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Early determinants of mental health

Katri Rikknen, Ph.D., Professor a,*,Anu-Katriina Pesonen, Ph.D., Senior Lecturer a,

Tessa J. Roseboom, Ph.D., Associate Professorb

,Johan G. Eriksson, M.D., Ph.D., Professor, Chief Physician c,d,e,f,g

a Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, The Netherlandsb Institute of Behavioral Sciences, University of Helsinki, Helsinki 00014, Finlandc Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finlandd Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finlande Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, FinlandfFolkhlsan Research Center, Helsinki, Finlandg Vaasa Central Hospital, Vaasa, Finland

Keywords:

behavior

cognition

emotion

lifespan

mental

postnatal

prenatal

programming

Environmental adversities in pre- and early postnatal life may havelife-long consequences. Based upon a series of epidemiological and

clinical studies and natural experiments, this review describes how

the early life environment may affect psychological functions and

mental disorders later in life. We focus on studies that have exam-

ined the associations of small body size at birth and prematurity as

proxies of prenatal environmental adversity. We also review liter-

ature on materno-fetal malnutrition, maternal prenatal glycyrrhizin

in licorice consumption and hypertension-spectrum pregnancy

disorders as factors that may compromise the fetal developmental

milieu and hence provide insight into some of the mechanisms that

may underlie prenatal programming. While effects of programming

mostly take place during the rst 1000 days after conception, wenally present evidence from prospective studies suggesting that

programming can occur also during later critical periods of devel-

opment or windows of plasticity. The studies may bear relevance

for future prevention and intervention programs targeting the

potentially modiable environmental factors that will aid at

promoting mental well-being and health of an individual.

2012 Published by Elsevier Ltd.

* Corresponding author. Institute of Behavioral Sciences, University of Helsinki, P.O. Box 9 (Siltavuorenpenger 1a), 00014

Helsinki, Finland.E-mail address: katri.raikkonen@helsinki. (K. Rikknen).

Contents lists available atSciVerse ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolismj o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / lo c a t e / b e e m

1521-690X/$ see front matter 2012 Published by Elsevier Ltd.

doi:10.1016/j.beem.2012.03.001

Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 599611
mailto:[email protected]:[email protected]://www.sciencedirect.com/science/journal/1521690Xhttp://www.elsevier.com/locate/beemhttp://dx.doi.org/10.1016/j.beem.2012.03.001http://dx.doi.org/10.1016/j.beem.2012.03.001http://dx.doi.org/10.1016/j.beem.2012.03.001http://dx.doi.org/10.1016/j.beem.2012.03.001http://dx.doi.org/10.1016/j.beem.2012.03.001http://dx.doi.org/10.1016/j.beem.2012.03.001http://www.elsevier.com/locate/beemhttp://www.sciencedirect.com/science/journal/1521690Xmailto:[email protected]


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Introduction

Early life environmental adversities may exert consequences upon the developing cells, tissues,

organs, their structure and function. The long-term consequences of these early adversities are thought

to be mediated by epigenetic mechanisms, resulting in phenotypic differences between individuals.

These phenotypic differences may persist throughout the lifespan. This phenomenon related to earlylife developmental plasticity has been labeled programming.13

It appears axiomatic that during pre- and early postnatal periods the brain is particularly suscep-

tible to environmental adversities. This presumably reects the sensitivity of the brain during periods

when it undergoes major developmental changes. The sensitive periods of the brain begin during the

embryonic state, and continue throughout the prenatal period.4 These reach a peak in the rst years of

life, and continue throughout childhood and adolescence, such that the brain does not reach its adult

state until the end of the second or the beginning of the third decade of life.4

Environmental adversities may, however, lead to different outcomes depending on the timing of

exposure. According to the life cycle model of stress adversities occurring at different stages in life

depend on areas of the brain that are undergoing change either developing/maturing or declining at

the time of exposure.4 The stress physiological systems, including the hypothalamic-pituitary-adrenocortical (HPA) axis, autonomic nervous system (ANS), and immune-inammatory system,

that are all implicated in mental health, may be particularly susceptible to prenatal environmental

adversity.5 This is because the hippocampus, the frontal cortex and the amygdala, which are important

in regulation of the physiological stress response, are under rapid development during this period. 4

