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RESEARCH ARTICLE
STRESS
2024, VOL. 27, NO. 1, 2321595
Dierential impact of prenatal PTSD symptoms and preconception
trauma exposure on placental NR3C1 and FKBP5 methylation
Laura R. Strouda,b, Nancy C. Jaoc, L. G. Warda,b, Sharon Y. Leea,b and Carmen J. Marsitd
aCOBRE Center for Stress, Trauma, and Resilience*, Center for Behavioral and Preventive Medicine, The Miriam Hospital, Providence, RI, USA;
bDepartment of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI, USA; cDepartment of Psychology,
Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA; dGangarosa Department of Environmental Health, Emory
University Rollins School of Public Health, Atlanta, GA, USA
ABSTRACT
Perinatal stress is associated with altered placental methylation, which plays a critical role in fetal
development and infant outcomes. This proof-of-concept pilot study investigated the impact of
lifetime trauma exposure and perinatal PTSD symptoms on epigenetic regulation of placenta
glucocorticoid signaling genes (NR3C1 and FKBP5). Lifetime trauma exposure and PTSD symptoms
during pregnancy were assessed in a racially/ethnically diverse sample of pregnant women (N = 198).
Participants were categorized into three groups: (1) No Trauma (−T); (2) Trauma, No Symptoms
(T − S); and (3) Trauma and Symptoms (T + S). Placental tissue was analyzed via bisulfite
pyrosequencing for degree of methylation at the NR3C1 promoter and FKBP5 regulatory regions.
Analyses of covariance were used to test group differences in percentages of NR3C1 and FKBP5
methylation overall and at each CpG site. We found a significant impact of PTSD symptoms
on placental NR3C1 methylation. Compared to the −T group, the T + S group had greater NR3C1
methylation overall and at CpG6, CpG8, CpG9, and CpG13, but lower methylation at CpG5. The T + S
group had significantly higher NR3C1 methylation overall and at CpG8 compared to the T − S group.
There were no differences between the T − S group and − T group. Additionally, no group differences
emerged for FKBP5 methylation. Pregnant trauma survivors with PTSD symptoms exhibited
differential patterns of placental NR3C1 methylation compared to trauma survivors without PTSD
symptoms and pregnant women unexposed to trauma. Results highlight the critical importance of
interventions to address the mental health of pregnant trauma survivors.
1. Introduction
It is estimated that one in every two women will experience
at least one traumatic event in their lifetime (National Center
for Posttraumatic Stress Disorder, 2021). Overall, women are
more likely than men to experience the kinds of traumatic
exposures most strongly associated with posttraumatic stress
disorder (PTSD), such as sexual violence and childhood sexual
abuse (Liu et al., 2017). In pregnant women, rates of perinatal
PTSD are estimated to be 3.3% in community samples (Cook
et al., 2018) and 18.95% in high-risk samples (Yildiz et al.,
2017), with estimates as high as 27–58% for the presence of
any PTSD symptoms among pregnant women with lifetime
trauma exposure (Harris-Britt et al., 2004; Seng et al., 2010).
Previous studies have linked both lifetime trauma exposure
and perinatal PTSD symptoms to adverse maternal health and
child development outcomes (Cook et al., 2018; Racine et al.,
2018). In particular, perinatal PTSD symptoms may confer
unique risk – above and beyond the effects of mere exposure
to trauma – for the transmission of trauma-related effects.
The hypothalamic-pituitary-adrenal (HPA) axis, which regu-
lates the neuroendocrine response to stress, plays a poten-
tially critical role in the intergenerational transmission of
trauma (Bowers & Yehuda, 2016). Glucocorticoids act as the
primary hormonal modulator of the endocrine stress response
by allowing, stimulating, and suppressing a stress response as
well as preparing the body for future stressors (Sapolsky
et al., 2000). Additionally, glucocorticoids modulate psycho-
logical responses to stress, including the encoding of stress
memory (Kaouane et al., 2012) and development of PTSD
(Szeszko et al., 2018). The NR3C1 promoter is one of the main
genes involved in glucocorticoid signaling and modulating
the stress response and can be altered via epigenetic pro-
gramming (Palma-Gudiel, Cordova-Palomera, Leza, et al.,
2015). Epigenetic regulation represents the control of gene
expression in a mitotically heritable fashion. The most studied
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
CONTACT Laura R. Stroud Laura_Stroud@brown.edu Center for Behavioral and Preventive Medicine, Coro West, Suite 309, 164 Summit Avenue, Providence,
RI 02906, USA
Supplemental data for this article can be accessed online at https://doi.org/10.1080/10253890.2024.2321595.
https://doi.org/10.1080/10253890.2024.2321595
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted
Manuscript in a repository by the author(s) or with their consent.
