Psychosocial Stress and Adversity: Effects from the

Perinatal Period to Adulthood

Alejandra Barrero-Castillero, MD, MPH,*†‡ Sarah U. Morton, MD, PhD,†‡ Charles A. Nelson III, PhD,‡x
Vincent C. Smith, MD, MPH‖**
*Division of Neonatology, Beth Israel Deaconess Medical Center, Boston, MA
†
Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA
‡
Department of Pediatrics, Harvard Medical School, Boston, MA
x
Harvard Graduate School of Education, Boston, MA
‖
Division of Neonatology, Boston Medical Center, Boston, MA
**Department of Pediatrics, Boston University, Boston, MA

Education Gaps
It is essential to acknowledge the significant effects of psychosocial
factors and resultant stress on outcomes and development of children.
Understanding how the effects of psychological stress can act additively or
synergistically with other biological and genetic influences can potentially lead
to the development of new approaches to improve patient care and outcomes.

Abstract
Early exposure to stress and adversity can have both immediate and lasting
effects on physical and psychological health. Critical periods have been
identified in infancy, during which the presence or absence of experiences can
alter developmental trajectories. There are multiple explanations for how
exposure to psychosocial stress, before conception or early in life, has an impact
on later increased risk for developmental delays, mental health, and chronic
metabolic diseases. Through both epidemiologic and animal models, the
mechanisms by which experiences are transmitted across generations are being
identified. Because psychosocial stress has multiple components that can act as
stress mediators, a comprehensive understanding of the complex interactions
between multiple adverse or beneficial experiences and their ultimate effects
on health is essential to best identify interventions that will improve health and
outcomes. This review outlines what is known about the biology, transfer, and
effects of psychosocial stress and early life adversity from the perinatal period to
AUTHOR DISCLOSURE Drs Barrero-Castillero,
adulthood. This information can be used to identify potential areas in which Morton, Nelson, and Smith have disclosed no
clinicians in neonatal medicine could intervene to improve outcomes. financial relationships relevant to this article.
This commentary does not contain a
discussion of an unapproved/investigative
use of a commercial product/device.

Objectives After completing this article, readers should be able to:

ABBREVIATIONS
ACE Adverse Childhood Experiences
1. Define stress taxonomy and describe the terms used to define stress and
EEG electroencephalography
stress transfer in humans. HPA hypothalamus-pituitary-adrenal

e686 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
2. Explain the biological and social basis for stress transfer between
generations.
3. Identify disruptive effects of toxic stress and early childhood adversity on
development and describe methods to support parents before, during,
and after pregnancy.

BACKGROUND offspring such as reduced attention, problems in behavior,

and increased risk in general susceptibility to mental health
Environmental and genetic influences on human neuro-
issues. (5) Potential mechanisms for the transfer of maternal
development begin prenatally and continue through ado-
stress responses to the fetus and potential intergenerational
lescence and early adulthood. (1) Although studies have
stressors include transplacental transfer of bioactive mole-
shown that the architecture of the brain is established
cules, autonomous fetal responses to changes in the uterine
during the early periods of development in utero, accumu-
environment, and epigenetic mechanisms. (6) In the case of
lating evidence has demonstrated that events before concep-
bioactive molecules, fetal exposure to increased maternal
tion, such as adverse psychosocial exposures (eg, history of
cortisol transfer across the placenta could lead to impaired
maltreatment when the pregnant woman was a child), (2)
development of the hypothalamus-pituitary-adrenal (HPA)
may influence the development of later generations. Tradi-
axis. Alterations in the reactivity of the HPA axis may then
tional understanding of human development has focused on
be a mechanism for the increased insulin resistance
the biological and genetic influences on development, health,
observed in populations exposed to adverse stressors.
and disease without considering psychosocial variables. More
(5)(7)(8) Other maternal stress-response molecules that have
recently, characterization of specific adverse exposures has
been described to cross the placenta in animal models
provided evidence supporting the critical role that psychoso-
include catecholamines, reactive oxygen species, cytokines,
cial factors have in modifying these developmental processes.
serotonin, and tryptophan.
However, the pathways by which adverse psychosocial expo-
In addition, alterations to the maternal microbiota could
sures influence outcomes are not well understood. Thus, the
affect the in utero environment indirectly or be transferred
relative risk associated with such exposures, and discovery of
to the neonate during delivery. These bioactive molecules
modifying factors that connect these exposures and neuro-
and microbiota could also act synergistically to alter neuro-
developmental outcomes, remain unclear. (3) This review
development. Recent reviews have discussed the vulnera-
aims to summarize what is known about the biological basis,
bilities to maternal adverse stressors during the embryonic
intergenerational transmission, and effects of psychosocial
and fetal periods. (2)(6)(9)
stress and early life adversity from the perinatal and newborn
Adverse in utero experiences may also directly affect the
period to adulthood. The Table provides definitions of terms
fetus. Potential autonomous effects of stress could be ex-
used in this review that are associated with stress and the
plained by biological aging with modification of telomere
transfer of stress in humans.
length, a marker of cellular aging that is associated with
physical health risk. (10) Environmental factors such as
maternal stress and socioeconomic status in utero are
HOW IS STRESS TRANSFERRED TO THE FETUS?
associated with accelerated telomere shortening at birth.
From a biological perspective, stress can be defined as an (11) Although no specific mechanism has been identified,
experience that leads to the activation of well-defined neu- indirect evidence suggests that maternal HPA axis func-
robiological systems that preserve viability through allo- tioning during pregnancy could be involved. (12)(13)
stasis. (4) Stress response is a part of our daily life as a Studies to assess the transfer of stress and the impact of
mechanism of survival. However, in chronic and persistent adverse experiences across multiple generations have used
degrees it is known to cause harm. But many details mice and other animals with rapid generation capabilities.
regarding which stressors undergo intergenerational trans- These studies have observed behavioral changes not only in
fer, and how such transfer occurs, remain unclear. the first offspring but also in subsequent generations.
Animal models have provided evidence that stress in (14)(15) In a study to test the intergenerational effect of early
pregnancy can lead to a range of long-term effects on the stress, mice exposed to chronic and unpredictable maternal

