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Infant Behavior & Development 34 (2011) 1–14

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Infant Behavior and Development

Review

Prenatal depression effects on early development: A review

Tiffany Fielda,b,!

a Touch Research Institute, University of Miami School of Medicine, United Statesb Fielding Graduate University, United States

a r t i c l e i n f o

Article history:Received 5 November 2009Received in revised form 17 August 2010Accepted 24 September 2010

Keywords:Prenatal depressionEarly development

a b s t r a c t

This review of recent research on prenatal depression suggests that it is a strong predic-tor of postpartum depression and is more common than postpartum depression. Prenataldepression has been associated with excessive activity and growth delays in the fetus aswell as prematurity, low birthweight, disorganized sleep and less responsiveness to stim-ulation in the neonate. Infants of depressed mothers have difficult temperament, and laterin development attentional, emotional and behavioral problems have been noted duringchildhood and adolescence, as well as chronic illnesses in adulthood. Several variables haveconfounded the effects of prenatal depression including comorbid anxiety and anger as wellas stressful life events. Potential mediating variables are low prenatal maternal dopamineand serotonin levels and elevated cortisol and norepinephrine. The associated intrauterineartery resistance may limit blood flow, oxygen and nutrients to the fetus. Some studies alsosuggest the heritability of developmental problems for the children of prenatally depressedmothers, including ADHD and antisocial behavior. Multivariate, longitudinal research isneeded to disentangle these confounding and mediating variables.

© 2010 Elsevier Inc. All rights reserved.

Contents

1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. Prevalence of prenatal depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

3.1. Prenatal depression as a predictor of postpartum depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33.2. Predictors of antenatal depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

4. Effects on the fetus and neonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44.1. Prenatal depression effects on the fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44.2. Prenatal depression effects on birth measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54.3. Newborns of depressed mothers are less responsive to stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

5. Prenatal depression effects on infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55.1. Early interactions and temperament . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55.2. Prenatal depression effects on infant sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

6. Prenatal depression effects on children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66.1. Physiological measures in infants and children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66.2. Developmental delays, emotional and behavioral problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

7. Prenatal depression effects on adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77.1. Health and immune function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

! Corresponding author at: Touch Research Institute, University of Miami School of Medicine, PO Box 016820, Miami, FL 33101, United States.Tel.: +1 305 243 6781.

E-mail address: [email protected].

0163-6383/$ – see front matter © 2010 Elsevier Inc. All rights reserved.doi:10.1016/j.infbeh.2010.09.008

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2 T. Field / Infant Behavior & Development 34 (2011) 1–14

7.2. Prenatal depression in men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78. Potential confounding variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

8.1. Comorbid anxiety and developmental outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88.2. Cortisol as a potential mediating variable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88.3. Neurotransmitter effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108.4. Other potential confounding variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108.5. Methodological limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108.6. Future research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

9. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1. Overview

Postpartum depression has received significant attention in the literature for its negative effects on child development(Field, 1998; Murray & Cooper, 1997). In contrast, there are very few prenatal depression effects studies, even thoughdiscussions of these effects date back to the time of Hippocrates (Huizink, Mulder, & Buitelaar, 2004). Some have speculatedthat prenatal depression was not recognized because depressed mood was the expected correlate of normal hormonalchanges such as increased cortisol across pregnancy (Field et al., 2004a). Others have cited the complexity of disentanglingprenatal depression effects from those of postpartum depression. Still others have addressed some of the confoundingprenatal variables such as the comorbidity of anxiety and depression, the use of medications as treatments for those mooddisturbances and the excessive use of alcohol, illicit drugs, nicotine and even caffeine (Diego, Field, Hernandez-Reif, Vera, &Gil, 2007; Field, Hernandez-Reif, & Diego, 2006c). With the primary focus having been on postpartum depression, much ofthe early research on prenatal depression focused on its ability to predict postpartum depression.

Despite the inherent problems of studying prenatal depression effects on early development, some researchers have,nonetheless, attempted to control for potentially confounding prenatal variables and for the postpartum depression variableand have shown the negative effects of prenatal depression (Deave, Heron, Evans, & Emond, 2008; Luoma et al., 2001).Others have implied long-term effects of prenatal depression from perinatal outcomes that are known to predict long-termproblems. For example, the risk of preterm delivery is significantly enhanced by prenatal depression, and preterm delivery,in turn, contributes to significant behavioral, cognitive and emotional problems in children (Li, Liu, & Odouli, 2009). Anotherexample is that prenatal depression results in elevated neonatal cortisol levels (Field et al., 2004b; Lundy et al., 1999) which, inturn, influence infant temperament and childhood psychopathology (Davis et al., 2007). Still another example is that prenataldepression leads to neonatal fussiness and sleep problems (Field et al., 2004a) which are the most common concerns reportedby parents to pediatricians and are linked to subsequent behavioral and physiological disturbances (Gregory et al., 2005;O’Connor et al., 2007).

This paper reviews the relatively sparse literature on prenatal depression effects on early development. The prevalencedata on prenatal depression and prenatal versus postpartum depression are given as well as research showing the predictivevalidity of prenatal depression for postpartum depression. Risk factors for prenatal depression as well as confounding andcomorbid variables are reviewed including stressful life events and anxiety which are also thought to affect early devel-opment. Effects on the fetus and newborn include growth and developmental delays followed by emotional and behaviorproblems in childhood and chronic illness in later development. Data are also reviewed on potential mediating biochemicalvariables including cortisol, norepinephrine, dopamine and serotonin. Finally, methodological limitations of the literatureare summarized, and suggestions are made for future research.