ARTICLE HISTORY
Received 4 September 2023
Accepted 16 February 2024
KEYWORDS
NR3C1; FKBP5; placenta;
trauma; PTSD; pregnancy
2 L. R. STROUD ET AL.
form of epigenetic regulation in humans is DNA methylation,
a modification of the cytosine nucleotide in a cytosine-guanine
(CpG) dinucleotide sequence. DNA methylation in the pro-
moter regions of genes is often indicative of gene silencing
while DNA methylation in other genic regions can have more
complicated effects on gene expression. While the majority of
cellular DNA methylation is erased and then reset in a cell
and tissue-specific fashion, there is evidence that some cases
of de novo methylation established in one generation may be
propagated into the subsequent generations or may be
established in offspring due to experiences of the parents
(Perez & Lehner, 2019). Lifetime trauma exposure and PTSD
symptoms can lead to epigenetic changes in the regulation
of the HPA axis as well as the NR3C1 promotor gene (González
Ramírez et al., 2020; Palma-Gudiel, Cordova-Palomera, Leza,
et al., 2015; Sheerin et al., 2020).
Prior research has demonstrated that epigenetic mecha-
nisms may mediate the effects of prenatal and early life stress
on offspring development by promoting changes in methyla-
tion of the promoter region of NR3C1 (Ostlund et al., 2016;
Parade et al., 2021; Tyrka et al., 2012). For instance, among
individuals with prenatal PTSD, infants’ cortisol levels have
been associated with their NR3C1 methylation levels
(Fransquet et al., 2022). This research mirrors rodent models
in which early life stress (modeled by very low levels of post-
natal care) alters hippocampal glucocorticoid regulation.
Specifically, early life stress increases methylation of the
rodent analog of NR3C1, the hippocampal glucocorticoid reg-
ulation gene (exon 17 of the NR3C1 promoter), which alters
binding of the transcription factor NGFI-A as well as other
aspects of the stress response (Meaney etal., 2007; Szyf etal.,
2007) – leading to exacerbated stress responses in offspring
well into adulthood. The majority of human-based research
on epigenetic programming related to maternal adversity and
mental health has measured NR3C1 promoter methylation in
buccal cells, or peripheral or cord blood of infant offspring
(Dereix et al., 2021; Mulligan et al., 2012; Ostlund et al., 2016;
Parade et al., 2021; Tyrka et al., 2012).
The placenta offers a unique window into the
maternal-fetal interface as it serves an important regulatory
role in gestational development, endocrine, and metabolic
transmission between mother and fetus as well as provides
fetal protection from potentially harmful elements of the
maternal environment (Bonnin & Levitt, 2011; Maccani &
Marsit, 2009). Prenatal exposure to traumatic events, such as
a natural disaster, has been associated with altered placental
gene expression (Zhang et al., 2020) and reprogramming of
the placental transcriptome which has been associated with
child HPA dysfunction (Nomura et al., 2021). Other psycho-
logical risk factors, such as trait and state prenatal anxiety
have been associated with increased methylation of placen-
tal NR3C1 (Capron et al., 2018; Dereix et al., 2021).
Associations between methylation of placental NR3C1 and
alterations in newborn neurobehavior and cortisol stress
reactivity have also been demonstrated (Appleton et al.,
2015; Bromer et al., 2013; Conradt et al., 2015), indicating
that placental NR3C1 methylation may mediate the effects
of maternal stress on infant outcomes. However, little is
known about the degree to which experiences of current
PTSD symptoms during pregnancy may affect the associa-
tion between maternal trauma exposure and methylation of
placental NR3C1.
Moreover, current PTSD symptoms during pregnancy may
have additional effects on methylation of placental NR3C1
that are above and beyond the effects of trauma exposure.
Some types of trauma exposure, such as early life stress, have
been shown to not only strongly associate with DNA methyl-
ation, but also interact with specific genes implicated in many
psychiatric disorders to predict PTSD (Caspi etal., 2010; Heim
& Binder, 2012). Indeed, a high number of glucocorticoid
receptors is a pre-trauma risk factor for PTSD development
(van Zuiden et al., 2013; Yehuda, 2009). Prior studies have
looked at the effects of either trauma exposure or PTSD on
NR3C1 methylation, but with inconsistent findings across
studies of the associated CpG sites within NR3C1 (Watkeys
et al., 2018), suggesting distinct contributions of trauma
exposure and trauma-related sequalae to NR3C1 methylation.
