Neuroscience and Biobehavioral Reviews 84 (2018) 262–271

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Preterm behavioral epigenetics: A systematic review T

⁎
Livio Provenzi , Elena Guida, Rosario Montirosso
0-3 Centre for the at-Risk Infant, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, LC, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Behavioral epigenetics is revealing new pathways that lead individuals from early adversity exposures to later-
Behavioral epigenetics in-life detrimental outcomes. Preterm birth constitutes one of the major adverse events in human development.
Developmental care Preterm infants are hospitalized in the Neonatal Intensive Care Unit (NICU) where they are exposed to life-saving
DNA methylation yet pain-inducing procedures and to protective care. The application of behavioral epigenetics to the field of
Epigenetics
preterm studies (i.e., Preterm Behavioral Epigenetics, PBE) is rapidly growing and holds promises to provide
Neonatal intensive care unit
NR3C1
valid insights for research and clinical activity. Here, the evidence of the epigenetic correlates of prenatal ad-
Preterm birth versities, NICU-related environment and development of preterm infants is systematically reviewed. The findings
SLC6A4 suggest that a number of prenatal adverse (e.g., maternal depression and stress) and post-natal (e.g., NICU-
Stress related pain-related stress) events affect the developmental trajectories of preterm infants and children via
epigenetic alterations of imprinted and stress-related genes. Nonetheless, the potential epigenetic vestiges of
early care and protective interventions in NICU have not been investigated yet and this represents a fascinating
challenge for future PBE research.

1. Introduction (2015) developed a theoretical model to guide research in what has

During the last decade, there has been growing evidence about the
effects of early adverse events on the developing biology of living or-
ganisms and, specifically, on the epigenetic modulation of DNA tran-
scriptional activity (Hyman, 2009). Epigenetics refers to the ways in
which heritable traits can be associated not with changes in nucleotide-
sequence, but with chemical modifications of DNA or of the structural
and regulatory proteins bound to it (Felsenfeld, 2014). Animal model
studies (Meaney and Szyf, 2005) as well as human research (Booij et al.,
2013) documented that a specific epigenetic process, i.e., DNA me-
thylation, is affected by environmental stimulations including early
caregiving (Curley et al., 2011) and adverse stressful events (Griffiths
and Hunter, 2014).
More recently, the epigenetic lens has been applied to the study of
early adversities in preterm infants, who are born with a neurobeha-
vioral immature profile and are precociously exposed to stressful pro-
cedures during the hospitalization in the Neonatal Intensive Care Unit
(NICU) (Montirosso and Provenzi, 2015). The preterm infant model has
been proposed as an elective population to assess the epigenetic effects
of early environmental conditions in human beings in a prospective
longitudinal way. Theoretical papers have highlighted the potential
implications and value of epigenetic studies for the study of preterm
infants’ development, including the identification of risk and protective
(Maddalena, 2013; Samra et al., 2012) factors. Montirosso and Provenzi
been called Preterm Behavioral Epigenetics (PBE). Evidence in this field
is rapidly accumulating and the present paper aims to review PBE lit-
erature to provide useful insights for future advances in the field and to
inform on smarter care for preterm infants (Marlow, 2015; Provenzi
and Barello, 2015).
1.1. DNA methylation
Epigenetics refers to alterations of the DNA which do not require
structural change of the dinucleotide sequence, resulting in altered
production of proteins without structural modifications of the DNA
sequence (Jaenisch and Bird, 2003). The epigenome describes the
pattern of functional modifications resulting from epigenetic mechan-
isms and it is specific for different tissues and cells. Among epigenetic
mechanisms, DNA methylation is by far the most investigated in animal
and human studies and occurs when a methyl group binds to specific 5′-
cytosine guanine-3′ dinucleotides (i.e., CpG sites). DNA methylation is
of specific concern for researchers and clinicians as it may lead to re-
duced transcriptional activity and gene silencing (Szyf, 2009). DNA
methylation is highly susceptible to environmental stimulations and
early experiences including both stressful and protective environmental
conditions (Champagne, 2011). Behavioral epigenetics is an emerging
field of research that investigates the antecedents and outcomes of
epigenetic modifications occurring in genes involved in different

⁎
Corresponding author at: 0-3 Center for the at-Risk Infant, Scientific Institute IRCCS Eugenio Medea, via Don Luigi Monza 20, 23842 Bosisio Parini, LC, Italy.
E-mail address: livio.provenzi@bp.lnf.it (L. Provenzi).

