fetal exposure to maternal depressive symptoms is … · fetal exposure to maternal depressive...

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Archival Report Biol
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Fetal Exposure to Maternal DepressiveSymptoms Is Associated With CorticalThickness in Late ChildhoodCurt A. Sandman, Claudia Buss, Kevin Head, and Elysia Poggi Davis

ABSTRACTBACKGROUND: Maternal depression is one of the most common prenatal complications. The consequences offetal exposure to maternal depression are poorly understood. The aim of this study is to examine the associationbetween fetal exposure to maternal depressive symptoms and cortical thickness in children 6–9 years old.METHODS: A prospective, longitudinal study of maternal depressive symptoms at 19, 25, and 31 weeks’ gestationwas followed by acquisition of a structural magnetic resonance imaging scan in 81 children (age, 86.1 6 9.9 months).RESULTS: Significant (p , .01) cortical thinning in children primarily in the right frontal lobes was associated withexposure to prenatal maternal depression. The strongest association was at 25 weeks’ gestation; exposure tomaternal depression at 25 gestational weeks was associated with cortical thinning in 19% of the whole cortex and24% of the frontal lobes, primarily in the right superior, medial orbital, and frontal pole regions of the prefrontal cortex(p , .01). The significant association between prenatal maternal depression and child externalizing behavior (p , .05)was mediated by cortical thinning in prefrontal areas of the right hemisphere.CONCLUSIONS: The pattern of cortical thinning in children exposed to prenatal maternal depression is similar topatterns in depressed patients and in individuals with risk for depression. Exposure to prenatal depression coupledwith subsequent cortical thinning was associated with presence of externalizing behavior in preadolescent childrenand may be prodromal markers of risk for dysphoria. Vulnerability to prenatal influences at 25 gestational weeks mayresult from the enormous growth and dramatic structural changes in the nervous system.

Keywords: Childhood risk, Externalizing behavior, Fetal programming, Maternal depression, Prefrontal cortex,Structural MRI

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http://dx.doi.org/10.1016/j.biopsych.2014.06.025

When the quality of maternal care is compromised by post-partum depression, infants experience pervasive and lingeringnegative health-related consequences (1,2), including pooremotional regulation (3–5); impaired cognitive, behavioral,and motor development (3,6–11); and mental health issues(3,12). These associations with maternal postpartum depres-sion are observed even if maternal depressive symptoms aresubclinical (13,14). Less is known about the consequences ofmaternal prenatal depression for child development, which issurprising because the rate of depressive symptoms duringpregnancy is higher than it is postpartum. Estimates suggestthat 13%–40% of women have symptoms of depressionduring their pregnancy making maternal depression one ofthe most common prenatal complications (15–17).

Most studies on the effects of prenatal maternal mood onbirth, infant and child outcomes have focused on fetal expo-sure to stress and anxiety (18–24). However, more recentevidence indicates that fetal exposure to antenatal depressionmay have larger effects on infant (25,26) and child outcomes(27) than either anxiety or postpartum depression (27,28). Forexample, Barker et al. (29) reported that prenatal maternaldepression, but not anxiety or postpartum depression,

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SEE COMMENTA

significantly increased the risk for externalizing behaviors andwas associated with significantly lower verbal intelligence in alarge sample (N 5 3298). In another large study (N 5 5029),prenatal, but not postnatal, depressive symptoms were asso-ciated with lower child intelligence (30). Early exposures tomaternal depression, including prenatally, were independentlyassociated with externalizing behaviors and low social com-petence in adolescent boys (31).

There is evidence that neurologic impairment, corticalthinning, and reduced cortical volume are associated withhistory of depression (32,33), current symptom severity inadults (32,34–36), and cumulative exposure to maternaldepression in children (37) and in individuals who are not illbut have familial risk for depression (32). Patterns of corticalthinning among individuals reporting depressive symptomshave been broadly distributed (32,35,36,38) but primarilyinvolve structures of the right hemisphere, including the para-central, frontal, and cingulate regions (32,34,39). The presentstudy is the first prospective, longitudinal evaluation of theassociation between fetal exposure to maternal depressivesymptoms, cortical thickness, and behavioral problems inchildren. If fetal exposure to maternal depression is associated

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Table 1. Sociodemographic Characteristics and BirthOutcomes

MRI Cohort Total

Cortical Effects of Prenatal Depression ExposureBiologicalPsychiatry

with eventual risk for depression, prodromal neurologicmarkers in children may be present, especially in the righthemisphere and areas of the frontal cortex.