Several studies have examined the associations of maternal
trauma and stress with placental NR3C1 methylation (see
Palma-Gudiel et al., 2018 for review), with some studies of
specifically maternal trauma exposure reporting increased
methylation (Mulligan et al., 2012; Nomura et al., 2021) and
others reporting reduced methylation (Kertes et al., 2016).
However, no studies to our knowledge have compared the
distinct contributions of lifetime trauma exposure and PTSD
symptoms to placental NR3C1 methylation.
In addition to NR3C1, FK506 binding protein 5, encoded by
the gene FKBP5, is a modulator of NR3C1 activity and the HPA
stress response, further justifying the importance of focusing
on both NR3C1 and FKBP5 methylation in relation to lifetime
trauma exposure and PTSD symptoms. When FKBP5 binds to
the glucocorticoid receptor, it decreases the ability of the glu-
cocorticoid receptor to bind to cortisol, resulting in reduced
glucocorticoid receptor sensitivity and impaired negative
feedback regulation of the HPA axis. FKBP5 demethylation has
been proposed as a mediator of the combined effects of
gene x environment on risk of PTSD development (Klengel
et al., 2013). FKBP5 methylation has been implicated in the
intergenerational transmission of trauma exposure, with
higher methylation found in Holocaust survivors compared to
controls but lower methylation found in survivors’ offspring
compared to the offspring of controls (Bierer et al., 2020;
Yehuda et al., 2016). In placental tissue specifically, higher
methylation at CpG1 and CpG2 sites in FKBP5 intron 7 has
been associated with high arousal in infants, reflecting hyper-
reactivity to environmental stimuli (Paquette etal., 2014).
This study is a proof-of-concept pilot study investigating
the differential impact of trauma exposure in addition to
current PTSD symptoms during pregnancy vs trauma expo-
sure without current PTSD symptoms on methylation of the
promoter region of placental NR3C1. We hypothesize that
trauma exposure combined with current PTSD symptoms
will lead to greater methylation of placental NR3C1, indicat-
ing potential changes in methylation for the fetus, com-
pared to trauma exposure without PTSD symptoms.
Additionally, given the role of FKBP5 in altering the
glucocorticoid receptor’s responsiveness to stress signaling,
we conducted exploratory analyses to test for differential
STRESS 3
impact of trauma exposure and current PTSD symptoms vs.
trauma exposure without PTSD symptoms on placental
FKBP5 methylation.
2. Methods
2.1. Participants
Participants were English-speaking, primarily low-income
pregnant women from a racially and ethnically diverse sam-
ple who completed the epigenetic sub-study of a prospective
study examining the effect of maternal behaviors in preg-
nancy and infant behavioral development over the first post-
natal month. Participants were recruited from obstetrical
offices, health centers, and community postings across south-
ern New England. Pregnant women were eligible for enroll-
ment if they were between 18 and 40 years old, had a
singleton pregnancy, did not have current/prior involvement
with child protective services, and had no illicit drug use
besides marijuana or serious medical conditions (e.g.
pre-eclampsia and severe obesity). Participants provided writ-
ten informed consent, and followed procedures reviewed and
approved by Institutional Review Boards at Women and
Infants Hospital and Lifespan Hospitals of Rhode Island. See
Supplementary Table 1 for enrollment flow chart.
2.2. Study procedures and measures
2.2.1. Maternal and infant characteristics
Pregnant women were interviewed prospectively over second
and third trimesters of pregnancy and at delivery (M = 3 inter-
views (range 2–4) between 24 and 42 weeks gestation). At
each interview, participants completed the calendar/
anchor-based Timeline Follow Back (TLFB) interview regarding
smoking, drug, and alcohol use over pregnancy and three
months prior to conception (Robinson etal., 2014). Participants
also completed a socioeconomic status (SES) interview from
which education, occupation, income, and Hollingshead
four-factor index of SES were extracted (Gottfried, 1985).
Information regarding maternal and infant health and medi-
cal conditions (e.g. pre-eclampsia and gestational diabetes)
was extracted by medical chart review. Tobacco use during
pregnancy was confirmed using cotinine from maternal saliva
collected at each interview as well as post-birth infant
meconium.