http://dx.doi.org/10.1016/j.neubiorev.2017.08.020
Received 10 March 2017; Received in revised form 28 June 2017; Accepted 30 August 2017
Available online 01 September 2017
0149-7634/ © 2017 Elsevier Ltd. All rights reserved.
L. Provenzi et al.
domains of physical and behavioral growth and development, including
imprinted and stress-related genes (Hunter, 2012). As such, behavioral
epigenetics studies how gene expression regulation is affected by en-
vironmental stimuli and contribute to the programming of health and
disease later in life (Groom et al., 2011).
1.2. Epigenetic regulation by early adverse experiences
The pioneering work by Meaney (Meaney, 2001) provided the first
evidence of DNA methylation changes in relation to adverse environ-
mental conditions. Meaney et al. (Weaver et al., 2004) examined the
effects of variations in the caregiving environment on the methylation
status of a specific gene, i.e., the NR3C1, which encodes for gluco-
corticoid receptors (GRs) in the brain. These receptors are key reg-
ulators of the stress reactivity in mammalians, since they regulate
through feedback mechanisms the hypothalamic-pituitary-adrenal
(HPA) axis (Tsigos and Chrousos, 2002). Rat pups with mothers pro-
viding low quality of caregiving − e.g., less engaged in receptive
nursing and in linking/grooming the offspring − were found to have
lower levels of GRs in the hippocampus and elevated stress reactivity
during adulthood (Francis and Meaney, 1999). Similar findings have
been documented in association with early maternal separation in ro-
dents: male offspring exposed to early maternal separation exhibited
behavioral inhibition in maze exploration, mediated by DNA hyper-
methylation of the gene encoding for the corticotropin-releasing hor-
mone, which is key regulator of the stress response (Kember et al.,
2012). Own et al. (Own et al., 2013) reported that in mice pups ma-
ternal separation also associates with increased methylation of another
stress-related gene, i.e., the SLC6A4, which encodes for the serotonin
transporter, the key regulator of the serotoninergic system (Lesch,
2011).
Human studies documented similar epigenetic alterations in young
individuals exposed to stressful adverse experiences during the prenatal
and the postnatal life (Provenzi et al., 2016). Importantly, both the HPA
axis functioning and serotoninergic system have shown to be suscep-
tible to epigenetic regulation in humans. Prenatal exposure to maternal
depression during the third trimester of pregnancy has been associated
in full-term newborns with the methylation status of a specific CpG site
of the NR3C1 gene, which encodes for the hippocampal GRs
(Oberlander et al., 2008). Interestingly, in the same study, the altered
methylation of NR3C1 gene was predictive of increased salivary cortisol
response to routine care-related stress at 3-month-age. More recently,
exposure to parental stress during infancy and childhood was found to
associate with differential methylation measured at 28000 CpG sites
from buccal epithelial cells in adolescents (Essex et al., 2013). As for
postnatal adverse exposure, the SLC6A4 methylation status of 5-to-14-
aged children with a previous history of parental abuse or neglect has
been compared with that of a counterpart of children without exposure
to family violence (Vijayendran et al., 2012). Maltreated and neglected
children showed lower methylation for CpG sites that were highly
methylated in the control group, and higher methylation for CpG sites
that were low-methylated in the control group. In another study, adults
with post-traumatic stress disorder and with history of early traumatic
experiences were compared to adults without post-traumatic stress
disorders who did not present adverse experiences in childhood (Mehta
et al., 2013). Individuals with a history of abuse showed non-over-
lapping areas of DNA methylation, when compared to individuals with
similar history of abuse, but without anxiety disorder. On the other
hand, the methylation status of the SLC6A4 gene, which encodes for the
5-HTT (i.e., serotonin transporter), is affected by maternal depression
during pregnancy (Devlin et al., 2010) and by post-natal adversities
(Wang et al., 2012).
1.3. Epigenetic regulation by early protective experiences
Animal studies also showed that DNA methylation is susceptible to
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Neuroscience and Biobehavioral Reviews 84 (2018) 262–271
caring and protective environmental conditions. Interestingly, when
rats born from mothers characterized by low quality of caregiving are
cross-fostered to mothers characterized by high quality of care they
show similar levels of Nr3c1 methylation of rats born and raised by
high-quality of care mothers (Hellstrom et al., 2012). Similarly, positive
experiences for rats, such as being sensitively touched during the early
post-natal period, has been shown to decreased the production of glu-
cocorticoids during the first day of life (Jutapakdeegul et al., 2003).
Recent research suggests that it might be possible to inquire the
epigenetic underpinnings of positive experiences also in humans.
Roberts et al. (Roberts et al., 2014) have measured the level of SLC6A4
methylation in children with anxiety disorder, before and after a cog-
nitive-behavioral psychotherapy intervention. Children who improved
after the intervention had significant changes of SLC6A4 methylation,
compared to peers showing no improvement. In a retrospective study,
infants from depressed mothers were found to have increased methy-
lation of the NR3C1 gene compared to infants from non-depressed
mothers (Murgatroyd et al., 2015). Nonetheless, the quality of early
caregiving, measured as the frequency of maternal stroking, was found
to reverse this effect, similarly to what has been documented in animal
models (Meaney and Szyf, 2005).
1.4. Preterm birth and NICU-related early adverse experiences
Preterm infants are hospitalized in the NICU, which constitutes a
stressful environment to which they are not prepared for without the
comforting and protective support of the maternal uterus (Altimier and
Phillips, 2013; Haumont et al., 2013). During this early period of de-
velopment, the infant brain is extremely sensitive to environmental