(n 5 82) Sample

Maternal Age 30.6 (6.3) 30.2 (5.3)

Race/Ethnicity

Non-Hispanic white 54% 48%Hispanic white 21% 25%African American 10% 11%Asian 7% 8%Other/multiethnic 8% 8%

Annual Household Income

$0–$30,000 21.5% 20.9%$30,001–$60,000 26.7% 28.9%$60,001–$100,000 33.0% 19.6%.$100,000 19.0% 22.2%

Maternal Depression

19 weeks’ gestation 1.60 (.45) 1.71 (.58)25 weeks’ gestation 1.64 (.51) 1.74 (.59)31 weeks’ gestation 1.76 (.51) 1.80 (.63)

Maternal Education

Less than high school 1.3% 2.8%High school 11.3% 14.5%Some college 37.5% 40.4%Undergraduate degree 40.0% 24.5%Graduate degree 10.0% 17.8%

5-Minute Apgar Score 9.0 (.2) 8.9 (.5)

Primiparous 55.6% 48.0%

Child Sex

Male 51.9% 51.3%Female 48.1% 48.7%

Length of Gestation (Weeks) 39.1 (1.6)(8.6% 34–36.9 weeks)

38.9 (2.1)

Birth Weight (Grams) 3476.5 (624.3)(4.9% , 2500 g)

3363.3 (597.2)

Whole numbers are mean. Values in parentheses are SD.MRI, magnetic resonance imaging.

METHODS AND MATERIALS

Participants

English-speaking, healthy pregnant women with singletonpregnancies were recruited by 15 gestational weeks. Exclu-sion criteria included 1) tobacco, alcohol, or other drug usein pregnancy; 2) uterine or cervical abnormalities; and 3)presence of conditions associated with neuroendocrinedysfunction. None of the women in this sample were orhad been treated for psychiatric disorders. There were 275women who consented to participate in a follow-up study oftheir children. From this sample, we report on 81 children, 6–9 years old, who completed artifact-free magnetic reso-nance imaging (MRI) scans. Parents and children gaveinformed (or affirmed) consent, and the study was approvedby the institutional review board for protection of humansubjects.

Assessments in Pregnant Women

Gestational age was determined by 1) last menstrual periodand 2) early uterine size and confirmed by obstetric ultrasoundbefore 20 weeks (40). Medical risk was defined as thepresence of certain medical conditions in the index or previouspregnancies (e.g., vaginal bleeding, pregnancy-induced hyper-tension, anemia, infection) (41). Of the women, 93% reportedone or fewer medical risks in the current or previous pregnan-cies, and no woman in the study required hospitalization tomanage risk. The sum of medical risk factors was calculatedas an indicator of presence of any current or historical riskconditions (42).

Maternal Depressive Symptoms

Maternal depressive symptoms using the Centers for Epide-miologic Studies Depression scale (43,44) were assessedfor each woman at 19 (6 .83, SD), 25 (6 .9), and 31 (6 .9)weeks’ gestation. Subjects indicated how often they hadexperienced each symptom of depression during the pastweek (Supplement 1). Levels of depressive symptoms at eachvisit and the average rating of depressive symptoms acrossgestation were used in the statistical analysis. Current mater-nal depressive symptoms were assessed with the BeckDepression Inventory (45). Prenatal depressive symptomsshared �9%–25% variance with current levels of maternaldepression but were not associated with maternal prenatalmedical risk, maternal age, or maternal education.

Assessments in Children

All children had a stable neonatal course (Table 1) and werewithout known neonatal illness or congenital, chromosomal, orgenetic anomalies. Participants had no evidence of neurologicabnormalities in the newborn period. Structural MRI obtainedin children was assessed by a neuroradiologist for anatomicappearance. Two children with abnormal scans (n 5 2) werenot included in the final sample (n 5 81). At 6–9 years of age,

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no emotional or physical conditions were reported by theparents in a structured interview (46). For 88% of the children,right hand was dominant (47).