Postnatal adversities may result in more widespread effects.4 Yet, some areas of the brain may be

more sensitive during specic periods: in infancy, the hippocampus is developing most rapidly, from

childhood to adolescence the amygdala undergoes rapid development, and from adolescence onwards

the frontal volume is increasing signicantly. Thus, different brain areas might be more vulnerable to

environmental adversities at different time periods, and therefore an adversity might result in different

long-term outcomes. While the timing of exposure to environmental adversity is emphasized in the life

cycle model of stress, the characteristics of the environmental adversity appears to be important aswell.4 For instance, the HPA axis seems to be hyper-responsive in individuals exposed to separation

from both biological parents in early childhood,6 while severe abuse may result in HPA axis hypo-

responsiveness.7 Thus, the physiological stress systems may differentiate as a function of the type of

early environmental adversity. It is also possible that adversity at a specic sensitive period may result

in different effects during the life cycle. For instance, low birth weight, a proxy of prenatal environ-

mental adversity, is according to some studies associated with a hyper-responsive HPA axis in chil-

dren,8 and a hypo-responsive HPA axis in older adults.9

This review describes evidence for the effects of early environmental adversity on mental health

using data from human studies. Mental health is considered broadly not restricted to describing

mental disorders. We use the concept of mental health to cover a full range of different human

functions ranging from cognition, behaviour, temperament and personality to a range of mentaldisorders differing in symptomatology and severity. The rationale behind this is that there is evidence

that poorer cognitive function, behavioural problems, negative affectivity-related temperament and

personality characteristics may compromise mental well-being and health, and co-occur with and

increase vulnerability of mental disorders. These endophenotypesof mental disorders have also been

repeatedly associated with altered HPA axis and ANS function.10

First, in this review, we describe the work conducted on pre- and postnatal growth and prema-

turity, considered as crude proxies of prenatal and early postnatal environmental adversity. Second,

we focus on three prenatal environmental adversities that may compromise the fetal developmental

milieu and, thus, underlie the associations of fetal growth and prematurity with mental health, namely

materno-fetal malnutrition, overexposure to glucocorticoids by maternal prenatal consumption of

glycyrrhizin in licorice confectionery, and hypertension-spectrum pregnancy disorders. We will notpresent evidence on prenatal stress, as this work has been recently thoroughly described in reviews by

Glover,11 Van Den Bergh,12 and Rikknen.13 Finally, we describe the work from prospective studies

that have tested the long-term mental health consequences of exposure to severe early life stress

(ELS).

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Pre- and postnatal growth and mental health

Findings in epidemiological studies from different parts of the world, including the Helsinki Birth

Cohort Study (HBCS),1416 suggest that slower growth during fetal life and in early childhood appear to

extend widespread consequences on mental health throughout the lifespan.

Cognitive function

Smaller weight, length, thinness and/or head circumference at birth, adjusted for length of gesta-

tion, have been shown to be associated with poorer cognitive performance in childhood, adolescence

and young adulthood.17,18 While there are studies suggesting that the effects of birth size do not persist

into old age19,20 or beyond the age of 40 years,21 recent data derived from the HBCS suggest that

smaller body size at birth extends effects to old age and may predict a more rapid age-related cognitive

decline.22 The associations with poorer cognitive performance are not restricted to the prenatal period,

but evidence suggests that those with poorer performance continue to grow slower also during

childhood and adolescence.14,23 The slower postnatal growth may, however, pertain specically to

height.14

Temperament and personality

Evidence also suggests that smaller body size at birth, adjusted for length of gestation, is related to

infant and child temperamental characteristics. At the age of 6 months infants with a mild growth

restriction (dened as a birth weight below 10th percentile for gestational age) were perceived by their

biological parents as more fearful and negatively reactive.24 Those born smaller continued to be

perceived by their mothers as more negatively affective, and showing more anger, discomfort, and

sadness-proneness at the age of 5 years.25 Similar ndings have also been reported elsewhere.26

Findings from the Generation R study, however, disagree with these ndings by showing that the

associations between birth weight and temperament were attenuated to non-signicance when

adjusting for maternal height, age, educational level, and national origin.27 While the sample size of the

Generation R study outweighs that of the other previous studies, the sample is highly heterogeneous innational/cultural origin, and therefore the ndings may not directly compare with those of the earlier

reports. Some evidence also suggests that birth weight may extend effects on temperament that

persists over decades.28 Weight and length at birth had curvilinear, reverse J-shaped effects on harm

avoidance temperament which was self-rated at the age of 63 years. Yet, the highest harm avoidance

scores were most characteristic of those born the smallest.