stimulations. As such, even in absence of medical complications, the
NICU is a source of enormous distress for preterm infants. NICU-related
stress includes physical and sensorial stimulations, painful procedures
and maternal separation.
NICU physical and sensorial stimulations are hardly tolerated by
neurobehavioral immature newborns (Brown, 2009; Ozawa et al.,
2010). High-intensity lights and noise are associated with physiological
and behavioral instability in preterm infants (Altuncu et al., 2009;
Graven, 2004; Lee et al., 2005). Moreover, life-saving procedures in-
clude intubations, venipunctures, arterial insertions and surgery. Due to
their immature neuro-developmental state, preterm infants have a
lower threshold and higher sensitization to external perturbations, so
that even routinely handling (e.g., diaper change) might be responded
to with heightened physiologic response. The immature neuro-devel-
opmental state of preterm infants includes less-than-optimal reflexes
and attentional skills, as well as reduced overall quality of movements,
difficulties in state regulation, hypo- and/or hyper-tonicity (Spittle
et al., 2016). Among NICU invasive procedures, skin-breaking proce-
dures have been largely studied as a source of pain for preterm infants
(Grunau, 2013). Skin-breaking interventions have been associated with
several detrimental consequences for brief- and long-term development
(Grunau et al., 2009), encompassing structural and functional altera-
tions of brain development and dysregulation of the HPA axis stress
response system (Provenzi, Giusti et al., 2016; Ranger et al., 2014;
Smith et al., 2011; Zwicker et al., 2013). Finally, the preterm newborn
is suddenly separated from the mother after birth. This forced separa-
tion is critical for both infants and their mothers, since it disrupts the
biological and emotional caregiving bonding which generally occurs
after birth (Latva et al., 2007) with long-lasting effects on preterm in-
fants’ stress regulation development (Mörelius et al., 2007).
1.5. Preterm birth and NICU-related early protective experiences
In order to manage the quality of life of preterm infants during the
early weeks of life, NICUs have progressively adopted family-centered
and developmental care (DC) strategies. The most investigated DC
strategy is the facilitation of early mother-infant contact through skin-
L. Provenzi et al.
to-skin kangaroo care (Feldman et al., 2002; Feldman and Eidelman,
2004). Skin-to-skin care consists in a prompt support for precocious
physical and emotional closeness, in which the infant is positioned
prone and upright on maternal chest. The preterm infant is kept dia-
pered, but unclothed, so that physical contact is favored.
Skin-to-skin care has shown to exert beneficial effects for the in-
fants, including the promotion of physiologic stability (Cong et al.,
2015), sleep organization (Calciolari and Montirosso, 2011), brain
maturation (Scher et al., 2009), behavioral (Kiechl-Kohlendorfer et al.,
2015), emotional development (Keren et al., 2003), and adaptive reg-
ulation of the HPA axis system (Mörelius et al., 2015).
1.6. A rationale for preterm behavioral epigenetics
In the light of the evidence reported above, one might wonder
whether altered patterns of DNA methylation are involved in preterm
infants’ development and how they associate with early exposures to
NICU-related adversity and care. PBE (Montirosso and Provenzi, 2015)
is an innovative field applying behavioral epigenetic research to the
study of prematurity and the effects of NICU stay, both through adverse
experiences and DC caregiver engagement practices (see Fig. 1). The
model assumes that various environmental conditions might contribute
to the developing trajectories and to the behavioral phenotype of pre-
term infants via epigenetic modifications (e.g., DNA methylation).
These conditions include known prenatal factors associated with in-
creased risk of preterm birth (e.g., maternal stress and depression) as
well as post-natal exposures to stress (e.g., pain-related stress) and DC
interventions during the NICU hospitalization.
1.7. The main aim of present study
Here we provide a systematic review of literature addressing epi-
genetic modifications observed in preterm infants in association with
prenatal and post-natal adverse and protective environmental condi-
tions. The main aims of this review are: (a) providing a comprehensive
account of PBE research state of the art; (b) highlighting future
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Neuroscience and Biobehavioral Reviews 84 (2018) 262–271
Fig. 1. Theoretical model for Preterm Behavioral
Epigenetics (PBE) research. Note. Adapted from
Montirosso and Provenzi (2015).
Note. Adapted from Montirosso and Provenzi (2015).
directions of research in this field; (c) describing the potential clinical
implications for early neonatal care of preterm infants.
2. Methods
2.1. Literature search
The systematic review was carried according to the Referred
Reporting Items for Systematic Review and Meta-Analysis (PRISMA)
guidelines (Liberati et al., 2009; Moher et al., 2015). Records were
searched on three databases (i.e., PubMed, Scopus, Web of Science)
until December 2016. The following search terms were used: [epige-
netics OR methylation OR DNA methylation] AND [preterm OR pre-
mature OR prematurity]. The search limits were set to English language
and human studies.
2.2. Selection
The records were checked for duplicates using Mendeley 1.17.6 (©
2008–2016 Mendeley Ltd). The remaining papers were then filtered
independently by two authors (LP and EG) by reading titles, abstracts
and full text. Disagreement was solved in conference through the sup-
port of a third author (LG). Exclusion criteria were: no epigenetics; no
preterm infants; theoretical papers; research not focused on stress ef-
fects. The whole study selection process is reported in Fig. 2.
2.3. Data abstracting
The records were reviewed and the following data were extracted:
authors, year of publication, infants’ characteristics, sample size, ad-
versity, time of adversity occurrence, time/tissue/method of epigenetic
assessment, targeted genes, direction of methylation change, outcome,
and time of outcome assessment.
L. Provenzi et al.
Fig. 2. Flow-chart of studies selection. Note. No stress effects included records focused on
