Stress exposure in intrauterine life is associated with
shorter telomere length in young adulthood
Sonja Entringera, Elissa S. Epelb, Robert Kumstac, Jue Lind, Dirk H. Hellhammere, Elizabeth H. Blackburnd, Stefan Wüstf,
and Pathik D. Wadhwaa,g,1
aDepartment of Pediatrics, University of California, Irvine, CA 92697;bDepartment of Psychiatry, University of California, San Francisco, CA 94143;
cDepartment of Psychology, University of Freiburg, 79104 Freiburg, Germany;dDepartment of Biochemistry and Biophysics, University of California, San
Francisco, CA 94143;eDepartment of Clinical and Physiological Psychology, University of Trier, 54290 Trier, Germany;fDepartment of Genetic Epidemiology in
Psychiatry, Central Institute of Mental Health, 68159 Mannheim, Germany; andgDepartments of Psychiatry and Human Behavior, Obstetrics and Gynecology,
and Epidemiology, University of California, Irvine, CA 92697
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved July 15, 2011 (received for review June 3, 2011)
Leukocyte telomere length (LTL) is a predictor of age-related
disease onset and mortality. The association in adults of psychoso-
cial stress or stress biomarkers with LTL suggests telomere biology
may represent a possible underlying mechanism linking stress and
healthoutcomes. It is, however,unknown whether stress exposure
in intrauterine life can produce variations in LTL, thereby poten-
tially setting up a long-term trajectory for disease susceptibility.
We, therefore, as a first step, tested the hypothesis that stress
exposure during intrauterine life is associated with shorter telo-
meres in adult life after accounting for the effects of other factors
on LTL. LTL was assessed in 94 healthy young adults. Forty-five
subjects were offspring of mothers who had experienced a severe
stressorin the indexpregnancy(prenatalstress group; PSG), and 49
subjects were offspring of mothers who had a healthy, uneventful
index pregnancy (comparison group; CG). Prenatal stress exposure
was a significant predictor of subsequent adult telomere length in
the offspring (178-bp difference between prenatal stress and CG;
d = 0.41 SD units; P < 0.05). The effect was substantially unchanged
after adjusting for potential confounders (subject characteristics,
birth weight percentile, and early-life and concurrent stress level),
and was more pronounced in women (295-bp difference; d = 0.68
SD units; P < 0.01). To the best of our knowledge, this study pro-
vides the first evidence in humans of an association between pre-
natal stress exposure and subsequent shorter telomere length. This
observation may help shed light on an important biological path-
way underlying the developmental origins of adult health and
developmental programming|fetal origin
related disorders that confer a major burden of disease can be
traced back to the intrauterine period of life (i.e., the concept of
fetal, or developmental, origins of health and disease risk). The
developing fetus responds to, or is acted upon by, conditions in
the internal or external environment during sensitive periods of
cellular proliferation, differentiation, and maturation. These re-
sponses, in turn, may resultin structural and/or functional changes
in cells, tissues, and organ systems that have important long-term
consequences for subsequent health and disease susceptibility
(1–5). Exposure to psychosocial stress and/or biological stress
mediators during gestation has been identified as one salient
condition that may underlie the long-term programming effects of
the intrauterine environment (2).
The link between psychosocial stress exposure and adverse
health outcomes is well established. In particular, psychosocial
stress appears to be an important risk factor for earlier onset of
complex, common age-related diseases (6, 7). The elucidation of
biological processes underlying this relationship is of considerable
ongoing interest. In recent years, accumulating evidence supports
the crucial role of telomere biology as a potential mechanism
linking psychosocial stress exposure and disease risk (8, 9).
