Research Article

PREGNANCY ANXIETY AND COMORBID DEPRESSIONAND ANGER: EFFECTS ON THE FETUS AND NEONATE

Tiffany Field,1n Miguel Diego,1 Maria Hernandez-Reif,1 Saul Schanberg,2 Cynthia Kuhn,2

Regina Yando,3 and Debra Bendell4

One hundred sixty-six women were classified as experiencing high or lowanxiety during the second trimester of pregnancy. The high anxiety women alsohad high scores on depression and anger scales. In a follow-up across pregnancy,the fetuses of the high anxiety women were noted to be more active and toexperience growth delays. The high anxiety mothers’ high prenatal norepi-nephrine and low dopamine levels were followed by their neonates having lowdopamine and serotonin levels. The high anxiety mothers’ newborns also hadgreater relative right frontal EEG activation and lower vagal tone. Finally, thenewborns of high anxiety mothers spent more time in deep sleep and less time inquiet and active alert states and showed more state changes and less optimalperformance on the Brazelton Neonatal Behavior Assessment Scale (motormaturity, autonomic stability and withdrawal). These data highlight the needfor prenatal intervention for elevated anxiety symptoms during pregnancy.Depression and Anxiety 17:140–151, 2003. & 2003 Wiley-Liss, Inc.

Key words: anxiety; depression; anger; fetus; newborn

PREGNANCY ANXIETY ANDCOMORBID DEPRESSION AND

ANGER EFFECTS ON THE FETUSAND NEONATE

Prenatal anxiety effects on the fetus have beenresearched for decades [Glover et al., 1999]. Morerecently prenatal depression effects on the fetusand neonate have been reported [Lundy et al., 1999;Field et al., 2001]. Prenatal anger effects have receivedless attention. These feeling states are oftenconfounded. Patients with depression very often reportfeeling anxious, without qualifying for a DSM‘‘certified’’ anxiety disorder [American PsychiatricAssociation, 1994], and, vice versa, patients with ananxiety disorder regularly feel depressed, withoutsuffering from a regular depression [Pini et al., 1997].Patients with depression have been noted to scoreequally high on depression as on anxiety scales in atleast two studies [Katz et al., 1989; Wetzler et al., 1990]and in one study, patients with major depression ordysthymia had even higher scores on anxiety scales than

patients with anxiety disorders [Di Nardo and Barlow,1990].

Aggression regulation disturbances are also a fre-quent component of mood disorders [Botsis et al.,1997]. The aggression is often turned inward, mani-festing itself as self-denigration or suicidality, oroutward with symptoms such as anger attacks. Anger

DEPRESSION AND ANXIETY 17:140–151 (2003)

1Touch Research Institutes, University of Miami School of

Medicine, Miami, Florida2Duke University School of Medicine, Durham, North Carolina3Harvard Medical School, Boston, Massachusetts4UCLA School of Medicine, Los Angeles, California

Contract grant sponsor: NIMH; Contract grant number: MH

00331, MH 46586; Contract grant sponsor: Johnson and

Johnson.

nCorrespondence to: Tif fany Field, PhD, Touch Research

Institutes, University of Miami School of Medicine, Department

of Pediatrics (D-820), PO Box 016820, Miami, FL 33101.

E-mail: tfield@med.miami.edu.

Received for publication 15 April 2002; Accepted 1 January 2002

Published online in Wiley InterScience (www.interscience.wiley.

com). DOI. 10.1002/da.10071

&& 2003 WILEY-LISS, INC.

attacks have been observed in approximately 30–40%of depressed patients, both in major depression anddysthymia [Fava et al., 1990, 1993]. From a meta-analysis of the comorbidity literature, Dobson andCheung [1990] concluded that in 42–100% (mean67%) of patients with depression, an anxiety disorderalso exists or has occurred, and in 17–65% (mean 40%)of patients with anxiety disorders depression is alsopresent. In family studies, moreover, a high rate ofcotransmission of mood and anxiety disorders wasfound [Rende et al., 1997].

Existing literature on the behavioral/physiological/biochemical effects of these prenatal states has focusedon one of these systems and on stress, anxiety, ordepression effects without considering that these maybe confounding states. Although separate systems/separate effects literature is reviewed here, the studyconducted involved all three systems (behavioral/physiological/biochemical) in a sample of women withhigh anxiety comorbid with depression and anger.

An association has been reported between maternalanxiety and increased uterine artery resistance,leading to reduced blood flow to the fetus [Teixeiraet al., 1999]. The mean uterine artery resistanceindex was higher in women who had high stateanxiety and high maternal heart rate. Anxiety andmaternal heart rate were the most significant predictorsin a regression analysis on mean uterine arteryresistance. We suggest that the hypothalamic-pitui-tary-adrenocortical (HPA) system (elevated cortisollevels), or sympathetic activation (elevated norepi-nephrine levels), contributed to these effects in the32-week-old fetuses.