Vol. 20 No. 12 D E C E M B E R 2 0 1 9 e687

Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
 TABLE. Definitions Associated with Stress and Transfer of Stress in
Humans
TERM DEFINITION

Allostasis Process (physiological or behavioral change) of adaptation by which the body responds to stressors to regain homeostasis
or balance. (16)(17)(18)(19)
Allostatic load Changes in the brain and body that can lead to disease from the burden of chronic stress.
Referenced as "the wear and tear on the body," which accumulates as the body is exposed to chronic and cumulative
stress. (17)(18)(19)
Biological A mechanistic process by which experience gets “under the skin” and alters health and development.
embedding of Developed by Hertzman in 2012 to help explain social gradients in health. (20)
adversity
Critical period in Windows of heightened plasticity during brain development.
development During this time, adequate environmental input is required for adequate development of particular brain circuits.
(21)(22)(23)
If there is no stimulus or a noxious one, the development could be compromised and lead to developmental delay.
Early life adversity Negative childhood experience associated with an increased lifetime risk of poorer health and social outcomes. (24)
This term has now been used widely to talk about psychosocial adversity. (25)
Eco-bio- Proposed by the American Academy of Pediatrics Committee on Psychosocial Aspects of Child and Family Health in 2012
developmental as a multidimensional framework (including personal experiences, environment, genetic predispositions) to understand
framework and approach health and disease.
It is a good illustration of how early experiences and environment can modify genetic predispositions, thus changing brain
architecture and as a consequence, long-term health. (26)
Epigenetics An epigenetic change happens with the combination of mechanisms that confer long-term programming to gene activity
and could change gene function without changing its gene sequence. (27)(28)
Epigenetic mechanisms regulate transcriptional processes where gene expression activates and deactivate genes and
determines which proteins are transcribed.
Epigenetic changes have been associated with different hypotheses involving social behavior (eg, stress) in animal models.
(28)(29)
Psychosocial Adverse experiences are psychosocial hazards that can affect development, particularly if present during critical periods of
adversity development.
Negative experiences relating to a child’s psychosocial environment (eg, maltreatment, caregiver psychopathology,
violence exposure, depriving care environments) and relationships that increase the risk of poorer health and social
outcomes over the life course. (30)
Stress Defined as “a physical, chemical, or emotional factor that causes bodily or mental tension and may be a factor in disease
causation.” (31)
Physiologic responses to stress through the activation of neurobiological systems (hypothalamus-pituitary-adrenal axis
and the sympathetic adrenomedullary system) have been well-defined for years. (19)(32)(33)(34)
Transient increases in stress hormones are protective and essential for survival, but excessively high levels or prolonged
exposures could be harmful. (35)
Toxic stress The National Scientific Council on the Developing Child described 3 concepts for the different types of stress responses in
children, including “positive, tolerable, and toxic” stress depending on the intensity and duration of response, and as a
result, the potential to cause long-lasting consequences. (36)(37)
Toxic stress is defined as the excessive or prolonged activation of the physiologic stress response systems in the absence of
the buffering support by a stable and responsive relationship that reinforces healthy adaptations to stress. (38)
Transgenerational Transmission of environmental adversity from F0 to F3 or F4—exposure of the past generation to the environment or
transmission* stressor during pregnancy that will still be present in the third generation (the first generation that is not directly
exposed), possibly because of epigenetic mechanisms. (29)(39)
Intergenerational Transmission of environmental adversity from F0 to F1—direct exposure of the parental (F0) and subsequent generation
transmission* (F1) to the stressor by the developing germ cell or fetus. (29)(39)

*Transmission of environmental adversity effects has been established in animal models.

separation in the first 2 weeks of postnatal age demonstrated maltreatment and separation was associated with altered
depressionlike behaviors as adult mice. (40) Similar results social behaviors, including increased fearfulness and anx-
have been seen in primate studies where exposure to early iety, as well as social and sexual dysfunction as adults. (41)