2. Prevalence of prenatal depression

Prenatal depression, referred to as antenatal depression in many parts of the world, has ranged in incidence/prevalencefrom 6% to 38% in the published literature. These figures have varied by the state or country where the research occurredand the type of reporting. For example, in one study from the U.S., groups were separated by those women who experienceddepression only during the antepartum period (that figure being a very low 6%) versus chronic depression (7%) and postpar-tum depression (9%) (Mora et al., 2009). Even within cultures such as the British culture, variations in prenatal depressionrates have been noted such as 20% in Canada (Bowen & Muhajarine, 2006) and 31% in England (Hay, Pawlby, Waters, & Sharp,2008). In most studies, the prevalence has hovered somewhere between 30% and 40%, such as 30% in Italy (with 12% beingmajor depression and 18% being minor depression) (Marchesi, Bertoni, & Maggini, 2009) to 37% in Hong Kong (Lee et al.,2007) and to 38% in the U.S. (Records & Rice, 2007) (USA).

When prenatal and postpartum depression figures have been compared, generally speaking, prenatal or antenataldepression has been more frequent. For example, in one study prenatal depression was almost twice that of postpar-tum depression (29% vs. 17%) (Andersson, Sundström-Poromaa, Wulff, Aström, & Bixo, 2006), and at least a statisticallysignificant greater incidence of prenatal depression was noted in another study (30% vs. 23%) (Edwards, Galletly, Semmler-Booth, & Dekker, 2008). The one exception was a recent study in which the prevalence was similar for the prepartum

T. Field / Infant Behavior & Development 34 (2011) 1–14 3

and postnatal periods (9% vs. 8%) (Milgrom et al., 2008). The relatively greater incidence of prenatal depression is strik-ing, especially given that the lion’s share of the research has been focused on postnatal versus prenatal depression. It isalso somewhat surprising that postpartum depression has been assumed to have greater effects on development than thecombination of prenatal environmental effects and a genetic predisposition that would be implied by prenatal depressioneffects.

3. Risk factors

3.1. Prenatal depression as a predictor of postpartum depression

Antenatal depression has been noted to significantly predict postpartum depression. For example, in one study, antenataldepression along with a prior history of depression and a low level of partner support were the strongest predictors of post-natal depression (Milgrom et al., 2008). Similarly, in another study, women who had antenatal depression were significantlymore likely to be depressed postnatally (Edwards et al., 2008). In still another study, both antenatal anxiety and depres-sion during the first, the second and third trimesters increased the risk of postpartum depression (Lee et al., 2007). Thus,the primary question that has been addressed in the literature has been answered in the positive, namely that prepartumdepression increases the likelihood of postpartum depression. This has clinical significance because of the long-term effectsof postpartum depression on the infant. Insofar as prenatal depression predicts postpartum depression and postpartumdepression predicts developmental problems, prenatal depression would be at least indirectly related to less optimal childand adolescent development.

Negative effects of postpartum depression have been noted for infant psychological and physiological development(Civic & Holt, 2000; Field, 1998; Miller, 2002). Postpartum depression has also predicted behavioral/emotional problems inchildren in a number of clinical and community samples (Field, 1992; Goodman & Gotlib, 1999; Murray & Cooper, 1997).These findings, of course, do not suggest that these effects on child development are primarily postnatal depression effectsinasmuch as many of these women likely experienced antenatal depression as well.

3.2. Predictors of antenatal depression

A recent review of the literature on predictors of prenatal depression suggested that antenatal depression may go undiag-nosed because the symptoms of depression are attributed to the physical and hormonal changes that are typically associatedwith pregnancy (Bowen & Muhajarine, 2006). These authors cite several other risk factors including a history of depression,a lack of a partner, marital difficulties, a lack of social support, poverty, increased life stress, substance abuse, a history ofprevious abortions, unplanned pregnancy, ambivalence toward the pregnancy and anxiety about the fetus. Different studieshave focused on different factors as well as the timing of those factors. For example, in one study, 46% of the variance of thirdtrimester depressive symptoms was due to brief and intermittent negative mood states that occurred primarily during thefirst trimester and a lack of marital satisfaction and social support (Records & Rice, 2007).

In a study from Lithuania, risk factors were differentiated according to the trimester of their occurrence. In the firsttrimester, a greater prevalence of depression was independently associated with unplanned and unwanted pregnancy, highneuroticism, low education and a previous history of depression (Bunevicius et al., 2009). In the second trimester, the riskfactors were unplanned and unwanted pregnancy and high neuroticism. And in the third trimester, unplanned and unwantedpregnancy, high neuroticism and the occurrence of psychosocial stressors during the last year were the greatest predictors.Interestingly, as in other studies in the literature, the greatest prevalence of depression was found in the first and lasttrimesters and the lowest in mid-pregnancy.

Others have differentiated the risk factors by major versus minor depression (Marchesi et al., 2009). In the Marchesi etal. (2009) study, the risk of developing major depression was predicted at the beginning of pregnancy by the presence ofprevious depressive episodes and conflicts with the husband/partner, whereas the risk of developing minor depression waspredicted by being a housewife, the presence of previous depressive episodes and whether the pregnancy was unwanted.

In a study from Spain, risk factors differed as a function of gender (Escribe-Aguir, Gonzalez-Galarzo, Barona-Vilar, &Artazcoz, 2008). In this study, the prevalence of prenatal depression was higher among women (10%) than among men (7%).In both sexes, the probability of depression during pregnancy was higher among those with marital dissatisfaction and aprevious history of depression. Unplanned pregnancy, unlike the findings of other studies reviewed, did not increase therisk of prenatal depression either in women or men. Gender differences were found on the impact of social support andthe partner’s depression. Among men, low affective social support and partner depression were associated with a higherprobability of reporting depression. Neither of these variables was related to women’s depression.

Other psychological risk factors reported in a study from Australia included low self-esteem, prenatal anxiety, negativecognitive style, major life events, low income and history of abuse (Leigh & Milgrom, 2008). There is some overlap in theserisk factors across studies, although there are also unique findings which may relate to cross-cultural differences. The factorsthat occurred across more than a few studies were life events stress, lack of social support, marital difficulties and unplannedor unwanted pregnancy.


Fig. 1. Delayed growth (femur length) in fetuses of depressed versus those of non-depressed women at 17–20 weeks gestational age.