In another study by Glover and colleagues [Gitau etal., 1998], fetal concentrations of cortisol weresignificantly related to maternal cortisol concentrations(r ¼ 0.62) in 30–35-week-old fetuses. Forty percent ofthe variance in fetal cortisol levels could be explainedby the maternal concentrations. Corticotropin releas-ing hormone (an hypothalamic neuropeptide that has amajor role in regulating pituitary-adrenal function andthe release of cortisol) has been noted to increase inpregnant women in response to stress at 28–30 weeksgestation and at that time was a significant predictor ofpreterm delivery (0.98 reliability) [Wadhwa et al.,1998]. Those infants who were subsequently bornprematurely had higher corticotropin releasing hor-mone levels than those who were born full-term.DiPietro et al. [1996] also reported increased activity offetuses of ‘‘stressed’’ mothers. Their more active fetuseswere subsequently more dif ficult, unpredictable, un-adaptable and active at 3–6 months post-delivery. Theprenatal stress and its associated preterm delivery[Wadhwa et al., 1998], low birthweight [Gitau et al.,1998; Glover et al., 1999; Tixeira et al., 1999] and lowhead circumference [Lou et al., 1992], the later increasein HPA responsiveness and the increased fetal activityand more dif ficult temperament [DiPietro et al., 1996]might be explained by a combination of depression and

anxiety that the above authors called stress effects[Wadhwa et al., 1998].

Although prenatal depression and prenatal anxietymight be expected to have similar effects on the fetus,data by Glover et al. [1999] suggest that anxiety anddepression may have different effects and may operateby dif ferent mechanisms. The association alreadynoted between maternal anxiety and increased uterineartery resistance [Teixeira et al., 1999] and thepresumed reduction of fetal blood flow associated withincreased uterine artery resistance, may contribute tothe intrauterine growth deprivation effects noted infetuses of high anxiety mothers. The strong relation-ships they reported between maternal cortisol levelsand fetal cortisol levels [Gitau et al., 1998] and theabsence of correlations between beta-endorphin ornorepinephrine levels in the mother and fetus suggestthat cortisol may be unique in its being transportedacross the placenta in amounts sufficient to affect thefetus [Glover et al., 1999]. The maternal-cortisol-infant-cortisol relationship may be less related toanxiety effects than to maternal depression effects,depression being typically accompanied by elevatedcortisol levels.

Anxiety and depression are more likely to becomorbid than non-comorbid in pregnant womenand thus the effects would combine to affect the fetuspossibly by still another mechanism. The more typicalcomorbidity of anxiety and depression may lead to bothshorter gestational age and reduced birthweight. Theproblem in the research to date has been that maternalstress, maternal anxiety and maternal depression haveall been confounded, as they may be in nature.

Two different physiological (EEG) profiles mayalso occur for depression and anxiety, again, if theywere not confounded with each other. Accordingto the predictions of Davidson [1998] and Fox[1994] and, before them, Robinson et al. [1984],depression and anxiety are likely to be manifested bydifferent EEG patterns, with left EEG hypoactivation(usually accompanying low approach behavior style)occurring in depressed individuals and right EEGhyperactivation (usually accompanying high inhibitionstyle) in individuals with anxiety disorder. Althoughseveral have noted the left hypoactive EEG pattern indepressed individuals [Field et al., 1996; Henriques andDavidson, 1990; Jones et al., 1998], the patternaccompanying anxiety has not been reported in theliterature.

At least one previous study has examined EEGasymmetries in controls, patients with major depres-sion and patients with major depression and anxiety[Bruder et al., 1997]. In this study, participants withmajor depression showed greater relative right frontalEEG asymmetry than controls. Furthermore, theanxiety and depression comorbid group exhibitedgreater right frontal EEG alpha asymmetries thandepressed and control subjects. These findings wereonly present in the alpha band.

Research Article: Anxiety Effects on the Fetus 141

Frontal EEG activation refers to differences in theamount of resting brain electrical activity (or power)between the left and right frontal hemispheres in thealpha frequency band (8–13 Hz) for adults and in the3–13 Hz frequency band for newborns. EEG Power inthese bands is inversely related to cortical activationwhere greater power suggests lower activation [David-son, 1995]. Frontal EEG activation has been describedin the context of approach/withdrawal behavior withgreater relative left frontal EEG activation beingassociated with approach behavior and greater relativeright frontal EEG activation being associated withwithdrawal behavior [Davidson and Fox, 1988; Fox,1994; Davidson, 1995]. In a description of the ways inwhich this EEG activity is organized by the behavioralactivation/inhibition system, Davidson [1998, 1995]and later Fox [1994] have suggested the followingEEG/behavior profiles: 1) greater relative left frontalEEG activation (typically seen in normal individualsduring positive mood states) is accompanied by activeapproach, exploring and positive affect; and 2) greaterrelative right frontal EEG activation is characterized byactive withdrawal and negative affect.

A potential model for the unconfounded profiles isdepicted in Figure 1. Superimposed on the frontalEEG activation model is the biochemical profile andthe behavioral (approach or inhibition) we mightexpect in anxiety and depression. As compared to anon-depressed/non-anxiety disorder group, a depres-sion group might be expected to have elevatednorepinephrine, low levels of dopamine and serotoninand elevated cortisol [Rogeness et al., 1992]. Anxiety ascompared to non-depression/non-anxiety might beaccompanied by elevated norepinephrine and dopa-mine, low levels of serotonin and elevated cortisollevels. Comparing the predicted depression and anxietyprofiles against each other, depression might beaccompanied by lower norepinephrine and dopaminelevels, similar serotonin levels and higher cortisollevels.

Further confounding the potential profile of anxietyaccompanied by depression remains a third feelingstate, anger. In a recent study on prenatal depressioneffects on the neonate we noted many more correla-tions between prenatal anger than prenatal depressionand neonatal outcome [Field et al., 2001]. Theexpected anger alone profile is also depicted inFigure 1. How these three profiles might combine isdif ficult to predict, but studying them as separate,unconfounded profiles would require a very largesample to yield large enough samples of pure profiles.Thus, in the present study we recruited on the anxietystate variable expecting to see depression and anger ascomorbid states.