Child Behavioral Problems

Child affective and conduct disorder problems were measuredby maternal report using the Child Behavior Checklist (48).Responses to the DSM-oriented affective problems and con-duct disorders scales were transferred to T scores based onsex-specific reference tables.

Structural MRI Acquisition

Structural MRI was acquired with a 3-T Philips Achieva system(Philips Healthcare, Andover, Massachusetts). Children woreearplugs and watched a movie while in the scanner. A high-resolution T1 anatomic scan was acquired in the sagittal planewith 1 mm3 isotropic voxel dimensions. An inversion-recoveryspoiled gradient recalled acquisition sequence with optimalparameters was applied: repetition time 5 11 msec; echotime 5 3.3 msec; inversion time 5 1100 msec; turbo field echofactor 5 192; number of slices 5 150; no SENSEivity Ecodingacceleration; flip angle 5 181; and shot interval (time frominversion pulse to the center of acquisition) 5 2200 msec.

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Processing of MRI Data

Cortical surface reconstruction and volumetric segmentationwas performed with FreeSurfer (Laboratory for ComputationalNeuroimaging, Charlestown, Massachusetts; http://surfer.nmr.mgh.harvard.edu/). Streamlined image processing provided inthis software package included application of intensity normal-ization before segmentation to minimize errors in identifyingthe boundaries (49), removal of nonbrain tissues (50), andtransforming images into the Talairach space (50,51). Pial andwhite matter surfaces were located by finding the highestintensity gradient (52–54). Surface inflation was applied toeach individual brain (55), and the inflated brains wereregistered to a spherical atlas. Cortical thickness was theclosest distance from the gray matter/white matter surface tothe pial surface at each vertex on the tessellated surface (53).

Cortical Thickness and Prenatal Depression

Spatially normalized cortical thickness maps and maternaldepression were entered into a linear regression model. Theassociation between prenatal depression and cortical thick-ness was analyzed at every node on the cortical surface.Gestational age at birth, age of the child at testing, sex,handedness, and current levels of maternal depression wereincluded as covariates. A threshold of p , .05 was used for allstatistical tests, and outcomes were corrected for multiplecomparisons using false discovery rate.

After false discovery rate false discovery rate corrections,the number of vertices that were significantly associated withmaternal depressive symptoms was determined and con-verted to percentage of the total in each region of the cortex.The same procedure was computed for the number ofsignificant vertices in each lobe. For hemispheric and whole-brain percentages, the procedure was the same except thetotal number of subcortical vertices was subtracted fromthe total.

RESULTS

Women whose children participated in the MRI study didnot differ significantly in sociodemographic characteristics(Table 1) from women in the general follow-up sample.

Prenatal Depression and Cortical Thickness

The association between the average level of maternaldepressive symptoms during pregnancy and child corticalthickness, adjusting for gestational age at birth, age of thechild, sex, handedness, birth outcome, and current maternaldepressive symptoms (Supplement 1), is presented inFigure 1. Figure 1 illustrates that 12% of the whole cortexis significantly thinner in children exposed to prenatal maternaldepressive symptoms (Table 2; Average column). The effect isspread among the frontal (14%), parietal (12%), and oc-cipital cortices (16%). The right frontal lobe (20%) is mostsignificantly associated with maternal prenatal depressivesymptoms. Children exposed to higher levels of prenatalmaternal depressive symptoms have a significantly thinnerlateral surface of the right frontal lobe with cortical thinning innearly 100% of the right frontal pole (Table 3). Thinner medial

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and lateral surfaces of the frontal cortex in the right hemi-sphere are associated with prenatal exposure to maternaldepressive symptoms. The paracentral region of the medialfrontal lobe is the only frontal area that is bilaterally thinner inchildren exposed to high levels of prenatal maternal depres-sive symptoms.

There are broadly distributed significant associationsbetween prenatal exposure to maternal depressive symptomsand cortical thinning at each gestational period. The associ-ation between fetal exposure to maternal depressive symp-toms and cortical thinning was identical across gestationin the supramarginal, postcentral, and paracentral areas(Figure 1C–E). The strongest association between corticalthinning and maternal depressive symptoms was at 25 weeks’gestation (Tables 2 and 3). In children whose mothers reportelevated levels of depression at 25 weeks’ gestation, 19% ofthe whole cortex is thinner compared with 8% at 19 weeks’gestation and 7% at 31 weeks’ gestation. The associationbetween cortical thinning and fetal exposure to maternaldepressive symptoms at 25 weeks’ gestation is more bilateraland stronger in some regions than the associations withdepressive symptoms averaged across gestation (Table 3).The effects at 25 weeks’ gestation are strongest in the righthemisphere and in the frontal lobes.