e688 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
One study characterized an example of transgenerational
effect (42) when stress and anxiety in adult mice were
induced by unforeseeable maternal separation and maternal
stress early in life (14 days after birth). Antisocial, depres-
sive, and risk-taking behaviors, as well as impaired memory
and altered serotonergic 1A receptor in the brain, were
found not only in the affected mice as adults but persisted
across 2 generations that had not been exposed to stress.
(42) Such multigenerational inheritance patterns could be
because of learned behaviors, but it is likely that adverse
experiences may mediate epigenetic modifications of DNA
that lead to changes in programming physiology and behav-
ior, ultimately modifying the risk factor for diseases in
adulthood. (43)(44) Thus, a deeper understanding of the
mechanisms could identify potential targets for therapeutic
interventions.
Although most studies describe descendant interactions
coming from mothers, a few studies describe a potential
influence of paternal stressor exposures via epigenetic variation
in the patriline. (45) In addition, fathers may indirectly influ-
ence the descendants by being supportive or not supportive
of their partners. (5)(6)(46)(47) To best care for the whole
family, ongoing work to better understand the contribution of
each family member to health and outcomes is important.
CONSEQUENCES OF PRENATAL EXPOSURE TO STRESS
AND ADVERSITY
It is known that the intrauterine environment significantly
influences growth and development in the prenatal period.
A detailed review of brain development has been previously
described. (48) In brief, brain development starts early in
the embryonic period that begins at conception through the
eighth week of gestation. During this period, rudimentary
structures of the brain and central nervous system are
defined. By the third week of gestation, through a process
called neurulation, the neural progenitor cells differentiate
and form the neural plate. The neural plate eventually
becomes the neural tube, the first brain structure that will
later differentiate into the spinal cord and the brain. While
these structures are forming, neuron production, migra-
tion, and differentiation take place. This long process con-
tinues through embryonic, fetal, and postnatal periods,
extending to late adolescence as neuronal connections con-
tinue to develop. (48)
Accumulating evidence has identified that adverse envi-
ronmental maternal factors during the fetal period, such as
poor maternal nutrition, maternal obesity, and adverse
stressors, are associated with effects that last well beyond
the fetal period. Both human and nonhuman animal studies
Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
have shown that fetal exposure to maternal stress can influ-
ence later stress responsiveness. (15)(49)(50) For example,
mice exposed to adverse prenatal stress, such as spatial
restriction and bright lights, were observed to have dis-
rupted sleep patterns, altered activity of the HPA axis,
increased anxiety-related behaviors, and difficulty with
memory. (15) Human fetuses and infants exposed to ma-
ternal anxiety or depression demonstrate increased meth-
ylation of the glucocorticoid receptor gene in cord blood
and increased cortisol responsiveness at 3 months of age,
highlighting the ability of psychosocial exposures to affect
gene expression. (49)
Vulnerable or critical periods have been identified during
gestation, and adverse exposures during these periods can
have negative effects on childhood behavior and emotional
development, as well as increase the risk for metabolic,
cardiac, and mental health problems later in life. (51)(52)
These initial periods of development are characterized by
increased brain plasticity, but also greater vulnerability. (9)
For example, acute stress in a pregnant woman, such as
experiencing a natural disaster, can alter the urine metabolic
profiles of her children, (53) indicating alterations in mul-
tiple biological pathways. Poor clinical outcomes in neo-
nates, such as the need for assisted ventilation or meconium
aspiration syndrome, have also been observed after natural
disasters. (54) In addition, elevated maternal stress has been
associated with prematurity and lower birthweight in mul-
tiple studies. (55) A detailed summary of the evidence can be
found in a recent critical review of the effects of prenatal
stress on fetal and child development. (56)
More recently, new studies have demonstrated that
infants exposed to maternal psychosocial stress have sig-
nificant changes in brain electrical activity as detected with
electroencephalography (EEG) as early as 2 months of age.
(57) EEG holds great promise as a noninvasive test that can
be performed serially during development. EEG was suc-
cessfully used as an index of the association between care-
giver stress and neurodevelopment in infants, making it a
promising tool to identify indicators of risk and resilience in
very young infants. (57)
EXPOSURE TO STRESS AND ADVERSITY DURING
INFANCY AND CHILDHOOD
During infancy and childhood, the brain continues to de-
velop at a rapid pace. Critical or sensitive periods also exist
after the fetal period, during which there is intense devel-
opment of specific neural circuits such as those related to
language development, hearing, vision, and socialization.
At this time, both positive and negative experiences create
Vol. 20 No. 12 D E C E M B E R 2 0 1 9 e689
 the foundation for future health and behaviors. (58)(59)
These critical periods occur mostly in the first years of life
when human brains have their greatest total number of
synapses. (60) A longitudinal study in 2000 was able to
demonstrate how these critical periods were affected in
children with poor exposure to social and environmental
stimulation when institutionalized at a very young age.
(60)(61)(62)(63) It was previously thought that once these
critical periods of development close, there was no way to
regain plasticity. However, more recent work in a nonhu-
man animal model suggests that there might be an oppor-
tunity to reopen the periods and recover some lost function
with appropriate stimuli. (21)(22) This indicates the poten-
tial for intervention after identification of at-risk individuals.
Early adversity during the postnatal period may modify
neuroendocrine responses to stress secondary to changes in
the developing neural circuits. This mechanism is thought
to explain how adversity may affect the reactivity to stress in
the future. (26)(64) Excessive or chronic stress activation
with no buffer during childhood, referred to as toxic stress,
(26)(36)(37) plays an important causal role in the intergen-
erational transmission of disparities in development, edu-
cational achievement, mental health, and health outcomes.
(26) Figure 1 shows a conceptual model proposed by Berens
et al about the different effects of early adversity across
different axes (neural, endocrine, immune, and metabolic)
and epigenetic processes during critical periods, which may
explain the “biological embedding of childhood adversity.”(24)
Figure 1. Biological embedding of early life adversity: A conceptual model. Printed and modified with permission from Anne Berens. Copyright
Registration Number / Date: VAu001275841 / 2016-07-07
e690 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
Experiences with adversity can be exemplified in many differ-
ent ways. Examples discussed in detail herein include poverty,
immigration, and early illness.
Poverty
In 2017, 17.5% (ie, 12.8 million) of the US population
younger than 18 years lived in poverty, which is about 1
in 5 children, compared with 1 in 8 adults. (65) Child poverty
has been used as an economic indicator of the well-being of
children who, at a point in time, live in families whose