We were interested in determining whether neonataloutcome measures would mimic prenatal maternalmeasures, as they did in our earlier samples. Based onat least two studies on depression in pregnancy andearly development, we expected the offspring of the

high anxiety women to exhibit EEG patterns similar totheir mothers’ EEG pattern [Field et al., 2001; Jonesand Field, 1999]. In addition, we expected their infants’biochemical profiles to mimic their mothers’ biochem-ical profiles [Lundy et al., 1999; Field et al., 2001].Studies of this kind have not yet been conducted withwomen with elevated anxiety levels. In our depressedmother studies we noted that newborns of depressedmothers carried out less optimally on the BrazeltonScale [Abrams et al., 1995] including poorer perfor-mance on the orientation cluster, less motor tone,lower activity levels and more irritability and lessrobustness and endurance (unavailability, lethargy andstress behavior) during the examination. Newborns ofmothers with depressive symptoms were also lessexpressive [Lundy et al., 1996] including showingfewer interest and more precry expressions during theBrazelton and they showed less orientation and fewerfacial expressions in response to modeled happy andsurprise facial expressions. We also noted that new-borns of mothers with depressive symptoms werephysiologically less developed [ Jones et al., 1998]including showing greater relative right frontal EEGasymmetry (due to reduced left hemisphere activation),and lower vagal tone.

These data suggested that maternal depressivesymptoms during pregnancy may be contributing tonewborn neurobehavioral functioning. We exploredprenatal depression effects on neonates’ cortisol andcatecholamine profiles [Lundy et al., 1999]. Duringtheir last trimester of pregnancy the depressed mothershad higher cortisol and norepinephrine levels andlower dopamine levels. Their newborns also had highercortisol and norepinephrine levels and lower dopaminelevels, thus mimicking their mothers’ biochemicalprofile. Stepwise regression analyses showed that thedepressed mothers’ prenatal norepinephrine and dopa-mine levels significantly predicted the newborns’norepinephrine and dopamine levels and their Brazel-ton scores, highlighting a prenatal biochemical influ-ence on neonatal outcome.

We also investigated prenatal depression effectson fetal activity [Dieter et al., 2001]. Across the secondand third trimesters fetal movements (single limb,multiple limb, gross body) were recorded for 5 minbefore a standard ultrasound examination. Theanalyses showed that the fetuses of depressed womenwere more active at 5, 6, and 7 months gestation.Growth delays were also noted [Field et al., 2001].On every growth measure (estimated weight,femur length, abdominal circumference, head circum-ference) the fetuses of depressed versus those ofnondepressed women showed growth delays. In addi-tion, 24% of the fetuses of depressed mothers (vs. 7%of the fetuses of non-depressed mothers) were bornprematurely.

This type of data have not yet been reported for highanxiety mothers, although much of the earlier literatureon stress effects may have relevance for anxiety effects

Field et al.142

as may the depressed mother literature because of thepotential confounding of anxiety, depression and angerstates. High vs. low anxiety mothers were identifiedprenatally. Because we had very small groups whentrying to identify a high anxiety alone group we electedto compare high anxiety (confounded by high depres-sion and anger scores) mothers with low anxiety (lowdepression and low anger) mothers and their offspring.

MATERIALS AND METHODS

PARTICIPANTS

One hundred sixty-six pregnant women were re-cruited during their first prenatal visit at approximately20 weeks at local hospital prenatal clinics. Afterattrition from the prenatal to the neonatal stage, 132women were in the final sample. The women wereprimarily middle socioeconomic status women (M ¼ 2on Hollingshead SES Index) and were distributedapproximately 48% Hispanic-American, 29% non-Hispanic Caucasian and 23% African-American.Thirty-one percent of the women were single and68% were married. Fifty-five percent of the offspringwere female. The pregnant women were given the TraitAnxiety, the CES-Depression and the POMS AngerScales. They were assigned to high anxiety and lowanxiety groups based on a median split on the TraitAnxiety Scale. Mothers with trait anxiety scores 438 (n¼ 66) were included in the high anxiety group andmothers with anxiety scores o38 (n ¼ 66) wereincluded in the low anxiety group. The median splitwas used because: 1) no clinical cutoff has beenestablished for the Trait Anxiety Scale; 2) an equalnumber of subjects would be in each group; and 3) themedian split would be a more conservative test ofdif ferential effects than comparing extreme groupssuch as top and bottom quartiles. The two groups didnot dif fer on the above demographic variables. Thedepression and anger scales were given because thecomparison between high and low anxiety women wasexpected to be confounded by depression (CES-D) andanger (POMS) scores. Prenatal anxiety effects are alsolikely to be confounded by other factors like maternalnutrition, alcohol and smoking during pregnancy,although those confounds are more difficult to assessbecause of the unreliability of recalling those accu-rately.

PROCEDURE

The mothers were given the following question-naires at 20 weeks gestation and at the neonatal stage:1) Sociodemographic Questionnaire (SES); 2) TraitAnxiety Inventory; 3) Center for Studies of Depression(CES-D); 4) POMS Anger Scale; and 5) BIS-BAS(Inhibition/Activation Scale). For all of the measuresbelow, the researchers were blind to the mothers’ andinfants’ group assignment.

Sociodemographic Questionnaire. The Sociode-mographic questionnaire is comprised of 11 itemsconcerning age, education, occupation, income, lengthof time couples were in the relationship, marital status,and the child’s age, gender, birth order, the number ofchildren in the family, and ethnicity.