Analysis within the major cortical lobes indicates that themedial and lateral surfaces of frontal areas, especially in theright hemisphere, are predominantly thinner in childrenexposed to maternal depressive symptoms at 25 gestationalweeks. The entire lateral surface of the right frontal pole and74% of the medial orbital frontal cortex are significantly thinnerin children exposed to prenatal depressive symptoms at 25weeks’ gestation. The left medial frontal cortex (48%–54%of the surface area) also is influenced by fetal exposure tomaternal reports of depression. As presented in Table 3(bottom panels), numerous areas are thinner in associationwith maternal depression at 25 gestational weeks.

Several of many significant associations between maternaldepressive symptoms at 25 weeks’ gestation and corticalthickness are illustrated in Figure 2. Figure 2A shows thesignificant association between the thickness of the medialsurface of the right frontal pole and levels of maternaldepression at 25 weeks’ gestation. Figure 2B–D illustratesother areas of the frontal lobes that are significantly thinner inchildren who were exposed to higher levels of maternaldepression at 25 weeks’ gestation.

Mediational Analysis

There were no significant relationships between prenatalmaternal depressive symptoms at the three gestational inter-vals and maternal ratings of childhood affective disorders(Child Behavior Checklist; adjusted for current levels of mater-nal depression). The nonsignificant correlations ranged from.16 to 2.06 (p . .15 to p . .84). None of the children wererated (range 50270) in the clinically impaired (.70) range. Aftercontrolling for current maternal affect, higher levels of prenatalmaternal depression were associated with child externalizingproblems. Because exposure to prenatal maternal depressivesymptoms was associated with both child externalizing behav-ior (range 33266) and cortical thinning in frontal regions, we

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A B

19 Weeks 25 Weeks 31 Weeks

fp

po

mof

sf

ppc ppcppc

pc pc pc

asf asf asf

C D E

Figure 1. Pial maps that illustrate the false discovery rate corrected relationship between cortical thickness in children and fetal exposure to maternaldepression across gestation. In children whose mothers reported higher levels of depressive symptoms, (A) ,.7% of the cortex is thicker (thicker—hot colors)compared with (B) massively thinner cortex in children exposed to higher levels of maternal prenatal depressive symptoms (thinner—cool colors). (C–E)Cortical thinning in children associated with fetal exposure to maternal depression at discrete gestational intervals. Labels in red indicate major areas ofthinning that are shared at the three gestational intervals. Labels in white indicate major areas that are significantly thinner and unique to fetal exposure tomaternal depressive symptoms at 25 weeks’ gestation. asf, anterior superior frontal in the medial view; fp, frontal pole; LH, left hemisphere; mof, medial orbitalfrontal lobe; pc, paracentral in the medial view; pcc, precentral and postcentral in the lateral view; po, paraorbitalis; RH, right hemisphere; sf, superiorfrontal lobe.


evaluated whether cortical thinning mediated (56) the associ-ation between exposure to prenatal depression and external-izing problems. Figure 3 illustrates that the significantassociation between levels of prenatal depression and childexternalizing behavior at 25 weeks’ gestation is mediated bycortical thinning in the right frontal pole. When the prefrontalregions that were most strongly (r values . .23, p values , .05)associated with prenatal maternal depression at 25 weeks’gestation (right frontal pole, right lateral orbital frontal cortexand the right medial orbital frontal cortex) are included in themodel, the relationship between prenatal depression and childbehavior was no longer significant (β 5 .17, p 5 .19). This finalmodel accounts for 12% of child behavioral problems andsupports the argument that the association between maternaldepressive symptoms and child behavioral problems is partiallyexplained by the effects of fetal exposures on the developmentof the prefrontal cortex.