In addition to temperament, smaller body size at birth has also been linked with adult personality.

Lower weight, thinness and smaller head circumference were associated with higher trait anxiety and

hostility characteristics at the age of 63 years.29,30 Individuals with higher trait anxiety and hostility

scores continued to be lighter and thinner throughout infancy, and from thereon put on weight more

rapidly.

Mental disorders

In a series of studies focusing on sub-clinical symptoms of mental disorders, lower birth weight,

shorter birth length, thinness and smaller head circumference at birth were associated with higher

parent-rated ADHD symptomatology of the child at 56 months of age. Children with higher ADHD

symptoms continued being thinner and had a smaller head circumference up to 56 months and gained

less weight in relation to height between 20 and 56 months. Thinness and smaller head circumference

at birth have predicted higher hyperactivity/impulsivity symptoms of ADHD in another study of 5-

year-old children.31 Lower birth weight has also been related to higher externalizing and internal-

izing behaviour problems in 79-year-old children.32

Of the sub-clinical symptoms of mental disorders in adults, depressive symptoms have gained most

research attention. The existing studies have consistently demonstrated that lower birth weight isassociated with higher frequency and severity of experiencing depressive symptoms at different stages

of adult life.3335 Though, some studies suggest that this effect may be conned to those who were born

with a low birth weight (


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traits, such as anhedonia and aberrant perceptions in women at the age of 33 years. 36 Thendings on

depressive symptoms and schizotypal traits suggest that prenatal growth may extend effects on mental

health also at stages that may precede and precipitate disorders.

A recent large register-based study using two inter-country population cohorts from Sweden and

Denmark showed that low birth weight (


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depressive symptoms, use antidepressant medication more frequently, report a physician-diagnosed

depressive episode more frequently,50 report more ADHD symptoms and more problems in

attention.51

Stress sensitivity

We are aware of only one study that has compared HPA axis responses in subjects born pretermand/or VLBW with those born at term: a study in 812-year-olds with all degrees of prematurity found

no differences in HPA axis responses.

Prenatal exposure to famine and mental health

Studies of populations born around the time of acute periods of famine have been used as a semi-

experimental design to investigate the effects of prenatal undernutrition on mental health. Such

studies started with the landmark studies of Stein and Susser performed in the early seventies

following the increasing awareness in the late 1960s that early nutritional deprivation might cause

irreversible damage to the brain.52 They studied the consequences of prenatal exposure to the Dutch

famine of 19441945 which was a 5 month period of acute starvation that struck the Dutch pop-ulation in the West of the Netherlands during the last months of the World War II using records of

military conscripts who had been born around the time of the Dutch famine. Since these early studies,

there has been an increasing body of evidence of studies in different populations using various study

designs that prenatal exposure to famine affects later mental health, specically the risk of schizo-

phrenia, depression, addiction, stress-responsivity and possibly some aspects of cognitive function in

later life. This suggests that undernutrition during critical periods of early brain development pro-

grammes mental health.

Although many characteristics of such studies indeed resemble experimental designs, an important

limitation of such studies is that the effects of undernutrition and stress are hard to disentangle.

However, most studies found no differences in mental health, cognition or stress responsiveness

among people who were born before the famine and those conceived after the famine, whereas onewould expect large differences in stress levels experienced by these mothers, suggesting that lack of

nutrients is an important factor in the early life programming of mental health.

Cognitive function

In their study of 19-year-old military conscripts Stein and Susser found no association between

famine exposure and intelligence in young adulthood.52 But more recently, two studies again

investigated effects of prenatal famine exposure on cognition, now in late adulthood. One study found

no associations between famine exposure and later cognitive performance,53 but, in the other study,

there were indications that maternal malnutrition during fetal life may negatively inuence some

aspects of cognitive function in later life.54 Men and women who had been exposed to famine during

early gestation performed worse on a selective attention task. In line with the other Dutch faminestudies, this study found no effects of prenatal famine exposure on general intelligence, nor on

memory or perceptual motor learning. The decreased selective attention in those exposed to famine

in early gestation might be an early manifestation of an accelerated aging process, since recent studies

have shown that poor performance on such tasks is a strong predictor for conversion to Alzheimers

disease even before memory decits are present.55 Also, the lower scores t with ndings of lower