Trait Anxiety Inventory. The Trait Anxiety In-ventory [Spielberger et al., 1970] is comprised of 20items and assesses how the subject usually feels in termsof severity (‘‘not at all’’ to ‘‘very much so’’). Character-istic items include ‘‘I feel nervous’’ and ‘‘I feel calm.’’Research has demonstrated that the Trait AnxietyInventory has adequate concurrent validity and internalconsistency (r ¼ 0.83).

Center for Epidemiological Studies DepressionScale. The CES-D [Radloff, 1977] is a 20-item self-report scale designed to measure depressive symptomsincluding depressed mood, feelings of guilt, worthless-ness, helplessness and hopelessness, loss of energy andsleep and appetite disturbances [Radloff and Teri,1986]. The 20 symptoms are rated for frequency (overthe past week) from ‘‘rarely or none of the time’’ to‘‘most or all of the time.’’ A summary score ranges from0–60 by summing all items. Reliability and validityhave been acceptable across a variety of demographiccharacteristics including age, education, geographicarea, and racial, ethnic and language groups [Radloffand Teri, 1986]. The CES-D was given to the motherat the time of prenatal recruitment and again within 24hr after delivery.

Profile of Mood States Anger Scale. The POMS[McNair et al., 1971] consists of 12 items on anger thatare rated on 5-point scales ranging from (0) ‘‘not at all’’to (4) ‘‘extremely’’, using words such as ‘‘mad’’ and canrange to 60 with a higher score being non-optimal.The scale has adequate concurrent validity and goodinternal consistency (r ¼ 0.95) [McNair and Lorr,1964].

Behavioral Inhibition and Behavioral ApproachSystem Questionnaire. The BIS/BAS [Carver andWhite, 1994] is a 24-item questionnaire consisting ofpersonal statements followed by four severity optionsranging from very true to very false. The BIS/BAS isdesigned to assess the tendency to have an approachresponse (BAS) or an avoidance or inhibited response(BIS) in situations. The BIS/BAS scales have adequateinternal reliability (0.66–0.74) and adequate convergentvalidity with other measures including Eysenck’sExtraversion scale [Carver and White, 1994]. BAS-BIS difference scores are obtained by subtracting z-transformed BIS scores from z-transformed BASscores. The BAS-BIS scores can range from �2.53–2.79 with more positive scores denoting greater BASactivity. This method has been used previously todocument the significant relation between the BIS/BAS and EEG activity [Diego et al., 2001b; Sutton andDavidson, 1997].

Fetal activity Fetal activity has been reportedlyhighly correlated with infant activity [DiPietro et al.,

Research Article: Anxiety Effects on the Fetus 143

1996] and emotional tone. Fetal activity was measuredby the same system we used in our pilot studies ondepressed women [Dieter et al., 2001] and withdrawnand intrusive depressed women [Diego et al., 2001a].This assessment was made at 18–24 weeks (M ¼ 22.9weeks). For this assessment the technician positionedthe scanner to obtain a lateral view of the fetus. Theobserver who was blind to the mother’s group assign-ment then watched the fetus for five consecutiveminutes. Every 3 s (a total of 100 samples), a tape-recorded cue (heard through an earphone) promptedthe observer to record the fetal activity categoriesincluding: 1) single limb movements; 2) multiple limbmovements; and 3) gross body movements. Interraterreliability, calculated on one-third of the sample fortwo observers, yielded the following k values: singlelimb movements ¼ 0.82; multiple limb movements ¼0.86; gross body movements ¼ 1.00. For the dataanalyses, the percent time the fetus engaged in totalmovement, as well as each movement category, wascalculated. No effort was made to discern fetalbehavior states because they cannot be reliablyidentified before 36 weeks gestation and most particu-larly during a 5-min clinical fetal ultrasoundexam without confirmation through fetal heart ratemonitoring.

Obstetric and postnatal complications. Obstetricand postnatal complications were recorded based onthe Littman and Parmelee [1978] scales of the samename. After delivery, obstetric complications andperinatal factors were quantified using the OCS andPNF scales. The OCS is a 41-item scale that assessesoptimality of the prenatal (e.g., maternal age, medicalproblems during pregnancy, length of time since lastpregnancy), obstetrics (e.g., delivery type, drugs givento mother during labor and delivery, fetal heart rateduring labor) and the neonatal period (e.g., placentaprevia, onset of stable respiration, Apgar scores).A higher score is optimal and indicates fewercomplications.

The PNF is a 10-item scale that assesses complica-tions of the newborns (e.g., respiratory distress,temperature disturbance, feeding within 48 h). Ahigher score is optimal. The OCS and PNF werecompleted after delivery from information collectedfrom the medical records.

Sleep/wake behavior. Sleep/wake behavior of theneonate was continuously videotaped in compressedtime (3 h sleep coded in 1 h using time-lapse video) foran inter-feeding interval (2–3 h) before the Brazeltonwas carried out on the first afternoon of life. Thoman’sstudies of term infants’ sleep patterns suggest that aninterfeeding interval time frame can provide a repre-sentative sample [Thoman, 1975], and Sostek andAnders [1975] have used "nap" recordings of thisduration. The videotapes were coded for all move-ments that occurred during that period into a laptopcomputer according to the procedures we have used inour other sleep studies [Field et al., 1986]. Before sleep

state coding the examiner was trained to 0.90reliability, and reliability coding of one-third of thevideotapes yielded moderate to high reliabilities (krange ¼ 0.73–0.87, M ¼ 0.81). Thoman’s Sleep StateCriteria were used to define sleep/wake behaviorcategories [Thoman, 1975] and indeterminate sleep(uncodable sleep) was assessed because indeterminatesleep was noted in infants of depressed mothers in oneof our recent studies [Jones et al., 1998].

