The Association Between Prenatal Maternal
Stress and Adolescent Affective Outcomes is Mediated by Childhood Maltreatment and
Adolescent Behavioral Inhibition System Sensitivity
Auteurs:
T. Sebők-Welker, E. Posta, K. Ágrez, A. Rádosi, E. A. Zubovics, M. J. Réthelyi, I. Ulbert, B. Pászthy, N. Bunford
Prenatal maternal stress is linked to offspring outcomes; however, there is
little research on adolescents, behavioral, transdiagnostic outcomes, or the mechanisms
through which relations operate. We examined, in N = 268 adolescents (Mage = 15.31 years; SD = 1.063; 57.8% boys)
whether prenatal maternal stress is associated with adolescent affective outcomes;
whether this association is mediated, serially, by childhood home atmosphere and
adolescent behavioral inhibition system (BIS) sensitivity; and whether mediational
effects are moderated by adolescent attention-deficit/hyperactivity disorder or maternal
internalizing symptomology. Prenatal maternal daily stress and major life events were
associated with adolescent outcomes through childhood negative atmosphere/neglect and
BIS sensitivity, with no evidence of moderation. Results have implications regarding the
effect of prenatal maternal stress on offspring outcomes and regarding corresponding
sensitive periods.
B. Pászthy and N. Bunford have contributed equally to this work.
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Introduction
Across the globe, the prevalence of pediatric mental health disorders and
problems has been increasing [1] and
currently, up to 20% of adolescents experience a mental health disorder, with the third
leading cause of death among adolescents (ages 15–19 years) being suicide [2]. The personal and societal burden of mental
disorders are great; 7% of all burden of disease as measured in disability adjusted life
years (DALYs) and 19% of all years-lived-with-disability are due to such disorders
[3]. Of note, 50% of mental health
disorders develop by the age of 14 years and for 75% of mental disorders, age-of-onset
is before 24 years [4]. Accordingly,
international policy guidelines underscore the importance of early identification and
prevention of precursors or signs of psychopathology. Early intervention is
cost-effective, can improve adult economic productivity [5] and adult health [6],
as well as lessen the risk of adult psychopathology [7].
A sensitive and relevant developmental period in this regard is the
prenatal period; as a result of the brain’s plasticity and sensitivity to environmental
influences, prenatal maternal experiences can affect offspring development and
functioning [8]. For example, prenatal
maternal pharmacological treatment, maternal exposure to various chemical and
non-chemical stressors (e.g., NO2, opioids), maternal
preconception and prenatal nutrition are each associated with childhood cognitive
outcomes [9], externalizing behaviors
[10], developmental disorders
[11] and neurodevelopment [12], and motor development [13]. Another aspect of the prenatal period, maternal
exposure to stress, has also been linked to offspring outcomes. In animals, a large body
of research indicates prenatal maternal stress affects offspring brain development,
across preclinical [14‐16] and non-human
primate studies [17, 18]. Specifically, in utero stress exposure affects
amygdala, corpus callosum, frontal cortex, hippocampus, and rostral anterior cingulate
cortex development [19] and, in accordance
with the functional neuroanatomy of these regions, results in attention deficits and
behaviors linked to anxiety and depression (e.g., learned helplessness and alterations
in circadian rhythm) [19]. Notably, in
animals, prenatal stress effects endure throughout the lifespan [20]. In humans, although there are considerable
differences across studies in methodology, e.g., with regard to the operationalization
of stress1 and also in terms of the exact findings, the literature is consistent in
indicating that prenatal maternal stress is associated with increased risk for offspring
behavioral, cognitive, and mental health problems [21]. Difficulties include cognitive deficits, a difficult temperament
(low effortful control, high negative affectivity, and atypical reward sensitivity) and
psychiatric disorders [21‐23].
Regarding pathways, although the precise mechanisms via which gestational
stress is associated with neurodevelopment and increases risk for offspring behavioral
and cognitive problems have yet to be elucidated [19], prenatal maternal stress (and its proxies, such as anxiety and
depression) impact development of the amygdala, limbic system, frontal lobes
[24‐27] and, via fetal
exposure to elevated cortisol, brain systems related to stress processing and
regulation, i.e., the hypothalamus [22] and
hypothalamic-pituitary (HPA) axis [28] as
well as the septohippocampal system [29].