the relationship between DNA methylation status/change and obesity (n = 1), placenta
infections (n = 1), maternal lifestyle (n = 1), preeclampsia (n = 5), maternal smoke
(n = 2), ethnic disparities (n = 1), clinical morbidities (n = 2), DNA methylation ana-
lyses unrelated to stressful conditions (n = 10).
Note. No stress effects included records focused on the relationship between DNA me-
thylation status/change and obesity (n = 1), placenta infections (n = 1), maternal life-
style (n = 1), preeclampsia (n = 5), maternal smoke (n = 2), ethnic disparities (n = 1),
clinical morbidities (n = 2), DNA methylation analyses unrelated to stressful conditions
(n = 10).
2.4. Quality appraisal
The methodological quality of the included papers was assessed
according to the Quality Assessment Tool for Quantitative Studies
(Jackson et al., 2005). Sections A-F (A, selection bias; B, study design;
C, confounders; D, blinding; E, data collection methods; F, withdrawal
and dropouts) were coded by two independent researchers (LP and EG)
as 3 (weak), 2 (moderate) or 1 (strong) according to the component
rating scale criteria. A summary 1-to-3 score is assigned to each paper
according to the presence of 2 or more weak scores (3, weak), only 1
weak score (2, moderate), no weak scores (1, strong). A 93% agreement
was reached for the A-F components. Disagreement was solved in
conference through the supervision of the third author (LG).
2.5. Data synthesis
Sample characteristics have been reviewed first, reporting in-
formation about infants and caregivers, as appropriate for each specific
included study. Second, methodological aspects have been reported
about epigenetic assessment and analyses. Third, the associations of
epigenetic variations with environmental conditions and outcomes
have been reported according to the PBE theoretical model: effects of
prenatal exposures, methylation profiling and effects of NICU-related
stress and care.
3. Results
3.1. Sample characteristics
A final pool of 9 studies was obtained (see Table 1). Five-out-of-nine
studies enrolled only very preterm infants (Chau et al., 2014;
Montirosso et al., 2016a, 2016b; Provenzi et al., 2015; Sparrow et al.,
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Neuroscience and Biobehavioral Reviews 84 (2018) 262–271
2016), whereas mixed sample of both moderate and very preterm
participated in the other four studies (Kantake et al., 2014; Lester et al.,
2015; Liu et al., 2012; Vidal et al., 2014). Gestational age ranged from
23 to 37 weeks and birth weight was comprised between 520 and
2265 g. In papers that did not assess the effects of maternal-related
stressors, all mothers were healthy.
3.2. Methodological aspects
Table 2 resumes the main characteristics of epigenetic analyses. The
quality appraisal results are reported in Table 3.
Most of the included papers focused on stress-related genes, i.e.,
SLC6A4, NR3C1, HSD11B2. The SLC6A4 gene encodes for serotonin
transporter (Canli and Lesch, 2007) and the NR3C1 gene encodes for
glucocorticoids receptors (Oberlander et al., 2008). The HSD11B2 is a
key regulator of the effects of maternal stress and depression on the
placental barrier and low expression of this gene associates with in-
creased risk of inflammations and excessive exposure to glucocorticoids
in the fetus (Appleton et al., 2015; Green et al., 2015). Only one study
reported initially a genome-wide epigenetic analysis and, in a second
step, analysis of DNA methylation at specific genes (Sparrow et al.,
2016). Two studies reported specifically on imprinted genes (Liu et al.,
2012; Vidal et al., 2014). Almost all the studies reported on specific
adversity exposures during pregnancy (Liu et al., 2012; Vidal et al.,
2014) or during early post-natal life (Chau et al., 2014; Kantake et al.,
2014; Montirosso et al., 2016a,b,; Provenzi et al., 2015). Only two
studies did not report on specific adversity exposures, assessing the link
between neurodevelopmental risk and epigenetic variations (Lester
et al., 2015; Sparrow et al., 2016). Five studies assessed the functional
consequences of altered DNA methylation, including behavioral pro-
blems (Chau et al., 2014), clinical complications (Kantake et al., 2014),
stress regulation capacities (Montirosso et al., 2016b), temperament
(Montirosso et al., 2016a), and brain development (Sparrow et al.,
2016). An overview of study design and timing of specific assessments
is reported in Fig. 3. In most of the studies, epigenetic and outcome
assessment overlapped, whereas Montirosso et al. (2016a,b) reported
on a longitudinal prospective study in which epigenetic assessment
preceded the evaluation of temperament and stress regulation at 3
months. The timing of outcome evaluation ranged from the first days
after preterm delivery to 7 years of age.
3.3. Epigenetic effects of prenatal conditions
Two studies focused on the association between prenatal adverse
conditions with changes in DNA methylation. Liu et al. (2012) enrolled
infants from depressed and non-depressed mothers, assessing DNA
methylation at imprinted genes (see Table 1). Infants from mothers
characterized by severe depressed mood (i.e., history of depression plus
depression in pregnancy) had higher methylation of MEG3 gene and
this difference was grater within female infants as well as in infants
from black women. No differences in MEG3 methylation emerged
among mothers with or without severe depression as well as those with
or without a preterm infant. Compared to normal birth weight infants,
low-birth weight infants had 1.6% lower IGF2 methylation and 5.9%
lower methylation at the PLAGL1 gene. Despite maternal stress was not
found to be associated with heightened risk of preterm birth, infants
from mothers who reported higher stress during pregnancy had 2.8%
increase in DNA methylation of the MEST gene, compared to control
infants (Vidal et al., 2014). This effect was more robust in females,
compared to male infants.
3.4. Epigenetic profile of preterm infants/children
Five studies highlighted an association between adverse conditions
and target genes’ methylation rate. Liu et al. (2012) showed that ma-
ternal depressed mood was associated with a more that 3-fold higher
L. Provenzi et al. Neuroscience and Biobehavioral Reviews 84 (2018) 262–271