Neonatal Behavior Assessment Scale. The Bra-zelton Neonatal Behavior Assessment Scale (BNBAS)[Brazelton, 1973] was administered midway betweenfeedings and after the sleep session observations. TheBrazelton scale is comprised of 20 neurological reflexitems and 27 other items summarized according toseven factors: habituation, orientation, motor behavior,range of state, regulation of state, autonomic stabilityand abnormal reflexes [Lester et al., 1982]. In addition,robustness (how strong the responses), excitability(how easily aroused and irritated) withdrawal (with-drawing from stimuli) and depressive (how inactive andlethargic) behavior were recorded. The Brazeltonexaminers were unaware of the infant’s group assign-ment and were trained to a 0.90 reliability criterionbefore the study. This assessment was included becauselower orientation and motor scores, less robustness andmore depressive behaviors were noted on the Brazeltonscale in our earlier studies on newborns of depressedmothers [Abrams et al., 1995; Lundy et al., 1999].

Vagal activity. Three EKG electrodes are placed onthe infant’s chest and three on the mother’s back in astandard lead configuration. The electrodes are con-nected to a preamplifier (Grass model 12, NeurodataAcquisition System; AstroMed, West Warwick, RI)with bandpass frequencies set at 1.0 and 100 Hz and again of 2,000. The EKG data are acquired using theHEM Data Corporation Snap-Series Software thatcontrols the A–D board and allows the sampling of theamplified bioelectric signal at user specified rates (inthis study, 1,000/s). The neonates’ EKG was recordedduring a quiet alert state with the infant lying in abassinet and the mother sitting quietly with eyesclosed. The recording lasted 10 min to ensure 3 minof artifact-free data.

The infant’s motor activity was coded second-by-second for limb movements, trunk movements andhead movements and entered as a covariate in the dataanalyses to control for that confound. Lower activitylevels have been reported in newborns of depressedmothers [Field, 1992], although higher activity levelswould have been predicted based on our recent datadocumenting higher activity levels in the fetuses ofdepressed mothers [Dieter et al., 2001]. The data wereconverted to inter-beat intervals (IBI) and to vagal toneusing Mixedit software (Delta-Biometrics, Bethesda,MD), which utilizes a method developed by Porges[1985]. Vagal tone was included because lower vagaltone has been noted in infants of depressed mothers ina previous study [Field et al., 1995].

Field et al.144

EEG for a baseline measure of relative right orleft frontal EEG activation. The neonatal EEG wasrecorded while the infant was in a quiet alert state in abassinet. EEG and behavior were recorded for 3 minwhile the infant was awake and alert. At a separate timeduring the session the mother’s EEG was recordedwhile she sat quietly with eyes open for 3 min. We havereported significant differences between the frontalEEG patterns of newborns of depressed and non-depressed mothers [ Jones et al., 1998], and 1–3-monthstability of EEG (r ¼ 0.45) [ Jones et al., 1997b] as wellas significant 3-month to 3-year stability [ Jones et al.,1997a].

EEG recording. The EEG for both the mother andinfant were recorded using Lycra stretchable caps(Electro-Cap, Eaton, OH) that were positioned on thesubject’s head using anatomical landmarks [Bloom andAnneveldt, 1982]. Electrode gel was injected into theelectrodes at the following sites: F3, F4, P3, P4, and Cz(used as the reference during recording), and impe-dances will be brought below 5,000 O. The vertexreference location was used because this reference sitehas been shown to produce comparable results to otherreference sites [Tomarken et al., 1992] and it is the leastinvasive location for newborns. Additional electrodeswere positioned on the external canthus and above thesupra orbit of the right eye to record the subject’sEOG, which was used to determine horizontal andvertical eye movement artifacts. The recording of themother’s EEG occurred while the infant was placed inanother room and the mother sat by herself quietlywith eyes open. The newborn EEG was recorded whilethe newborn laid in quiet alert state wrapped in acotton blanket in an age appropriate infant seat tilted301 with the mother outside the EEG recording room.

The EEG signal was passed through a BiopacMP100 Acquisition System with amplifiers set asfollows: low frequency filter: 1 Hz; high frequencyfilter: 100 Hz; Amplification: 20,000. The linefrequency filter was on for all channels. The outputfrom the amplifiers was directed to a laptop computer(Inspiron 7000; Dell). The signal was sampled at a rateof 512 Hz and streamed to hard disk using dataacquisition software (Acq Knowledge v. 3.5; BiopacSystems, Santa Barbara, CA).

EEG analyses. EEG data were analyzed using anEEG analysis software package (EEG Analysis Systemv. 5.3, James M. Long, 1987–1990). This processinvolves the manual elimination of sections of datathat are unusable due to artifact (eye movements,muscle activity, or technical dif ficulties). Theremaining artifact-free data were spectrally analyzedusing discrete Fourier transforms using a HanningWindow with a 50% overlap to yield power datafor specific frequency bands in pW O (1 mV2). Forthe mothers, the analyses yielded power data forthe 8–13 Hz frequency band. This frequencyband has been used in previous EEG asymmetryresearch [Davidson, 1998; 2000 for reviews] as

power in the a (8–13 Hz for adults) frequency bandis inversely related to cortical activation [Shagass, 1972]and asymmetries in a power are more consistentlyrelated to affective states than other band powerasymmetries [Davidson, 1995].