The HPA axis is a neuroendocrine axis comprised of a brain system (the
hypothalamus), the non-neural part of the pituitary (adenohypophysis) and the adrenal
cortex. These interact with each other via a complex set of direct influences and
feedback interactions to regulate bodily reactions to stress. The hypothalamus releases
corticotrophin-releasing factor (CRF), thereby affecting the pituitary gland, which, in
response releases adrenocorticotropic hormone (ACTH), which causes the adrenal cortex to
release glucocorticoids, e.g., cortisol. Cortisol, in turn, affects HPA axis regulation
[30]. Prenatal maternal stress, via
hypoactivity of a placental enzyme 11-beta hydroxysteroid dehydrogenase-2 (11ß-HSD2)
responsible for regulating the amount of cortisol passing through the placenta, may
result in elevated fetal exposure to cortisol [31‐33] and this may affect fetal HPA-axis development and results in
offspring HPA-axis hyperresponsiveness [34]. The septohippocampal system comprises the hippocampus and the septum
[35] and is implicated in the resolution
of goal conflict [36]. Specifically, the
septohippocampal system, and its monoaminergic brainstem afferents are implicated in
sensitivity of the behavioral inhibition system (BIS) [36, 37].
The BIS is part of a larger architecture of attention- and
motivation-regulating systems involving the behavioral activation system (BAS), the BIS,
and the fight/flight/freeze system (FFFS) [38]. The functioning of this architecture of systems rests on
functional distinctions between behaviors; e.g., behaviors that remove an organism from
a source of danger (e.g., flight, fight, or freezing), a function governed by the FFFS,
are different from those that allow it to assess a potential source of danger so as to
determine an appropriate response, a function governed by the BIS [29]. As such, the BIS is a conflict detecting,
monitoring, and resolving system that functions as a comparator of inputs to determine course of action [29, 36,
37]. Accordingly, although termed the
‘behavioral inhibition system’, the BIS both inhibits pre-potent behavior and generates
additional outputs of attention and arousal to support exploratory behavior designed to
resolve conflict [29]. Therefore, a
function of the BIS is making assessments in situations involving approach-avoidance,
approach-approach, and avoidance-avoidance conflicts [29, 36, 37]. The BIS is not only associated with anxiety and
stress but its sensitivity is positively associated with ‘neuroticism’, or variously
termed negative affectivity (NA) [39],
i.e., the stable tendency to experience negative emotions [40].
Taken together, evidence indicates maternal prenatal stress is associated
with offspring outcomes, and it stands to reason that the former exerts its effects on
the latter including via its impact on the offspring stress systems, such as the
septohippocampal system and its bio-behavioral correlate, the BIS. However, gaps in
knowledge remain.
First, focus with regard to offspring
outcomes has mostly been on infants and young children, without consideration of
long-term effects observable in adolescence. Adolescence is a sensitive period from the
perspective of brain development, as during this developmental period, enhanced
neuroplasticity and structural and functional changes confer both advantages (e.g.,
skill learning facility) [41] and
vulnerabilities (e.g., psychopathology risk) [41, 42]. Adolescent
events of neuromaturation indicate this developmental phase may be a relatively
sensitive window into the effects of earlier influences on neurodevelopment; adolescent
developmental processes may reveal differences that were masked previously [43]. Better understanding the relation between
prenatal maternal stress and adolescent offspring outcomes may be particularly relevant
in this regard, as a host of mental health difficulties emerge in adolescence
[44]. Early life adversity may set forth
a “cascade” of molecular, cellular and/ or network-level effects in the developing brain
[19, 45, 46], yet these may
not manifest until later [47‐49], such as in
adolescence. In studies where adolescent or adult outcomes of prenatal maternal stress
were examined, associations and differences on both a neural and a behavioral level were
observed. On a neural level, prenatal maternal stress has been linked to adolescent
offspring lower overall grey matter volume, especially in cortical regions associated
with depression [50], adolescent offspring
enhanced event-related potentials during endogenous cognitive control [51], and young adult offspring enhanced functional
brain connectivity (which, in turn, correlated with depressive symptoms) [52]. On a behavioral level, prenatal maternal stress
has been related to both higher externalizing [53, 54] and internalizing
[53, 55‐57] symptoms, ADHD and impulsivity [58‐60] and differences in endogenous/exogenous control [51, 61].
Second, although there has been focus
on offspring externalizing and internalizing disorders, there is a relative paucity of
studies focused on transdiagnostic characteristics (but see the studies by [50] indicating prenatal maternal stress was
associated with adult offspring affect dysregulation; by [51, 61, 62] and [63] indicating prenatal maternal stress was associated with
differences in neuropsychological outcomes including inhibition and working memory).
Transdiagnostic characteristics would be key to study in relation to prenatal maternal
stress, as they are applicable, beyond clinical samples, to the general population and
might result in adverse outcomes for youth, even in the absence of a diagnosable
psychopathology [22].