resources are below a consistent threshold that is considered
to be sufficient to meet basic needs (59) such as food security
and stable housing. For example, 3 forms of housing insta-
bility (being behind on rent, experiencing multiple moves,
and history of homelessness) have been associated with
increased adjusted odds of adverse health outcomes com-
pared with stable housing. (66)
Additional data suggest an increased risk of poor out-
comes, particularly cognitive impairment and poor educa-
tional attainment, for children of low-income families. A
cross-sectional study of children (ages 4–22 years) showed
that children who live in low-income families had reduced
gray matter volumes in the frontal and temporal cortex and
the hippocampus, areas that have been associated with
school readiness and achievement. A second study of chil-
dren (ages 3–20 years) found similar effects of household
income on brain development, particularly when income
was below the poverty line; the study also demonstrated a
relationship among elevated cortisol levels, poverty, and
measures of executive function. (32) Outcome disparities
in children from low-income families have been associated
with reduced parental cognitive input and increased envi-
ronmental pollution. Being born into a poor family has been
shown to strongly predict poverty status in the future. (33)
All these data suggest that factors associated with poverty,
not only income, are associated with increased risk for poor
outcomes. Thus, poverty is more than just an indicator of
material hardship but includes multiple layers of complexity
that add or even interact synergistically.
Immigration
As of 2017, about 44.5 million immigrants are living in the
United States, and about 25% of those individuals are
undocumented immigrants. (67) Between 2012 and 2016,
5.1 million children younger than 18 years lived in a house-
hold with an undocumented immigrant, which corresponds
to 7% of the US population. (67)(68) Immigrant or foreign-
born status has been identified as a risk factor for poor health
for many reasons, such as migration itself being a period of
significant adjustment and stress. (69) Immigrants are also
more likely to have low socioeconomic status than nonim-
migrant residents of the United States; in 2017, the poverty
rate in the foreign-born population in the United States was
14.5% compared with 11.9% in the native-born population.
(65) It is known that fear of deportation and anxiety in
undocumented immigrants causes high levels of stress
and anxiety to not only the undocumented individual but
also the family as a whole because of the possibility of
separation, economic hardship from deportation or deten-
tion, and adversity from discrimination. (70)
Growing evidence, mostly from observational studies,
has shown an increased risk for different adverse health
outcomes associated with political events and racial and
ethnic discrimination, as well as anti-immigrant rhetoric.
(71)(72)(73)(74)(75) For example, a cohort study of US-born
Latino adolescent children of immigrant parents in Califor-
nia demonstrated that “perceived immigration policy vul-
nerability” was associated with increased anxiety levels,
sleep problems, and blood pressure changes. (76) Research
has mainly focused on the impact of an individual percep-
tion of stress and anxiety associated with undocumented or
mixed-status families (members of these families are both
US born as well as immigrants with different documen-
tation status). We know much less about the potential in-
tergenerational and transgenerational effects of children
affected by the parental documentation status. (71)(77)
Ethnicity-related stress or discrimination during preg-
nancy and its effect on infant outcomes, particularly on
Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
low birthweight, were observed in a few studies in infants of
mothers with Arabic names 6 months after the 9/11 terrorist
attacks in the United States (72) and in Latina mothers after
a major immigration raid. (73) More recently, a population-
based study found an association between the US presiden-
tial election in 2016 and an increase in preterm births
among US Latina women demonstrating the potential
effects of “political determinants of health.” (74)(75) On
the other hand, a recent study demonstrated that protecting
unauthorized immigrant mothers had a positive effect on
their children’s mental health. (77)
Evidence in this area continues to build. However, con-
siderably less is known about the accompanying fear, anx-
iety, and acculturative stress of being an immigrant (both
documented and undocumented), how to measure it, and
how it affects health behaviors, particularly in this era of
constant changes and awareness of immigration policies.
More evidence is needed to understand severe types of
adversity arising from deportation and family separation,
as well as of immigration as part of a continuum of daily
experiences that can contribute to psychosocial stress or
resilience. Daily factors potentially associated with having a
foreign-born status such as limited English proficiency,
acculturation, low socioeconomic status, restricted access
to health care and social services, immigration status, and
perceived discrimination to name a few, have been only
partially characterized. Further research will be necessary to
understand how changes in immigration policy and appli-
cant detention practices affect our children, their families,
and their communities.
Infant and Parental Stress in the NICU
Families of infants hospitalized in NICUs may experience
high levels of both psychological and biological stress
because of many aspects of admission, including separa-
tion, alterations in the parenting relationship, exposure to a
technical and noisy environment, appearance of a small and
fragile infant, need for multiple invasive procedures, uncer-
tainty, financial burden, and prolonged hospitalization.
(78)(79)
Many families with adverse experiences in the NICU and
after their infant’s discharge have shared their stories in the
lay press reporting high levels of stress, anxiety, depression,
guilt, and shame. (80)(81) Several studies have replicated
these findings among many different ethnic and cultural
groups as well as in different countries. (82) A study con-
ducted by the Bliss Foundation found that among 600 NICU
parents surveyed in the United Kingdom, 23% were diag-
nosed with anxiety, 16% with post-traumatic stress disorder,
and 14% with postnatal depression. (83) Among affected
Vol. 20 No. 12 D E C E M B E R 2 0 1 9 e691
 parents, 45% reported no access to “formal psychological
support” since leaving the NICU, (83) highlighting the
importance of close multidisciplinary follow-up after NICU
discharge.
Some studies have described the association between
maternal anxiety in the NICU and later developmental
outcomes in the offspring (eg, lower neurodevelopmental
scores at age 20 months) (84); however, the available evi-
dence makes it difficult to infer causation of neurodevelop-
mental delays because of maternal mental health problems
(eg, depression, anxiety, and perinatal-specific post-
traumatic stress), particularly in children with an increased
risk at baseline. A review of the mental health of parents in
the NICU reports that mental health issues are common
across diverse ethnocultural groups and countries. (82)
In addition to psychosocial stress, infants admitted to the
NICU are subject to multiple lifesaving but painful and
invasive procedures, (85) noise, (86) separation from par-
ents, and altered parent-infant bonding. This is particularly
true for extremely preterm infants (<28 weeks’ gestational
age) who have a higher risk for neurodevelopmental delays.
(87) Given the high co-occurrence of multiple stressors, the
nature of the association among these stressors (psychoso-
cial and biological) is important to study.