4. Effects on the fetus and neonate

4.1. Prenatal depression effects on the fetus

In one of the first studies on prenatal depression effects on the fetus, our group showed that fetuses of depressed mothersspent a significantly greater percentage of time being active (44% vs. 28%) (Dieter et al., 2001) (see Fig. 1). A stepwise regressionsuggested that 29% of the variance in fetal activity was explained by prenatal depression scale scores, with anxiety scalescores adding 6% to that variance to total 35% of the variance. In a similar study, behavior and heart rate responsivity tovibratory stimulation were measured in mid-trimester fetuses using a habituation paradigm (Emory & Dieter, 2006). Thefetuses of prenatally depressed women showed less total movement and a heart rate increase as opposed to the heart ratedecrease shown by the fetuses of nondepressed women (a heart rate decrease typically being associated with attention toa stimulus).

Some have speculated that excessive fetal activity may lead to delayed fetal growth. To identify whether prenatal depres-sion is a risk factor for fetal growth restriction, the estimated fetal weight and birthweight data were used to compute fetalgrowth rates (Diego et al., 2009). The depressed women had elevated prenatal cortisol levels, and their fetuses were smallerand had slower fetal growth rates as well as lower birthweight. The depressed women had a 13% greater incidence ofpremature delivery, and their neonates had a 15% greater incidence of low birthweight. Regression analyses revealed thatmaternal cortisol levels were potential mediators of the relationship between maternal depression symptoms and both thefetal growth rate and gestational age. After controlling for maternal demographic variables, prenatal maternal cortisol levelswere associated with 14% of the variance in the rate of fetal growth and with 30% of the variance in gestational age.

In another study, we attempted to differentiate the effects of prenatal dysthymia (chronic) versus major (acute) depres-sion on maternal cortisol and fetal growth (Field et al., 2008c). The women with major depression had more self-reportedsymptoms of depression, anxiety and anger, and they had more daily hassles than the women with dysthymia. However,the dysthymic group had higher prenatal cortisol levels and lower fetal growth measurements (estimated weight, femurlength, abdominal circumference) as measured at their first ultrasound (mean = 18 weeks gestation) (see Fig. 2). Prenataldepression had significant effects on both fetal activity and fetal growth rate which, in turn, were related to shorter gestation

Fig. 2. Greater percent time in movement by fetuses of depressed versus those of non-depressed women from 5 to 7 months gestational age.


and lower birthweight. The elevated prenatal maternal cortisol levels could be mediating the effects of depression on thesegrowth delays.

4.2. Prenatal depression effects on birth measures

As already mentioned, prenatal depression has resulted in shorter gestation and lower birthweight (Diego et al., 2009;Field et al., 2004a). Preterm delivery is the leading cause of infant mortality and morbidity as well as inflated hospitaland medical costs that have been estimated at around $26 billion in the U.S. (Armstrong, 2007). The incidence of pretermdelivery remains at about 14% in the U.S. and is still of unknown etiology. Various psychopathological factors are thought tobe potentially important risk factors for preterm delivery (Alder, Fink, Bitzer, Hosli, & Holzgreve, 2007; Neggers, Goldenberg,Cliver, & Hauth, 2006). Depression has been noted to increase placental hormones including corticotrophic releasing hormone(Wadhwa, Dunkel-Schetter, Chicz-DeMet, Porto, & Sandman, 1996) and cortisol (Field et al., 2004b). In one study, womenwith CES-D scores greater than 16 had almost twice the risk of preterm delivery compared to women without depressivesymptoms (Li et al., 2009). In that study, the risk of preterm delivery increased with the increasing severity of depressionand, unlike many other studies, the relationship between prenatal depression and preterm delivery was not confounded bythe use of antidepressants.

In studies in other countries, for example in France, prenatal depression has also been associated with preterm delivery,although the rate of preterm birth there is typically lower than in the U.S. (Dayan et al., 2006). In this French study, therate of preterm delivery was significantly higher for women with high depression scores (10%) than for other women (4%).Depression and low birthweight have also been associated, for example in Italy (Maina et al., 2008) and in Pakistan (Rahman,Bunn, Lovel, & Creed, 2007).

In studies by our group, chronic prenatal depression was associated with both shorter gestational age and lower birth-weight (Field et al., 2008e). However, like many other studies, comorbid problems were prevalent including chronicallyhigh anxiety, anger, sleep disturbance and pain scores. In a follow-up on prenatal dysthymic versus major depression effectson the fetus, we reported that the newborns of dysthymic versus major depression mothers had a significantly shortergestational age, lower birthweight, shorter birth length and more obstetric complications (Field, Diego, & Hernandez-Reif,2008a). And, of course, being born prematurely itself has developmental challenges independent of maternal depressioneffects. Although, even full-term infants of prenatally depressed mothers have developmental problems including being lessresponsive to stimulation. And, the neonates of dysthymic mothers also had lower orientation and motor scale scores andmore depressive symptoms on the Brazelton Neonatal Behavior Assessment scale. These findings were not surprising to usgiven the higher prenatal maternal cortisol levels and the inferior fetal measures including lower fetal weight, fetal length,femur length and abdominal circumference already noted in our earlier study on fetuses of dysthymic pregnant women(Field et al., 2008c).

4.3. Newborns of depressed mothers are less responsive to stimulation

In several studies that have been reviewed elsewhere full-term newborns of depressed mothers showed inferior per-ception of various stimuli including smooth versus nubby nipples, different weight objects (plastic vials with high and lownumbers of pellets) and different temperature (warm and cool) tubes see (Field, Hernandez-Reif, & Diego, 2009c) for a review.In another review, we reported their lesser responsiveness to faces and voices, suggesting that infants of depressed mothersshow less orienting to the live face/voice of the Brazelton scale examiner and to their own and other infants’ recorded crysounds (Field, Diego, & Hernandez-Reif, 2009a). This lesser responsiveness was attributed to higher arousal, less attentive-ness and less “empathy.” Delayed heart rate deceleration to instrumental and vocal music sounds by newborns of depressedmothers has also been attributed to their delayed attention and/or slower processing.