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DISCUSSION

This is the first report of persisting neurologic consequencesfor children born to mothers who reported symptoms ofdepression during pregnancy. Significant associationsbetween maternal reports of prenatal depressive symptomsand cortical thickness in children were observed in .12% ofthe whole cortex. The largest associations between prenatalmaternal depression and cortical thickness were in theprefrontal, the medial postcentral, and the lateral ventralprecentral and postcentral regions of the right hemisphere.Mediational analysis indicated that thinning in prefrontalregions may underlie the association between levels ofprenatal depression and child externalizing problems. Therewas no evidence the cortex was thicker in association withprenatal maternal depression.

The cortical areas significantly associated with maternaldepressive symptoms at each gestational interval included the



Table 2. Percentage of Whole Cortex and Different CorticalRegions That Are Significantly Thinner in Children Exposedas Fetuses to Maternal Depressive Symptoms AcrossGestation (Average) and at Three Separate GestationalIntervals

Average 19 Weeks 25 Weeks 31 Weeks

Whole Brain 12 8 19 7

Frontal Cortex 14 8 24 10

Parietal Cortex 12 10 19 5

Temporal Cortex 7 6 10 5

Occipital Cortex 16 14 20 9

Cingulate/Limbic 4 3 13 3


precentral and postcentral regions of the right hemisphere.The precentral area is the primary motor cortex and isresponsible for executing movements through connectionsto the spinothalamic tract. The postcentral region is a topo-graphically organized, functionally defined area responsible forintegrating somatosensory information such as touch and

Table 3. Percentage of Structures of the Frontal Lobe ThatAveraged Across Gestation and at 25 Weeks’ Gestation

Average Across

LH Medial Surface Percent of Structure

Orbital Frontal 17

Paracentral 32

LH Lateral Surface Percent of Structure

Superior Frontal 6

Rostral Middle Frontal 6

Frontal Pole 0

Pars Triangularis 16

Pars Orbitalis 3

Lateral Orbital Frontal 1

Pars Opercularis 0

Caudal Middle Frontal 4

Precentral 9

Insula 0

25 Weeks’ G

LH Medial Surface Percent of Structure

Orbital Frontal 47

Paracentral 54

LH Lateral Surface Percent of Structure

Superior Frontal 26


Frontal Pole 0


Pars Orbitalis 20


Pars Opercularis 9


Precentral 10

Insula 3

The results are presented for the left and right hemispheres and for lateLH, left hemisphere; RH, right hemisphere.


proprioception. Neither motor nor somatosensory functionswere assessed in the children included in the current study.However, there is functional MRI evidence that depression isassociated with activity of the “medial” cortex. This area is lessactive in depressed patients when they are asked to self-reflect but more active in tasks without self-reference (57). It ispossible that the similar patterns of cortical thinning observedat each gestational interval reflect a neurologic index of familialor genetic risk associated with maternal depression.

The strongest association between maternal depressivesymptoms and cortical thickness was observed at 25 gesta-tional weeks. Fetal exposure to maternal depressive symp-toms at 25 weeks’ gestation was associated with corticalthinning in 19% of the whole brain and 24% of the frontallobes. Cortical thinning was significantly associated withdegree of maternal depression in the superior, medial orbital,and frontal pole regions of the prefrontal cortex primarily in theright hemisphere only at 25 weeks’ gestation. There is con-siderable overlap between the findings observed here and thereports of thinning in the precentral and postcentral, frontal,and prefrontal areas of the right hemisphere in young patients

Are Thinner in Children Exposed to Maternal Depression

Gestation

RH Medial Surface Percent of Structure

Orbital Frontal 40

Paracentral 35

RH Lateral Surface Percent of Structure

Superior Frontal 19


Frontal Pole 99


Pars Orbitalis 30


Pars Opercularis 7


Precentral 19

Insula 11

estation

RH Medial Surface Percent of Structure

Orbital Frontal 74

Paracentral 23

RH Lateral Surface Percent of Structure

Superior Frontal 26


Frontal Pole 100


Pars Orbitalis 44


Pars Opercularis 20


Precentral 21

Insula 12

ral and medial surfaces.