rapidly growing body of empirical evidence suggests the
origins of susceptibility for many common, complex age-
Telomeres are DNA–protein complexes that cap chromosomal
ends, promoting chromosomal stability. When cells divide, the
telomere is not fully replicated because of limitations of the DNA
polymerases in completing the replication of the ends of the
linear molecules, leading to telomere shortening with every rep-
lication (10). Telomeres that are shortened past a critical length
cause the cell to enter a state of arrest (i.e., cell senescence) when
cells can no longer divide. Telomeres shorten with age in all
replicating somatic cells, including leukocytes (11). Telomerase,
a cellular enzyme, provides maintenance of telomeres and can
counteract shortening and its functional consequences by adding
telomeric DNA to shortened telomeres. Telomere maintenance
has relevance for long-term health. Shortened telomere length
and/or reduced telomerase activity have been consistently asso-
ciated with health risk and diseases (12–15). Declines in the
telomere/telomerase maintenance system may play a causal role
in aging, serve as a biomarker of aging, or both. A recent study in
mice suggests that telomerase plays a causal role in aging and
regeneration of cells, tissues, and physiological function (16).
Several cross-sectional studies in humans have reported
associations between telomere biology and high levels of psy-
chosocial stress exposure (8, 17, 18) or stress biomarkers (17, 19),
suggesting that stress-related changes in telomere integrity may
be one possible mechanism linking psychosocial stress and age-
related disease (20). Experimentally, high levels of cortisol ex-
posure (a potent stress hormone) have been shown to dampen
telomerase activity in leukocytes (21). Behavioral interventions
that reduce stress have also been linked to higher telomerase
activity. For example, in one study, an intensive lifestyle change
program consisting of dieting, counseling, and stress manage-
ment was associated with increases in telomerase activity (22),
and in a second study, intensive meditation was associated with
higher postintervention telomerase (23).
Many, but not all, studies in humans have found an association
between exposure to adverse conditions in early postnatal life
(infancy and childhood) and subsequent telomere length (24–
28). One important question that has yet to be addressed to our
awareness is whether exposure to stress during intrauterine de-
velopment can produce variations in telomere length, thereby
potentially setting up a long-term trajectory at birth that defines
Author contributions: S.E., D.H.H., S.W., and P.D.W. designed research; S.E. and R.K. per-
formed research; S.E., J.L., and E.H.B. analyzed data; and S.E., E.S.E., E.H.B., and P.D.W.
wrote the paper.
Conflict of interest statement: E.S.E., J.L., and E.H.B. are cofounders of Telome Health,
a company focused on telomere measurement.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.
1To whom correspondence should be addressed. E-mail: firstname.lastname@example.org.
See Author Summary on page 13377.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.
| August 16, 2011
| vol. 108
| no. 33
or contributes to individual susceptibility for complex, common
age-related diseases. Stress exposure during fetal development is
an important factor shaping adult health and has been linked to
adverse outcomes including, but not limited to, immune, endo-
crine, and metabolic dysregulation and related disorders (29–34).
However, we are aware of no studies to date that have examined
the relationship between prenatal stress exposure and telomere
length. Evidence linking other adverse conditions during fetal
development with subsequent telomere length provides bi-
ological plausibility for this relationship. Several studies in ani-
mals have reported that intrauterine adversity is associated with
shorter telomeres in cells of different tissues. For instance, ex-
perimentally induced fetal growth restriction in rodents has been
shown to produce significant telomere attrition in the kidneys
(35), and manipulations of maternal diet during pregnancy have
produced shortening of telomere length in aortic and pancreatic
islet cells (36, 37). In humans, telomeres in placental trophoblasts
are found to be shorter in pregnancies complicated with in-
trauterine growth restriction (38). Last, one study in preschool-
age children found that children who were born low birth weight
had shorter leukocyte telomere length (LTL) than age-matched
children who had a normal birth weight (39).
The objective ofthepresentstudywastotestthehypothesisthat
maternal psychosocial stress exposure during pregnancy is asso-
ciated with shorter telomeres in their offspring in adult life. Be-
human pregnancy, we approximated experimental exposure by
using a quasiexperimental design by enrolling young adults whose
mothers happened to have experienced a high level of psychoso-
cial stress during pregnancy (a major negative life event) and
compared them with a group of subjects whose mothers had not
been exposed to negative life events during pregnancy. Prenatal
stress exposure was assessed retrospectively by using a semi-
structured interview of major life events in the index pregnancy.