Third, there are examinations of
biological moderators (e.g., 5-HTTLPR [64]
and mediators (e.g., DNA methylation [65‐67], glucocorticoids [68]) of the link between prenatal maternal stress and offspring
biological outcomes (i.e., offspring BMI and central adiposity [66], c-peptide secretion [67], cytokine production [65]). However, when it comes to individual
differences in bio-behavioral and affective
functioning, the majority of the literature is focused on bivariate
associations, without consideration of boundary conditions (moderators; for whom or when
effects operate) and mechanisms (mediators; how effects operate) of the relation between
prenatal maternal stress and offspring outcomes [69]. Exceptions are a handful of studies assessing moderation, with
mixed results. Across these studies, moderators tested were brain-derived neurotrophic
factor (BDNF) genotype [57], COMT genotype
[60], serotonin transporter polymorphism
5-HTTLPR [64] and maternal stress
[70]. Outcomes of interest were
offspring ADHD symptoms/working memory [60], behavioral disturbance [64], and internalizing symptoms [57, 70]. Across studies,
the predictor was prenatal maternal anxiety [70]. Further exceptions are a comparably small number of
investigations of mediation. Mediators tested were offspring childhood maltreatment
[71, 72], executive functioning [73], HPA axis regulation [74], and temperamental negativity [75], as well as maternal general anxiety and mindful parenting
[69]. Outcomes were offspring emotion
regulation at three and 6 months of age [75]; internalizing problems in childhood [69]; academic achievement [73], antisocial behavior [72], and depression [74]
in adolescence; and depression in adulthood [71]. Across studies, the predictor was prenatal maternal anxiety
and/or depression [72].
To begin filling gaps in knowledge about adolescent affective outcomes of
prenatal maternal stress, including more minor stress (and not only at more severe
levels, as in anxiety and depression), with consideration of bio-behavioral mechanisms,
our aim in the current study was to examine the relations between prenatal maternal
stress, indices of adolescent emotion processing, specifically, affectivity, aggression,
and emotion regulation, and how individual differences in adolescent BIS sensitivity
affect these relations.
Beyond BIS sensitivity however, a conceptually and empirically relevant
variable that prenatal maternal stress is related to and that might mediate or modulate
the effects of such stress is the postnatal/early childhood home environment. Data show,
for example, a positive association between prenatal stress and postnatal
hostile-reactive parenting (Hentges et al. 2019) and that compared to non-exposed
offspring, adult offspring exposed to prenatal maternal depression are over twice as
likely to have experienced child maltreatment (Plant et al. [71]).
The negative effects of prenatal maternal stress through the postnatal
home environment may operate through a diathesis-stress effect where negative outcomes
result from an interaction between a predispositional vulnerability, i.e., the diathesis
(e.g., prenatal maternal stress), and stress caused by life experiences (e.g., negative
postnatal home environment) [76‐78].
An alternative is that prenatal maternal stress may not only function as a
diathesis but also as a source of developmental plasticity [78]. The differential susceptibility hypothesis
extends the diathesis-stress model in positing that not only are certain individuals
more vulnerable to the “risk” effects of negative environments but that certain
individuals are (also) more vulnerable to the “protective effects” of positive
environments, i.e., they are developmentally plastic [79]. Experimental findings with animals and observational data with
humans support this hypothesis [71,
78, 80‐83]. In humans, data show negative affectivity and physiological
reactivity are well documented consequences of prenatal maternal stress. Individuals
high on negative affectivity and physiological reactivity, when in aversive rearing
environments, exert greatest deficits and difficulties across a variety of behavioral
and psychological phenotypes but when in a supporting environment, exert greatest
benefits on such measures (with individuals lower on negative affectivity falling
in-between these extremes) [78].
In addition to findings indicating an association between prenatal
maternal stress and postnatal home environment, results also suggest childhood
maltreatment may affect child reinforcement sensitivity and emotion regulation; results
show that young adults who were chronically mistreated as children exhibit greater
threat sensitivity than their nonchronically mistreated or non-mistreated counterparts
(Thompson et al. 84). Also, adults with a
history of childhood interpersonal trauma exhibit higher punishment and lower reward
sensitivity as well as greater BIS sensitivity (Miu et al. [85]). Accordingly, it stands to reason that prenatal
maternal stress exerts its influence on adolescent outcomes through the early childhood
environment which, in turn, alters the child’s reinforcement, i.e., BIS sensitivity,
which, in turn is what results in negative outcomes.