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RH Lateral Orbital Frontal

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Figure 2. Scatterplots of cortical thickness in right frontal lobes of children with fetal exposure to maternal depressive symptoms (expressed as total score)at 25 weeks’ gestation. (RH frontal pole, r 5 2.46, p , .001; RH lateral orbital frontal, r 5 2.30, p 5 .01; RH medial orbital frontal, r 5 2.28, p 5 .01; RH parsorbitalis, r 5 2.39, p , .001.) CESD, Centers for Epidemiologic Studies Depression scale; RH, right hemisphere.


with “attenuated” syndromes (58) and in a mixed group ofchildren and adults with familial risk for major depression butwithout a history of depression or current depressive symp-toms (32). Cortical thinning has been reported in adults (34,36),adolescents and young adults (58), and children with depres-sion. Although there are differences across studies, there isgeneral agreement that depression is associated with region-specific cortical thinning, reduced volume (32,34,58,59), and less activity (60,61) of the frontal and prefrontalcortex, especially in the right hemisphere.

Meta-analysis of functional MRI studies have implicatedreduced activity in the frontal areas of patients with depression(62,63), and this association was independent of medicationuse or current depressive state (64). Peterson and Weissman(33) concluded that a profile of cortical thinning constituted abrain-based endophenotype for depression because a thinnercortex was observed in high-risk individuals who have neverhad or been treated for depression or anxiety. Our findingscomplement these conclusions. First, there are areas in whichthe association of depression and cortical thinning overlap at

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all three gestational intervals; this is plausible support thatthese overlapping areas may represent familial risk for depres-sion without evidence of current clinically significant symp-toms in the mother or child. Second, the unique profileobserved at 25 gestational weeks may reflect the independentcontribution to neurologic risk that is associated with fetalexposure to maternal depressive symptoms and the physio-logic changes that may affect the developing fetal brain. Third,the observed effects remained after controlling for currentlevels of maternal depression reducing the possibility thatpostnatal factors associated with maternal emotional statemight influence cortical structure in children. The distributionof prenatal and current levels of maternal depression wasskewed in the euthymic direction further eliminating the argu-ment that only clinically significant maternal depressive symp-toms influence child outcome. Fourth, none of the children inour study had clinically significant affective symptoms. Theassociation between fetal exposure to maternal depressivesymptoms and cortical thickness was not related to currentchildhood affective symptoms.



Figure 3. Mediation of prenatal maternal depres-sion on child externalizing behavior by child corticalthinning in the right frontal pole. The mediationalhypothesis is tested following the four-step sugges-tions of Baron and Kenny (56). Mediation is supportedbecause 1) prenatal maternal depressive symptoms(at 25 weeks’ GA) are associated significantly (solidarrows) with cortical thinning and with child exter-nalizing behavior, 2) child cortical thinning is asso-ciated with child externalizing behavior, and 3) theassociation between prenatal maternal depressivesymptoms and child externalizing behavior is notsignificant (dotted arrow) after controlling for corticalthinning. GA, gestational age; ns, not significant.


There is substantial evidence that fetal exposures to variouspsychobiological stressors at specific intervals during gesta-tion are associated with distinctive patterns of behavior andbrain structures that persist into preadolescence (65–67).We have reported that the behavioral consequences offetal exposure to maternal depression are different andindependent from the patterns from fetal exposure to maternalreports of anxiety associated with pregnancy (25,68). We alsoreported that fetal exposure to pregnancy-specific anxiety onlyat 19 weeks’ gestation is associated with decreased corticalvolume (voxel-based morphology) in areas extending from thefrontal to occipital regions (21). The evidence reported heregenerally supports the previous finding that fetal exposure tomaternal psychosocial stress (depression in this case) isassociated with decreased cortical thickness or volume. Thenew findings are that the association between depression andcortical thickness was observed at each gestational intervaland that exposure at 25 weeks’ gestation was a sensitiveperiod for the fetus resulting in broad cortical patterns ofthinning.