5. Prenatal depression effects on infants

5.1. Early interactions and temperament

At 3–6 months, the infants of prenatally depressed mothers showed less negative responding to their mother’s noncon-tingent and still-face behavior, suggesting that they were more accustomed to this behavior in their mothers (Field et al.,2009a). The less responsive behavior of the depressed mothers was further compounded by their comorbid mood statesof anger and anxiety and their difficult interaction styles including withdrawn or intrusive interaction styles (Field et al.,2009a). The dysthymic mothers’ and infants’ interactions were inferior to those of mothers with major depression (Field,Diego, Hernandez-Reif, & Ascencio, 2009b). The dysthymic group mothers, for example, spent less time smiling, touchingand imitating their infants. Their infants spent less time smiling and more time showing distress behaviors.

Infants of depressed mothers also cry significantly more times a day based on 24-h diaries completed by their motherswhen the infants were 3-month old (Milgrom, Westley, & McCloud, 1995). Another study examined prenatal variables thatpredicted the excessive crying of 3-month-old infants of depressed mothers (Van der Wal, van Eijsden, & Bonsel, 2007). Inthis follow-up study, prenatal depression, anxiety and job strain were associated with excessive infant crying.


Prenatal depression has also been related to difficult infant temperament in general. In one study, prenatally depressedmothers reported more difficult temperament in their infants at both 2 and 6 months postpartum (McGrath, Records, &Rice, 2008). These differences remained after controlling for prenatal anxiety which occurred more often in the depressedmothers. In a similar study, prenatal depression, but not postpartum depression, predicted the ratings of negative affect ininfants at 6 months postpartum (Huot, Brennan, Stowe, Plotsky, & Walker, 2004).

5.2. Prenatal depression effects on infant sleep

Just as infants’ wakeful behaviors have been notably affected by prenatal depression, their sleep problems have also beenassociated with prenatal depression. Sleep problems are the most common concern reported to pediatricians, with a rangeof 20–30% of children being affected (Gaylor, Burnham, Goodlin-Jones, & Anders, 2005; Liu, Liu, Owens, & Kaplan, 2005). Inturn, infant sleep problems are correlated with many childhood behavioral and physiological conditions including depression(O’Connor et al., 2007) and neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (Gruber, Sadeh,& Raviv, 2000; Stores, 2001)

Research from our lab has documented prenatal depression and postnatal depression effects on sleep disturbances,fussing and crying in neonates (Diego, Field, & Hernandez-Reif 2005). In that study, infants of mothers with both prenataland postnatal depression were the most sleep-disturbed. In a subsequent study, we showed that prenatally depressedwomen who had their own sleep disturbances had infants who spent less time in deep sleep, more time in disorganizedsleep and more time fussing and crying (Field et al., 2007).

Prenatal depression has also contributed to sleep problems in later infancy and early childhood (O’Connor et al., 2007).Sleep disturbances in this study included refusing to go to bed, waking up early, having difficulty going to sleep, havingnightmares, continuing to get up after being put to bed, waking in the night and getting up after only a few hours of sleep.Prenatal depression predicted sleep problems at both 18 and 30 months of age independent of postnatal mood and obstetricand psychosocial variables. The authors speculated, based on animal data, that the HPA axis (hypothalamic pituitary adrenalaxis) was an underlying mechanism for the effects of prenatal depression on sleep problems (Ader, 1975). At least one studyhas reported a relationship between the diurnal pattern in cortisol and sleeping through the night in infancy (de Weerth,van Hees, & Buitelaar, 2003). We have also noted relationships between prenatal depression, sleep and cortisol levels (Fieldet al., 2004b) and the confounding effects of prenatal anxiety and anger, as already noted.

6. Prenatal depression effects on children

6.1. Physiological measures in infants and children

In several studies on prenatal depression effects on neonatal outcome, we have reported lower vagal tone (which isassociated with lesser attentiveness) and greater relative right frontal EEG activation (which is associated with withdrawalbehavior) (Field et al., 2004b; see Field & Diego, 2008 for a review). In all of this research, the depressed women had lowervagal tone and greater relative right frontal EEG activation. Their infants, in turn, mimicked these physiological profiles. Inaddition, these vagal tone and EEG profiles persisted from the neonatal stage to early infancy to the preschool years (seeField & Diego, 2008 for a review; Jones, Field, Davalos, & Pickens, 1997).

Another group in the Netherlands also measured the high frequency component of heart rate variability as an indicatorof vagal tone in 14-month-old infants (Dierckx et al., 2009). In this study, prenatal depression symptoms were associatedwith a higher mean heart rate and a lower high frequency component of heart rate variability, meaning lower vagal tone, inthe infants.

6.2. Developmental delays, emotional and behavioral problems

In the Avon Longitudinal Study of Parents and Children (ALSPAC) (that takes place in Avon, England), developmentaldelays were noted at 18 months for the offspring of prenatally depressed women (Deave et al., 2008). A similar longitudinalstudy in the Netherlands reported externalizing and internalizing behavior problems in children between 14 and 54 monthsof age from depressed mothers (de Bruij, van Bakel, & van Baar, 2009). Uniquely, first trimester prenatal depression wasassociated with internalizing behavior problems for boys, and third trimester prenatal depression was associated withinternalizing as well as externalizing behavior problems for girls. These results are complex and difficult to interpret.

In still another longitudinal study from Finland, prenatal depression predicted behavior problems based on the ChildBehavior Problem Checklist at both 4–5 and 8–9 years of age, with prenatal depression being assessed in the third trimester(Luoma et al., 2004, 2001). In these studies, only externalizing behaviors were predicted by prenatal depression. The lack ofassociation between prenatal maternal depression and internalizing problems for the children was an unexpected finding.Similarly, prenatal depression has predicted major depression and conduct disorder in adolescence, although these findingswere based on retrospective data (Allen, Lewinson, & Seeley, 1998).