2.2.2. Self-reported trauma history and symptoms
Utilizing the Psychiatric Diagnostic Screening Questionnaire
(PDSQ) self-report measure (Zimmerman & Mattia, 2001), par-
ticipants were asked whether they have ever experienced or
witnessed a potentially traumatic event (e.g. combat, rape,
assault, sexual abuse). Participants who endorsed experienc-
ing or witnessing a potentially traumatic event were asked
whether they experienced any of the 13 symptoms based on
Diagnostic and Statistical Manual of Mental Disorders IV
(DSM-IV) criteria for PTSD within the last two weeks (e.g.
intrusive thoughts, negative emotions, upsetting dreams,
jumpiness, emotional numbness, and flashbacks related to
the traumatic event) (American Psychiatric Association, 1994).
Participants were then categorized into one of three trauma
groups: (1) individuals who denied ever experiencing or wit-
nessing a traumatic event were categorized in the “–T” (i.e. no
trauma) group; (2) individuals who endorsed ever experienc-
ing or witnessing a traumatic event, but denied any
PTSD-related symptoms were categorized in the “T–S” (i.e.
trauma without symptoms) group; and (3) individuals who
endorsed ever experiencing or witnessing a traumatic event,
and also endorsed experiencing any PTSD-related symptoms
in the last two weeks were categorized in the “T + S” (i.e.
trauma with symptoms) group.
2.2.3.Placental NR3C1 and FKBP5 methylation
Following birth, placental tissue that was free from maternal
decidua was excised and placed immediately in RNAlater
solution at 4 degrees Celsius (Life Technologies, Grand Island,
NY). After 72 h, placental tissue samples were removed from
the RNAlater solution, blotted dried, snap-frozen in liquid
nitrogen, pulverized to homogeneity, and stored at −80 °C.
Placental genomic DNA was extracted using the QIAmp DNA
Mini kit (Qiagen, Inc., Valencia, CA) and assessed for quantity
and quality using a ND-1000 Spectophotometer (Nanodrop,
Wilmington, DE). DNA samples were sodium bisulfite modi-
fied using the EZ DNA Methylation Kit (Zymo Research,
Irvine, CA), with degree of methylation at the NR3C1 pro-
moter and FKBP5 regulatory regions examined via quantita-
tive pyrosequencing (Dupont, 2004; Oberlander, 2008) using
the PyroMark MD Pyrosequencing System. The NR3C1 pro-
moter region analyzed encompasses exon 1 F (human homo-
logue of rat exon 17), and contains 13 CpG sites, while the
regulatory region in intron 7 of FKBP5 containing 2 CpG sites
(CpG1 and CpG2) was analyzed. Methylation in both of these
regions has been shown to negatively correlate with gene
expression (Bromer et al., 2013; Paquette et al., 2014). See
Supplementary Table 2 for corresponding genomic coordi-
nates. Reactions were performed in triplicate, with SDs for
individual sites calculated. Any sample with SD > 3% was
re-analyzed. Sodium bisulfite-modified, fully-methylated ref-
erent positive control, and fully unmethylated (whole genome
amplified) negative control DNA (Qiagen, Valencia, CA) were
also included with each batch.
2.3. Statistical analysis
All statistical analyses were conducted using IBM SPSS Statistical
version 27 (IBM Corp., Armonk, NY). Differences between the
three trauma group categories (−T vs. T − S vs. T + S) in maternal
and infant characteristics were assessed using chi-square and
analysis of variance (ANOVA). Due to non-normal distributions,
CpG methylation outcomes for NR3C1 and FKBP5 were natural
logarithm transformed. We then compared differences in meth-
ylation percentages between trauma groups overall and at
each CpG site utilizing separate analyses of covariances
(ANCOVA) controlling for maternal education, gravida, and
tobacco use. Post-hoc pairwise comparisons adjusted with
Bonferroni corrections were also conducted to examine specific
between-group differences.
4 L. R. STROUD ET AL.
3. Results
3.1. Participant characteristics
The sample included 198 pregnant women (Mage = 25.4,
SD = 5.0) of whom 50% were tobacco users. A total of 133
(67.2%) participants denied any history of trauma or current
PTSD symptoms (−T group), 23 (11.6%) participants endorsed
a history of trauma but denied any current PTSD symptoms
(T − S group), and 42 (21.2%) participants endorsed both a
history of trauma and current PTSD symptoms (T + S group).
In the T + S group, participants endorsed an average of 4.02
(SD = 3.21) PTSD symptoms. Participant sociodemographic
characteristics overall and by group (−T vs. T − S vs. T + S) are
detailed in Table 1. Regarding maternal characteristics, there
were statistically significant differences in gravida (p = 0.006)
and parity (p = 0.015) between trauma groups, where the T + S
group reported higher gravida and parity compared to the − T
group. There was also a difference in amount of tobacco use
during pregnancy between trauma groups (p = 0.004), where
69.0% of the T + S and 60.9% of the T − S groups had tobacco
use during pregnancy compared to 41.4% of the −T group.