Figure 2. Implications of stress and potential interventions in the NICU. Images printed and modified with permission from Anne Berens. Copyright
Registration Number / Date: VAu001275841 / 2016-07-07

e692 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
STRESS AND ADVERSITY DURING CHILDHOOD AS A may last a lifetime. A better understanding of the biologic
CAUSE OF ADULT DISEASE mechanisms as well as identifying methods for mitigating
stressors and finding markers of resilience are important in
Toxic stress can play an important role in disrupting the
the future to mitigate stress effects as early as possible.
architecture of the developing brain, and as a result, in-
The generational transmission of toxic stress and early
fluence behavioral, educational, economic, and health out-
life adversity play a potential role in the pathogenesis of
comes later in life during adulthood and in later
health disparities, which highlights the importance of effec-
generations. (38) In 1998, the Adverse Childhood Experi-
tive monitoring of significant risk factors. The infant born
ences (ACE) Study demonstrated a linear and robust asso-
prematurely or with a medical condition that requires
ciation between a mix of experiences that were considered as
intervention and hospitalization in an intensive care unit
adverse during childhood and lifetime risk for certain
setting is at a higher risk for neurodevelopmental delays,
illnesses and poor quality of life. Participants were asked
and exposure to additional stressors for both the infant and
about a number of experiences, including “physical, sexual,
the parents. However, every system that interacts with chil-
and emotional abuse; physical and emotional neglect;
dren and their families offers an opportunity to influence
whether the mother was treated violently; household sub-
and strengthen the foundation of a healthy development.
stance abuse; household mental illness; parental separation
Thus, having “extra” time during hospitalization and at least
or divorce; and whether a household member had been
3 to 5 years of additional outpatient monitoring in “high-risk
incarcerated.” (25) Importantly, the more adverse experi-
infant clinics” or “infant follow-up clinics” can help identify
ences (counted as the number of experiences, not the degree
children and families at risk for toxic stress. (38) Such
of adversity) present in childhood, the higher the likelihood
monitoring can provide additional support for parents to
of outcomes such as higher risk of metabolic diseases,
adequately support the health and development of their
cancer, mood disorders, and premature mortality, as well
infants. The use of traditional or novel biomarkers and
as adverse social outcomes such as lower educational achieve-
physiologic measurements such as EEG to detect the early
ments in the future. (88)(89)(90)(91) ACE Study has added
effects of adverse experiences in neonates will allow for
greatly to the evidence of the impact of toxic stress and early
improved identification of at-risk individuals. Such mea-
life adversity on the development of physical and mental
sures can also be used to assess the efficacy of bedside and
impairments. (25) The implications of these findings have
home interventions to ameliorate the effects of stress faced
changed the way we think about adult disease and how many
by families and infants in the NICU (Fig 2).
of the adult impairments can be seen as developmental
disorders that begin early in life and persist for a lifetime.
This may explain persistent health disparities in generations
associated with poverty, maltreatment, and discrimination
American Board of Pediatrics
during childhood. Prevention efforts to change adult behav- Neonatal-Perinatal Content
ior can begin with reducing toxic stress during childhood. Specifications
(26) A recent study assessing the cumulative risk and latent • Know the effects of socioeconomic factors on the results and
class approach to adverse childhood experiences showed generalizability of outcome studies of NICU graduates.
that a different combination of adverse childhood experi- • Know the effects of family risk factors (low socioeconomic status,
ences could have different risk on health outcomes. For mental health problems) on cognitive outcomes.

example, a subgroup of children exposed to both parental
mental illness and poverty showed a higher risk for special
health-care needs compared with other groups, suggesting
the importance of specific combinations and not only the
number of adverse childhood experiences. (92)
CONCLUSIONS AND FUTURE DIRECTIONS FOR THE
NICU POPULATION
Adverse experiences and psychosocial stress have biologic
implications for those who experience them as well as future
generations. The effect of toxic stress starts in utero and
• Know the effects on the fetus and/or newborn infant of maternal
psychiatric disorders and their treatment.
References
1. Ernst M, Korelitz KE. Cerebral maturation in adolescence:
behavioral vulnerability. Encephale. 2009;35(suppl 6):S182–S189
2. Moog NK, Entringer S, Rasmussen JM, et al. Intergenerational
effect of maternal exposure to childhood maltreatment on newborn
brain anatomy. Biol Psychiatry. 2018;83(2):120–127
3. Committee on Psychosocial Aspects of Child and Family Health.
American Academy of Pediatrics. The new morbidity revisited: a