The potential confounding effects of other sociodemographic,
obstetric, medical, and behavioral risk factors were addressed by
using a stringent set of exclusionary criteria. Moreover, because
prenatal stress exposure may be associated with subsequent con-
ditions that may influence telomere length, such as presence of
postnatal early-life adversity, inadequate parental care, or con-
current stress level, we assessed these constructs to statistically
account for their possible residual confounding effects.
Subject Characteristics. Table 1 provides the subject characteristics
for the two groups, including sociodemographic factors, birth
outcomes, and the childhood and adult variables of interest. As
depicted in the table, there were no differences between the two
groups in any of the subject characteristics except body mass
index (BMI), which was marginally higher (P = 0.07) in the
prenatal stress group (PSG) than in the comparison group (CG).
Telomere Length. The mean LTL (±SD) was 1.23 ± 0.18 telomere
repeat copy number-to-single gene copy number (T/S) ratio
(which is equivalent to 6,234 ± 431 bp). LTL was normally dis-
tributed (Fig. 1).
In the unadjusted univariate regression models, a crude re-
lationship between prenatal stress and telomere length was found,
with prenatal stress exposure predicting significantly shorter LTL
[unstandardized β = −0.074; 95% confidence interval [CI],−0.146
to −0.001; P < 0.05) (Fig. 1). Birth weight percentile (birth weight
adjusted for gestational age at delivery) also was significantly as-
sociated with LTL [β = 0.002; 95% CI = 0.000 to 0.003; P < 0.05),
replicating an association that has been previously reported (39).
Results from the fully adjusted multivariate regression model
[that, in addition to prenatal stress exposure, included subject
characteristics (e.g., age, BMI sex), birth weight percentile, post-
natal early-life adversity (e.g., early trauma, maternal care), and
exposure to concurrent life stress (e.g., chronic stress, depressive
symptoms)] indicate this adjustment produced a small increase in
the prenatal stress coefficient (β = −0.090; 95% CI = −0.179 to
−0.001; P < 0.05). Birth weight percentile remained a significant
Table 1. Subject characteristics
Variable PSG (n = 45)CG (n = 49)P value
25 ± 0.8024 ± 0.60NS
High school, %
Perceived stress (PSS, mean item score)
Depressive symptoms (CES-D)
Birth weight (g)
Birth weight percentile
Length of gestation (wk)
High school, %
College graduate, %
Presence of childhood traumatic events
Perceived maternal care (PBI)
Factors controlled for by study design
Current chronic diseases
Obstetric risk condition during mother’s pregnancy
0.0724.50 ± 4.5823.05 ± 2.96
1.87 ± 0.54
11.11 ± 7.62
1.75 ± 0.52
9.86 ± 6.89
3331 ± 549
42.18 ± 26.84
39.23 ± 1.88
3272 ± 420
41.13 ± 24.19
39.53 ± 1.50
24.80 ± 9.15
25.91 ± 8.04
Values presented as means ± SD where applicable. CES-D, Center for Epidemiological Studies–Depression scale; PBI, Parental
| www.pnas.org/cgi/doi/10.1073/pnas.1107759108Entringer et al.
predictor of LTL (β = 0.002; 95% CI = 0.001 to 0.004; P < 0.01),
suggesting the effects of prenatal stress exposure and birth weight
percentile were independent of one another, and that the effect
of prenatal stress on LTL was not mediated via a reduction in
The separate analyses stratified by sex (i.e., women-only and
men-only groups) suggest that the effect of prenatal stress ex-
posure was more pronounced in women: the unadjusted (β =
−0.122; 95% CI, −0.205 to −0.039; P < 0.01) as well as fully
adjusted (β = −0.141; 95% CI = −0.240 to −0.041; P < 0.01)
prenatal stress coefficients were larger in the women-only mod-
els. The coefficients for all covariates for the unadjusted and fully
adjusted regression models predicting LTL are depicted in Table
S1. In the interest of presenting complete data, we include
the regression coefficients for the men-only group; however, the
relatively smaller number of men in the study sample and the
larger variation in their estimates of LTL preclude inference
regarding possible sex-specific effects.
