressive symptoms. using a 32-channel head coil. During their scan, children
Because earlier ndings relating depressive symptoms and were either awake and watching a movie or sleeping naturally.
childrens brain outcomes were specic to the second trimes- T1-weighted anatomical imaging was acquired using a
ter (29), we examined correlations in each trimester of spoiled gradient echo sequence with .9 3 .9 3 .9 mm3
pregnancy separately. spatial resolution, echo time/repetition time 5 3.8/8.2 ms.
Diffusion tensor imaging (DTI) data were acquired using single-
METHODS AND MATERIALS shot spin-echo echo planar imaging with 30 diffusion encod-
ing gradient directions at b 5 750 s/mm2 and 5 images at
Participants
Participants were 52 women recruited during pregnancy and
the children (32 male/20 female) from those pregnancies. Table 1. Descriptive Information for Women and Their
Women and children were recruited from an ongoing, pro- Children
spective study examining maternal nutrition, mental health,
Range Mean (6 SD) n
and offspring outcomes (32). Table 1 summarizes character-
Women
istics of the women and children, including maternal age at
childs birth, maternal postsecondary education (used as a Age at childs birth (years) 2638 32.1 6 3.0 52
proxy for socioeconomic status), breastfeeding status at 3 Postsecondary education (years) 010 4.7 6 2.9 52
months postpartum, and childs gestational age and weight at EPDS rst trimester 016 4.7 6 3.6 23
birth. At the time of MRI scanning, children were aged 2.6 to EPDS second trimester 016 4.7 6 4.2 47
5.1 years (3.6 6 .5 years). EPDS third trimester 017 4.8 6 3.2 51
EPDS postpartum 019 4.4 6 4.1 52
Depressive Symptoms Breastfeeding/formula at 28 exclusive breastfeeding, 51
3 months postpartum 6 mixed, 17 formula
Symptoms of maternal depression were assessed using the
Children
Edinburgh Postnatal Depression Scale (EPDS), a measure
Sex 20 female; 32 male 52
validated for assessment of depressive symptoms both pre-
partum and postpartum (33,34). Women completed the EPDS Gestational age at birth (weeks) 35.041.9 39.2 6 1.4 52
once during each trimester of pregnancy (rst trimester: 11 6 Birth weight (g) 22304610 3369 6 473 52
2.5 weeks, n = 23; second trimester: 17 6 2.2 weeks, n = 47; Age at scan (years) 2.65.1 3.6 6 .5 52
third trimester: 32 6 1.1 weeks, n = 51) and at 2 to 3 months EPDS, Edinburgh Postnatal Depression Scale.

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Maternal Depression and Childrens Brain Structure
b 5 0 s/mm2, echo time/repetition time 5 79/6750 ms. Each
sequence lasted approximately 4 minutes.
Image Processing and Analysis
T1-weighted data were quality checked and processed through
FreeSurfer 5.3 (Laboratory for Computational Neuroimaging,
Charlestown, Massachusetts) (36). Images were skull stripped
and automatically parcellated to provide thickness values across
the cortex. Each parcellation was manually checked and corrected
if necessary. FreeSurfers QDEC was used for whole-brain
analysis of cortical thickness using a linear regression with
maternal depressive symptoms at each trimester and postpartum
as the predictors and childrens current age and sex, gestational
age at birth, and birth weight and maternal postsecondary
education as covariates. Multiple comparison correction was
performed using Monte Carlo simulations at p , .05. In each
region showing signicant relations, average cortical thickness
was extracted for follow-up analysis of DTI data.
DTI data were processed through in-house software to
remove motion-corrupted volumes and then eddy current
corrected before calculation of the tensor in FMRIB Software
Library (Analysis Group, FMRIB, Oxford, United Kingdom).
Signicant regions from the cortical thickness analysis were
warped to native DTI space for each individual and used as
regions of interest for deterministic tractography in TrackVis
(Ruopeng Wang, Van J. Wedeen, Boston, Massachusetts) (37).
Within the entire resulting tract, fractional anisotropy and radial
diffusivity, axial diffusivity, and mean diffusivity values were
calculated for each voxel and averaged to create one frac-
tional anisotropy, radial diffusivity, axial diffusivity, and mean
diffusivity measure for each subject. These DTI measures were
then tested for partial correlations with EPDS scores for the
relevant time period, controlling for childrens age, sex, and
gestational age and weight at birth and maternal postsecon-
dary education; statistical analysis was conducted in SPSS
version 22 (IBM Inc., Armonk, New York).
To determine the specicity of ndings, correlations with
prenatal depressive symptoms were corrected for postpartum
depressive symptoms in a follow-up analysis. Similarly, post-
partum results were corrected for average prenatal EPDS
scores and separately for second trimester prenatal EPDS
scores, as these were the only ones signicantly related to
brain structure in children.
Sex Differences
Sex was controlled for in the original analysis. However, sex
differences and sex-by-maternal depressive symptom inter-
actions were examined in post hoc tests (analysis of variance)
for all imaging measures, including childrens age, sex, gesta-
tional age at birth, and birth weight and maternal postsecon-
dary education as additional covariates.
RESULTS
Maternal Depressive Symptoms and Cortical
Thickness
Cortical thickness in two right hemisphere areas was neg-
atively correlated with second trimester maternal depressive
Biological
Psychiatry
symptoms, controlling for childs age, sex, gestational age,
and weight at birth and maternal postsecondary education
(Figures 1 and 2). One region was located in the right inferior
frontal area, including much of the pars opercularis and pars
triangularis, and small sections of the precentral and rostral
middle frontal areas (r = 2.71, p , .001); the other area was
located in the middle and superior temporal regions and
included small sections of the inferior temporal and supra-
marginal areas (r = 2.61, p , .001). Correlations with second
trimester EPDS scores remained strong after controlling for
postpartum EPDS scores (r = 2.64, p , .001; r = 2.58, p ,
.001, respectively). Depressive symptoms during the rst and
third trimesters were not signicantly related to cortical
thickness.