7. Prenatal depression effects on adults

7.1. Health and immune function

Prenatally depressed women have poorer self-reported health and functioning than their non-depressed counterparts.This has been demonstrated in one of our studies in which a greater incidence of prenatally depressed women reportedthe use of antibiotics (Field et al., 2004b). In another study, using self-report measures, health problems were noted inprenatally depressed women along with limited functional status (activities of daily living) (Orr, Blazer, James, & Reiter2007). These women had approximately twice the risk of poorer self-reported health and functional status than those withlower scores on the CES-D after adjustment for age, marital status, smoking, education, insurance, trimester of pregnancyand race.

Prenatal origins of illnesses have also been documented, lending support for the phenomenon that diseases often havetheir origins during fetal development (Barker, 2002; Kajantie, 2006). Studies have reported, for example, associationsbetween birth complications such as low birthweight and subsequent risk of disease in adult life including hypertension,coronary heart disease, diabetes, depression and other cognitive and affective disorders (Cannon, Jones, & Murray, 2002;Gluckman & Hanson, 2004). Others have presented data suggesting that the relationship between prenatal stress and adultdiseases is not necessarily mediated by birth complications but may be directly related to prenatal maternal stress (Entringeret al., 2008). Still others reviewed data on immune cells with receptors for hormones associated with the hypothalamicpituitary adrenal axis and the sympathetic adrenal medullary axis (Glaser & Kiecolt-Glaser, 2005). These authors showedthat during stress, there was a shift from the Th1 to the Th2 cytokine system that suppressed cellular immunity and wasrelated to inflammation. This shift from the Th1 to the Th2 system may be related to changes in stress catecholamines (Elenkov& Chrousos, 1999). Possible mechanisms for how this occurs are: (1) maternal stress hormones crossing the placenta to thefetus; (2) the release of placental hormones that enter fetal circulation; and (3) physiological changes such as increaseduterine artery resistance that limits blood flow and thus the provision of nutrients and oxygen to the fetus (Huizink et al.,2004).

As some have suggested, maternal stress during pregnancy may delay postpartum immune adaptation (Knackstedt,Hamelmann, & Arck, 2005). According to these authors, the immune system of the neonate is basically a Th2system, and early in life, there is a natural shift from Th2 to Th1 immunity. But, increased production of Th2cytokines such as IL-4 has been noted in newborns who later developed atopic disease. This happens because ofthe increased levels of IgA and the high numbers of eosinophils. Other cytokine-inducing problems are anxiety,depression and cognitive deficits. The immune system changes that follow from prenatal depression are thoughtto disrupt the communication between the immune system, endocrine system and central nervous system, mak-ing prenatally stressed individuals more vulnerable to these problems (Kohman, Tarr, Day, McLinden, & Boehm,2008).

7.2. Prenatal depression in men

Prenatal depression has typically been more prevalent among women than men. For example, in one study, prenataldepression occurred in 10% of women and 7% of men (Escribe-Aguir et al., 2008). In men and women, the probabilityof depression was higher in those with marital dissatisfaction and among those with a previous history of depression.Two factors that were related to a higher probability of depression in men were low affective social support and partnerdepression. These variables did not affect women’s depression. In a study we conducted, depressed men as compared tonondepressed men not only had higher depression scores but also higher anxiety and daily hassles scores (Field et al., 2006b).Although the pregnant women in general had lower anxiety, anger and daily hassles scores than the men, the scores on thedepression measures for depressed fathers and depressed mothers did not differ. However, paternal depression had less effectthan maternal depression on their partners’ scores. Nonetheless, the similarities between the scores of depressed mothersand depressed fathers highlights the importance of screening for depression of fathers-to-be as well as mothers-to-be duringpregnancy.

In another publication form the Avon Longitudinal Study of Parents and Children, prenatal depression was measuredin fathers, and later behavioral/emotional and psychiatric problems were assessed in the children (at 3! and 7 years)(Ramchandani et al., 2008). The children whose fathers were depressed had the highest risk for psychopathology as measuredby behavior problems at age 3! and a psychiatric diagnosis at 7 years of age. This was particularly true for the sons ofdepressed fathers.

In another study based on the Minnesota twin family study database, the investigators explored whether major depres-sion and/or antisocial behavior tended to occur more frequently among partners of depressed mothers (compared to partnersof nondepressed mothers) and to examine how these paternal disorders related to psychopathology in their offspring(Marmorstein, Malone, & Iacono, 2004). In that study, depressed mothers tended to have antisocial partners. Depressionin the mothers and antisocial behavior in the fathers were both significantly and independently associated with depressionand conduct disorder in the 17-year-old offspring.


8. Potential confounding variables

8.1. Comorbid anxiety and developmental outcomes

Anxiety is often comorbid with depression. In many studies those born to women who have experienced comorbiddepression and anxiety are at particularly high risk for later developmental and social-emotional problems (Field et al.,2004a; Wadhwa, 2005). Women with high depression and anxiety scores are more likely to deliver preterm infants whoare small for gestational age and, in turn, have other developmental problems. For example, in one study, depression andanxiety scores obtained during the third trimester of pregnancy predicted 27% and 20% of the variance of an infant’s observedbehavioral reactivity at 4 and at 9 months respectively (Davis et al., 2004). In a longer-term study, anxiety during pregnancyaccounted for 22% of the variance in symptoms of ADHD in 8-year-old children (Van den Bergh & Marcoen, 2004). Similarly,depressed women in the top 15% for symptoms of anxiety at 32 weeks gestation had double the risk of having children withbehavior problems at 4 and at 7 years of age (O’Connor, Heron, Golding, Glover, & The ALSPAC Study Team, 2003). The riskfor this group of women was greater for having children with ADHD, anxiety or depression and conduct disorder. Prenataldepression/anxiety has also been noted to predict childhood anxiety and depression as late as 10 years of age (Leech, Larkby,Day, & Day, 2006).

Some have suggested that maternal prenatal anxiety predicts child outcomes more strongly than depression. For example,in one study, although antenatal depression was associated with child behavior problems, the associated effect size wassmaller for depression than for anxiety (O’Connor, Heron, Golding, Beveridge, & Glover, 2002). These authors noted thatthe association between prenatal anxiety and child behavior problems was separate and additive to the effects of prenataldepression.