Onaverage, there was a 178-bp difference in LTLbetween PSG
and CG in the whole group [i.e., unadjusted effect; effect size
[Cohen’s d] = 0.41 SD units], and a 295-bp difference in LTL
between PSG and CG in the women-only group (d = 0.68
To the best of our knowledge, this is the first report in humans
that demonstrates that exposure to maternal psychosocial stress
during intrauterine life is associated subsequently with signifi-
cantly shorter LTL in young adulthood. This effect persists after
adjusting for a number of potential confounders, including age,
sex, BMI, birth weight, postnatal/early-life adversity, and con-
current life stress. This finding suggests that cellular aging in
humans may be influenced by prenatal stress, thereby potentially
increasing the susceptibility of prenatally stressed individuals for
complex, common age-related diseases. The magnitude of the
observed difference in LTL between the prenatal stress exposure
group and the CG is striking (0.41 SD units), and particularly so
in the female offspring (0.68 SD units). The LTL of individuals
in the prenatally stressed individuals was, on average, 178 bp
shorter than that of individuals in the CG (and 295 bp shorter in
female subjects). The most recent and comprehensive review of
studies of age-related attrition in telomere length suggests that,
in adults, telomere length attrition averages approximately 60
bp/y at 20 y of age, and the attrition rate appears to decrease to
approximately 20 bp/y by age 80 y (40). Given that the partic-
ipants in our study were approximately 25 y old, translating
telomere shortening of this observed difference of 178 bp (295
bp for the women-only group) to years of aging indicates that the
lymphocytes individuals in the PSG had aged the equivalent of
approximately 3.5 additional years (5 additional years in the
women-only group) relative to those in the CG.
One of the major paradigms to explain variation in suscepti-
bility for complex, common adverse health disorders in adult life
is the fetal or developmental origins model, which is believed to
act through “biological embedding”—the ability of early life ex-
perience to change biology (41–44). Classic examples include
fetal programming effects, such as maternal stress or under-
cerebral development, catch-up growth, and early onset of insulin
resistance and adult cardiometabolic diseases (1, 2, 45, 46). It has
been suggested that telomere length may, in part, underlie this
association (47–49). Telomere length differs widely at birth be-
tween babies. Okuda et al. (50), one of the few groups of inves-
tigators who have studied LTL in early life, state that “the
variability in telomere length among newborns and synchrony in
telomere length within organs of the newborn are consistent
with the concept that variations in telomere length among adults
are in large part attributed to determinants that start exerting
their effect in utero.” Accordingly, it has been hypothesized that
prenatal stress in utero would lead to shorter adult LTL (9). Our
findings lend support for this concept.