Vol. 20 No. 12 D E C E M B E R 2 0 1 9 e693

Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
 renewed commitment to the psychosocial aspects of pediatric care.
Pediatrics. 2001;108(5):1227–1230
4. Gunnar M, Quevedo K. The neurobiology of stress and
development. Annu Rev Psychol. 2007;58(1):145–173
5. Beijers R, Buitelaar JK, de Weerth C. Mechanisms underlying the
effects of prenatal psychosocial stress on child outcomes: beyond
the HPA axis. Eur Child Adolesc Psychiatry. 2014;23(10):943–956
6. Provençal N, Binder EB. The effects of early life stress on the
epigenome: from the womb to adulthood and even before. Exp
Neurol. 2015;268:10–20
7. Davis EP, Sandman CA. The timing of prenatal exposure to
maternal cortisol and psychosocial stress is associated with human
infant cognitive development. Child Dev. 2010;81(1):131–148
8. McGowan PO, Matthews SG. Prenatal stress, glucocorticoids, and
developmental programming of the stress response. Endocrinology.
2018;159(1):69–82
9. Franke K, van den Bergh B, de Rooij SR, et al. Effects of prenatal
stress on structural brain development and aging in humans.
bioRxiv. 2017; June12. doi: 10.1101/148916
10. Dagan O, Asok A, Steele H, Steele M, Bernard K. Attachment
security moderates the link between adverse childhood experiences
and cellular aging. Dev Psychopathol. 2018;30(4):1211–1223
11. Marchetto NM, Glynn RA, Ferry ML, et al. Prenatal stress and
newborn telomere length. Am J Obstet Gynecol.
2016;215(1):94.e1–94.e8
12. Bosquet Enlow M, Bollati V, Sideridis G, et al. Sex differences in
effects of maternal risk and protective factors in childhood and
pregnancy on newborn telomere length. Psychoneuroendocrinology.
2018;95:74–85
13. Bosquet Enlow M, Sideridis G, Bollati V, Hoxha M, Hacker MR,
Wright RJ. Maternal cortisol output in pregnancy and newborn
telomere length: Evidence for sex-specific effects.
Psychoneuroendocrinology. 2019;102:225–235
14. Buss C, Entringer S, Moog NK, et al. Intergenerational transmission
of maternal childhood maltreatment exposure: Implications for
fetal brain development. J Am Acad Child Adolesc Psychiatry.
2017;56(5):373–382
15. Darnaudéry M, Maccari S. Epigenetic programming of the stress
response in male and female rats by prenatal restraint stress. Brain
Res Brain Res Rev. 2008;57(2):571–585
16. Sterling P, Eyer J. Biological basis of stress-related mortality. Soc Sci
Med E. 1981;15(1):3–42
17. McEwen BS, Wingfield JC. The concept of allostasis in biology
and biomedicine. Horm Behav. 2003;43(1):2–15
18. McEwen BS. The neurobiology of stress: from serendipity to
clinical relevance. Brain Res. 2000;886(1-2):172–189
19. McEwen BS. Physiology and neurobiology of stress and adaptation:
central role of the brain. Physiol Rev. 2007;87(3):873–904
20. Hertzman C. Putting the concept of biological embedding in
historical perspective. Proc Natl Acad Sci USA. 2012;109(suppl
2):17160–17167
21. Hensch TK. The power of the infant brain. Sci Am.
2016;314(2):64–69
22. Hensch TK, Bilimoria PM. Re-opening windows: manipulating
critical periods for brain development. Cerebrum. 2012;2012:11
23. Hensch TK. Critical period plasticity in local cortical circuits.
Nat Rev Neurosci. 2005;6(11):877–888
e694 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
24. Berens AE, Jensen SKG, Nelson CA III. Biological embedding of
childhood adversity: from physiological mechanisms to clinical
implications. BMC Med. 2017;15(1):135
25. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood
abuse and household dysfunction to many of the leading causes of
death in adults. The Adverse Childhood Experiences (ACE) Study.
Am J Prev Med. 1998;14(4):245–258
26. Shonkoff JP, Garner AS; Committee on Psychosocial Aspects of
Child and Family Health; Committee on Early Childhood,
Adoption, and Dependent Care; Section on Developmental and
Behavioral Pediatrics. The lifelong effects of early childhood
adversity and toxic stress. Pediatrics. 2012;129(1):e232–e246
27. National Institutes of Health, Genetics Home Reference. What is
epigenetics? Available at: https://ghr.nlm.nih.gov/primer/
howgeneswork/epigenome. 2019. Accessed September 8, 2019
28. McGowan PO, Szyf M. The epigenetics of social adversity in early
life: implications for mental health outcomes. Neurobiol Dis.
2010;39(1):66–72
29. Klengel T, Dias BG, Ressler KJ. Models of intergenerational and
transgenerational transmission of risk for psychopathology in mice.
Neuropsychopharmacology. 2016;41(1):219–231
30. Anderson EL, Caleyachetty R, Stafford M, et al. Prospective
associations of psychosocial adversity in childhood with risk factors
for cardiovascular disease in adulthood: the MRC National Survey of
Health and Development. Int J Equity Health. 2017;16(1):170
31. Merriam-Webster’s Dictionary. Stress. Available at: https://
www.merriam-webster.com/dictionary/stress. Accessed September
27, 2019
32. Blair C, Raver CC. Poverty, stress, and brain development: New
directions for prevention and intervention. Acad Pediatr. 2016;16(3
Suppl):S30–S36
33. Ratcliffe C, Mckernan S Childhood poverty persistence: facts and
consequences. 2010. Available at https://www.urban.org/research/
publication/childhood-poverty-persistence-facts-and-
consequences. Accessed September 8, 2019
34. Johnson SB, Riley AW, Granger DA, Riis J. The science of early life
toxic stress for pediatric practice and advocacy. Pediatrics.
2013;131(2):319–327. doi: 10.1542/peds.2012-0469
35. McEwen BS. Central effects of stress hormones in health and
disease: Understanding the protective and damaging effects of
stress and stress mediators. Eur J Pharmacol. 2008;583(2-3):174–185
36. Shonkoff JP. Building a new biodevelopmental framework to guide
the future of early childhood policy. Child Dev. 2010;81(1):357–367
37. National Scientific Council on the Developing Child. Excessive
stress disrupts the development of brain architecture: working
paper no. 3—updated edition. Available at: https://
developingchild.harvard.edu/resources/wp3/. Accessed September
8. 2019
38. Garner AS, Shonkoff JP, et al; Committee on Psychosocial Aspects