For the infants, the analyses produced power forsingle-Hertz frequency bins from 1–20 Hz. Powervalues were then used to construct spectral plots,which showed that the majority of activity occurredwithin the 3–13 Hz frequency band. This is consistentwith previous research indicating that the majority offrontal and parietal EEG power in newborns resides inthe 3–13 frequency band and is consistent with thefrequency band used previously to assess EEGasymmetry in newborns [Fox and Davidson, 1986;Jones et al., 1998]. EEG power values for the mothersand newborns were then log transformed to normalizethe data and frontal and parietal EEG asymmetryscores were computed. The asymmetry score is adifference score reflecting the power in onehemisphere relative to the power in the contralateralhemisphere [Ln (Right) � Ln (Left)]. A score ofzero represents hemispheric symmetry, a negative scorerepresents relative right frontal activation and apositive score represents relative left frontal activation.Greater relative right frontal EEG activation hasconsistently been noted in our studies on depressedmothers and infants [Field et al., 1995; Jones et al.,1997a, 1998] as well as those of Dawson et al. [1999].This would be expected in the mothers as depressedadults are noted to have greater relative right frontalEEG activation even when they are experiencingremission of behavioral symptoms [Henriques andDavidson, 1990]. Fox [1994] and Davidson [1998] havesuggested that greater relative right frontal EEGactivation is typically associated with negative affectand withdrawal behavior. EEG patterns have not beennoted to dif fer across depressed and non-depressedinfants in other regions of the brain (e.g., parietal area)or in other frequency bands (e.g., b).

Urine assays. First morning urine samples werecollected from the mothers at the fetal ultrasound andfrom the mothers and infants (first morning diapersqueezed) at the newborn period. They were thenfrozen and subsequently shipped via express courier toSaul Schanberg at Duke University Medical Schoolwhere they were analyzed for: 1) norepinephrine as acorrelate of sympathetic activation that would beexpected to be high in both depression and anxietybut higher in anxiety; 2) dopamine that would beexpected to be low in depression and high in anxiety;3) serotonin that would be expected to be low in bothgroups; and 4) cortisol as a measure of stress that wouldbe expected to be high in both groups but higher in thedepressed group, as it was notably elevated and apredictor of prematurity for stressed (depressed)women in the Wadhwa et al. [1998] study.

Several factors must be kept in mind in evaluating thesignificance of urine measures. First, unchanged

Research Article: Anxiety Effects on the Fetus 145

neurotransmitters reflect a small percentage oftotal excretion, although for catecholamines (norepi-nephrine, dopamine), at least, the correlation withphysiologically released norepinephrine is quite good.Second, norepinephrine and serotonin metabolitesreflect release from both peripheral and centralneurons. Literature exists implicating various neuro-transmitter and endocrine substances as etiologicfactors in depression. There has been little character-ization, however, on a neurochemical level of maternaland infant depression and virtually none on elevatedanxiety.

Biological studies of depression have focused on thefollowing neurotransmitter/neuroendocrine systems: 1)norepinephrine and serotonin, the neurotransmittersmost commonly implicated in depression, withnorepinephrine levels typically being high andimplicated in sympathetic-adrenocortical activity,anxiety, and behavioral inhibition and serotonin typi-cally being low and implicated in the inactivity noted indepressed individuals; 2) cortisol, as an index ofhypothalamo-pituitary-adrenal function, which is mark-edly abnormal in depression [Kennerley and Gath,1986; Rogeness et al., 1992], and 3) dopamine, highlyrelated to serotonin in its behavioral activation proper-ties. Weiss et al. [1998] have explored an animal (rat)model of increased norepinephrine/decreased dopaminebeing linked to depression. Our pilot data suggest thatdepressed mothers have low dopamine levels [Field etal., 2001]. Depressed dopamine levels would in turn beexpected to lead to psychomotor retardation, dysphoriaand anhedonia. Elevated dopamine accompanied by lowserotonin might be expected to accompany elevatedanxiety.

MANOVA were carried out separately for eachgroup of variables: 1) prenatal and postnatal self-reportvariables; 2) biochemical data; 3) fetal activity, obstetriccomplications and EEG measures; 4) sleep-wakebehavior; and 5) Brazelton scores. These were followedby ANOVA on the individual variables and Bonferronit-tests for interaction effects.

RESULTSAs can be seen in Table 1, the high anxiety group

women also had high depression and high anger scoresboth prenatally and postnatally. In addition, the highanxiety group women had elevated norepinephrine andlow dopamine levels prenatally (Table 2). Their fetuses,in turn, had higher activity levels, lower fetal weightand lower abdominal circumferences as measured bythe ultrasonographer (Table 3). At the postnatal periodthe infants of high anxiety mothers had lowerdopamine and serotonin levels. Newborns of highanxiety mothers were also more likely to be born under2,500 g than newborns of non-anxiety mothers (34% ofhigh anxiety mothers delivered infants o2,500 gramsvs. 12% of low anxiety mothers, w2 ¼ 7.80, P o .01).

Table 4 indicates that high anxiety mothers hadgreater postnatal complications and their infants wereshowing greater relative right frontal EEG activation,and lower vagal tone. As noted in Table 5, the infants ofhigh anxiety mothers during the sleep observationsspent more time in deep sleep and less time in quietand active alert states. They also spent less time cryingand showed more state changes (Table 6).

Table 5 shows the Brazelton Neonatal BehaviorAssessment Scale scores. The infants of the highprenatal anxiety mothers had lower motor organizationand autonomic stability and higher withdrawal scores.