There were no significant differences between groups for any
other maternal or infant characteristics (ps > 0.068).
3.2. Association between trauma groups and placental
NR3C1 and FKBP5 methylation
Figure 1 shows differences between groups in raw means for
percentage of NR3C1 methylation (n = 166 with available data on
NR3C1) overall and at each individual CpG site. There was a sta-
tistically significant effect of trauma group categorization on per-
centage of placental gene methylation across all CpG sites
(F(2,165) = 4.797, p = 0.009), where the T + S group had signifi-
cantly higher percentages of methylation overall compared to
the −T and T − S groups (T + S vs. −T, p = 0.020; T + S vs. T − S,
p = 0.009). For individual CpG sites, there was a statistically
significant effect of trauma group categorization on the percent-
ages of placental gene methylation at the CpG5 (F(2,165) = 5.985,
p = 0.003), CpG6 (F(2,165) = 5.611, p = 0.004), CpG8 (F(2,165) =
4.650, p = 0.011), CpG9 (F(2,165) = 4.517, p = 0.012), and CpG13
sites (F(2,165) = 5.309, p = 0.006). Specifically, compared to the − T
group, the T + S group had a significantly lower percentage of
methylation at the CpG5 site (p = 0.009), but significantly higher
percentages of methylation at the CpG6 (p = 0.003), CpG8
(p = 0.021), CpG9 (p = 0.019), and CpG13 (p = 0.006) sites. The T + S
group also had a significantly higher percentage of methylation
at the CpG8 site compared to the T − S group (p = 0.037), but
there was not a statistically significant effect of trauma group cat-
egorization at the CpG7 (F(2,165) = 1.326, p = 0.268) or CpG4
(F(2,165) = 2.259, p = 0.108) sites. In examining percentage of
FKBP5 methylation at each site (n = 156 with available data on
FKBP5), there were no significant effects of trauma group catego-
rization on placental gene methylation overall, or at either the
CpG1 or CpG2 site (ps > 0.05), as shown in Figure 2. See Table 2
for unadjusted and adjusted group comparisons of placental
NR3C1 and FKBP5 methylation.
4. Discussion
This study provides suggestive evidence that prenatal PTSD symp-
toms uniquely contribute to patterns of placental NR3C1 methyla-
tion that are not solely explained by trauma exposure alone.
Overall, we found the Trauma + PTSD Symptoms (T + S) group
demonstrated higher placental NR3C1 methylation compared to
the No Trauma (−T) and Trauma without PTSD symptoms (T − S)
groups. Specifically, the T + S group had higher methylation at the
CpG6, CpG8, CpG9, and CpG13 sites compared to the −T group,
with the exception of the CpG5 site, as well as higher methylation
at the CpG8 site compared to the T − S group.
Although this study is the first, to our knowledge, to inves-
tigate the impact of both trauma exposure and PTSD symp-
toms on placental NR3C1 methylation, findings complement
Table 1. Participant characteristics.
Overall
(N = 198)
Trauma groups
p
No trauma
(−T; n = 133)
Trauma without
PTSD symptoms
(T − S; n = 23)
Trauma with PTSD
symptoms
(T + S; n = 42)
Maternal characteristics
Age (mean, SD)25.4 (5.0) 25.3 (5.1) 26.4 (4.8) 25.4 (4.9) 0.602
Ethnicity (% Hispanic) 39.3% 37.4% 26.1% 52.4% 0.087
Race (% non-White) 60.6% 63.2% 39.1% 64.3% 0.080
% American Indian/Alaskan Native 3.0 1.5 13.0 2.4 –
% Asian 3.0 2.3 4.3 4.8 –
% Black/African American 19.7 24.1 4.3 14.3 –
% White 39.4 36.8 60.9 35.7 –
% More than one race 8.1 7.5 8.7 9.5 –
% Unknown/not reported 26.8 27.8 8.7 33.3 –
Education (% high school or less) 53% 55.6% 30.4% 57.1% 0.068
Hollingshead SES index (% low SES) 57.2% 59.2% 45.5% 57.1% 0.482
Gravida (mean, SD)2.5 (1.6) 2.3 (1.5) 2.6 (1.7) 3.2 (1.8) 0.006*
Parity (mean, SD)0.90 (1.09) 0.78 (.99) 0.83 (.89) 1.33 (1.39) 0.015*
Infant characteristics
Sex (% female) 49.5 % 50.4% 36.4% 53.7% 0.398
GA in weeks (mean, SD)39.4 (1.4) 39.4 (1.4) 39.6 (.85) 39.3 (1.6) 0.685
Birth weight in grams (mean, SD)3351.56 (494.8) 3342.2 (490.3) 3362.6 (393.2) 3374.9 (565.2) 0.931
Small for gestational age (% yes) 5.9% 4.0% 4.5% 12.5% 0.133
Any tobacco exposure (% exposed) 49.5% 41.4% 60.9% 69.0% 0.004*
Note. *p < 0.05, signicant dierences between trauma groups based on chi-square and ANOVA analyses.