Cortical thickness in the right superior frontal area (both
lateral and medial surfaces and including small sections of the
caudal middle frontal and precentral areas) was negatively
correlated with maternal postpartum depressive symptom
scores (Figures 3 and 4; r = 2.51, p , .001), after controlling
for childs age, sex, gestational age at birth, and birth weight
and maternal postsecondary education. This correlation
remained strong after correcting for second trimester prenatal
EPDS (r = 2.45, p = .004) or average prenatal EPDS (r = 2.35,
p = .019).
Prenatal and postpartum correlations remained signicant
after removing the woman who took antidepressant medica-
tion from the analysis.
Maternal Depressive Symptoms and Diffusion
Measures
Cortical areas associated with prenatal or postnatal depres-
sive symptoms were used as seeding regions for tractogra-
phy. In the bers emanating from the inferior frontal region,
which included lateral portions of the uncinate, inferior fronto-
occipital, and arcuate fasciculi, radial and mean diffusivity had
signicant correlations with second trimester EPDS scores (r =
2.34, p = .027; r = 2.33, p = .033, respectively); axial
diffusivity showed a trend association with second trimester
EPDS (r = 2.29, p = .068; Figures 1 and 2). White matter
emanating from the middle temporal region, which included
much of the uncinate, inferior longitudinal, and inferior fronto-
occipital fasciculi, had no signicant correlations with second
trimester EPDS scores. Fibers connecting the inferior frontal
and middle temporal regions (primarily the lateral portions of
the uncinate and arcuate fasciculi) showed only a trend
association between radial and mean diffusivity and second
trimester EPDS (r = 2.30, p = .057; r = 2.26, p = .092), after
controlling for childs age, sex, gestational age at birth, and
birth weight and maternal postsecondary education. No
diffusion parameter correlations with second trimester EPDS
remained signicant after controlling for postpartum EPDS (all
p . .2).
Axial, radial, and mean diffusivity in the ber tracts emanat-
ing from the superior frontal region were negatively correlated
with maternal postpartum depressive symptoms (r = 2.30, p =
.041; r = 2.39, p = .008; r = 2.39, p = .007, respectively;
Figures 3 and 4), controlling for childs age, sex, gestational
age at birth, and birth weight and maternal postsecon-
dary education. These correlations remained signicant after
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Biological
Psychiatry Maternal Depression and Childrens Brain Structure

Figure 1. Brain areas with signicant associations to maternal prenatal depression scores. Two regions demonstrated signicant negative correlations
between cortical thickness and second trimester maternal depressive symptoms: (A) a cluster in the right middle temporal region (red) and a cluster in the right
inferior frontal region spanning the pars orbitalis and pars triangularis (blue). The white matter bers emanating from each of these two regions: (B) pinkbers
emanating from the middle temporal area included the uncinate and inferior longitudinal fasciculi; (C) cyanbers emanating from the inferior frontal area
included the uncinate, arcuate, and inferior fronto-occipital fasciculi are shown, as well as the bers that pass through both regions; (D) yellowprimarily the
lateral portions of the uncinate and arcuate fasciculi. Fibers from the inferior frontal region demonstrated a signicant negative correlation between maternal
second trimester depressive symptoms and radial and mean diffusivity. Correlations of second trimester Edinburgh Postnatal Depression Scale with cortical
thickness, but not those with diffusivity, remained signicant after controlling for postpartum depressive symptoms. A, anterior; L, left; P, posterior; R, right.

controlling for average prenatal EPDS (r = 2.33, p = .027;
r = 2.30, p = .048; r = 2.34, p = .024, respectively) and after
removing the woman taking antidepressant medication from
the analysis. All correlations except for axial diffusivity
remained signicant if corrected for second trimester EPDS
instead of average prenatal EPDS scores (r = 2.28, p = .082; r
= 2.37, p = .019; r = 2.37, p = .018).
Sex Differences
An analysis of variance revealed signicant main effects of sex
on axial diffusivity in the tracts emanating from the superior
frontal area (p = .039); axial diffusivity was higher in male
subjects. No other thickness or diffusion measurements had
signicant sex effects when controlling for childs age, gesta-
tional age at birth, and birth weight and mothers postsecon-
dary education. There was a signicant sex-by-depressive
symptoms interaction in the right middle temporal area (p =
.049), where the correlation between second trimester mater-
nal EPDS and cortical thickness was weaker in boys than in
girls (r = 2.55, p = .006; r = 2.80, p , .001, respectively;
Figure 2). There were also signicant sex-by-postpartum
EPDS score interactions for axial, radial, and mean diffusivity
values in white matter tracts emanating from the superior
frontal region (p 5 .047, p 5 .049, p 5 .029, respectively). In
these tracts, the relation between maternal postpartum EPDS

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Maternal Depression and Childrens Brain Structure
and childrens axial, radial, and mean diffusivity was stronger
in male than in female subjects (r 5 2.46, p 5 .015; r 5 2.57,
p 5 .002; r 5 2.56, p 5 .003, respectively, in male subjects;
r 5 .09, r 5 2.07, r 5 2.04, all nonsignicant at p . .5,
respectively, in female subjects).