Table 1
Studies included in the systematic review and main characteristics.

Study Infants characteristics Sample size Adversity Outcome

Liu et al. (2012) Preterm 464 (70 preterm) Maternal prenatal depression n.a.
Chau et al. (2014) Very preterm 111 (61 preterm) Pain-related stress Behavioral problems
Kantake et al. (2014) Preterm 40 (20 preterm) Pain-related stress Clinical complications
Vidal et al. (2014) Preterm 537 (79 preterm) Maternal prenatal stress n.a.
Lester et al. (2015) Preterm 67 (all preterm) Neurobehavioral risk n.a.
Provenzi et al. (2015) Very preterm 88 (56 preterm) Pain-related stress n.a.
Montirosso et al. (2016a) Very preterm 78 (48 preterm) Pain-related stress Temperament
Montirosso et al. (2016b) Very preterm 59 (32 preterm) Pain-related stress Stress regulation
Sparrow et al. (2016) Very preterm 72 (36 preterm) Unspecified White matter integrity

Note. n.a., not applicable.

Table 2
Description of epigenetic analyses and findings.

Study Tissue for methylation analysis Targeted genes Epigenetic variation

Liu et al. (2012) Peripheral blood IGF2, MEG3, MEST, PEG3, PEG10, NNAT, PLAGL1 ↑ MEG3; ↓ IGF2
Chau et al. (2014) Saliva SLC6A4 ↑ SLC6A4
Kantake et al. (2014) Cord blood, Peripheral blood NR3C1 ↑↓ SLC6A4
Vidal et al. (2014) Cord blood H19, IGF2, MEG3, MEST, PEG10, PEG3, NNAT, PLAGL1 ↑ MEST
Lester et al. (2015) Oral epithelial cells NR3C1, HSD11B2 ↑ NE3C1; ↓ HSD11B2
Provenzi et al. (2015) Cord blood, Peripheral blood SLC6A4 ↑ SLC6A4
Montirosso et al. (2016a) Cord blood, Peripheral blood SLC6A4 ↑ SLC6A4
Montirosso et al. (2016b) Cord blood, Peripheral blood SLC6A4 ↑ SLC6A4
Sparrow et al. (2016) Saliva Genome-wide ↑↓ genome-wide

Note. ↑, increase in methylation; ↓, decrease in methylation.

Table 3 and higher methylation in 1 CpG site of the NR3C1 gene in VPT new-
Quality appraisal of the included studies. borns compared to FT peers at birth. Notably, specific factors emerged
as predictors of CpG-specific methylation increases among preterm in-
Study A B C D E F FINAL
fants, including lower Apgar scores at 1 and 5 min, admission in NICU,
Liu et al. (2012) 2 2 1 2 1 2 1 and mode of delivery. A similar increment of NR3C1 methylation was
Chau et al. (2014) 2 2 2 2 1 3 2 detected in another study (Lester et al., 2015) in preterm infants. More
Kantake et al. (2014) 2 2 3 2 1 3 3
specifically, preterm infants who showed high risk of neurobehavioral
Vidal et al. (2014) 2 2 1 2 1 2 1
Lester et al. (2015) 2 2 1 2 1 3 2 problems at discharge had doubled methylation of the NR3C1 CpG3 site
Provenzi et al. (2015) 2 2 1 1 1 3 2 compared to the counterpart with low neurobehavioral risk. By con-
Montirosso et al. (2016a) 2 2 1 2 1 2 1 verse, lower methylation of the HSD11B2 gene at CpG3 was found to be
Montirosso et al. (2016b) 2 2 1 2 1 3 2 linked with higher neurobehavioral risk in the same sample. Chau et al.
Sparrow et al. (2016) 2 2 3 1 1 3 3
(2014) assessed the epigenetic profile of children born preterm at seven
Note. Labels: A, Selection bias; B, Study design; C, Confounders; D, Blinding; E, Data years, comparing them to full-term controls. Very preterm children had
collection methods; F, withdrawals and droup-outs. Quality codes: 1, strong; 2, moderate; significantly higher methylation of the SLC6A4 promoter (i.e., CpG sites
3, weak. 7-to-10). Sparrow et al. (2016) found an association between preterm
birth and hypo-methylation of SLC7A5 and SLC1A2. The SLC7A5 gene
risk of low birth weight. Newborn at low birth weight, in turn, had down-regulation is associated with impaired cell cycles (He et al., 2016)
1.6% lower IGF2 when compared with normal birth weight newborns. and it has a prominent role in the thyroid hormone uptake in fetal
This epigenetic effect was larger in females and newborns from black cortex (Chan et al., 2011). The SLC1A2 gene is the principal membrane-
women. Kantake et al. (2014) found lower methylation in 3 CpG sites bound transporter that clears the excitatory neurotransmitter glutamate

Fig. 3. Timing of adversity, methylation and

outcome assessment in the included studies.
Note. In Chau et al. (2014) paper the length
of NICU stay is not reported. Light and dark
blue striped markers indicate that, at least
partially, gestation and adversity exposure
overlapped. Violet and grey striped markers
indicate that epigenetic and outcome as-
sessment overlapped. (For interpretation of
the references to colour in this figure legend,
the reader is referred to the web version of
this article.)