Finally, a stepwise regression was conducted todetermine the relative amounts of outcome varianceon a key neonatal outcome variable (infant EEG) thatcould be explained by prenatal anxiety, depression andanger. As can be seen in Table 7, only anger entered theequation to explain only 13% of the variance.

DISCUSSIONIt is not surprising that the high anxiety group

experienced high depression and anger scores giventheir comorbidity in other studies [Field et al., 2001;Glover et al., 1999; Pini et al., 1997]. In our regression

TABLE 1. Means for self-report measures prenatally and postnatally

Group

Variables Low anxietyn High anxietyn F P

Prenatal anxiety (STAI) 29.15 (6.79) 46.93 (7.47) 200.62 .001Postnatal anxiety (STAI) 30.78 (7.70) 41.49 (8.73) 54.83 .001Prenatal depression (CES-D) 10.03 (7.06) 20.23 (9.87) 46.23 .001Postnatal depression (CES-D) 8.62 (8.04) 14.11 (10.64) 11.09 .001Anger (POMS) 5.76 (7.14) 13.70 (8.70) 32.36 .001BAS-BIS differencea 0.03 (.87) �0.02 (0.86) 0.10 NS

nValues are expressed as mean score (sd ).aBAS-BIS Difference Score is the BAS (behavioral activation) minus the BIS (behavioral inhibition) scale score, which yields a positive score if thewomen are more activated or approach-oriented and a negative score if the women are more withdrawal or inhibition-oriented.CES-D, Center for Studies in Depression; POMS, Profile of Mood States Anger Scale; STAI, Spielberger Trait Anxiety Inventory; NS, notsignificant.

Field et al.146

TABLE 2. Prenatal and postnatal neurotransmitters and neurohormones

Group

Biochemical variables Low anxietyn High anxietyn F P

Prenatal (mother)Cortisol 329.56 (189.56) 294.61 (160.59) 0.39 NSNorepinephrine 47.72 (19.57) 58.54 (21.00) 3.69 .05Epinephrine 4.11 (2.75) 5.47 (3.86) 1.49 NSDopamine 371.44 (125.36) 273.92 (127.12) 5.72 .01Serotonin 4,758.65 (1856.23) 4,393.89 (2231.43) 0.29 NS

Postnatal (mother)Cortisol 219.39 (159.70) 225.80 (171.07) 0.01 NSNorepinephrine 42.65 (23.17) 46.40 (19.11) 0.31 NSEpinephrine 4.59 (3.05) 4.98 (2.54) 0.19 NSDopamine 268.26 (88.43) 286.30 (68.81) 0.53 NSSerotonin 4,711.81 (3640.30) 4,554.16 (2360.61) 0.03 NS

InfantCortisol 413.37 (223.20) 508.86 (198.30) 2.01 NSNorepinephrine 79.67 (37.71) 79.15 (45.43) 0.01 NSEpinephrine 4.45 (3.47) 4.91 (2.87) 0.20 NSDopamine 516.30 (277.05) 369.79 (276.77) 3.67 .05Serotonin 10,881.94 (6212.65) 6,319.74 (5331.64) 6.16 .01

nValues are expressed as mean, ng/mg (sd ).NS, not significant.

TABLE 3. Means for fetal measurements

Group

Variables Low anxietyn High anxietyn F P

Fetal activity (% time) 29.00 39.00 8.50 .005Fetal weight (g)a 406.19 (261.72) 128.06 (301.90) 0.84 .05Biparietal diameter (cm) 4.67 (1.02) 4.37 (.67) 1.76 NSAbdominal circumference (cm) 15.64 (3.69) 14.11 (2.61) 3.52 .05Femur length (cm) 3.19 (.91) 3.07 (.71) 0.30 NSHead circumference (cm) 15.93 (4.22) 15.96 (2.48) 0.80 NS

nValues are expressed as mean (sd ).aCalculated using the formula of Shepard et al., 1982.NS, not significant.

TABLE 4. Obstetric/postnatal complications and physiological variables

Group

Variables Low anxietyn High anxietyn F P

Obstetric complicationsa 99.32 (30.35) 94.74 (19.99) 0.40 NSPostnatal complicationsa 148.00 (26.43) 130.59 (36.73) 3.47 .05Frontal asymmetry F mother �0.02 (0.15) �0.09 (0.20) 1.51 NSFrontal asymmetry F infant �0.03 (0.11) �0.04 (0.11) 5.57 .05Vagal tone F mother 4.05 (0.51) 3.91 (0.24) 1.71 NSVagal tone F infant 4.72 (1.36) 4.25 (0.34) 3.08 .05

nValues are expressed as mean (sd ).aHigher score is optimal.NS, not significant.

Research Article: Anxiety Effects on the Fetus 147

TABLE 5. Means for newborn sleep variables

Group

Variables Low anxietyn High anxietyn F P

Sleep StatesDeep sleep 25.63 (27.65) 41.46 (26.86) 3.47 .05Active sleep 10.44 (10.91) 15.50 (12.93) 1.74 NSREM sleep 12.81 (19.38) 15.71 (17.56) 0.26 NSQuiet alert 9.25 (11.35) 3.79 (9.09) 3.07 .05Active alert 8.13 (11.38) 1.43 (2.54) 9.05 .005Fussing 4.81 (7.75) 3.00 (7.40) 0.59 NSCrying 6.13 (8.20) 1.79 (4.09) 5.52 .05Indeterminate sleep 43.88 (26.19) 46.25 (21.86) 0.10 NSNo. state changes 36.50 (23.56) 49.42 (27.60) 3.47 .05Total movement 0.61 (0.26) 0.58 (0.26) 0.38 NS

nValues are expressed as mean % time in each state (sd ).NS, not significant.