Current Study
Our aims in the current study were to examine, for the first time, in a
large sample of middle-late adolescents, whether (1) prenatal maternal stress—using
measures of both more minor, daily stressors and of more major, life events stressors—is
associated with indices of emotion processing, specifically, affectivity, aggression,
and emotion regulation and (2) these associations are mediated, serially, by differences
in the postnatal home environment and by reinforcement sensitivity, indexed by
behavioral inhibition system (BIS) sensitivity. (3) Furthermore, given that parental
psychopathology may affect the examined relations, insofar as it may affect the
postnatal home environment, e.g., in the form of parenting style [86], and as it is a proxy for genetic predisposition
to offspring psychopathology [87], our goal
was to examine whether any of the mediational effects are moderated by maternal
internalizing problems.
Method
Procedures
Data were collected in the context of a larger longitudinal project,
the (BLINDED) study, aimed at identifying behavioral and biological protective and
risk factors of behavior problems and functional impairments in adolescents
exhibiting a range of attention-deficit/hyperactivity disorder (ADHD) symptoms but
oversampled for ADHD. Data were obtained during the second year (baseline
assessments) in the current study.
Adolescents between the ages of 14 and 17 years were recruited mainly
from public middle-, technical and vocational-, and high schools as well as two child
and adolescent psychiatry clinics in Budapest, Hungary. In case of schools, research
staff visited classrooms and presented on the opportunity to participate in a
research program. In case of clinics, research staff distributed an e-mail and fliers
with information on the research program. Exclusionary criteria were cognitive
ability at or below the percentile rank corresponding to an FSIQ of 80 across
administered indices; autism spectrum disorder (severity ≥ 2); neurological illness;
and having visual impairment as defined by impaired vision < 50 cm, unless
corrected by glasses or contact lenses.
Parents and participants (i.e., adolescents) provided written informed
consent (and assent). Adolescents underwent a series of tests, including assessment
of cognitive ability and a structured clinical interview, followed by buccal swab and
passive drool genetic sampling, and completion of questionnaires across two sessions.
Self-report questionnaires completed by adolescents (detailed below) were assessments
of affectivity, emotion dysregulation, reinforcement sensitivity, aggression and of
the early childhood home environment. Questionnaires completed by parents involved
parent-report measures of adolescent behavior and functioning (including ADHD) and
parental self-report measures of prenatal maternal stress and parental
psychopathology. All questionnaires were completed digitally, on a computer or
tablet, using the Psytoolkit platform [88, 89] and the
Qualtrics software, Version June 2020–March 2021 (Qualtrics, Provo, UT). This
research was approved by the National Institute of Pharmacy and Nutrition
(OGYÉI/17089-8/2019) and has been performed in accordance with the ethical standards
laid down in the 1964 Declaration of Helsinki and its later amendments.
All (but ADHD and externalizing) diagnoses were determined using a
combination of the Mini-International Neuropsychiatric Interview for Children and
Adolescents (MINI Kid) [90] and the
Structured Clinical Interview for DSM-5 Disorders, Clinical Version (SCID-5 CV)
[91]. ADHD diagnoses were determined
using parent-report on the ADHD Rating Scale-5 (ARS-5) [92]. For an ADHD diagnosis, adolescents had to
meet a total of five (in case of youth < 17 years old) or six (in case of
youth ≥ 17 years old) (or more) of the Diagnostic and Statistical Manual of Mental
Disorders (5th ed; DSM-5) [93]
inattention or hyperactivity/impulsivity symptoms and exhibit impairment (i.e.,
rating of 2 = moderate impairment or 3 = severe impairment) in at least three areas
of functioning (G. DuPaul, personal communication, July 19, 2021). Unanimous
agreement by two licensed child psychiatrists was required for ADHD diagnoses.
Participants
Participants included in the current study were 268 adolescents between
the ages of 14 and 18 years (Mage = 15.31 years; SD = 1.063; 57.8% boys),
n = 66 met criteria for ADHD. The majority
(96.3%) identified as White and 3.7% identified as part of an ethnic minority group
in Hungary. Average cognitive ability was in the 61.79th percentile (SD = 20.86),
with estimated VCI percentile rank: M = 66.42,
SD = 22.98, estimated PRI percentile rank M = 57.16, SD = 26.33. Participants were from an above-average
socioeconomic background based on parental income (average family net income fell in
the 5 001–700 000 HUF/month range, with average net income in Hungary being 289 000
HUF/month) [94].