of Child and Family Health; Committee on Early Childhood,
Adoption, and Dependent Care; Section on Developmental and
Behavioral Pediatrics. Early childhood adversity, toxic stress, and the
role of the pediatrician: translating developmental science into
lifelong health. Pediatrics. 2012;129(1):e224–e231
39. Yehuda R, Lehrner A. Intergenerational transmission of trauma
effects: putative role of epigenetic mechanisms. World Psychiatry.
2018;17(3):243–257
40. Franklin TB, Russig H, Weiss IC, et al. Epigenetic transmission of
the impact of early stress across generations. Biol Psychiatry.
2010;68(5):408–415
41. Sánchez MM, Ladd CO, Plotsky PM. Early adverse experience as a
developmental risk factor for later psychopathology: evidence
from rodent and primate models. Dev Psychopathol. 2001;13(3):
419–449
42. Franklin TB, Linder N, Russig H, Thöny B, Mansuy IM. Influence of
early stress on social abilities and serotonergic functions across
generations in mice. PLoS One. 2011;6(7):e21842
43. Barnes SK, Ozanne SE. Pathways linking the early environment to
long-term health and lifespan. Prog Biophys Mol Biol.
2011;106(1):323–336
44. Cao-Lei L, Massart R, Suderman MJ, et al. DNA methylation
signatures triggered by prenatal maternal stress exposure to a
natural disaster: Project Ice Storm. PLoS One. 2014;9(9):e107653
45. Curley JP, Mashoodh R, Champagne FA. Epigenetics and the
origins of paternal effects. Horm Behav. 2011;59(3):306–314
46. Braun K, Champagne FA. Paternal influences on offspring
development: behavioural and epigenetic pathways.
J Neuroendocrinol. 2014;26(10):697–706
47. Glover V, Capron L. Prenatal parenting. Curr Opin Psychol.
2017;15:66–70
48. Stiles J, Jernigan TL. The basics of brain development. Neuropsychol
Rev. 2010;20(4):327–348
49. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin
AM. Prenatal exposure to maternal depression, neonatal
methylation of human glucocorticoid receptor gene (NR3C1) and
infant cortisol stress responses. Epigenetics. 2008;3(2):97–106
50. Brand SR, Engel SM, Canfield RL, Yehuda R. The effect of maternal
PTSD following in utero trauma exposure on behavior and
temperament in the 9-month-old infant. Ann N Y Acad Sci.
2006;1071:454–458
51. Rakers F, Rupprecht S, Dreiling M, Bergmeier C, Witte OW,
Schwab M. Transfer of maternal psychosocial stress to the fetus
[published online ahead of print February 22]. Neurosci Biobehav
Rev. 2016. doi: 10.1016/j.neubiorev.2017.02.019
52. Ulmer-Yaniv A, Djalovski A, Priel A, Zagoory-Sharon O,
Feldman R. Maternal depression alters stress and immune
biomarkers in mother and child. Depress Anxiety. 2018;35(12):
1145–1157
53. Paxman EJ, Boora NS, Kiss D, et al. Prenatal maternal stress from a
natural disaster alters urinary metabolomic profiles in project ice
storm participants. Sci Rep. 2018;8(1):12932
54. Currie J, Rossin-Slater M. Weathering the storm: hurricanes and
birth outcomes. J Health Econ. 2013;32(3):487–503
55. Bussières EL, Tarabulsy GM, Pearson J, Tessier R, Forest JC,
Giguère Y. Maternal prenatal stress and infant birth weight and
gestational age: a meta-analysis of prospective studies. Dev Rev.
2015;36:179–199. doi: 10.1016/j.dr.2015.04.001
56. Graignic-Philippe R, Dayan J, Chokron S, Jacquet AY, Tordjman S.
Effects of prenatal stress on fetal and child development: a critical
literature review. Neurosci Biobehav Rev. 2014;43(43):137–162
57. Pierce LJ, Thompson BL, Gharib A, et al. Association of perceived
maternal stress during the perinatal period with
electroencephalography patterns in 2-month-old infants. JAMA
Pediatr. 2019;173(6):561–570
58. Knudsen EI. Sensitive periods in the development of the brain and
behavior. J Cogn Neurosci. 2004;16(8):1412–1425
59. Chaudry A, Wimer C. Poverty is not just an indicator: The
relationship between income, poverty, and child well-being. Acad
Pediatr. 2016;16(3 suppl):S23–S29
Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
60. Fox SE, Levitt P, Nelson CA III. How the timing and quality of early
experiences influence the development of brain architecture. Child
Dev. 2010;81(1):28–40
61. Nelson CA, Furtado EA, Fox NA, Zeanah CH. The deprived human
brain. Am Sci. 2009;97(3):222. doi: 10.1511/2009.78.222
62. Nelson CA, Zeanah CH, Fox NA. How early experience
shapes human development: rhe case of psychosocial
deprivation. Neural Plast. 2019;2019:1676285. doi: 10.1155/2019/
1676285
63. Berens AE, Nelson CA. The science of early adversity: is there a role
for large institutions in the care of vulnerable children? Lancet.
2015;386(9991):388–398
64. Szyf M, McGowan P, Meaney MJ. The social environment and the
epigenome. Environ Mol Mutagen. 2008;49(1):46–60
65. Fontenot K, Semega J, Kollar M. Income and poverty in the United
States: 2017. US Census Bur Curr Popul Reports; 2018. Available at:
https://www.census.gov/library/publications/2018/demo/p60-
263.html. Accessed September 8, 2019
66. Sandel M, Sheward R, Ettinger de Cuba S, et al. Unstable housing
and caregiver and child health in renter families. Pediatrics.
2018;141(2):e20172199
67. Zong J, Batalova J, Hallock J; Migration Policy Institute. Frequently
requested statistics on immigrants and immigration in the United
States. Available at: https://www.migrationpolicy.org/article/
frequently-requested-statistics-immigrants-and-immigration-
united-states. Accessed September 8, 2019
68. Passel JS, Krogstad JM, Barrera-Gonzales A. As growth stalls,
unauthorized immigrant population becomes more settled: Pew
Research Center Hispanic trends. Available at: https://
www.pewhispanic.org/2014/09/03/as-growth-stalls-unauthorized-
immigrant-population-becomes-more-settled/. 2014. Accessed July
2, 2019
69. Pérez Cuadrado S, Muñoz Avalos N, Robledo Sánchez A, Sánchez
Fernández Y, Pallás Alonso CR, de la Cruz Bértolo J. Characteristics
of immigrant women and their neonates [in Spanish]. An Pediatr
(Barc). 2004;60(1):3–8
70. Martínez AD, Ruelas L, Granger DA. Household fear of deportation
in Mexican-origin families: Relation to body mass index percentiles