Stroop scores achieved by people suffering from schizophrenia which have been suggested to be

caused by a dysfunction of the anterior cingulated gyrus, which may play an important role in

selective attention56,57 White-matter lesions have also been associated with reduced Stroop task

performance58,59 and increase with age, supporting the above-mentioned suggestion that the

decreased Stroop performance in those exposed to famine in early gestation is because of an accel-

erated aging process.An alternative explanation for the association between prenatal famine exposure and poorer

selective attention may be vascular-related rather than neurodegenerative, which would t with the

increased rates of coronary heart disease found in the cohort6062 Prenatal undernutrition may

possibly lead to poorer selective attention performance via increased vascular damage. The reported

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increase in white-matter lesions among those prenatally exposed to famine also t this explanation, as

white-matter lesions are strongly related to cardiovascular risk factors and disease.63,64

In addition to effects of prenatal famine exposure on selective attention, those exposed to famine

prenatally had smaller head circumferences at the ages of 5659 years, which was related to decreased

cognitive abilities.54 Whether this is associated with actual smaller brain size is currently being

investigated.

Stress sensitivity and personality

People exposed to the Dutch famine in early gestation have been shown to have increased blood

pressure responses to a psychosocial stress protocol, which suggests that stress appraisal may be

higher in those prenatally exposed to famine,65 there was no evidence, however, that this was

mediated by alterations in the HPA axis.39,66 The blood pressure response to stress, however, was found

to be strongly linked to methylation patterns of the glucocorticoid receptor, suggesting epigenetic

processes might play a role.67 There were subtle differences in personality according to timing of

famine exposure in utero, that appeared to be sex-specic.68 Men exposed to famine during early

gestation scored a little lower on conscientiousness and women exposed to famine during early

gestation scored a little higher on agreeableness, but these differences did not survive a correction formultiple testing and otherwise there were no differences between those exposed and those unexposed

to famine in utero in personality traits.68

Mental disorders

Stein and Susser initially reported an excess of congenital nervous system anomalies in individuals

who had been conceived towards the end of the Dutch famine52 suggesting direct harmful effects of

undernutrition on the developing nervous system. However, they found no evidence of effects on mental

health (severe or mild mental retardation) nor on cognition in a large-scale study of military recruits.

Later, it became clear that the congenital anomalies were mainly neural tube defects, and it seems likely

that this was due to periconceptional folate deciency. In this context, Ezra Susser, Stein and Sussers son

reanalyzed the original data and investigated whether there was also an excess of schizophrenia whichmany consider to be a neurodevelopmental disorder. He found that men and women who had been

conceived during the Dutch famine had a twofold increased risk of schizophrenia.69 Subsequently, he

found an excess of schizophrenia spectrum personality disorders among those conceived during

famine.70 A small study suggested that the effects of famine exposure on later schizophrenia risk was

associated with changes in brain morphology.Schizophrenic patients whohad beenexposed to faminein

early gestation had decreased intracranial volume and increased white-matter hyperintensities

compared to schizophrenic patients who had not been exposed to famine prenatally.63 These ndings of

lasting effects of prenatal famineon later mental health are supported by large scalestudies performed in

China investigating effects of prenatal exposure to the Great Leap Forward famine that followed Maos

ambition to rapidly transform China from an agrarian economy into a modern communist society. The

Great Leap Forward had devastating consequences for food availability, causing widespread famine andtens of millions of deaths due to undernutrition. People conceived around the time of the 19591961

Great Leap Forward famine were also found to have doubled rates of schizophrenia71 The consistent

results of these studies in different settings and populations strongly suggests that early prenatal famine

is linked to an increase in the risk of schizophrenia in later life.

Prenatal exposure to the Dutch famine has also been related to other psychiatric disorders in

adulthood, including antisocial personality disorders,72 affective psychoses (many of which would

today be classied as mood disorders but not psychoses),73 and depression, though not all studies

replicated thisnding.67,73 Also, a casecontrol study found evidence that exposure to famine in early

gestation was associated with an increased risk of addictive disorders in adult life,74 especially among

men.