There are several mutually nonexclusive pathways that may
have led to the striking observation in the present study. There
may be latency effects from early life that emerge at a later time
point, or pathway effects wherein early stress leads to later vul-
nerability throughout the lifespan (4, 41). In terms of biological
mechanisms, prenatal psychosocial stress exposure could affect
cellular aging through several mechanisms: changes in immune
function, changes in metabolic and oxidative stress-related path-
ways, and/or changes in telomerase activity. These changes, in
turn, maybemediated by epigeneticmodifications,thereby setting
up long-term trajectories (27, 51). Stress is transduced from the
pregnant mother to her fetus through various pathways, including
transplacental transport of the stress hormone cortisol, maternal
stress-induced release of placental hormones that enter the fetal
maternal stress-induced effects on placental physiology, including
alterations in blood flow and changes in metabolism impacting
oxygen and glucose availability and use (52, 53). Exposure to high
levels of maternal stress hormones during pregnancy is known to
produce deleterious effects on the offspring’s developing immune
system (32, 54, 55), and our previously published studies in this
cohort have reported that the prenatally stressed individuals
higher phytohemagglutinin-stimulated levels of IL-6, a proin-
flammatory cytokine that has been associated with shorter telo-
mere length (56, 57). We also have found that the prenatally
stressed individuals in this cohort exhibited insulin and leptin re-
sistance, as well as a higher BMI (31). As insulin resistance is
associated with chronological age, and longstanding insulin re-
sistance can accelerate biological aging (58–60), it is possible that
insulin resistancealso may have contributed to more rapid cellular
aging in the PSG individuals. Notably, we have described in this
adrenal axis in the PSG individuals (34). Finally, other studies
found that blood levels of oxidative stress—a factor promoting
telomere shortening (61)—may be elevated, in part, by stress
hormones and insulin (62). Although we have previously reported
these associations between prenatal stress exposure and immune,
(PSG; n = 45) and CG subjects (n = 49). Lines indicate group means.
Dot plot illustrating LTL (T/S ratio) in prenatally stressed individuals
Entringer et al. PNAS
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| vol. 108
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metabolic, and endocrine dysregulation in this study cohort, and
the current report extends these findings to shortened telomere
length, the cross-sectional design of this study precludes us from
determining the temporal sequence and interrelationships be-
tween these different outcomes. Prospective, longitudinal studies
are currently under way to address this important question.
The caveat that correlation cannot establish causality is well
recognized. Although the use of animal models confers many
benefits, such as the ability to perform experimental manipu-
lations, one of their major limitations, particularly for research in
the area of intrauterine development, is the considerable inter-
species variation in the physiology of pregnancy and in the devel-
opmental timeline (63, 64). Because it is not possible to randomly
assign humans to prenatal stress exposure, we approximated ex-
by Bradford Hill in his seminal 1965 article (65), and elaborated
subsequently by others (66–68)]. It is possible that the effects of
prenatal stress exposure may be confounded or exacerbated or
attenuated by postnatal experience. However, another strength of
the present study was the ability to eliminate the potential con-
founding effects of many of these factors by study design (exclu-
sionary criteria, e.g., obstetric risk, adverse birth outcomes,
smoking, concurrent diseases). In addition, we assessed and ac-
counted for the possible effects of several other key potential
postnatal/early-life adversity, and exposure to concurrent life
stress. The effect was substantially unchanged after adjusting for
these potential confounders. Furthermore, the effect was not al-
tered after entering birth weight into the model, suggesting that
the association between prenatal stress and LTL was independent
of alterations in birth weight. Last, it is established that stressful
life events occur more frequently in individuals of lower socio-
economic status; however, we note that the SES range was narrow
and did not differ across groups.
The present study had some limitations. First, prenatal stress
exposure was assessed retrospectively. Although retrospective
assessments of psychosocial factors such as stress are prone to
biases such as “after-the-fact” reporting (i.e., individuals who
develop health disorders are more prone to retrospectively report
higher levels of adverse exposures before the development of the
disorder) and those produced by memory and current psycho-
logical state (affect/mood), we believe it is unlikely these biases
significantly impacted our assessment of prenatal stress in the
present study. All subjects were healthy young adults (i.e., with no
underlying disease); they received identical information before
and upon entering the study; they were not provided any in-
formation about the study hypotheses; and they (as well as the
experimenters) were blinded to and had no a priori knowledge
about the expected direction of study findings. Subjects in the two
groups did not differ in their current baseline psychological state
(e.g., depressive symptoms, perceived stress) or memory perfor-
mance scores. Moreover, our use of major negative life events to
retrospectively assess psychosocial stress exposure provides
greater confidence for construct validity than would have been the
case for retrospective assessments of other components of stress,
such as perceived severity of stress appraisals or stress symptoms.