STRESS 5
prior studies of maternal stress, broadly defined. A
meta-analysis of seven studies concluded that different
types of prenatal stress are associated with increased off-
spring CpG site-specific methylation in the exon 1 F of
NR3C1 (Palma-Gudiel, Córdova-Palomera, Eixarch, et al.,
2015). However, whether higher placental NR3C1 methyla-
tion associated with maternal PTSD symptoms impacts
infant development remains to be investigated. Prior studies
suggest greater methylation of placental genes may selec-
tively affect some infant outcomes but not others, such as
infant temperament (Finik et al., 2020). Greater placental
methylation related to maternal psychopathology, in partic-
ular, may confer risk for poorer infant development (Conradt
et al., 2013). Compared to infants with mothers who did not
report depression, infants of depressed mothers with greater
placental NR3C1 CpG2 methylation demonstrated poorer
self-regulation, more hypotonia, and more lethargy on neu-
robehavioral assessments (Conradt et al., 2013). Future
research is needed to elucidate whether and precisely which
epigenetic mechanisms mediate the effects of maternal
trauma exposure and PTSD symptoms on infant stress
response and neurobehavioral development.
Figure 1. Mean (SEM) of % NR3C1 Methylation, overall and at each CpG site. Note. *p < 0.05; **p < 0.01; ***p < 0.005. Raw mean (SEM) scores are depicted here
prior to logarithmic transformations. Signicant between group dierences are depicted based on pairwise comparisons controlling for gravida and adjusted for
multiple comparisons with Bonferroni correction.
Figure 2. Mean (SEM) of % FKBP5 Methylation, overall and at each CpG site. Note. *p < 0.05, **p < 0.01, ***p < 0.005. Raw mean (SEM) scores are depicted here
prior to logarithmic transformations. Signicant between group dierences are depicted based on pairwise comparisons controlling for gravida and adjusted for
multiple comparisons with Bonferroni correction.
6 L. R. STROUD ET AL.
Our findings highlight the importance of identifying fac-
tors that may offset the impact of maternal stress on the
infant stress response and development. Animal studies with
mice have shown that a stress reduction intervention (i.e.
chew toy) buffered the effects of prenatal stress on NR3C1
methylation (Kubo etal., 2019). In addition to reducing mater-
nal stress, reducing infant stress reactivity via the buffering
effects of maternal caregiving on NR3C1 methylation may be
another point of intervention (Conradt et al., 2019).
Interestingly, this buffering effect was only observed in female
infants, indicating the effect of maternal care behaviors may
vary by infant sex.
In contrast to our findings for NR3C1, our exploratory
analyses of FKBP5 did not show significant differences in
placental gene methylation at either CpG1 or CpG2 site
based on trauma group categorization. Although NR3C1
and FKBP5 work in concert to regulate the glucocorticoid
response pathway, prior factor analytic work on the asso-
ciation between placental methylation and infant neuro-
development profiles has shown that, while many of the
NR3C1 CpGs loaded onto the same methylation factor,
FKBP5 CpG1 and CpG2 did not load onto any factor
(Paquette et al., 2015), and so it is not surprising to only
identify relationships with one of these genes. In contrast
to studies of Holocaust survivors and their offspring (Bierer
et al., 2020; Yehuda etal., 2016), we did not find evidence
of transmission of maternal trauma via FKBP5 methylation,
which may be due to differences in trauma type, popula-
tion, or samples (blood vs. placental tissue). The lack of
significant associations of trauma exposure or PTSD symp-
toms with placental FKBP5 methylation in this study can
be considered in the context of a study that examined the
association between warzone trauma and placental FKBP5
methylation (Kertes et al., 2016). The effect of warzone
trauma was only observed at one site within the gene
body and no effect of warzone trauma was observed
within the gene promoter region. The differential effects
of trauma exposure by placental FKBP5 gene region may
be attributable to different trauma types across studies
and highlight further work is needed to reconcile differen-
tial findings across studies.