DISCUSSION
We report here, for the rst time in preschool children,
associations between maternal prenatal and postnatal depres-
sive symptoms and white and gray matter brain structure. The
thinner cortex and lower diffusivity we observed suggest
altered brain development in children exposed to higher levels
of maternal depressive symptoms. During childhood, the
cortex thins (22,38) and white matter diffusivity decreases
(23,39) as part of normal maturation processes, including
synaptic pruning (40) and myelination (41). In this study,
thinner cortex and lower diffusivity may indicate earlier brain
maturation in children exposed to higher levels of maternal
Biological
Psychiatry
Figure 2. Correlations between
brain structure and maternal prenatal
depressive symptoms. Maternal
depressive symptoms in the second
trimester were signicantly correlated
with cortical thickness in two regions,
as well as with radial and mean diffu-
sivity in the white matter emanating
from one region. Scatter plots show
second trimester maternal Edinburgh
Postnatal Depression Scale (EPDS)
scores versus cortical thickness in
each region (A, B) and radial (C) and
mean diffusivity (D) of the white mat-
ter bers passing through the inferior
frontal region; all imaging parameters
are corrected for maternal postse-
condary education and childs age,
sex, gestational age at birth, and birth
weight. Cortical thickness in the right
middle temporal area showed a sig-
nicant EPDS-sex interaction, with
girls showing a stronger and more
negative association between EPDS
scores and cortical thickness than
boys. EPDS correlations with cortical
thickness remained signicant after
controlling for postpartum depressive
symptoms, but the diffusivity correla-
tions did not. corr., corrected.
depressive symptoms. This is in line with life history theory
wherein the timing of key developmental achievements is
altered by exposure to early adversity (42), a theory supported
by evidence that childhood stress can lead to earlier repro-
ductive development (43,44). Limited brain data also support
this theory: early weaning can lead to premature myelination in
mice (45), and early life adversity in children is associated with
a more adult-like arrangement of amygdala connectivity (46).
Maternal perinatal depression, acting as an early adverse
experience, may lead to earlier brain development in children
via premature myelination and synaptic pruning. This early
development occurs at the expense of extended brain plasti-
city, as underused neural connections that could ultimately
have been useful may be prematurely pruned, affecting
cognitive and behavioral outcomes throughout life.
The right frontal and temporal regions observed here have
been consistently implicated in tasks involving inhibition and
attention control (4751), executive functions that can be
impaired in children of mothers with perinatal depression
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Biological
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Figure 3. Brain areas with signicant correlations to maternal postpartum
depression scores. One cluster in the right superior frontal region had
signicant negative correlations between maternal depressive symptoms at 3
months postpartum and childrens cortical thickness (top). Diffusivity in the
white matter bers emanating from this region (bottom; primarily the anterior
and superior frontal callosal tracts and part of the anterior corona radiata) also
demonstrated signicant negative correlations with maternal postpartum de-
pressive symptoms. All correlations held after controlling for prenatal depres-
sive symptoms. A, anterior; L, left; P, posterior; R, right.
(6,13). The thinner frontal cortex we observed in children of
mothers with higher perinatal depressive symptoms is con-
sistent with the only previous study of maternal prenatal
depressive symptoms and brain structure in children (29).
Reduced cortical thickness in the right frontal lobe is also a
common nding in studies of children and adolescents with
depression (52) and those at risk of depression (53,54), and
right frontal cortical thinning is associated with anxiety and
depressive symptoms even in healthy children (55,56). Electro-
encephalography studies demonstrated alterations in neural
activity observed in right frontal electrodes in infants and
children of depressed mothers (57,58). The lower diffusivity
observed in frontal white matter connections in this study is
consistent with observations of higher anisotropy and/or lower
diffusivity in frontal white matter in adolescents with depres-
sion (59), children whose mothers had more stressful life
events during pregnancy (60), and adults who experienced
childhood adversity (61). Consistencies between our ndings
and those of adolescents with depression suggest brain
structure as a possible mechanism via which children of
mothers with perinatal depression are more vulnerable them-
selves to depression later in life (8,9).
We observed associations between childrens cortical thick-
ness and maternal depressive symptoms in the second trimes-
ter and postpartum only, suggesting that these may be
particularly vulnerable times for brain development. Other
studies have also found relations specic to the second trim-
ester, linking maternal depressive symptoms (29) and anxiety
(62) during this time to childrens gray matter structure. The
second trimester is an important period of fetal brain develop-
ment during which much gyrication occurs (6366), with
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Maternal Depression and Childrens Brain Structure
inferior frontal and superior temporal areas developing more
rapidly than the rest of the brain (66). After birth, cortical
thickness changes throughout infancy and childhood, again
with regional variation in trajectories (22,38,67). Interestingly,
while the cortical thickness results held after controlling for
prenatal or postnatal depressive symptoms, the correlations
between second trimester depressive symptoms and diffusivity
disappeared after controlling for postpartum EPDS scores. This
suggests that while prenatal and postnatal depressive symp-
toms are independently associated with cortical thickness,
postnatal depressive symptoms may be more uniquely related
to white matter structure, at least in the areas investigated.
Myelination of brain white matter begins in the second or third
trimester of pregnancy but is most rapid in early infancy (41,68),
a time period that also includes major white matter volume
growth (30,69). Thus, while the developing brain is likely always
vulnerable to adverse experiences, the second trimester and
postpartum periods may convey special risks that are associ-
ated with later cortical structure, and the postpartum period
may be the most vulnerable for white matter developmental
disruptions. Future studies with more data points, particularly in
the rst trimester where we had missing data, are necessary to
properly determine whether these results are unique to the
second trimester and postpartum periods.