266
L. Provenzi et al.
from the extracellular space at synapses in the central nervous system
(Sparrow et al., 2016). Moreover, they found that specific risk mod-
ulators of neurodevelopmental outcome after preterm birth (gender,
chorioamnionitis and early nutritional factors) explained a modest but
significant proportion of the variance in DNA methylation.
3.5. Epigenetic effects of NICU-related stress
As for NICU-related detrimental effects, such as the exposure to
painful procedures, environmental stressors and alteration of maternal
care, Kantake et al. (2014) that NR3C1 methylation increased at 11 CpG
sites and decreased at one CpG site from birth to day 4 in the preterm
newborns’ group, whereas it remained stable in term newborns across
the same post-natal period. Provenzi et al. (2015) reported that SLC6A4
methylation at CpG sites 5 and 6 significantly increased from birth to
NICU discharge. Importantly, the significant SLC6A4 increase was ob-
served only in very preterm infants exposed at high levels of pain-re-
lated stress, whereas it remained stable in the counterpart exposed to
low pain-related stress. When very preterm have been assessed at
school-age (i.e., 7 years), a different effect of NICU exposure to pain-
related stress was detected. Higher pain exposure during NICU stay was
significantly linked with lower methylation of SLC6A4, but only in
children carrying the met-homozygous genotype of the COMT
val158met polymorphism (Chau et al., 2014).
3.6. Developmental outcomes of epigenetic alterations in preterm infants/
children
Another issue concerning epigenetic modifications in preterm in-
fants is to assess how those changes are going to influence the future
development of the child. Sparrow et al. (2016) showed an association
between DNA methylation and white matter integrity and shape in the
phenotype of preterm infant at birth. This finding indirectly supports
the idea that preterm birth is a detrimental environmental stressor that
is closely associated with long-term alterations in connectivity of neural
systems. In preterm infants which were assessed for NR3C1 methylation
at birth and 4 days of life, a significant increase in methylation of the
CpG16 was associated with higher risk of complications during neo-
natal period (Kantake et al., 2014). Montirosso et al. (2016b) assessed
very preterm infants’ socio-emotional stress regulation at 3 months
(corrected age for prematurity) and compared them with a control
group of age-paired full-term controls. Socio-emotional stress regula-
tion was observed in response to acute and repeated exposures to ma-
ternal unresponsiveness (i.e., double-exposure Still-Face paradigm;
Provenzi et al., 2016; Tronick et al., 1978). In the Still-Face paradigm,
infants face socio-emotional stress elicited by the maternal display of
still and unexpressive face for about 2 min (Adamson and Frick, 2003;
Tronick et al., 1978). This experimental paradigm is a well-established
procedure to assess socio-emotional stress in healthy full-term
(Montirosso et al., 2015) and preterm (Montirosso et al., 2010) infants.
Greater SLC6A4 CpG2 methylation at NICU discharge predicted poorer
stress regulation in response to repeated socio-emotional stress ex-
posure in VPT infants compared to FT infants. Moreover, in the same
sample, greater SLC6A4 CpG5 methylation at NICU discharge predicted
less-than-optimal temperament profile at 3 months (Montirosso et al.,
2016a). Very preterm infants with higher CpG2 methylation of the
SLC6A4 gene had lower duration of orienting and approach compared
to full-term infants. Chau et al. (2014) highlighted that the amount of
behavioral problems reported by the mothers in very preterm 7-year-
old children were significantly associated with greater SLC6A4 me-
thylation. The same association was not highlighted in full-term age-
paired children.
4. Discussion
The present paper reports a systematic review of literature
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Neuroscience and Biobehavioral Reviews 84 (2018) 262–271
addressing epigenetic modifications observed in preterm infants in as-
sociation with prenatal and post-natal adverse and protective environ-
mental conditions.
4.1. PBE state of the art
First, the epigenetic effects of prenatal exposure to adverse condi-
tions in preterm infants have been assessed in two studies (Liu et al.,
2012; Vidal et al., 2014). Preterm infants from depressed mothers have
been found to have increased methylation of the MEG3 imprinted gene
(Liu et al., 2012), whose regions have been identified and hypothesized
to affect growth and development in both the placenta and the fetus
(Kagami et al., 2010; Skaar et al., 2012). Similarly, Vidal et al. (2014)
reported increased methylation of the MEST gene in preterm infants
exposed to maternal stress during pregnancy compared to controls from
mothers without significant depressive symptoms before delivery. The
MEST gene is involved in the metabolism pathways that affect growth
and maintenance of mesodermal cells (Kobayashi et al., 1997). Recent
studies on animal models suggest that this gene is up-regulated in off-
spring exposed to stress (Takahashi et al., 2005). Taken together, these
findings extend previous evidence on full-term infants to preterm ones,
suggesting that early exposure to adverse events during the third tri-
mester of pregnancy is capable to alter the epigenetic status of im-
printed and placenta-related genes which have relevant implications for
fetal development and preterm infants’ HPA stress reactivity during
infancy.
Second, five studies contributed to a preliminary profiling of pre-
term infants during the neonatal and perinatal period (Kantake et al.,
2014; Lester et al., 2015; Liu et al., 2012; Provenzi et al., 2015; Sparrow
et al., 2016). Kantake et al. (2014) highlighted differences in the me-
thylation rate of NR3C1. Preterm infants showed a significant increase
of CpG-specific NR3C1 methylation between postnatal days 0 and 4 and
after day 4 when compared to full-term infants, whose methylation
remained stable across the same post-natal period. Similarly, Lester
et al. (2015) described an increase of NR3C1 methylation associated
with preterm birth and high-risk neurobehavioral profiles. Sparrow
et al. (2016) documented a significant relationship between preterm
birth and hypo-methylation of SLC7A5 and SLC1A2 which are involved
in cell growth and regulate the synaptic cleft (Fiorentino et al., 2015).
On the other hand, Provenzi et al. (2015) reported that SLC6A4 me-
thylation at CpG sites 5 and 6 significantly increased from birth to NICU
discharge, while at birth there was no epigenetic difference between FT
and PTB. This conflicting data suggests a need for further studies aimed
to unearth possible epigenetic alterations specifically connected to
preterm birth.
Third, the effects of NICU-related stress on the epigenome of pre-
term infants were investigated in a subset of studies (Chau et al., 2014;
Kantake et al., 2014; Provenzi et al., 2015). Kantake et al. (2014) have
the merit of suggesting that the postnatal environment influences epi-
genetic programming in premature infants: NICU hospitalization was
correlated to higher DNA methylation. Nonetheless, no specific in-
formation about NICU-related stressful factors was provided. To this