We note, however, that the occurrence of a major negative life
event in the index pregnancy does not constitute a single, discrete
programming event; it is well established that acute circumstances
such as stressful life events produce chronic psychological distress
and a concomitant cascade of progressive alterations in stress-
related immunological, endocrine, and cellular physiological pro-
cesses. Second, men were underrepresented in the study. We
speculate that the difference in the numbers of men and women
who volunteered to participate may relate to the observation that
women are likely to be more interested in issues and questions
concerning pregnancy. Some studies suggest there are sex-specific
the larger variation in the distribution of their LTL, we, un-
fortunately, did not havethestatisticalpowertoexamineand draw
any inferences about possible sex-specific programming effects.
To summarize, prenatal stress exposure was a significant pre-
dictor of subsequent LTL, a marker of cellular aging, in young
adults. The predicted decrease in LTL was unchanged after
adjusting for several key potential confounding factors and was
particularly pronounced in women. The magnitude of the effect
equates to a difference of approximately 0.41 SD units (and 0.68
SD units among female subjects), and translates clinically in
terms of the lymphocyte aging rate to an approximate difference
of 3.5 y (and 5 y among female subjects). Many questions remain,
such as those regarding the exact mechanisms underlying pre-
natal programming of telomere length and the directionality of
the associations between prenatal stress, telomere length, and
later health outcomes (i.e., whether shortened telomeres pre-
cede and play a causal role in the onset of insulin resistance,
immune dysfunction, and other markers of physiological dysre-
gulation in prenatally stressed individuals, or whether prenatal
stress, through a common mechanism, simultaneously influences
telomere length and physiological function). To address these
questions, a multilevel approach is required that includes mo-
lecular and cellular studies, the use of appropriate animal
models, and well designed prospective, longitudinal human
studies. Nonetheless, the results of the present study are an
important first step, and they add further evidence to the growing
awareness that predisease pathways for common, complex age-
related disorders may have their foundations very early in life.
Sample. The study sample consisted of 94 subjects: 45 whose mothers ex-
perienced a high level of psychological stress during the index pregnancy (as
detailed later) constituted the PSG and 49 whose mothers had a healthy,
uneventful index pregnancy constituted the CG. All subjects were of Western
European decent. The characteristics of the study population are provided
in Table 1.
Procedures. Study participants were recruited in Trier, Germany, through an
announcement in local newspapers and a solicitation to local university
students. Before entering the study, the absence of acute or chronic health
conditions was ascertained by self-report and confirmed by a medical ex-
amination. All subjects were nonsmokers and reported to be medication-free
except for oralcontraceptives. A copy ofthe prenatal medical record (which is
provided to every mother during her prenatal care) was obtained from each
participant. From this record, information was abstracted about maternal
age, parity, obstetric complications (e.g., gestational diabetes, hypertension/
preeclampsia, infection), birth outcomes (length of gestation/preterm birth
and birth weight/small-for-gestational-age birth, height, and head circum-
ference at birth), and newborn complications. Participants received a modest
monetary compensation on completion of the study assessments. All inves-
tigations were conducted in accordance with the guidelines described in the
Declaration of Helsinki, the study protocol was approved by the ethics
committee of the German Psychological Society, and written informed
consent was obtained from all participants.
Prenatal Stress Measurement. We adopted a conservative strategy for the
conceptualization of prenatal stress (as described elsewhere; e.g., refs. 31,
34). Briefly, we defined a high level of prenatal psychosocial stress exposure
as the presence of major negative life events that occurred to the mother
during her index pregnancy (i.e., after conception and before birth). We
selected a list of negative life events that are considered highly stressful
across individuals [e.g., death or sudden severe illness of an immediate
family member, loss of primary residence (34)]. All subjects underwent
semistructured interviews about maternal exposure to these major negative
life events during gestation and were instructed to review the items with
their mothers before the interview. To minimize potential self-selection bias
and retrospective after-the-fact recall bias, subjects were not informed
about the study hypotheses, all subjects received the same information be-
| www.pnas.org/cgi/doi/10.1073/pnas.1107759108Entringer et al.
fore entering the study, and the experimenters were blind to subject group
status (PSG or CG).