TABLE 6. Brazelton Neonatal Behavior Assessment Scale scores

Group

Brazelton variable Low anxietyn High anxietyn F P

Habituation 5.72 (1.69) 5.08 (2.28) 2.18 NSOrientation 4.52 (1.61) 4.04 (1.82) 1.75 NSMotor organization 4.62 (.98) 3.91 (1.35) 8.11 .005Range of state 3.79 (1.10) 3.56 (1.20) 0.91 NSState regulation 4.23 (1.40) 4.07 (1.72) 0.23 NSAutonomic stability 6.71 (1.34) 5.39 (2.04) 12.89 .001Reflexes 2.65 (2.38) 2.72 (1.85) 0.03 NSWithdrawal symptomsa 2.39 (1.57) 3.59 (2.24) 8.47 .005Excitabilitya 2.06 (1.74) 2.46 (1.54) 1.33 NSDepressiona 2.81 (2.92) 3.75 (2.81) 2.42 NS

nValues are expressed as mean score (sd ).aLower scores are optimal.NS, not significant.

FIGURE 1. EEG activation and hypoactivation

EEG activation EEG Hypoactivation

Left NormalHIGH BAS

Right AnxietyHIGH BIS

Left DepressionLOW BAS

Right AngerLOW BIS

Norepinephrine m m m kDopamine m m k mSerotonin m k k kCortisol k m m k

BAS, behavioral activation; BIS, behavioral inhibition

TABLE 7. Stepwise regression on newborn electroencephalogram

R R2 R2adjusted F P

Anger .38 .15 .13 8.83 .004

Field et al.148

analysis on neonatal EEG, only anger entered theequation, and it contributed to only 13% of thevariance, suggesting that other prenatal variables needto be considered. The finding of elevated norepinephr-ine during the prenatal period was consistent withelevated norepinephrine noted in high anxious womenby Glover et al. [1999]. The elevated norepinephrinelevels of the high anxiety mothers may account for thegreater activity levels observed in the fetuses of thesemothers. Maternal norepinephrine is related to uterineartery resistance that may affect blood flow to the fetusand thereby affect its activity levels [Glover et al., 1999;Teixeira et al., 1999]. The low dopamine levels have notbeen reported for anxiety during pregnancy in previousliterature. They have been noted, however, to accom-pany pregnancy depression [Field et al., 2001].

The similar biochemistry of the mothers and infantsis paralleled by data on depressed mothers and infantsinasmuch as at the postnatal period the infants of highanxiety mothers had levels that mimicked theirmothers’ prenatal values including lower dopamineand serotonin levels. Although this matching of profileshas been previously reported for prenatal depression[Field et al., 2001; Lundy et al., 1999], this is the firsttime that this matching of prenatal maternal andneonatal biochemical profiles has been reported forhigh anxiety women.

Lower vagal tone and greater relative right frontalEEG activation was noted in the newborns of highanxiety mothers as well as a greater number ofpostnatal complications. These are similar to datareported for newborns of depressed mothers [Field etal., 2001; Jones et al., 1996].

Their spending more time in deep sleep is somewhatsurprising inasmuch as stressed infants typically spendless time in deep sleep. One possibility is that thegreater amount of quiet sleep is a conservation with-drawal phenomenon for the infants of depressedmothers such as that observed in newborns aftercircumcision. Information processing for both auditoryand visual stimulation has been notably altered indepressed individuals during deep sleep [Roeschke etal., 1996]. These findings may not apply to infants ofdepressed mothers but they suggest the importance offurther study of sleep in infants of depressed mothers.

Their spending less time in quiet alert and activealert states and their having a greater number of statechanges is consistent with the literature on disorga-nized sleep and consistent with the report of greaterindeterminate sleep being noted in infants of depressedmothers [Field et al., 2001; Jones et al., 1996] and morerecently for the infants of high anger mothers [Fieldet al., 2001]. The inferior scores on the BrazeltonNeonatal Behavior Assessment Scale includinglower motor organization and autonomic stability andhigher withdrawal scores are again consistent withreports on the infants of depressed mothers and infantsof high anger mothers in previous studies by Field et al.[2001].

Although these data are preliminary given the largenumber of outcome variables for the sample size andthe possibility of colinearity, these non-optimal neo-natal outcomes tentatively suggest the need for prenatalintervention for women who are experiencing highanxiety, comorbid depression and anger and associatedphysiological arousal. In previous studies we haveshown that pregnancy massage therapy can reduce atleast depression and its associated elevated stresshormones/neurotransmitters, resulting in more opti-mal neonatal outcomes [Field et al., 2001]. In additionto finding cost-effective prenatal interventions, re-search is needed on separating the effects of prenatalanxiety and the comorbid states of depression andanger. If, like depression, anxiety can contribute to lowbirthweight as it has been suggested by Glover et al.[1999], a prenatal marker variable that could predictlow birthweight such as that discovered by Wadwha etal. [1998] for premature delivery would help predictthose who needed early intervention. Early interven-tions could then be mounted to prevent this outcomefor women with high anxiety and comorbid depressionand anger during pregnancy.

Acknowledgments. We thank the mothers and infantswho participated in this study. This research wassupported by an NIMH Senior Research ScientistAward (MH 00331) and an NIMH merit award (MH46586) to T. Field, and by funding from Johnson andJohnson.

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