extent, Provenzi et al. (2015) observed a significant association be-
tween frequent painful procedures and higher SLC6A4 methylation.
Chau et al. (2014) pointed out a negative association between pain
exposure and SLC6A4 methylation at 7 years. Although further studies
are needed to deeply understand the direction of epigenetic modifica-
tions connected to NICU-related stress, these findings are consistent and
suggest a specific epigenetic effect of early pain exposure which might
persist during childhood.
Finally, developmental outcomes associated with early epigenetic
markers of adversity in preterm infants have been addressed by five
studies (Chau et al., 2014; Kantake et al., 2014; Montirosso et al.,
2016a,b; Sparrow et al., 2016). Concerning behavioral outcomes, Chau
et al. (2014) pointed out that mothers of 7-years-old very preterm
children reported grater amount of behavioral problems, and this was
L. Provenzi et al.
associated with greater SLC6A4 methylation. On the socio-emotional
development side, Montirosso et al. (2016a,b) showed that greater
SLC6A4 CpG2 methylation at NICU discharge was associated with
poorer stress regulation in response to repeated socio-emotional stress
in very preterm infants and less-than-optimal temperament profile at 3
months. Moreover, very preterm infants had lower duration of orienting
and approach compared to full-term infants. The same association was
not highlighted in full-term age-paired children. In another study, a
significant association between DNA methylation and white matter
integrity and shape in the phenotype of preterm infant at birth emerged
(Sparrow et al., 2016). In Kantake et al. (2014) NR3C1 methylation
increase predicted higher risk of complications during neonatal period.
Taken together these findings suggest that precocious NICU-related
epigenetic alterations of stress-related genes associated with less-than-
optimal developmental outcomes. As such, precocious methylation of
these genes (e.g., SlC6A4, NR3C1) appears to be a potential biomarker
of early adversity which contributes to detrimental consequences for
neurobehavioral and socio-emotional development later in life.
4.2. Future directions in this field
The findings reported here are promising. Nonetheless, we are still
at the beginning of our exploration of PBE. Here we would like to
highlight specific issues and directions for future research.
First, as preterm infants have been found to exhibit altered methy-
lation at both imprinted and stress-related genes, these alterations de-
serve future investigation. Imprinted genes function as critical growth
effectors and regulators of development since they are maintained in all
somatic tissues (Ideraabdullah et al., 2008). Altered methylation of
these genes affect embryonic growth and development in the placenta.
Understanding imprinted genes regulation is critical, as a significant
proportion of these human genes are implicated in complex diseases
(Vickers, 2014) and in the mechanisms that lead to preterm birth (Liu
et al., 2012). Furthermore, a proper human imprintome map would
enhance the ability to identify risk factors of preterm birth end, even-
tually, prevent it (Skaar et al., 2012). Stress-related genes epigenetic
alterations due to early adverse experiences have been associated to
HPA and serotoninergic system modifications (Griffiths and Hunter,
2014). For this reason, NICU-related stress contributes to heightened
risk for altered stress regulation capacities in preterm infants and the
study of increased methylation of stress-related genes is warranted to
become of specific scientific and clinical concern in this population. The
epigenetic approach might help to fill the explanatory gaps between the
influences of gene and environment on stress responsiveness, revealing
pathways through which early adversities are embedded in the devel-
oping biology of children, and the contribute of these genes on the long-
lasting programming of health and disease (Roth and Sweatt, 2011).
The papers reported here only partially covered the PBE areas of
scientific investigations (Montirosso and Provenzi, 2015). Emerging
evidence corroborates the hypothesis that preterm infants might pre-
sent altered epigenetic status of imprinted and stress-related genes and
that these alterations might be at least partially related to the early
exposure to prenatal and post-natal adverse environments. Nonetheless,
it is still uninvestigated the hypothesis that NICU-related protective
factors (e.g., DC strategies) might exert significant buffering effects in
the face of early stress-related epigenetic variations. These variations
have been found to have long-lasting behavioral and neurological
outcomes for short- (Montirosso et al., 2016a,b) and long-term (Chau
et al., 2014) development. As such, we suggest that future research
should investigate the potential protective role of NICU-related DC in-
terventions in reversing or partially reducing the methylation increased
status observed in preterm infants exposed to maternal depression/
stress as well as high levels of pain-related stress during NICU stay.
Intriguingly, Murgatroyd et al. (2015) reported that increased maternal
stroking at 5 weeks specifically reduced NR3C1 methylation in infants
exposed to maternal depression. By contrast, there was no effect of
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Neuroscience and Biobehavioral Reviews 84 (2018) 262–271
maternal stroking at 9 weeks of age, highlighting the importance of
timing of early intervention and caregiving support. Speculatively, one
might wonder if DC strategies which are directed at supporting the
early mother-infant contact and bonding in NICU by favoring physical
contact exert similar benefits to preterm infants.
Moreover, it should be considered that preterm infants represent a
heterogeneous group, varying on the basis of a set of perinatal and
medical variables (e.g., birth weight, gestational age, clinical compli-
cations, etc.). As such, preterm infants born at different gestational ages
and birth weight, for instance, might present very different develop-
mental trajectories. It appears reasonable to speculate that extremely
preterm infants (< 28 weeks gestational age) and/or very preterm in-
fants (28 to < 32 weeks gestational age) might be exposed to greater
and prolonged stressors during a period in which they are much more
immature and sensitive to environmental stimulations compared to late
preterm counterparts (gestational age > 34 weeks). Consequently, re-
search is needed to investigate how epigenetic mechanisms might be
involved among different preterm infants’ populations.
Finally, we need prospective longitudinal studies in the PBE field of
research (Provenzi and Montirosso, 2015). Many researches are sug-
gesting that the exposure to precocious adversities, such as the medi-
calized and technological environment of the NICU, is able to program
the risk of later-in-life chronic health conditions (Vaiserman, 2015). At
least partially, this programming of health and disease is owing to
epigenetic processes. The application of epigenetic research to the field
of prematurity holds the promise of revealing the biochemical pathways
bridging the gap between early stress and the programming of health