Measures
For detailed description of measures, see Supplement. Cognitive
functioning was estimated using abbreviated versions of the Wechsler Intelligence
Scales [95, 96]. Minor prenatal stress was measured using the
perceived stress scale (PSS) [97] and
major prenatal stress using the prenatal life event scale (PLES) [98]. Affectivity, aggression, and emotion
regulation were assessed via the positive and negative affect schedule (PANAS)
[99], the difficulties in emotion
regulation scale (DERS) [100] and the
Buss-Perry aggression questionnaire (BPAQ) [101], respectively. The postnatal home environment was measured
with the Neglect/Negative Home Atmosphere subscale of the child abuse and trauma
scale (CATS) [102]. BIS sensitivity was
measured with the BIS subscale of the Reinforcement Sensitivity Theory of Personality
Questionnaire (RST-PQ) [103]. Maternal
internalizing problems were assessed on the Internalizing Problems subscale of the
Adult Self-Report 18–59 [104].
Adolescent ADHD status was determined using the home version of the ADHD rating
scale-5 (ARS 5) [92].
Analytic Plan
We collected questionnaire data digitally, which requested a response
for all questions. Due to sensitive issues, however, items from the CATS
questionnaire were not mandatory, thus data on some items were missing for some
participants; of the 38 CATS items 24 had missing data from ≥ one participant. Of the
268 adolescents, 242 responded to all CATS questions and 9 had missing data on ≥ one
(typically, one to four) item, with a total of 88 missing CATS data points. Multiple
imputation was used to substitute missing data; consistent with this method, five
alternative iterations were created for possible responses to missing data points and
the mean of these five iterations were used for imputation.
To examine the association among study variables, bivariate
correlations were computed. To examine whether associations between prenatal maternal
stress (as indexed by maternal report on the PLES and PSS) and adolescent offspring
outcomes of interest (i.e., self-report affectivity, ED, and aggression) are mediated
by childhood maltreatment variables (as indexed by CATS subscales) and BIS
sensitivity as serial mediators, we used PROCESS Version 3.5 [105] to calculate 95% CIs around the indirect
effect with 5000 bootstrap resamples,2 implementing a heteroscedasticity-consistent standard error estimator.
For all mediation findings, we report the completely standardized indirect
effect(s).
Bivariate correlations were repeated with the subsample where the
mother completed the Adult Self-Report (as interest was in maternal internalizing
symptoms; n = 244). In addition to maternal
internalizing psychopathology, as (1) our sample was oversampled for ADHD and (2)
there are sex differences in the effects of prenatal stress [106], and sex differences in the incidence and
prevalence of mental disorders begin to emerge during adolescence [107, 108], we also examined whether adolescent ADHD status and sex
moderate the mediational effect of CATS neglect/negative atmosphere and BIS
sensitivity. To this end, we conducted follow-up moderated mediational analyses in
case of models that were supported in the serial mediational analyses. Adult
Self-Report Internalizing Problems T Score, adolescent ADHD diagnosis, and adolescent
sex were examined as moderators of the indirect path (from prenatal maternal stress
to adolescent outcomes through CATS neglect/negative atmosphere and BIS sensitivity)
and the direct path (from prenatal maternal stress to adolescent outcomes) in the
mediational model, also using PROCESS Version 3.5 [105] and 5000 bootstrap resamples, implementing a
heteroscedasticity-consistent standard error estimator.
For all mediation findings, we report the completely standardized
indirect effect(s). Indirect effect 1 corresponds to the effect of the prenatal
maternal stress variable(s) on the outcome through childhood maltreatment
variable(s), Indirect effect 2 corresponds to the effect of the prenatal maternal
stress variable(s) on the outcome through BIS sensitivity, and Indirect effect 3
corresponds to the serial mediation effect, i.e., the effect of the prenatal maternal
stress variable(s) on the outcome through childhood maltreatment variable(s) and BIS
sensitivity operating serially.
Results
Descriptive Analyses
Regarding prenatal maternal substance use, 19 (7.09%) mothers reported
any kind of substance use while pregnant; 70 (26.12%) mothers reported their child
was not born to term (i.e., was more than a week either pre-term or late term), 81
(30.22%) reported they experienced some form of complication during or after giving
birth, 70 (26.12%) reported they had a high risk pregnancy, 18 (6.72%) reported they
had an inflammatory disease while pregnant, and 16 (5.97%) reported their child was
born with a lower than average birth weight (see Supplementary Table S1).