Studies have reported sex differences in children of
mothers who experience stress during pregnancy in terms
of childrens behaviors (18), stress responses (19), and
amygdala volume (17). Animal models also support sex-
differentiated effects of maternal stress on gray matter
structure (70) and of early life stress on white matter structure
(45). We found no signicant sex differences in cortical
thickness and only a barely signicant sex difference in axial
diffusivity of the superior frontal tracts. We did, however, nd
sex-by-depressive symptom interactions in the middle tem-
poral cortex (Figure 2) and in diffusivity of white matter tracts
from the superior frontal area (Figure 4). Girls had a more
negative association between maternal prenatal depressive
symptoms and cortical thickness than boys, while boys had
more negative correlations between maternal postpartum
EPDS and diffusivity. Previous studies have found sex-by-
diagnosis interactions in children with attention-decit/hyper-
activity disorder (71,72), including reduced white matter
volume in the medial prefrontal area in boys but not girls
(73) and thinner middle temporal cortex in girls than in boys
(74), in line with our current ndings. Exposure to depression
in utero and postpartum has been associated with sex-
specic development of neurobiological pathways involved
in stress regulation (17,75,76) and may be relevant to sex
differences in the incidence of affective problems later in
childhood (18,77). Imaging studies demonstrate sex differ-
ences in cortical (78) and white matter (79) maturation
trajectories during childhood. Other prenatal inuences, such
as alcohol exposure, are associated with sex-differentiated
effects on cortical development (80), so perinatal maternal
depressive symptoms may also differentially alter brain
development in male and female individuals. Though more
data are needed to clearly understand sex differences, our
ndings provide strong evidence for sex-differentiated effects
of perinatal maternal depressive symptoms on childrens
brain structure.

Maternal Depression and Childrens Brain Structure
The mechanisms underlying the observed associations
remain unclear. Possible explanations include dysregulation
of the hypothalamic-pituitary-adrenal (HPA) axis, nutritional
deciencies, and epigenetics. Depression and stress are
associated with dysregulation of the HPA axis and elevated
cortisol levels (81), even during pregnancy (82). Chronic stress
in animal models is associated with abnormal HPA axis
function and altered brain structure (70), and even when stress
occurs at a very young age, brain structure can be impacted
into adulthood (83). However, many previous studies have not
found links between maternal cortisol and child outcomes
following maternal depression (6,29), so if HPA function plays
a role, it is likely a complex one. Another possible mechanism
is nutrition, which is associated with maternal mood (8486)
and linked with fetal brain development (87,88). Maternal
nutrition can also impact infant brain development via
nutrients passed during breastfeeding or nutritional differences
associated with formula feeding. Formula feeding and breast-
feeding are associated with different patterns of brain struc-
ture in children (89), and depressed women are less likely to
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Psychiatry
Figure 4. Correlations between
maternal depressive symptoms post-
partum and brain structure. Correla-
tions between maternal postpartum
depressive symptoms and childrens
cortical thickness in the right superior
frontal region were signicant, as
were correlations with diffusivity in
white matter bers emanating from
this region. Scatter plots are shown
for cortical thickness (A) and axial
(B), radial (C), and mean diffusivity
(D) versus postpartum depressive
symptoms. Imaging parameters are
corrected for childs age, sex, gesta-
tional age at birth, and birth weight
and maternal postsecondary edu-
cation. All correlations remained sig-
nicant after correcting for prenatal
Edinburgh Postnatal Depression
Scale (EPDS) scores. corr., corrected.
breastfeed (90), offering an additional mechanism by which
postpartum depression and nutrition could affect childrens
brain structure. However, in our sample, breastfeeding was not
associated with depressive symptoms at any time point.
Future studies of relationships between breastfeeding, brain
structure, and depressive symptoms may be useful to clarify
interactions among these factors. Genetics inuence both
structural brain development (91,92) and depressive symp-
toms (93) and therefore are highly likely to play a role in the
observed effects.
This study has several limitations. Only 44% of women in
this study provided EPDS scores during the rst trimester due
to difculties in recruiting women early in pregnancy. This
reduced the power to detect associations between rst
trimester depressive symptoms and brain structure, so it is
unclear whether the correlations we observed are truly unique
to the second trimester and postpartum periods. Future
studies that recruit women earlier in their pregnancies are
required to appropriately answer this question. We had MRI
data from only one time point in childhood, which precludes
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Biological
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testing the effects of perinatal depressive symptoms on rates
of brain development; longitudinal data are necessary to
examine brain changes over time. Furthermore, our data span
a relatively wide age range (2.6 to 5.1 years) for young
children, allowing for signicant age-related brain differences
between our youngest and oldest participants. Although we
controlled for age in all analyses, a tighter age range and/or
longitudinal data are necessary to further elucidate the effects
of perinatal maternal depression on brain maturation in
children. Some of the covariates included were highly corre-
lated and were difcult to properly control, while others may
have been mediators rather than covariates. Mediation models
are not feasible for whole-brain approaches like that used
here, but future studies focused on specic brain regions may
be able to use more sophisticated modeling strategies to
further disentangle the effects of prenatal and postnatal
environment on brain structure in young children. Finally, the
women in our sample had relatively mild depressive symp-
toms, with only 4% to 17% of women meeting screening
cutoffs for depression. Nonetheless, we observed strong
correlations between maternal EPDS scores and childrens
brain structure, suggesting that important relations exist even
in women with mild depressive symptoms.
In conclusion, we have demonstrated signicant associa-
tions between maternal prenatal and postnatal depressive
symptoms and altered brain structure in young children,
suggesting premature brain development and reduced plasti-
city in children exposed to higher levels of maternal depressive
symptoms. These effects were sexually dimorphic, suggesting
greater vulnerability of female subjects to prenatal depressive
symptoms and greater vulnerability of male subjects to post-
natal depressive symptoms. Both cortical gray matter thick-
ness and white matter diffusivity in right frontal and temporal
areas, regions known to be associated with depression later in
life, were related to maternal depressive symptoms. This study
highlights the importance of monitoring and appropriately
treating maternal depression throughout the prenatal and
postpartum periods to minimize risks to normal brain develop-
ment in children.
ACKNOWLEDGMENTS AND DISCLOSURES
This work was supported by the Canadian Institutes of Health Research
(CIHR) (funding Grant Nos. IHD-134090 and MOP-136797), Alberta Inno-
vates - Health Solutions, and the National Institute of Environmental Health
Sciences (Grant No. 5R21ES021295-03).