Prenatal anxiety has also been predictive of illnesses like asthma in childhood (Cookson, Granell, Joinson, Ben-hlomo,& Henderson, 2009). After adjusting for postnatal anxiety and a number of other confounding variables, asthma at age 7!years was more likely to occur in the group whose mothers were in the highest compared to the lowest quartile of prenatalanxiety. In at least two studies, prenatal anxiety was associated with elevated cortisol in the offspring later in childhood.In one study, prenatal anxiety was associated with elevated cortisol in 10-year-old children (O’Connor, Ben-Shlomo, Heron,Adams, & Glover, 2005). In another study, prenatal anxiety was associated with a flattened cortisol daytime profile which,in turn, was related to depressive symptoms (Van den Bergh, Van Calster, Smits, Van Huffel, & Lagae, 2008).

In most of these studies, depression and anxiety were confounded, as it is difficult to find samples of pregnant womenwho are high anxiety but not depressed. The incidence of comorbid depression and anxiety is very high, and it is virtuallyimpossible to statistically control for these confounding variables. Thus, it can be assumed that findings related to prenataldepression may also be related to prenatal anxiety and vice versa.

Still other emotions may affect prenatal depression and the related physiological reactions and biochemical profiles.Anger has been noted to accompany both prenatal depression and anxiety (Field et al., 2002). And other kinds of emotionsmight also have negative effects such as guilt and insensitivity. Different types of depression style in the mothers, e.g.intrusion versus withdrawal, also differentially impact the fetus and newborn (Field, Diego, & Hernandez-Reif, 2006a).

8.2. Cortisol as a potential mediating variable

Maternal stress during pregnancy is noted to increase cortisol and corticotrophin releasing hormone levels in the motherand the fetus (Field et al., 2004b; Weinstock, 2008). Placental corticotrophic hormone is released into fetal circulation (Alderet al., 2007). In addition, elevated estrogen levels in pregnancy lead to a doubling of corticosteroid-binding globulin levels,resulting in a low breakdown of cortisol. This confounds the steady increase of cortisol levels across pregnancy, peaking inthe third trimester at about two to three times the non-pregnant values. Fetal cortisol concentrations are linearly relatedto maternal concentrations (a maternal-fetal ratio of 12–1) (Gitau, Cameron, Fisk, & Glover, 1998). Although there is asubstantial amount of maternal cortisol being inactivated in the placenta by 11beta-hydroxisteriod-dehydrogenase type 2,there is still a contribution of 10–20% of maternal cortisol (Challis et al., 2001). As these authors suggest, the second possiblepathophysiological effect of prenatal depression and anxiety is via the effect of intrauterine artery blood flow. As alreadymentioned, increased uterine artery resistance limits uterine blood flow and therefore the supply of oxygen and nutrientsto the fetus (Sjostrom, Valentin, Thelin, & Marsal, 1997; Teixeira, Fisk, & Glover, 1999). Elevated norepinephrine is thoughtto mediate the effects of prenatal depression on increased uterine artery resistance.

These hormones may contribute to behavior disorders in the offspring including attention and learning deficits, gen-eralized anxiety and depression. Hypothalamic pituitary adrenal axis changes have been induced by prenatal stress inrats and non-human primates (Darnaudery & Maccari, 2008). Variables that affect these changes are the timing of thestress, its intensity and duration and the gender of the offspring. Structural changes occur in the hippocampal region,frontal cortex, the amygdala and the nucleus accumbens. During adulthood the animals exposed to these early stressorsshowed high anxiety levels and depression-like behavior as well as memory impairments on hippocampus-dependent func-tions like memory. These dysfunctions, however, appear to be reversible by environmental enrichment and anti-depressiontreatments.

Maternal stress not only increases corticosteroid levels in the fetal brain but also decreases fetal testosterone in males andalters catecholamine activity in female fetuses (Weinstock, 2007). Learning deficits related to neurogenesis and dendritic


Fig. 3. Path analysis showing cortisol as significant predictor of prematurity (contributing to 24% of the variance).

spine density in the prefrontal cortex and hippocampus are more readily seen in prenatally stressed males, while anxiety,depression and an increased response of the HPA axis to stress are more prevalent in females.

In the human model, elevated mid-pregnancy corticotrophin releasing hormone has been associated with prenataldepression (Rich-Edwards et al., 2008). And elevated mid-pregnancy prenatal cortisol contributed to 24% of the variancein preterm delivery in our study (Field et al., 2004b) (see Fig. 3). In our comparison on pregnant women diagnosed withdysthymia versus major depression (Field et al., 2008b), the dysthymic group had higher prenatal cortisol levels and lowerfetal growth measures including estimated weight, femur length and abdominal circumference as measured at the firstultrasound. Thus, elevated cortisol appears to contribute to delayed fetal growth and preterm delivery.

Fetal exposure to maternal cortisol is reputedly regulated by the placental hormone, 11beta-hydroxysteroid dehydro-genase type 2, which oxidizes cortisol to its inactive form cortisone. Although that hormone increases across gestation,it only partially protects the fetus from the effects of maternal cortisol (Seckl & Meaney, 2004). As already mentioned, asmuch as 10–20% of maternal cortisol passes through the placenta, and fetal cortisol levels are significantly correlated withmaternal levels (Gitau, Fisk, Teixerira, Cameron, & Glover, 2001). As in the rat model, chronically high levels of cortisol canhave negative effects on human brain structure and function (Hillshouse & Grammatopoulos, 2002).

Increased fussiness and negative behavior have, for example, been noted in the infants of at least two samples of motherswho had elevated prenatal cortisol (Davis et al., 2007; de Weerth et al., 2003). Elevated prenatal maternal cortisol at 30–32weeks gestation was significantly associated with maternal reports of infant negative reactivity in one sample (Davis etal., 2007). Comorbid prenatal anxiety and depression predicted even more difficult infant temperament. The associationbetween maternal cortisol and prenatal depression remained after controlling for postpartum depression. Although thenegative infant temperament in this study was based on a self-report measure, difficult infant temperament was based onbehavioral observations over the first 5 postnatal months in the second study (de Weerth et al., 2003). Higher levels of thirdtrimester maternal cortisol predicted increased fussing, crying and negative facial expressions, particularly during the firsttwo postnatal months. And, in turn, infants with negative temperament were more likely to become behaviorally inhibitedas children in a longitudinal study (Pfeifer, Fisk, Teixerira, Cameron, & Glover, 2002).