On the PLES, items most frequently endorsed and rated as at least
“moderately negative or undesirable” were: “13. Did you have
serious arguments several times with someone?” (n = 44 [16.30%]); “9. Did you have unusual
financial pressures or trouble with money?” (n = 32 (11.80%)); “24. During your pregnancy,
did you or a close family member or friend experience serious physical injury,
illness, or hospitalization?” (n = 27 (10%)); “8. Did you have unusually big
pressures or conflicts at work?” (n = 22 (8.20%)); (see Supplementary Table S2).
On the PSS, items most frequently endorsed as at least ‘fairly often’
(or ‘sometimes’ in case of reverse-scored items) were: “12.
found yourself thinking about things that you have to accomplish?”
(n = 105 (38.90%)); “1.
been upset because of something that happened unexpectedly?” (n = 47 (17.40%)); “3. felt
nervous and “stressed”?” (n = 41
(15.20%)); “8. found that you could not cope with all the
things that you had to do?” (n = 40
(14.90%)); “11. been angered because of things that were
outside of your control?” (n = 40
(14.80%)); (see Supplementary Table S2).
Bivariate Correlation Analyses
The prenatal maternal stress variables were positively correlated, with
the correlation coefficient corresponding to a medium effect (Table 1). Greater PLES scores were associated with greater
CATS neglect/negative atmosphere and BIS sensitivity—all small effects; PSS scores
were associated with these variables as well as positively associated with greater ED
and NA—also a small effect (Table 1). The two
hypothesized mediators, CATS neglect/negative atmosphere and BIS sensitivity were
positively correlated with each other, with the correlation coefficient corresponding
to a medium effect, and both were positively correlated with all hypothesized
outcomes (i.e., NA, ED, and aggression—CATS neglect/negative atmosphere and outcomes:
medium to large effects and BIS sensitivity and outcomes: also medium (aggression) to
large (NA, ED) effects) indicating the proposed mediator-outcome combinations are
suitable for mediation analysis [109]
(Table 1). NA, ED, and aggression were also
positively related—all medium to large effects (Table 1). Girls reported greater CATS neglect/negative atmosphere, ED, NA
and greater BIS sensitivity and older age was associated with greater ED, NA and BIS
sensitivity (small effects).
Table 1
Bivariate correlations among study variables
1
2
3
4
5
6
7
8
9
1. ADHD status
r (p)
–
Bootstrap
Bias (SE)
–
95% CI
–
2. ED
r (p)
0.196
(0.002)
–
Bootstrapc
Bias (SE)
0.000 (0.064)
–
95% CI
0.074; 0.322
–
3. NA
r (p)
0.162
(0.009)
0.709
(< 0.001)
–
Bootstrapc
Bias (SE)
0.001 (0.066)
0.001 (0.037)
–
95% CI
0.029; 0.290
0.625; 0.774
–
4. CATS NNA
r (p)
0.128
(0.040)
0.494
(< 0.001)
0.502
(< 0.001)
–
Bootstrapc
Bias (SE)
0.000 (0.060)
− 0.001 (0.064)
0.000 (0.059)
–
95% CI
0.000; 0.252
0.366; 0.614
0.381; 0.614
–
5. Aggression
r (p)
0.055 (0.380)
0.392
(< 0.001)
0.457
(< 0.001)
0.346
(< 0.001)
–
Bootstrapc
Bias (SE)
0.001 (0.067)
0.003 (0.058)
0.002 (0.055)
0.004 (0.064)
–
95% CI
− 0.077; 0.193
0.277; 0.502
0.347; 0.564
0.224; 0.469
–
6. BIS
r (p)
0.024 (0.705)
0.707
(< 0.001)
0.702
(< 0.001)