We thank the other members of the Alberta Pregnancy Outcomes and
Nutrition study team: Catherine J. Field, Rhonda C. Bell, Francois P. Bernier,
Marja Cantell, Linda M. Casey, Misha Eliasziw, Anna Farmer, Lisa Gagnon,
Laki Goodewardene, David W. Johnson, Libbe Kooistra, Brenda M.Y.
Leung, Donna P. Manca, Jonathan W. Martin, Linda J. McCargar, Maeve
OBeirne, Victor J. Pop, and Nalini Singhal.
CLs spouse is an employee of General Electric Healthcare. The other
authors report no biomedical nancial interests or potential conicts of
interest.
ARTICLE INFORMATION
From the Departments of Radiology (CL), Pediatrics (GFG, BJK, DD),
Psychiatry (NL), and Community Health Sciences (BJK, DD); Medical
Sciences Program (MW); Faculty of Nursing (NL); Child & Adolescent
Imaging Research Program (CL, MW); and Alberta Childrens Hospital
8 Biological Psychiatry ]]], 2016; ]:]]]]]] www.sobp.org/journal
Maternal Depression and Childrens Brain Structure
Research Institute (CL, MW, NL, GFG, BJK, DD), University of Calgary,
Calgary, Alberta, Canada.
Address correspondence to Catherine Lebel, Ph.D., University of
Calgary, Alberta Childrens Hospital, Room B4-513, 2888 Shaganappi Trail
NW, Calgary, Alberta T3B6A8, Canada; E-mail: clebel@ucalgary.ca.
Received Aug 6, 2015; revised Dec 8, 2015; accepted Dec 9, 2015.
REFERENCES
1. Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G,
Swinson T (2005): Perinatal depression: A systematic review of
prevalence and incidence. Obstet Gynecol 106:10711083.
2. Bennett HA, Einarson A, Taddio A, Koren G, Einarson TR (2004):
Prevalence of depression during pregnancy: Systematic review.
Obstet Gynecol 103:698709.
3. Gaynes B, Gavin N, Meltzer-Brody S, Lohr K, Swinson T, Gartlehner
G, et al. (2005): Perinatal Depression: Prevalence, Screening, Accu-
racy, and Screening Outcomes. Research Triangle Park, NC: Agency
for Healthcare Research Quality.
4. Evans J, Melotti R, Heron J, Ramchandani P, Wiles N, Murray L, Stein
A (2012): The timing of maternal depressive symptoms and child
cognitive development: A longitudinal study. J Child Psychol Psy-
chiatry 53:632640.
5. Gaynes BN, Gavin N, Meltzer-Brody S, Lohr KN, Swinson T, Gar-
tlehner G, et al. (2005): Perinatal depression: Prevalence, screening
accuracy, and screening outcomes. Evid Rep Technol Assess (Summ)
119:18.
6. Stein A, Pearson RM, Goodman SH, Rapa E, Rahman A, McCallum M,
et al. (2014): Effects of perinatal mental disorders on the fetus and
child. Lancet 384:18001819.
7. Kersten-Alvarez LE, Hosman CM, Riksen-Walraven JM, van Doesum
KT, Smeekens S, Hoefnagels C (2012): Early school outcomes for
children of postpartum depressed mothers: Comparison with a
community sample. Child Psychiatry Hum Dev 43:201218.
8. Verbeek T, Bockting CL, van Pampus MG, Ormel J, Meijer JL,
Hartman CA, Burger H (2012): Postpartum depression pred-
icts offspring mental health problems in adolescence independ-
ently of parental lifetime psychopathology. J Affect Disord 136:
948954.
9. Murray L, Arteche A, Fearon P, Halligan S, Goodyer I, Cooper P
(2011): Maternal postnatal depression and the development of
depression in offspring up to 16 years of age. J Am Acad Child
Adolesc Psychiatry 50:460470.
10. Goodman SH, Rouse MH, Connell AM, Broth MR, Hall CM, Heyward
D (2011): Maternal depression and child psychopathology: A meta-
analytic review. Clin Child Fam Psychol Rev 14:127.
11. Letourneau NL, Tramonte L, Willms JD (2013): Maternal depression,
family functioning and childrens longitudinal development. J Pediatr
Nurs 28:223234.
12. Waters CS, Hay DF, Simmonds JR, van Goozen SH (2014): Antenatal
depression and childrens developmental outcomes: Potential mech-
anisms and treatment options. Eur Child Adolesc Psychiatry 23:
957971.
13. Barker ED, Jaffee SR, Uher R, Maughan B (2011): The contribution of
prenatal and postnatal maternal anxiety and depression to child
maladjustment. Depress Anxiety 28:696702.
14. Hay DF, Pawlby S, Waters CS, Perra O, Sharp D (2010): Mothers
antenatal depression and their childrens antisocial outcomes. Child
Dev 81:149165.
15. Hay DF, Mundy L, Roberts S, Carta R, Waters CS, Perra O, et al.
(2011): Known risk factors for violence predict 12-month-old infants
aggressiveness with peers. Psychol Sci 22:12051211.
16. Davis EP, Snidman N, Wadhwa PD, Dunkel Schetter C, Glynn L,
Sandman CA (2004): Prenatal maternal anxiety and depres-
sion predict negative behavioral reactivity in infancy. Infancy 6:
319331.
17. Buss C, Davis EP, Shahbaba B, Pruessner JC, Head K, Sandman CA
(2012): Maternal cortisol over the course of pregnancy and subse-
quent child amygdala and hippocampus volumes and affective
problems. Proc Natl Acad Sci U S A 109:E1312E1319.

Maternal Depression and Childrens Brain Structure
18. Sandman CA, Glynn LM, Davis EP (2013): Is there a viability-
vulnerability tradeoff? Sex differences in fetal programming. J Psy-
chosom Res, 75, 327335.