The negative infant temperament findings are perhaps not surprising given that maternal depression and elevated pre-natal cortisol levels have been associated with increased infant cortisol levels (Brennan et al., 2008; Field et al., 2004a).Comorbid depression/anxiety has also been related to infant cortisol reactivity at 6 months (Brennan et al., 2008). The prob-lem, once again, was that this study did not have a large enough comparison group of depressed women without anxietyto assess its independent effects on infant cortisol levels. The comorbid depression/anxiety disorder mothers may have suf-fered from more severe depression than the noncomorbid group, and the increased severity of depression itself may haveimpacted infant cortisol levels.

Elevated prenatal cortisol has also been related to later emotional and cognitive development including the increased riskof anxiety and depression as well as attentional deficits/hyperactivity and language delays (Talge, Neal, Glover, & the EarlyStress, Translational Research and Prevention Science Network, 2007). Although many of these findings are independentof the effects of postpartum depression and anxiety, understanding the mechanisms is complex given that the childhoodproblems may also be mediated by elevated infant cortisol. Elevated cortisol in infancy, for example, has been associatedwith childhood behavior problems, especially social withdrawal (Essex, Klein, Cho, & Kalin, 2002). Similarly, higher cor-tisol levels at preschool age have been associated with internalizing problems at kindergarten age (Goldsmith & Lemery,2000).

Elevated cortisol is also associated with immune dysfunction including the dominance of the Th2 cytokine systemwhich suppresses cellular immunity and activates humoral immunity (Glaser & Kiecolt-Glaser, 2005). Almost all immunecells have receptors for hormones that are associated with the HPA axis and the sympathetic-adrenal-medullary (SAM)axis (Glaser & Kiecolt-Glaser, 2005). This may explain the association between prenatal depression, preterm delivery and


other immune disorders such as asthma and allergies (Kajantie, 2006; Remes & Pekkanen, 2005). These may be medi-ated by the overproduction of interleukin-4 (IL-4), IL-6 and IL-10 following stress and elevated cortisol (Entringer et al.,2008).

In looking for cortisol-lowering interventions, the use of antidepressants by pregnant women lowered infant cortisol inat least one study (Brennan et al., 2008). Although this finding is controversial inasmuch as some researchers have failed tofind negative effects of maternal antidepressants on child behavior and development (Nulman et al., 2002) while others havenoted negative effects. Negative effects include selective serotonin reuptake inhibitors taken during pregnancy contributingto neonatal withdrawal syndrome (Sanz, De-las-Cuevas, Kiuru, Bate, & Edwards, 2005) and to infant pulmonary hypertension(Chambers et al., 2006).

8.3. Neurotransmitter effects

At least three neurotransmitters have been implicated in prenatal depression effects including elevated norepinephrineand low levels of dopamine and serotonin. In one study from our lab, elevated norepinephrine and low levels of dopamineand serotonin were noted in depressed pregnant women at 20 weeks gestation (Lundy et al., 1999). In a subsequent study,similarly high levels of norepinephrine and low levels of dopamine and serotonin were noted in pregnant women again atapproximately 20 weeks gestation (Field et al., 2004b). In this study, the neonates of the depressed women had biochemicalprofiles that mimicked their mothers’ profiles including elevated norepinephrine and low levels of dopamine and serotonin.Elevated norepinephrine is a risk factor because of its association with intrauterine artery resistance and limited transportof oxygen and nutrients to the fetus (Teixeira et al., 1999).

In a subsequent study we divided a sample of depressed pregnant women into high and low prenatal maternal dopaminegroups based on a tertile split on their dopamine levels at 20 weeks gestation (Field et al., 2008b). The low dopamine grouphad higher depression scores and higher norepinephrine at the 20-week gestational age visit as well as lower dopamine andserotonin levels at both the 20 and 32 weeks gestational age visits. The neonates of the mothers with low versus high prenataldopamine levels also had lower dopamine and serotonin levels as well as higher cortisol levels. Finally, the neonates in the lowdopamine group had lower scores on the Brazelton autonomic stability and excitability scales. Thus, lower prenatal maternaldopamine levels associated with prenatal depression were related to low levels of neonatal dopamine and dysregulation inthe neonate, although all of these effects were confounded by low serotonin levels. In another study, splitting the group ofdepressed women into high and low serotonin groups resulted in similar negative effects (Field et al., 2008d).

8.4. Other potential confounding variables

Although prenatal stress effects have been recorded since the time of Hippocrates and the origins of medicine, thevariability in the definition and measurement of prenatal stress has made it difficult to group studies and perform meta-analyses (Huizink et al., 2004). In addition to the depression/anxiety comorbidity, cortisol and neurotransmitter confoundsalready mentioned, several other confounding variables have been studied for their negative effects on the fetus includingstressful life events, daily hassles and other markers of stress (see Beydoun & Saftlas, 2008 for a review). Others havesimilarly noted the problem of misinterpreting the symptoms of depression (sleep problems, energy and appetite changes)as normative experiences of pregnancy rather than depression (Marcus, 2009). In this review, additional complications ofpregnancy that were associated with depression included inadequate weight gain, under-utilization of prenatal care, poorhealth, lower SES and alcohol use.