0.512
(< 0.001)
0.355
(< 0.001)
–
Bootstrapc
Bias (SE)
0.001 (0.067)
0.001 (0.033)
0.001 (0.031)
0.000 (0.056)
0.002 (0.065)
–
95% CI
− 0.100; 0.158
0.636; 0.769
0.644; 0.761
0.398;0.614
0.219; 0.482
–
7. PSS
r (p)
0.307
(< 0.001)
0.255
(< 0.001)
0.170
(0.006)
0.233
(< 0.001)
0.009 (0.892)
0.174
(0.005)
–
Bootstrapc
Bias (SE)
− 0.002 (0.059)
0.000 (0.057)
0.003 (0.060)
0.002 (0.058)
0.000 (0.063)
0.000 (0.057)
–
95% CI
0.190; 0.425
0.137; 0.365
0.052; 0.291
0.122; 0.345
− 0.115; 0.131
0.060; 0.280
–
8. PLES
r (p)
0.133
(0.032)
0.113 (0.070)
0.116 (0.063)
0.130
(0.038)
0.002 (0.973)
0.124
(0.047)
0.384
(< 0.001)
–
Bootstrapc
Bias (SE)
0.001 (0.066)
0.003 (0.058)
0.003 (0.052)
0.004 (0.056)
0.000 (0.062)
0.004 (0.063)
0.000 (0.058)
–
95% CI
0.002; 0.265
0.004; 0.223
0.015; 0.225
0.029; 0.248
− 0.117; 0.130
0.000; 0.244
0.276; 0.497
–
9. Age
r (p)
− 0.019 (0.758)
0.130
(0.038)
0.144
(0.021)
0.073 (0.246)
0.096 (0.124)
0.223
(< 0.001)
−0.045 (0.478)
− 0.064 (0.308)
–
Bootstrapc
Bias (SE)
0.000 (0.063)
− 0.001 (0.058)
0.000 (0.060)
− 0.001 (0.062)
0.000 (0.060)
− 0.001 (0.059)
0.000 (0.059)
0.001 (0.063)
–
95% CI
− 0.140; 0.108
0.019; 0.242
0.020; 0.263
− 0.046; 0.202
− 0.020; 0.213
0.103; 0.336
− 0.156; 0.072
− 0.183; 0.062
–
10. Sex
r (p)
− 0.136
(0.029)
0.180
(0.004)
0.161
(0.010)
0.272
(< 0.001)
− 0.060 (0.337)
0.273
(< 0.001)
0.083 (0.186)
− 0.242
(< 0.001)
− 0.067 (0.283)
Bootstrapc
Bias (SE)
0.000 (0.061)
− 0.001 (0.059)
− 0.003 (0.060)
− 0.001 (0.055)
− 0.004 (0.063)
− 0.003 (0.057)
0.000 (0.064)
− 0.001 (0.057)
0.000 (0.062)
95% CI
− 254; − 0.011
0.060; 0.293
0.038; 0.274
0.157; 0.376
− 0.194; 0.063
0.155; 0.386
− 0.048; 0.206
− 0.348; − 0.121
− 0.183; 0.056
Significant correlations are in bold
PLES prenatal life events scale,
PSS perceived stress scale, CATS NNA child abuse and trauma survey,
neglect/negative home atmosphere subscale, BIS behavioral inhibition system, NA negative affectivity, ED emotion dysregulation
When repeating bivariate correlations restricted to the portion of the
sample whose mothers completed the Adult Self-Report (as interest was in maternal
internalizing symptoms; n = 244), the pattern of
correlations among hypothesized predictor, mediator, outcome, sex, and age variables
was the same as in the overall sample (Table 2). Maternal internalizing symptoms were positively associated with
PLES (r = 0.229, p < 0.001) and PSS (r = 0.475,
p < 0.001) scores (a small and a medium
effect, respectively) and also with adolescent offspring BIS sensitivity (r = 0.236, p < 0.001) and NA (r = 0.256,
p < 0.001) (medium effects) and ED
(r = 0.253 p < 0.001) (a borderline medium effect) and CATS neglect/negative
atmosphere (r = 0.168 p = 0.009) (Table 2).
Table 2
Bivariate correlations among study variables restricted to a
subsample (n = 244) with available
maternal internalizing symptoms data
1
2
3
4
5
6
7
8
9
10
1. ADHD status
r (p)
–
Boot
Bias (SE)
–
95% CI
–
2. Int
r (p)
0.229
(< 0.001)
–
Boot
Bias (SE)
− 0.001 (0.062)
–
95% CI
0.108; 0.344
–
3. Age
r (p)
− 0.001 (0.993)
− 0.049 (0.447)
–
Boot
Bias (SE)
− 0.004 (0.063)
0.002 (0.068)
–
95% CI
− 0.129; 0.113
− 0.179; 0.088
–
4. Sex
r (p)
− 0.126
(0.049)