19. Yong Ping E, Laplante DP, Elgbeili G, Hillerer KM, Brunet A, OHara
MW, King S (2015): Prenatal maternal stress predicts stress reactivity
at 2(1/2) years of age: The Iowa Flood Study. Psychoneuroendocri-
nology 56:6278.
20. Pearson RM, Evans J, Kounali D, Lewis G, Heron J, Ramchandani PG,
et al. (2013): Maternal depression during pregnancy and the postnatal
period: Risks and possible mechanisms for offspring depression at
age 18 years. JAMA Psychiatry 70:13121319.
21. Lovejoy MC, Graczyk PA, OHare E, Neuman G (2000): Maternal
depression and parenting behavior: A meta-analytic review. Clin
Psychol Rev 20:561592.
22. Brown TT, Kuperman JM, Chung Y, Erhart M, McCabe C, Hagler DJ
Jr, et al. (2012): Neuroanatomical assessment of biological maturity.
Curr Biol 22:16931698.
23. Hermoye L, Saint-Martin C, Cosnard G, Lee SK, Kim J, Nassogne MC,
et al. (2006): Pediatric diffusion tensor imaging: Normal database and
observation of the white matter maturation in early childhood. Neuro-
image 29:493504.
24. Norton ES, Beach SD, Gabrieli JD (2015): Neurobiology of dyslexia.
Curr Opin Neurobiol 30:7378.
25. Cao M, Shu N, Cao Q, Wang Y, He Y (2014): Imaging functional and
structural brain connectomics in attention-decit/hyperactivity disor-
der. Mol Neurobiol 50:11111123.
26. Tseng WL, Leibenluft E, Brotman MA (2014): A systems neuroscience
approach to the pathophysiology of pediatric mood and anxiety
disorders. Curr Top Behav Neurosci 16:297317.
27. Rifkin-Graboi A, Bai J, Chen H, Hameed WB, Sim LW, Tint MT, et al.
(2013): Prenatal maternal depression associates with microstructure
of right amygdala in neonates at birth. Biol Psychiatry 74:837844.
28. Rifkin-Graboi A, Meaney MJ, Chen H, Bai J, Hameed WB, Tint MT,
et al. (2015): Antenatal maternal anxiety predicts variations in neural
structures implicated in anxiety disorders in newborns. J Am Acad
Child Adolesc Psychiatry 54:313321 e312.
29. Sandman CA, Buss C, Head K, Davis EP (2015): Fetal exposure to
maternal depressive symptoms is associated with cortical thickness in
late childhood. Biol Psychiatry 77:324334.
30. Deoni SC, Dean DC 3rd, OMuircheartaigh J, Dirks H, Jerskey BA
(2012): Investigating white matter development in infancy and early
childhood using myelin water faction and relaxation time mapping.
Neuroimage 63:10381053.
31. Weitzman C, Wegner L, Section on Developmental and Behavioral
Pediatrics, Committee on Psychosocial Aspects of Child and Family
Health, Council on Early Childhood, Society for Developmental and
Behavioral Pediatrics, American Academy of Pediatrics (2015): Pro-
moting optimal development: Screening for behavioral and emotional
problems. Pediatrics 135:384395.
32. Kaplan BJ, Giesbrecht GF, Leung BM, Field CJ, Dewey D, Bell RC,
et al. (2014): The Alberta Pregnancy Outcomes and Nutrition
(APrON) cohort study: Rationale and methods. Matern Child Nutr
10:4460.
33. Cox JL, Holden JM, Sagovsky R (1987): Detection of postnatal
depression. Development of the 10-item Edinburgh Postnatal Depres-
sion Scale. Br J Psychiatry 150:782786.
34. Adouard F, Glangeaud-Freudenthal NM, Golse B (2005): Validation of
the Edinburgh Postnatal Depression Scale (EPDS) in a sample of
women with high-risk pregnancies in France. Arch Womens Ment
Health 8:8995.
35. Kozinszky Z, Dudas RB (2015): Validation studies of the Edinburgh
Postnatal Depression Scale for the antenatal period. J Affect Disord
176:95105.
36. Fischl B (2012): FreeSurfer. Neuroimage 62:774781.
37. Wang R, Benner T, Sorensen AG, Wedeen VJ. (2007): Diffusion Toolkit: A
Software Package for Diffusion Imaging Data Processing and Tractog-
raphy. Presented at the 15th Annual Meeting of the International Society
for Magnetic Resonance in Medicine. Berlin, May 2007.
Biological
Psychiatry
38. Zhou D, Lebel C, Treit S, Evans A, Beaulieu C (2015): Accelerated
longitudinal cortical thinning in adolescence. Neuroimage 104:
138145.
39. Lebel C, Beaulieu C (2011): Longitudinal development of human brain
wiring continues from childhood into adulthood. J Neurosci 31:
1093710947.
40. Huttenlocher PR (1979): Synaptic density in human frontal cortex -
developmental changes and effects of aging. Brain Res 163:195205.
41. Yakovlev PI, Lecours A-R (1967): The myelogenetic cycles of regional
maturation of the brain. In: Minkowski A, editor. Regional Develop-
ment of the Brain Early in Life. Boston: Blackwell Scientic Publica-
tions Inc., 370.
42. Ellis BJ (2004): Timing of pubertal maturation in girls: An integrated life
history approach. Psychol Bull 130:920958.
43. Chisholm JS, Quinlivan JA, Petersen RW, Coall DA (2005): Early stress
predicts age at menarche and rst birth, adult attachment, and
expected lifespan. Hum Nat 16:233265.
44. Hulanicka B, Gronkiewicz L, Koniarek J (2001): Effect of familial
distress on growth and maturation of girls: A longitudinal study. Am
J Hum Biol 13:771776.