The precise mechanism by which the pregnant womancommunicates depressive symptoms to her fetus is unknown,but one possibility is that prenatal depression exposes thefetus to dysregulated levels of maternal stress hormones. Wedid not discover a significant association between maternaldepressive symptoms and maternal salivary cortisol levelsassessed at a single time at each gestational interval in oursample (Supplement 1). However, we are reluctant to draw theconclusion based on our methods that maternal cortisol is notan important signal to the fetus of maternal depressive state.For instance, morning salivary cortisol levels are higher inpatients with a diagnosis of depression than they are inindividuals with no history of depression (69–71), and differentforms of depression (melancholic and atypical) are associatedeither with hyperactivation or hypoactivation of the hypo-thalamic-pituitary-adrenal (HPA) axis (72). Hyperactivity ofthe HPA axis in major depression is one of the most reliablyreported neurobiological characteristics of affective disorders(73), and when depression is linked with elevated or temporallydysregulated cortisol secretion, the symptoms are moresevere (74). Symptoms of depression can be induced inexperimental animals by intracerebroventricular injection of


corticotropin-releasing hormone, and depression is a frequentside effect of glucocorticoid treatment and is a symptom ofCushing syndrome in humans (75). Fetal exposure to maternaldepression is associated with increased methylation of theglucocorticoid receptor gene in neonates and with increasedHPA responses to stress or adversity (76). The plausibility of aconnection between maternal depression and the maternalHPA axis is supported by findings that infants born to womenwith symptoms of depression, even in the absence of majordepression, have significant adrenocorticotropin elevation atbirth (77). These results suggest that fetal exposure tomaternal affect may be communicated to the fetus throughthe maternal stress system that establishes a developmentaltrajectory, which includes reduced cortical thickness duringpreadolescence.

There are substantial links between the stress system andthe areas of the brain associated with fetal exposure tomaternal depression. A corticolimibic network is implicatedin emotional regulation in depressive disorders, and areas ofthe prefrontal region including dorsal and ventral lateralprefrontal cortex, medial prefrontal cortex, and especially theorbitofrontal cortex play an inhibitory role over subcorticalareas in healthy subjects (61). There is strong evidence thatthe fetal prefrontal cortex is sensitive to maternal distress (78),is involved in the regulation of stress hormone secretion (79),and has an abundance of glucocorticoid receptors (80). Fetalexposure to elevated levels or dysregulation of cortisol alterslimbic structures in animal models and humans, includingreduction of hippocampal size (81), cortical thinning in therostral anterior cingulate (82), neuronal loss in the dentategyrus (83), and increased volume in the amygdala (84). There isstrong evidence that the neurologic consequences of fetalexposure to maternal depression can be transmitted throughthe maternal stress system.

One significant finding from this study was that corticalthinning in children was most strongly associated with fetalexposure to maternal depressive symptoms at 25 weeks’gestation. There is evidence that �25 weeks’ gestation is asensitive interval for the effects of maternal depression on fetaldevelopment. Both motor and mental development amonginfants was associated with maternal prenatal reports ofdepression (18), and this effect was strongest at 25 weeks’

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gestation. Maternal levels of corticotropin-releasing hormoneat 25 weeks’ gestation predict infant temperament (85), andthis stress signal (86) and other stress hormones (87) at 25weeks predict maternal postpartum depression. All majorstress hormones increase across gestation, and the mostrapid changes occur around the late second trimester andearly third trimester (18). The human fetus may be especiallyvulnerable to rapid changes in maternal stress signals at 25weeks’ gestation because there are crucial developments,such as expression of structural asymmetries in the nervoussystem through midgestation, that are essential for subse-quent neurologic function (88). There is enormous growth ofthe fetal nervous system during midgestation; between gesta-tional weeks 20 and 24, axons form synapses with the corticalplate organizing cortical circuits (89,90), and by gestationalweek 28, the proliferation of neurons is 40% greater than inthe adult (90–92). All primary sulci are formed during fetal lifewith development of the superior frontal, rhinal, temporal, andprecentral and postcentral sulci complete by 25–26 weeks’gestation (93). The molecular level of the human nervoussystem, especially in the frontal lobes, is shaped duringmidgestation by regressive apoptotic mechanisms (94). Celldecline in layer 1 during this time of enormous growth is due tocell death, in contrast to cell migration, which occurs later.Transcriptome studies of the human brain indicate that mostgenes (.76%) (88) are expressed in many brain regions, andthe largest temporospatial differences in gene expressionacross the brain are observed before birth (95). There isapproximately twofold greater gene expression in the fetalbrain (primarily the frontal lobe) compared with the adult brain(88), and some genes are expressed at midgestation and thendecline by early childhood (95). The fetal brain at midgestationis rapidly developing, and because of these critical changes, itis a likely target for organizing and disorganizing programminginfluences.