Prenatal exposure to glycyrrhizin in licorice and mental health

Glycyrrhizin (3b-D-diglucuronyl-18b-glycyrrhetinic or 3b-D-diglucuronyl-18b-glycyrrhizic acid) is

a natural constituent of licorice. Its synthetic analogue, carbenoxolone, frequently used in animal



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models,75 is a well-known inhibitor of the placental 11-HSD2 function. Evidence from experimental

studies on human placentas suggests that glycyrrhetinic acid inhibits 11-HSD2 function allowing

a direct placental by-pass for maternal circulating cortisol to the fetus. 76 Evidence on the long-term

effects of prenatal exposure to glycyrrhizin on the offspring mental health is, however, scarce. This

is somewhat surprising, given that glycyrrhizin is found also in other foodstuffs apart from licorice

confectionery.The existing evidence on the longer-term effects of prenatal glycyrrhizin exposures has shown that

at the average age of eight years, those children who were exposed to higher levels glycyrrhizin as

a consequence of maternal intake of licorice confectionery, dened as 500 mg/week representing

the upper 10th percentile of the samples of 1049 pregnant women, performed poorer in cognitive

tests measuring verbal and visuospatial reasoning and narrative memory than those children who

were prenatally exposed to no or 299 mg/week.77 In addition, children in the high-exposure group

had signicant increases in externalizing symptoms, attention, rule breaking, and aggression prob-

lems.77 The effects on cognitive performance and externalizing symptoms were not restricted to

children exposed to doses 500 mg/week, but the effects appeared dose-related. None of the asso-

ciations were affected by birth weight or duration of gestation and other pre- and perinatal, maternal,

and child characteristics implicated as risks for pregnancy and/or cognitive and psychiatricoutcomes.77

The HPA axis activity of these children was also affected. Children of mothers consuming high levels

of glycyrrhizin had a higher salivary cortisol peak and area under the curve upon awakening and higher

overall salivary cortisol throughout the Trier Social Stress Test for Children.78 These ndings, thus,

suggest that high maternal licorice consumption during pregnancy may exert deleterious effects upon

cognitive and psychiatric outcomes and HPA axis functioning in children. The ndings do counsel

caution in using glycyrrhizin containing foodstuffs during pregnancy.

Hypertension-spectrum pregnancy disorders and mental health

Hypertensive disorders in pregnancy, including chronic hypertension, gestational hypertension,and (pre)eclampsia, complicate approximately 1016% of all pregnancies.79,80 These disorders

threaten the health and well-being of both the mother and the fetus, and are among the key

underlying causes of prematurity and intrauterine growth restriction (IUGR). 81,82 Hypertension in

pregnancy may induce fetal malnutrion and oxidative distress83,84 and activate similar sympathetic

nervous system responses in the mother that are often seen under psychosocial stress. 85,86 Some

evidence also suggests that placental 11-HSD2 deciency may be characteristic to pregnancies

complicated by pre-eclampsia,87,88 and infants born with intrauterine growth restriction/small-for-

gestational age.89 Thus, by compromising the prenatal developmental environment, hypertensive

disorders in pregnancy may provide another experimental platform to study the mechanisms

underlying prenatal programming.

Studies that have tested associations between hypertension-spectrum pregnancy disorders andmental health outcomes of the offspring are few and the ndings are inconsistent. With regard to

cognitive abilities, the existing evidence shows that hypertensive pregnancy disorders are not asso-

ciated with cognitive abilities of the offspring,9093 some studies suggest that they are associated with

poorer94101 and some that they are associated with even better cognitive abilities of the offspring.102

One recent study demonstrated that the association between hypertensive pregnancy disorders and

poorer cognitive abilities in young adulthood in male offspring was particularly characteristics to those

born after primiparous pregnancies and, contrary to expected, to those with a high childhood socio-

economic background.103

The associations of hypertension-spectrum pregnancy disorders with mental disorders do not form

a consistent picture. Gestational/chronic hypertension has been associated with higher risk of inter-

nalizing behaviour problems in adolescents,

104

and with higher risk of any mental disorder and ofmood disorder in adulthood.104 Pre-eclampsia has, in turn, been associated with higher levels of self-

reported depressive symptoms in the offspring in their late adulthood,105 but also with lower risk of

internalizing behaviour problems in children,104 and with lower risk of any mental disorder and of

substance use disorder specically in men in adulthood.106



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Early life stress and mental health

Although programming effects are mostly taken place during the rst 1000 days after conception,

programming can occur also during later critical periods of development or windows of plasticity. A

series of studies have provided evidence that exposure to severe early life stress (ELS) exerts long-term

mental health consequences. However, very few studies have been able to provide evidence that isbased on objectively documented exposure to ELS. Below we describe prospective evidence from one

such study which provides objectively documented evidence on temporary separations in early

childhood from both biological parents due to child evacuations to foster care abroad during World

War II in conjunction with longitudinal data on mental health outcomes across lifespan.