45. Ono M, Kikusui T, Sasaki N, Ichikawa M, Mori Y, Murakami-Murofushi
K (2008): Early weaning induces anxiety and precocious myelination in
the anterior part of the basolateral amygdala of male Balb/c mice.
Neuroscience 156:11031110.
46. Gee DG, Gabard-Durnam LJ, Flannery J, Goff B, Humphreys KL,
Telzer EH, et al. (2013): Early developmental emergence of human
amygdala-prefrontal connectivity after maternal deprivation. Proc Natl
Acad Sci U S A 110:1563815643.
47. Vara AS, Pang EW, Vidal J, Anagnostou E, Taylor MJ (2014): Neural
mechanisms of inhibitory control continue to mature in adolescence.
Dev Cogn Neurosci 10:129139.
48. Liddle PF, Kiehl KA, Smith AM (2001): Event-related fMRI study of
response inhibition. Hum Brain Mapp 12:100109.
49. Rubia K, Smith AB, Brammer MJ, Taylor E (2003): Right inferior
prefrontal cortex mediates response inhibition while mesial prefrontal
cortex is responsible for error detection. Neuroimage 20:351358.
50. Konishi S, Nakajima K, Uchida I, Kikyo H, Kameyama M, Miyashita Y
(1999): Common inhibitory mechanism in human inferior prefrontal
cortex revealed by event-related functional MRI. Brain 122:981991.
51. Hampshire A, Chamberlain SR, Monti MM, Duncan J, Owen AM
(2010): The role of the right inferior frontal gyrus: Inhibition and
attentional control. Neuroimage 50:13131319.
52. Marrus N, Belden A, Nishino T, Handler T, Tilak Ratnanather J, Miller
M, et al. (2015): Ventromedial prefrontal cortex thinning in preschool-
onset depression. J Affect Disord 180:7986.
53. Peterson BS, Warner V, Bansal R, Zhu H, Hao X, Liu J, et al. (2009):
Cortical thinning in persons at increased familial risk for major
depression. Proc Natl Acad Sci U S A 106:62736278.
54. Foland-Ross LC, Gilbert BL, Joormann J, Gotlib IH (2015): Neural
markers of familial risk for depression: An investigation of cortical
thickness abnormalities in healthy adolescent daughters of mothers
with recurrent depression. J Abnorm Psychol 124:476485.
55. Ducharme S, Albaugh MD, Hudziak JJ, Botteron KN, Nguyen TV,
Truong C, et al. (2014): Anxious/depressed symptoms are linked to
right ventromedial prefrontal cortical thickness maturation in healthy
children and young adults. Cereb Cortex 24:29412950.
56. Boes AD, McCormick LM, Coryell WH, Nopoulos P (2008): Rostral
anterior cingulate cortex volume correlates with depressed mood in
normal healthy children. Biol Psychiatry 63:391397.
57. Field T, Diego M, Hernandez-Reif M, Figueiredo B, Deeds O, Ascencio
A, et al. (2010): Comorbid depression and anxiety effects on preg-
nancy and neonatal outcome. Infant Behav Dev 33:2329.
58. Dawson G, Ashman SB, Panagiotides H, Hessl D, Self J, Yamada E,
Embry L (2003): Preschool outcomes of children of depressed
mothers: Role of maternal behavior, contextual risk, and childrens
brain activity. Child Dev 74:11581175.
59. Aghajani M, Veer IM, van Lang ND, Meens PH, van den Bulk BG,
Rombouts SA, et al. (2014): Altered white-matter architecture in
Biological Psychiatry ]]], 2016; ]:]]]]]] www.sobp.org/journal 9
Biological
Psychiatry
treatment-naive adolescents with clinical depression. Psychol Med
44:22872298.
60. Sarkar S, Craig MC, DellAcqua F, OConnor TG, Catani M, Deeley Q,
et al. (2014): Prenatal stress and limbic-prefrontal white matter
microstructure in children aged 6-9 years: A preliminary diffusion
tensor imaging study. World J Biol Psychiatry 15:346352.
61. Ugwu ID, Amico F, Carballedo A, Fagan AJ, Frodl T (2015): Childhood
adversity, depression, age and gender effects on white matter micro-
structure: A DTI study. Brain Struct Funct 220:19972009.
62. Buss C, Davis EP, Muftuler LT, Head K, Sandman CA (2010): High
pregnancy anxiety during mid-gestation is associated with decreased
gray matter density in 6-9-year-old children. Psychoneuroendocrinol-
ogy 35:141153.
63. Widjaja E, Geibprasert S, Mahmoodabadi SZ, Blaser S, Brown NE,
Shannon P (2010): Alteration of human fetal subplate layer and
intermediate zone during normal development on MR and diffusion
tensor imaging. AJNR Am J Neuroradiol 31:10911099.
64. Bendersky M, Musolino PL, Rugilo C, Schuster G, Sica RE (2006):
Normal anatomy of the developing fetal brain. Ex vivo anatomical-
magnetic resonance imaging correlation. J Neurol Sci 250:2026.
65. Garel C, Chantrel E, Elmaleh M, Brisse H, Sebag G (2003): Fetal MRI:
Normal gestational landmarks for cerebral biometry, gyration and
myelination. Childs Nerv Syst 19:422425.
66. Rajagopalan V, Scott J, Habas PA, Kim K, Corbett-Detig J, Rousseau
F, et al. (2011): Local tissue growth patterns underlying normal fetal
human brain gyrication quantied in utero. J Neurosci 31:28782887.
67. Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos
A, et al. (1999): Brain development during childhood and adolescence:
A longitudinal MRI study. Nat Neurosci 2:861863.
68. Barkovich AJ, Kjos BO, Jackson DE Jr, Norman D (1988): Normal
maturation of the neonatal and infant brain: MR imaging at 1.5 T.
Radiology 166:173180.