Cortical thinning in children may reflect acceleratedmaturation. We reported that widespread cortical thinningin preadolescent children was associated with advancingage (96). There is separate evidence that exposure topsychological adversity early in development is associatedwith accelerated maturation influencing viability (97), growth,and reproduction (98–100). Our findings are adjusted for age,so a strictly maturational influence on the nervous systemcan be ruled out. Functionally, cortical thinning may reflectthe density of connections between neurons—decreaseddendritic arbor of neurons or decreased myelination of axonsthat lie within the gray matter (101), each of which is relatedto a significant impairment in information processing andmay be a risk factor for cognitive and emotional problems(102). Inattention and poor visual memory have beenreported in individuals at risk for depression and who hadpatterns of cortical thinning similar to the patterns observedin this study (32).

Our finding of increased incidence of externalizing problemsin children exposed to prenatal maternal depression is con-sistent with reports that prenatal maternal depression signifi-cantly increased the risk for externalizing behaviors in toddlers(29) and adolescents (31). The association between prenatalexposure to maternal depression and externalizing problemswas partially mediated by cortical thinning in the frontal lobes.

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When the contribution of cortical thinning in the frontal lobeswas included in the mediational model, the significantassociation between prenatal depression and externalizingproblems disappeared. This finding argues that prenataldepression influences cortical thinning with the consequenceof an increased risk for externalizing problems in the children.

This study has some limitations. The women in thisstudy were not clinically depressed, and their self-reportedsymptoms were within a narrow range. It is unknown if theassociations between maternal depressive symptoms andchild neurologic integrity would be stronger in a clinicalpopulation. Also, it is unknown if the consequences of fetalexposure to maternal depression has clinically significantconsequences for the child; we are currently following thesechildren to assess this possibility.

In conclusion, despite these limitations, assessment andintervention in pregnant women with symptoms of depressionwould reduce the risk of postpartum depression and protectthe developing fetal nervous system. Because the pattern ofcortical thinning observed in children with prenatal exposure tomaternal depressive symptoms is similar to the patternexhibited by individuals who are clinically depressed, it isplausible that the pattern may be a prodromal risk factor foraffective problems later in life. Children considered at risk foraffective and conduct disorders because of maternal emo-tional problems during pregnancy can be identified, andpreventive treatment can be provided.

ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by National Institutes of Health GrantNos. NS-41298, HD-51852, and HD-28413 (to CAS) andConte Center Award No. MH-96889. The funding sourcesdid not contribute to the design or conduct of the study;collection, management, analysis, or interpretation of the data;or preparation, review, or approval of the manuscript.

We thank compensated staff, Kendra Leak, B.A. (participantrecruitment, scheduling), Cheryl Crippen, Ph.D. (data collec-tion, preliminary data analysis), Christina Canino, M.A. (datacollection, database management), Natalie Hernandez, B.A.(subject recruitment, data collection), and Mariann Howland,B.A. (manuscript preparation) for their expert assistance andthe families who participated in our studies. The resultsreported in this work were included as part of the MaternalStress in Pregnancy symposium presented at the 166thAnnual Meeting of the American Psychiatric Association,May 21, 2013.

All authors collaborated in the collection and analysis of thedata and reviewed and edited iterations of the manuscript. Theprincipal investigator is independent of any commercial funderand had full access to all the data in the study and takesresponsibility for the integrity of the data and the accuracy ofthe data analysis. The authors report no biomedical financialinterests or potential conflicts of interest.

ARTICLE INFORMATION

From the Department of Psychiatry and Human Behavior(CAS, KH, EPD), University of California, Irvine, Orange,California; Department of Pediatrics (CB), University of




California, Irvine, Orange, California; Institut für MedizinischePsychologie, Charité Centrum für Human-und Gesundheits-wissenschaften, Charité Universitätsmedizin, Berlin, Germany;and Department of Psychology (EPD), University of Denver,Denver, Colorado.

Address correspondence to Curt Sandman, Ph.D., EarlyHuman and Lifespan Development Program, University ofCalifornia, Irvine, One University Drive, Orange, CA 92866;E-mail: [email protected].

Received Oct 14, 2013; revised Jun 19, 2014; acceptedJun 27, 2014.

Supplementary material cited in this article is availableonline at http://dx.doi.org/10.1016/j.biopsych.2014.06.025.

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