Cognitive function

In this study, we measured cognitive abilities of former child evacuees in their young adulthood as

military conscripts. In comparison to those who were not separated from their parents, those who were

separated performed poorer in tests measuring verbal, arithmetic and visuospatial cognitive abilities at

the age of 20.107 The poorer cognitive abilities were shown to translate into socioeconomic disad-

vantage in adult life. In comparison to men and women who were not separated from their biologicalparents in early childhood, those who were separated had attained a lower lifetime socioeconomic

position, as indicated by their own highest attained occupational status, educational level and taxable

incomes across years from young to late adulthood.108

Mental disorders

Severe ELS has also been associated with sub-clinical symptoms of mental disorders. One study

focusing upon child evacuations during WWII has demonstrated that in comparison to the non-

separated children, those who were separated display over 20% higher levels of self-reported

depressive symptoms in late adulthood.109 They also appear to suffer more frequently from any

mental disorder, substance use disorders and personality disorders requiring hospitalization or being

the primary, intermediate or contributing cause of death in adulthood. However, the risk of seriousmental disorders seems to be characteristic to those separated individuals who had a better childhood

socioeconomic status.110 In those from lower childhood socioeconomic background, the temporary

separations did not add to the increased risk of mental disorders already associated with the lower

socioeconomic status.110

Stress sensitivity

The separated men and women have also been shown to display an altered pattern of HPA axis

activity in response to TSST stress in late adulthood. In comparison to their non-separated peers, the

separated men and women have been shown to display 2025% higher overall salivary cortisol and

plasma ACTH levels, and their salivary cortisol levels have been shown to increase more in response to

the TSST stress.111

Conclusions

Environmental adversities in early pre- and postnatal life seem to have widespread consequences

on mental health outcomes later in life. The existing literature reviewed here is not entirely consistent

and suggests relatively non-specic effects on mental health outcomes. The non-specicity of the

effects may relate to programming of the physiological stress systems. Altered HPA axis responsiveness

has been repeatedly implicated as a factor that co-occurs with poorer cognitive and affective function,

with temperament and personality traits acting as vulnerability factors for mental disorders, and with

mental disorders differing in symptomatology and severity.

While exposures to speci

c pre- and postnatal adverse environments may offer insight into theunderlying mechanisms above and beyond the information provided by body size at birth and

prematurity, the exact underlying mechanisms remain unknown. Epigenomic mechanisms inuencing

gene expression at the level of the placenta and the offspring may play key roles. Indeed, evidence has

started to accumulate showing alterations in methylation sites of various candidate and/or imprinted



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genes and/or epigenome-wide in the offspring at the age of 60 years in relation prenatal famine, 112 in

the placental tissue in relation to IUGR/small-for-gestational age,113 in brain tissue of adult suicide

victims exposed to abuse in childhood,114 and in buccal cells of adolescents exposed to parental stress

in infancy and/or early childhood.115 One recent study has demonstrated that higher level of maternal

anxiety a day before an elective caesarean section was associated with lower post-partum placental

11-HSD2 mRNA level; no association was found with the 11-HSD2 enzyme activity, probablyreecting the small sample size in these analyses.116 Further studies along these lines will provide

insight into the mechanisms underlying early life programming of mental health. These studies will

also provide information for future prevention and intervention programs targeting the potentially

modiable environmental factors that will aid at promoting mental well-being and health of an

individual.

Acknowledgements

The study was sponsored by the European Science Foundation (EuroSTRESS), the Finnish Academy,

and the Netherlands Organization for Scientic Research.

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Main clinical practice points

Mental health cognitive, behavioral and emotional functioning and mental disorders, mayhave origins in prenatal and early postnatal adverse environments.

The early environmental adversities seem to have non-specic and widespread effects on

various psychological functions and mental disorders of different severity and

symptomatology.

Many of the environmental factors are potentially modiable.

By targeting the potentially modiable environmental factors future prevention and inter-

vention programs utilizing this information will benet health and well-being of an

individual.

Additional research needed

Additional research is needed in humans that focuses on the mechanisms that underlie the

associations of early environmental adversities and mental health.

Human studies focusing on epigenomic mechanisms inuencing gene expression at the level

of the placenta and the offspring may provide insight into the underlying mechanisms.



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