69. Matsuzawa J, Matsui M, Konishi T, Noguchi K, Gur RC, Bilker W,
Miyawaki T (2001): Age-related volumetric changes of brain gray and
white matter in healthy infants and children. Cereb Cortex 11:335342.
70. McEwen BS (2007): Physiology and neurobiology of stress and
adaptation: Central role of the brain. Physiol Rev 87:873904.
71. Dirlikov B, Shiels Rosch K, Crocetti D, Denckla MB, Mahone EM,
Mostofsky SH (2015): Distinct frontal lobe morphology in girls and
boys with ADHD. Neuroimage Clin 7:222229.
72. Onnink AM, Zwiers MP, Hoogman M, Mostert JC, Kan CC, Buitelaar J,
Franke B (2014): Brain alterations in adult ADHD: Effects of gender,
treatment and comorbid depression. Eur Neuropsychopharmacol 24:
397409.
73. Mahone EM, Ranta ME, Crocetti D, OBrien J, Kaufmann WE, Denckla
MB, Mostofsky SH (2011): Comprehensive examination of frontal
regions in boys and girls with attention-decit/hyperactivity disorder. J
Int Neuropsychol Soc 17:10471057.
74. Almeida Montes LG, Prado Alcantara H, Martinez Garcia RB, De La
Torre LB, Avila Acosta D, Duarte MG (2013): Brain cortical thickness in
ADHD: Age, sex, and clinical correlations. J Atten Disord 17:641654.
75. Davis EP, Glynn LM, Waffarn F, Sandman CA (2011): Prenatal
maternal stress programs infant stress regulation. J Child Psychol
Psychiatry 52:119129.
76. Sandman CA, Davis EP, Buss C, Glynn LM (2011): Prenatal program-
ming of human neurological function. Int J Pept 2011:837596.
10 Biological Psychiatry ]]], 2016; ]:]]]]]] www.sobp.org/journal
Maternal Depression and Childrens Brain Structure
77. Davis EP, Pfaff D (2014): Sexually dimorphic responses to early
adversity: Implications for affective problems and autism spectrum
disorder. Psychoneuroendocrinology 49:1125.
78. Lenroot RK, Gogtay N, Greenstein DK, Wells EM, Wallace GL, Clasen
LS, et al. (2007): Sexual dimorphism of brain developmental trajecto-
ries during childhood and adolescence. Neuroimage 36:10651073.
79. Seunarine KK, Clayden JD, Jentschke S, Munoz M, Cooper JM,
Chadwick MJ, et al. (2015): Sexual dimorphism in white matter
developmental trajectories using tract-based spatial statistics [pub-
lished online ahead of print November 30]. Brain Connect.
80. Lebel C, Mattson SN, Riley EP, Jones KL, Adnams CM, May PA, et al.
(2012): A longitudinal study of the long-term consequences of drinking
during pregnancy: Heavy in utero alcohol exposure disrupts the
normal processes of brain development. J Neurosci 32:1524315251.
81. Gold PW (2015): The organization of the stress system and its
dysregulation in depressive illness. Mol Psychiatry 20:3247.
82. Giesbrecht GF, Campbell T, Letourneau N, Kooistra L, Kaplan B,
APrON Study Team. (2012): Psychological distress and salivary
cortisol covary within persons during pregnancy. Psychoneuroendoc-
rinology 37:270279.
83. Sanchez MM, Ladd CO, Plotsky PM (2001): Early adverse experi-
ence as a developmental risk factor for later psychopathology:
Evidence from rodent and primate models. Dev Psychopathol 13:
419449.
84. Kaplan BJ, Crawford SG, Field CJ, Simpson JS (2007): Vitamins,
minerals, and mood. Psychol Bull 133:747760.
85. Beard JL, Hendricks MK, Perez EM, Murray-Kolb LE, Berg A, Vernon-
Feagans L, et al. (2005): Maternal iron deciency anemia affects
postpartum emotions and cognition. J Nutr 135:267272.
86. Wojcik J, Dudek D, Schlegel-Zawadzka M, Grabowska M, Marcinek A,
Florek E, et al. (2006): Antepartum/postpartum depressive symptoms
and serum zinc and magnesium levels. Pharmacol Rep 58:571576.
87. Ojha S, Fainberg HP, Sebert S, Budge H, Symonds ME (2015):
Maternal health and eating habits: Metabolic consequences and
impact on child health. Trends Mol Med 21:126133.
88. Steer CD, Lattka E, Koletzko B, Golding J, Hibbeln JR (2013): Maternal
fatty acids in pregnancy, FADS polymorphisms, and child intelligence
quotient at 8 y of age. Am J Clin Nutr 98:15751582.
89. Deoni SC, Dean DC 3rd, Piryatinsky I, OMuircheartaigh J, Waskiewicz
N, Lehman K, et al. (2013): Breastfeeding and early white matter
development: A cross-sectional study. Neuroimage 82:7786.
90. Grigoriadis S, VonderPorten EH, Mamisashvili L, Tomlinson G, Dennis
CL, Koren G, et al. (2013): The impact of maternal depression during
pregnancy on perinatal outcomes: A systematic review and meta-
analysis. J Clin Psychiatry 74:e321e341.
91. Lenroot RK, Schmitt JE, Ordaz SJ, Wallace GL, Neale MC, Lerch JP,
et al. (2009): Differences in genetic and environmental inuences on
the human cerebral cortex associated with development during
childhood and adolescence. Hum Brain Mapp 30:163174.
92. Chiang MC, McMahon KL, de Zubicaray GI, Martin NG, Hickie I, Toga
AW, et al. (2011): Genetics of white matter development: A DTI study
of 705 twins and their siblings aged 12 to 29. Neuroimage 54:
23082317.
93. Smoller JW (2016): The genetics of stress-related disorders: PTSD,
depression, and anxiety disorders. Neuropsychopharmacology 41:
297319.