and salivary uric acid. Am J Hum Biol. 2017;29(6). doi: 10.1002/
ajhb.23044
71. Bean FD, Brown SK, Bachmeier J. Parents without Papers: The
Progress and Pitfalls of Mexican American Integration. New York, NY:
Russell Sage Foundation; 2017
72. Lauderdale DS. Birth outcomes for Arabic-named women in
California before and after September 11. Demography.
2006;43(1):185–201
73. Novak NL, Geronimus AT, Martinez-Cardoso AM. Change in birth
outcomes among infants born to Latina mothers after a major
immigration raid. Int J Epidemiol. 2017;46(3):839–849
74. Gemmill A, Catalano R, Casey JA, et al. Association of preterm
births among US latina women with the 2016 presidential election.
JAMA Netw Open. 2019;2(7):e197084
75. Montoya-Williams D, Fuentes-Afflick E. Political determinants of
population health. JAMA Netw Open. 2019;2(7):e197063
76. Eskenazi B, Fahey CA, Kogut K, et al. Association of perceived
immigration policy vulnerability with mental and physical health
among US-born Latino adolescents in California [published online
ahead of print June 24]. JAMA Pediatr. 2019
Vol. 20 No. 12 D E C E M B E R 2 0 1 9 e695
 77. Hainmueller J, Lawrence D, Martén L, et al. Protecting
unauthorized immigrant mothers improves their children’s mental
health. Science. 2017;357(6355):1041–1044. doi: 10.1126/
science.aan5893
78. Miles MS, Funk SG, Carlson J. Parental Stressor Scale: neonatal
intensive care unit. Nurs Res. 1993;42(3):148–152
79. Ichijima E, Kirk R, Hornblow A. Parental support in neonatal
intensive care units: a cross-cultural comparison between New
Zealand and Japan. J Pediatr Nurs. 2011;26(3):206–215
80. Wallwork E. 80% of parents with babies in intensive care say their
mental health has suffered. https://www.huffingtonpost.co.uk/
entry/parents-with-babies-in-neonatal-care-mental-health_
uk_5b4f0341e4b0fd5c73c08fb7?guccounter¼1&guce_
referrer¼aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&
guce_referrer_sig¼AQAAAJX3SOvaVqX_04aIE8Po-
Mc4TNW6DOrdOfWV-75CfgjuAPINRr2z06BQa. Accessed
September 8, 2019
81. BBC News. Parents of premature babies face a further trauma:
PTSD. https://www.bbc.com/news/health-44888954. July 23,
2018. Accessed September 8, 2019
82. Roque ATF, Lasiuk GC, Radünz V, Hegadoren K. Scoping review of
the mental health of parents of infants in the NICU. J Obstet Gynecol
Neonatal Nurs. 2017;46(4):576–587
83. Bliss. Bliss releases new research on mental health. Available at:
https://www.bliss.org.uk/news/bliss-releases-new-research-on-
mental-health. Accessed September 8, 2019
84. Greene MM, Rossman B, Meier P, Patra K. Elevated maternal
anxiety in the NICU predicts worse fine motor outcome in VLBW
infants. Early Hum Dev. 2018;116(116):33–39
e696 NeoReviews
Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019
85. Cruz MD, Fernandes AM, Oliveira CR. Epidemiology of painful
procedures performed in neonates: a systematic review of
observational studies. Eur J Pain. 2016;20(4):489–498
86. Casavant SG, Bernier K, Andrews S, Bourgoin A. Noise in the
neonatal intensive care unit: what does the evidence tell us?
Adv Neonatal Care. 2017;17(4):265–273 10.1097/
ANC.0000000000000402
87. Pascal A, Govaert P, Oostra A, Naulaers G, Ortibus E, Van den
Broeck C. Neurodevelopmental outcome in very preterm and very-
low-birthweight infants born over the past decade: a meta-analytic
review. Dev Med Child Neurol. 2018;60(4):342–355
88. Boullier M, Blair M. Adverse childhood experiences. Paediatr Child
Heal (United Kingdom). 2018;28(3):132–137
89. Center on the Developing Child at Harvard University. The impact
of early adversity on children’s development. Available at: https://
developingchild.harvard.edu/resources/inbrief-the-impact-of-
early-adversity-on-childrens-development/. 2017. Accessed
September 8, 2019
90. Chapman DP, Whitfield CL, Felitti VJ, Dube SR, Edwards VJ, Anda
RF. Adverse childhood experiences and the risk of depressive
disorders in adulthood. J Affect Disord. 2004;82(2):217–225
91. Dong M, Giles WH, Felitti VJ, et al. Insights into causal pathways
for ischemic heart disease: adverse childhood experiences study.
Circulation. 2004;110(13):1761–1766
92. Lanier P, Maguire-Jack K, Lombardi B, Frey J, Rose RA. Adverse
childhood experiences and child health outcomes: comparing
cumulative risk and latent class approaches. Matern Child Health J.
2018;22(3):288–297
 Psychosocial Stress and Adversity: Effects from the Perinatal Period to
Adulthood
Alejandra Barrero-Castillero, Sarah U. Morton, Charles A. Nelson III and Vincent C.
Smith
NeoReviews 2019;20;e686
DOI: 10.1542/neo.20-12-e686

Updated Information & including high resolution figures, can be found at:
Services http://neoreviews.aappublications.org/content/20/12/e686
References This article cites 76 articles, 8 of which you can access for free at:
http://neoreviews.aappublications.org/content/20/12/e686.full#ref-lis
t-1
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Pediatric Drug Labeling Update
http://classic.neoreviews.aappublications.org/cgi/collection/pediatric
_drug_labeling_update
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
https://shop.aap.org/licensing-permissions/
Reprints Information about ordering reprints can be found online:
http://classic.neoreviews.aappublications.org/content/reprints

Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019

 Psychosocial Stress and Adversity: Effects from the Perinatal Period to
Adulthood
Alejandra Barrero-Castillero, Sarah U. Morton, Charles A. Nelson III and Vincent C.
Smith
NeoReviews 2019;20;e686
DOI: 10.1542/neo.20-12-e686

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/20/12/e686

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication,
it has been published continuously since 2000. Neoreviews is owned, published, and trademarked
by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,
Illinois, 60007. Copyright © 2019 by the American Academy of Pediatrics. All rights reserved.
Online ISSN: 1526-9906.

Downloaded from http://neoreviews.aappublications.org/ at Bibliotheque Univ Paris V on December 7, 2019