and disease in later life. For this reason, longitudinal and perspective
studies looking at the effects of early NICU related stress on behavioral,
emotional and neurological development are expected to deepen our
understanding of the pathways leading to heightened risk for adverse
developmental outcomes in preterm infants (Provenzi et al., 2017).
4.3. Methodological challenges for future research
The application of the epigenetics lens to the study of human de-
velopment − especially in at risk infants and children − is also fea-
tured with specific methodological challenges. Moreover, the PBE re-
search field implies specific challenges which should be addressed in
future research. Here we review some of these challenges, as they arose
from the literature to date.
First, it should be considered that despite all the included studies
reported on the tissue on which methylation was assessed, the specifi-
cation of cell types was not always stated. The cell-type source of me-
thylation data should be clearly reported in future studies as it might be
a non-controlled source of variation which can seriously impact on
generalizability and consistency among different studies with the risk of
misleading conclusions for the same population of infants and children
(e.g., preterm birth status). Second, it is obvious that brain tissue is not
accessible in living humans and behavioral epigenetic studies are often
conducted using peripheral tissue for identifying methylation markers.
Unfortunately, we only have partial confirmation that methylation as-
sessed among different tissue types is comparable (Iwamoto et al.,
2011; Roth, 2013). Nonetheless, it should be highlighted that previous
research is suggestive of partial concordance between methylation
measured in umbilical cord blood cells and peripheral blood cells in
healthy individuals (Tabano et al., 2010). Similarly, DNA methylation
from saliva appears to be partially similar to patterns of methylation
from brain tissues, including cerebellum, frontal cortex, entorhinal
cortex, and superior temporal gyrus (Smith et al., 2016).
Third, when it comes to the PBE research field, further challenges
arise, including the need of careful and precise segmentation of the
sample, careful longitudinal assessments, and adequate control of
clinical confounders. As reported in the present review, it is fairly
common that preterm samples include infants with different gender and
race. These variables are not secondary and should be part of adequate
L. Provenzi et al.
balancing when samples of preterm infants are included in PBE research
projects. Indeed, we know that there are well-acknowledged racial and
ethnic disparities in preterm birth and both genetic and environmental
factors might be involved (Burris et al., 2011; Fiscella, 2005). Dukal
et al. (2015) showed that female newborns have higher stress- and
genotype-independent cord-blood methylation of the serotonin trans-
porter gene compared to males. Other variables should be considered in
defining the sample. Low birth weight is not synonymous of premature
delivery and recent research documents altered HSD11B2 methylation
patterns in small for gestational age newborns, which suggests that
birth weight and gestational age might be differentially implicated in
epigenetic changes at birth (Lazo-de-la-Vega-Monroy et al., 2017).
Additionally, many preterm infants develop neurobehavioral and sen-
sory deficits, mainly in association with brain injuries which are only
limitedly evident at birth (Volpe, 2009). The multiple clinical con-
founders result in limited sample availability and the presence of
morbidities in these infants should be continuously monitored
throughout the NICU stay and, once clinical morbidities are considered
exclusion criteria, this may lead to high mortality rates for the sample
in longitudinal studies.
4.4. Clinical implications
The PBE research area holds the potential to be beneficial for
perinatal care in NICUs. Here, we would like to highlight three main
consequences of PBE research findings which might inform better and
smarter strategies of preterm infants’ care during early life.
First, PBE research might contribute to the precocious individuation
of biological markers of early adversities and developmental risk as-
sociated with prematurity and early exposure to NICU-related stress.
Indeed, the research reviewed here suggests that early epigenetic al-
terations might impact the development of stress regulation capacities
with associated detrimental consequences for behavioral, neurological
and socio-emotional development.
Second, as future research is going to address the epigenetic vestiges
of protective interventions, it might be speculated that PBE studies
might document (de-)methylation mechanisms associated with DC
strategies, thus revealing potential markers of protective care in NICU
(Maddalena, 2013). Previous animal studies, suggested that early ex-
posure to high-quality caregiving (e.g., adequate maternal care in rats,
Meaney and Szyf, 2005) is capable to reverse early methylation in-
creases associated with stressful conditions. It is intriguing to hy-
pothesize that NICU-related care might provide such an epigenetic
protection to the neurobehavioral and socio-emotional development of
infants and children born preterm.
Third, by highlighting multiple sources of environmental con-
tributors to epigenome regulation, the PBE research field might help to
avoid a reductionist approach to human behavioral epigenetics.
Obviously, the methylation changes related to the exposure to early
adversities and protective environments is meant to be considered as
one potential mechanism of the developmental origin of health and
disease in at-risk populations. Our point of view is that epigenetics
might help us in understanding more deeply the mechanisms thorough
which the quality of early developmental contexts contribute to the
phenotype of individuals later in life. Nonetheless, there are more
factors beside the epigenetic ones that are involved and are key to the
developmental trajectories of human infants and children. Notably,
researchers in the field of human behavioral epigenetics have been
recently warned about the lure of epigenetics and the risk of translating
animal results and interpreting human findings in a strict deterministic
way (Richardson et al., 2014). As preterm birth and NICU stay is
characterized by numerous protective and risk-related environmental
factors, PBE would stand as a paradigmatic case to show that epigenetic
mechanisms are only a piece of the puzzle and PBE investigations
should be embedded within more complex theoretical and methodo-
logical frameworks.
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Neuroscience and Biobehavioral Reviews 84 (2018) 262–271
Conflicts of interest
None.
Funding source
This study was supported by the Italian Ministry of Health (RC/01-
03, 2012-2014 and RC/01-05, 2015-2017).
Acknowledgments
We would like to thank Caterina Sala, librarian at the Scientific
Institute IRCCS Eugenio Medea for her help in data mining and ab-
stracting. Finally, we are specially thankful to Renato Borgatti for his
invaluable support and mentoring activity.
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