Our results also showed that trauma-exposed individu-
als who reported PTSD symptoms during pregnancy exhib-
ited significantly different patterns of placental NR3C1
methylation than trauma-exposed individuals who did not
report PTSD symptoms. Although further research and
replication is needed in order to explore mechanisms and
other pathways of trauma transmission, our findings high-
light that interventions to support maternal mental health
and wellbeing for trauma survivors may disrupt one
potential pathway of transmission of maternal trauma.
Pregnancy and childbirth can be especially challenging for
survivors of trauma due to pregnancy-related body
changes and sensations, increased risk of pregnancy com-
plications, a heightened sense of vulnerability, and inva-
sive medical procedures (Gokhale et al., 2020). The
American College of Obstetricians and Gynecologists
(ACOG) recommends screening for trauma in each trimes-
ter and postpartum, including lifetime sexual violence
(ACOG, 2019). With effective screening, a history of trauma
exposure can be identified and resources can be provided
to reduce the likelihood of development of PTSD and pro-
mote resilience, including behavioral health referrals, doula
support, and trauma-focused patient education (Rosenblum
et al., 2017). Since screening for trauma exposure and
related symptoms can be difficult in a busy clinical setting
and not all survivors may choose to disclose to providers,
a universal trauma-informed approach to care can reduce
the likelihood of inadvertently re-traumatizing patients
during routine care procedures and decrease patients’ sus-
ceptibility to develop PTSD symptoms during pregnancy
(Ward, 2020). Overall, it remains important to promote
Table 2. Estimated means for dierences between trauma groups: raw and adjusted model comparisons.
Raw models Adjusted models
Means
p
Means
p
No trauma
(−T)
Trauma without
PTSD symptoms
(T − S)
Trauma with PTSD
symptoms
(T + S)
No trauma
(−T)
Trauma without
PTSD symptoms
(T − S)
Trauma with PTSD
symptoms
(T + S)
NR3C1
Overall 1.50 1.43 2.04 0.003* 0.37 0.35 0.40 0.009*
CpG1 0.37 0.35 0.50 0.450 0.33 0.46 0.34 0.652
CpG2 0.33 0.46 0.30 0.576 0.78 0.64 0.81 0.809
CpG3 0.78 0.64 0.99 0.379 0.19 0.35 0.21 0.753
CpG4 0.19 0.35 0.19 0.256 0.68 0.17 0.16 0.108
CpG5 0.68 0.17 0.16 0.012* 0.63 0.71 0.76 0.003*
CpG6 0.63 0.71 1.21 0.003* 3.48 3.64 3.60 0.004*
CpG7 3.48 3.64 3.96 0.103 1.40 1.31 1.56 0.268
CpG8 1.40 1.31 2.20 <0.001* 2.85 2.58 3.12 0.011*
CpG9 2.85 2.58 4.30 0.002* 2.47 2.35 2.61 0.012*
CpG10 2.47 2.35 3.21 0.010* 1.66 1.70 1.88 0.088
CpG11 1.66 1.70 2.68 0.005* 2.86 2.53 3.00 0.057
CpG12 2.86 2.53 3.71 0.014* 1.85 1.81 2.11 0.080
CpG13 1.85 1.81 3.13 <0.001* 1.50 1.43 1.61 0.006*
FKBP5
Overall 87.69 86.35 87.78 0.224 4.47 4.46 4.47 0.176
CpG1 83.48 83.74 84.02 0.572 4.43 4.42 4.43 0.849
CpG2 91.90 88.95 91.53 0.056 4.52 4.48 4.52 0.072
Note. *p < 0.05, Adjusted models show log-transformed means and group comparisons adjusted for gravida and multiple comparisons.
STRESS 7
and emphasize the mental health of women during preg-
nancy to mitigate the potential maternal-fetal transmis-
sion of stress and trauma.
Results should be considered in the context of limitations.