Additional risk factors are depression history, lack of a partner, marital difficulties, lack of social support, poverty, familyviolence, increased life stress, substance use, history of previous abortions, unplanned pregnancy, ambivalence towards thepregnancy and anxiety about the fetus (Bowen & Muhajarine, 2006). Prenatal alcohol exposure, for example, has contributedto externalizing (aggression) and internalizing (anxious/depressed) problems (Sood et al., 2001). And, alcohol exposure dur-ing the first and second trimesters has been related to childhood IQ as late as 10 years (Willford, Leech, & Day, 2006).Antidepressants are another potentially confounding factor. Reputedly, 13% of depressed pregnant women use antidepres-sants (Marcus & Flynn, 2008). Antidepressants are noted to have negative effects on the fetus and neonate including shortergestational age and a greater rate of prematurity (14% versus 5%) (Suri et al., 2007).

8.5. Methodological limitations

Unfortunately, very few longitudinal, multivariate studies have been conducted on prenatal depression effects. Most of thedata come from short-term univariate studies. For example, increased prenatal depression was related to increased cortisolwhich, in turn, predicted prematurity, as reported by our group (Field et al., 2004a). A separate group of investigators reportedthat prematurity predicted developmental problems. Thus, separate research groups have studied the relationships betweendepression, cortisol and prematurity and the relationships between prematurity and developmental problems. However,no long-term studies have been conducted on all factors in the same sample. In addition, not all elevated cortisol mothershave preterm infants. Only 24% of the variance in prematurity was explained by increased cortisol in our study (Field etal., 2004a). A similar point can be made about depression being associated with increased norepinephrine and increasednorepinephrine being associated with premature delivery (Lundy et al., 1999). However, as has been noted, the effects of


norepinephrine may be mediated by increased uterine artery resistance which, in turn, could contribute to prematurity byreducing oxygen and nutrient supply (Teixeira et al., 1999).

Another example of this problem is the literature on comorbid depression/anxiety leading to long-term increases in cor-tisol or cortisol dysregulation, implying that increased cortisol is associated with prenatal depression and anxiety. However,in the long-term studies on increased cortisol and cortisol dysregulation, prenatal cortisol was not measured. Comorbiddepression/anxiety has also been related to chronic illness in adults. The implied increase in cortisol makes sense inasmuchas increased cortisol decreases immune cells, most especially natural kill (NK) cells as well as NK cell activity. Then again,however, no long-term studies have been conducted that include prenatal depression, prenatal cortisol and follow-ups tolong-term immune function and illness.

As was mentioned earlier, the problem of depression and anxiety being comorbid has confounded the prenatal depressioneffects, and attempts to unconfound them are difficult inasmuch as individuals with depression alone or with anxiety aloneare difficult to find. Prenatal and postpartum depression are also confounded. Although long-term effects have been notedfor postpartum depression (Hay et al., 2008; Murray & Cooper, 1997), postpartum depression effects may in fact be prenataldepression plus postpartum depression effects inasmuch as: (1) prenatal depression is the strongest predictor of postpartumdepression; (2) a prenatal depression alone sample is difficult to find; (3) the additive effects of postpartum depression aredifficult to control statistically; and (4) prenatal effects on neonatal outcome are difficult to separate into genetic and prenatalenvironmental determinants.

In addition, the studies have varied on diagnostic measures and definitions of depression. And none of the studies haveexplored the antecedent of depressive episodes as, for example, if the prenatal depression was ongoing from childhoodor related to recent losses or traumas, pregnancy factors, illnesses, or family history. And, investigators did not ask aboutdepression before pregnancy.

These, then, are some methodological limitations of the existing data. Nonetheless, the research suggests long-termeffects of prenatal depression on both behavior problems and cognitive development on the offspring. Disentangling causalfactors and mediating variables will require more sophisticated, multivariate, longitudinal research designs. The existingdata also suggest the need for interventions to reduce prenatal depression and its associated biochemical and immunologicaleffects.

8.6. Future research

Associations between prenatal environmental factors and childhood disease may be attributable to true prenatal envi-ronmental effects or to the “confounding” effects of a genetic predisposition that is shared by the mother and her offspring(Thapar et al., 2007). Studies have been conducted involving embryo transfer in animals, but genetic research designs havenot been adequate for assessing these effects in humans. In the Thapar et al. (2007) study, genetically related offspring (invitro fertilization/sperm donation) were compared to a group of offspring who were genetically unrelated to the womanwho was pregnant (egg donation/embryo donation). This group of investigators used this model for studying the effectsof prenatal smoking, which were found to reduce birthweight in both unrelated and related offspring (Rice et al., 2009). Incontrast, the association between prenatal smoking and offspring antisocial behavior depended on inherited factors becausethat association was only present in mothers and their genetically related offspring. Similarly, the link between prenatalstress and offspring attention deficit hyperactivity disorder was only present in related mother–offspring pairs, thereforeattributable to inherited factors as reported by the same group of investigators (Rice, Jones, & Thapar, 2007). This may be amodel for future research that attempts to disentangle genetic from prenatal environment effects.

9. Summary

In summary, maternal prenatal depression is the strongest predictor of postpartum depression and is believed to bemore common than postpartum depression. Prenatal depression has been associated with excessive activity and growthdelays in the fetus as well as prematurity, low birthweight, disorganized sleep and less responsiveness to stimulation inthe neonate. Infants of depressed mothers have difficult temperament, and attentional, emotional and behavioral problemshave been noted in childhood and adolescence as well as chronic illness in adulthood. Several variables confound theeffects of prenatal depression including comorbid anxiety effects and anger as well as stressful life events. And othersnot measured such as insensitivity and withdrawal may further confound these effects. Potential mediating variables arelow prenatal maternal dopamine and serotonin levels and elevated cortisol and norepinephrine. The associated intrauterineartery resistance may limit blood flow, oxygen and nutrients to the fetus. Cross-fostering developmental studies also suggestthe heritability of developmental problems including ADHD and antisocial behavior. Multivariate, longitudinal research isneeded to disentangle these confounding and mediating variables.

Acknowledgements

This research was supported by a Merit Award (MH # 46586), NIH grants (AT#00370 and HD#056036) and SeniorResearch Scientist Awards (MH#00331 and AT#0011585) and a March of Dimes Grant (#12-FY03-48) to Tiffany Field andfunding from Johnson and Johnson Pediatric Institute to the Touch Research Institute


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