Measurement of Potential Postnatal Confounders. As it is possible that pre-
natal stress exposure is associated with adverse postnatal experiences such as
the presence of other stressors and adverse conditions during childhood, we
assessed and controlled for these potential confounding factors, including
the presence of traumatic events in childhood (including death of a close
relative, separation from a parent, and sexual or physical abuse), self-
reported quality of maternal care, and concurrent levels of chronic stress and
depressive symptoms at the time of the study assessments (refs. 31, 34 de-
scribe the measures).
Telomere Length Assay. Blood was drawn from the participants in the early
afternoon and stored at −80 °C for the assessment of LTL. An additional
peripheral blood sample was collected at the same time point to determine
total number of leukocytes, lymphocytes, as well as lymphocyte sub-
populations [CD3−/CD19+(B cells), CD3+/CD4+(T-helper cells), CD3+/CD8+
(T-cytotoxic cells), CD3−/CD16, 56+(NK cells); methods described in ref. 32)].
PSG and CG subjects did not differ significantly in any of these measures.
Whole blood samples were shipped for telomere length assays to the
Blackburn laboratory at the University of California, San Francisco. The
laboratory personnel were blinded to group membership status of the blood
samples (PSG or CG). DNA was extracted by using a QIAamp DNA blood mini
kit. Measurement of relative telomere lengths (i.e., T/S ratios) by quantitative
PCR were adapted from a validated published method (69) and performed as
described previously (70). The conversion from T/S ratio to base pairs was
calculated based on the mean telomeric restriction fragment length from
Southern blot analysis and the slope of the plot of mean telomeric re-
striction fragment length versus T/S for these samples. This was expressed as
the following formula:
Base pair ¼ 3;274 + 2;413∗ðT=SÞ
Data Analysis. We first determined whether the effects of prenatal stress
exposure and other covariates were statistically significant by using un-
adjusted and fully adjusted regression models. Next, for statistically signifi-
cant effects, we calculated a standardized effect size (Cohen d effect size
statistic) to place effects expressed in the original raw units of measurement
(i.e., T/S ratio) in the more generic and dimensionless context of SD units
(71). Finally, we expressed significant effect sizes in terms of their clinical or
practical significance [i.e., difference in years of cellular aging (34)].
To examine the associations between prenatal stress and LTL, unadjusted
and fully adjusted regression models were conducted, beginning with simple
and telomere length (i.e., unadjusted models) and then adding variables that
could confound the association or that could be in the causal pathway. These
variables included subject characteristics that have been associated with LTL
in previous studies (i.e., age, BMI, sex), birth weight percentile (as a marker of
other intrauterine conditions over and above prenatal stress exposure),
postnatal/early-life adversity (i.e., childhood trauma exposure and perceived
maternal care), and current chronic stress and depressive symptom levels.
Because sex-specific effects of prenatal stress exposure have been reported
for other outcomes in previous studies (72, 73), we were interested in
addressing this question in the context of LTL. However, given the relatively
smaller number of men and larger variation in the distribution of LTL
compared with women in our study population, we were unable to model
a statistical interaction between prenatal stress exposure and sex. We in-
stead ran the same sets of regression models separately stratified by sex.
The unstandardized regression (β) coefficients from these models indicate
the change in the T/S ratio associated with prenatal stress exposure and
a one-unit change in other predictor variables. All statistical analyses were
run using SPSS software (version 18), and the significance level was set at an
α level of 0.05.
ACKNOWLEDGMENTS. We thank Claudia Buss, Daniel L. Gillen, Keith
M. Godfrey, Christopher W. Kuzawa, and James M. Swanson for useful
discussions. This study was supported by US Public Health Service (National
Institutes of Health) Grants R01 HD-06028 and P01 HD-047609 (to P.D.W.)
and R01 HD-065825 (to S.E.), and by the Barney and Barbro Fund (E.H.B.).
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