Although our sample was racially/ethnically diverse and
included predominantly low-income women, generalizability
to national and international or non-English speaking popula-
tions may be limited due to the cross-sectional design exam-
ining English-speaking, pregnant women in one Northeast
U.S. region. As small effect sizes were shown in this proof-of-
concept pilot study, actual effect sizes may also be larger
than observed in this study. Additionally, the use of a
gold-standard assessment, such as the Clinician-Administered
PTSD Scale, may allow for future investigation of whether
dose-response relationships exist between PTSD symptom
severity and degree of placental gene methylation. Use of the
candidate gene approach is another limitation of this study
and future studies should employ genome-wide approaches
and other biological markers of stress (e.g. cortisol) to study-
ing complex biobehavioral processes underlying transmission
of trauma. In particular, comparisons of methylation patterns
in placental samples vs. maternal whole blood may elucidate
epigenetic differences at the maternal-fetal interface. We also
recognize that the placenta is a heterogeneous tissue, and
although we performed sampling and sample preparation
steps to reduce heterogeneity, there can be differences in the
underlying cellular populations within samples that could be
confounding our results. Finally, given consistent sex differ-
ences in clinical and preclinical prenatal programming studies
and in glucocorticoid signaling, future research should exam-
ine sex differences and/or stratify by infant sex to investigate
the impact of PTSD symptoms on placental methylation lev-
els (Bulka et al., 2023).
5. Conclusion
This proof-of-concept study is the first to demonstrate the
impact of prenatal PTSD symptoms on epigenetic regulation
of placenta glucocorticoid signaling. Specifically, trauma survi-
vors with prenatal PTSD symptoms exhibited differential pat-
terns of methylation for multiple placental NR3C1 sites
compared to women without trauma exposure or PTSD
symptoms. Future research is needed to investigate mecha-
nisms of this association, impact on infant neurodevelopment,
and genome-wide approaches. Results highlight the critical
importance of effective interventions to support perinatal
mental health for survivors of trauma.
Acknowledgments
We are grateful to the pregnant individuals who contributed to this
study. We also thank the Maternal-Infant Studies Laboratory staff for their
assistance with data collection.
Disclosure statement
All authors have no conicts of interest to declare.
Notes on contributors
Laura R. Stroud, PhD, is a Professor of Psychiatry and Human Behavior,
Warren Alpert Medical School of Brown University, and directs the
COBRE Center for Stress, Trauma, and Resilience (STAR) at The Miriam
Hospital. Her research focuses on biobehavioral mechanisms underlying
the intergenerational transmission of stress, trauma, and substance use.
Nancy C. Jao, PhD, is an Assistant Professor in the Department of
Psychology at Rosalind Franklin University of Medicine and Science.
Dr. Jao’s research investigates biopsychosocial and behavioral risk
factors aecting health outcomes and disparities, particularly focus-
ing on tobacco use and marginalized or vulnerable populations.
L. G. Ward, Ph.D., is a Clinical Psychologist and Assistant Professor of
Psychiatry and Human Behavior at the Warren Alpert Medical School
of Brown University and the Center for Preventive and Behavioral
Medicine. Dr. Ward’s research focuses on strategies to promote
trauma-informed obstetric care.
Sharon Y. Lee, PhD, is an Assistant Professor of Psychiatry and Human
Behavior at the Warren Alpert Medical School of Brown University. Dr.
Lee’s research focuses on biobehavioral mechanisms linking psychological
trauma and stress with increased risk for cardiovascular and other diseases.
Carmen J. Marsit, PhD, is Rollins Distinguished Professor in the
Ganagarosa Department of Environmental Health at the Emory Rollins
School of Public Health. He is a molecular epidemiologist whose
research examines the mechanisms underlying the developmental ori-
gins of health and disease focusing on impacts to the placenta.
CRediT author statement
Laura R. Stroud: Conceptualization, Methodology, Investigation, Resources,
Supervision, Project Administration, Funding Acquisition, Writing – Review
and Editing.
Nancy C. Jao: Conceptualization, Methodology, Formal Analysis, Data
Curation, Visualization.
L. G. Ward: Writing – Original Draft.
Sharon Y. Lee: Writing – Original Draft.
Carmen J. Marsit: Supervision, Writing – Review and Editing.
Funding
Funding for this study and manuscript preparation was supported by the
National Institutes of Health (NIH) under grants R01DA031188, R01DA044504,
R01DA045492, R01DA056787, and P20GM139767 to LRS, and U24ES028507
to CJM and LRS. NCJ was supported by grants T32HL076134 and
K01HL164670. LGW was supported by K23HD107296. SYL was supported by
T32HD101392, P20GM139767, and American Heart Association
23CDA1039160. The content is solely the responsibility of the authors and
does not necessarily represent the ocial views of NIH. NIH had no role in
the study design, collection, analysis, or interpretation of the data, writing
the manuscript, or the decision to submit the article for publication.
ORCID
Carmen J. Marsit http://orcid.org/0000-0003-4566-150X
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