0.049 (0.447)
− 0.086 (0.183)
–
Boot
Bias (SE)
0.001 (0.062)
0.002 (0.061)
0.000 (0.064)
–
95% CI
− 0.241; − 0.004
− 0.064; 0.175
− 0.216; 0.042
–
5. ED
r (p)
0.228
(< 0.001)
0.253
(< 0.001)
0.140
(0.028)
0.193
(0.002)
–
Boot
Bias (SE)
0.003 (0.069)
0.002 (0.061)
0.001 (0.063)
− 0.001 (0.061)
–
95% CI
0.095; 0.368
0.135; 0.372
0.015; 0.271
0.063; 0.310
–
6. NA
r (p)
0.190
(0.003)
0.256
(< 0.001)
0.148
(0.021)
0.166
(0.009)
0.708
(< 0.001)
–
Boot
Bias (SE)
0.000 (0.068)
− 0.004 (0.064)
− 0.001 (0.063)
− 0.001 (0.064)
− 0.002 (0.038)
–
95% CI
0.056; 0.324
0.117; 0.371
0.022; 0.271
0.026; 0.281
0.630; 0.774
–
7. CATS NNA
r (p)
0.125
(0.051)
0.168
(0.009)
0.085 (0.186)
0.276
(< 0.001)
0.506
(< 0.001)
0.513
(< 0.001)
–
Boot
Bias (SE)
0.001 (0.071)
−0.002 (0.055)
0.000 (0.066)
0.001 (0.057)
− 0.002 (0.065)
− 0.003 (0.060)
–
95% CI
− 0.017; 0.268
0.060; 0.266
− 0.050; 0.209
0.161; 0.385
0.366; 0.621
0.383; 0622
–
8. Agg
r (p)
0.084 (0.190)
−0.019 (0.767)
0.109 (0.090)
− .073 (0.253)
0.383
(< 0.001)
0.450
(< 0.001)
0.358
(< 0.001)
–
Boot
Bias (SE)
0.003 (0.069)
0.000 (0.070)
−0.001 (0.064)
− 0.001 (0.063)
−0.002 (0.063)
− 0.002 (0.057)
0.000 (0.065)
–
95% CI
− 0.044; 0.225
− 0.149; 0.124
− 0.027; 0.230
− 0.197; 0.050
0.256; 0.495
0.325; 0.555
0.234; 0.487
–
9. BIS
r (p)
0.049 (0.445)
0.236
(< 0.001)
0.223
(< 0.001)
0.272
(< 0.001)
0.712
(< 0.001)
0.705
(< 0.001)
0.531
(< 0.001)
0.340
(< 0.001)
–
Boot
Bias (SE)
0.001 (0.073)
−0.001 (0.060)
0.000 (0.062)
−0.002 (0.059)
−0.002 (0.034)
− 0.001 (0.031)
− 0.001 (0.056)
0.000 (0.069)
–
95% CI
− 0.099; 0.192
0.115; 0.347
0.102; 0.348
0.146; 0.380
0.636; 0.768
0.639; .760
0.413; 0.630
0.200; 0.472
–
10. PSS
r (p)
0.298
(< 0.001)
0.475
(< 0.001)
− 0.039 (0.543)
0.109 (0.088)
0.288
(< 0.001)
0.189
(0.003)
0.244
(< 0.001)
0.036 (0.580)
0.198
(0.002)
–
Boot
Bias (SE)
0.002 (0.060)
− 0.002 (0.050)
− 0.001 (0.063)
− 0.001 (0.062)
− 0.001 (0.055)
− 0.002 (0.060)
− 0.004 (0.063)
− 0.002 (0.065)
− .002 (0.057)
–
95% CI
0.181; 0.410
0.374; 0.567
− 0.156; 0.094
− 0.017; 0.234
0.177; 0.398
0.063; 0.303
0.119; 0.364
− 0.096; 0.157
0.084; 0.307
–
11. PLES
r (p)
0.114 (0.074)
0.229
(< 0.001)
− 0.057 (0.378)
0.009 (0.890)
0.124 (0.053)
0.131
(0.040)
0.125 (0.051)
0.037 (0.565)
0.178
(0.005)
0.387
(< 0.001)
Boot
Bias (SE)
0.000 (0.071)
0.002 (0.055)
0.001 (0.067)
− 0.002 (0.064)
0.001 (0.057)
0.000 (0.055)
0.000 (0.061)
0.000 (0.066)
− 0.001 (0.060)
0.003 (0.058)
95% CI
− 0.025; 0.260
0.122; 0.338
− 0.181; 0.080
− 0.115; 0.139
0.019; 0.242
0.029; 0.246
0.014; 0.256
− 0.091; 0.170
0.057; 0.297
0.272; 0.501
Significant correlations are in bold
Boot bootstrap, Int maternal anxiety and depression problems as
indexed by the Adult Self-Report Form, Internalizing Problems T score,
ED emotion dysregulation as measured
by the difficulties in emotion regulation scale, NA negative affectivity, CATS
NNA child abuse and trauma scale–neglect/negative home
atmosphere subscale, Agg aggression,
BIS behavioral inhibition system,
PSS perceived stress scale, PLES prenatal life events scale
Mediation Analyses with the PLES as the Predictor
Negative Affectivity as the Outcome
CATS neglect/negative atmosphere (NNA) and BIS sensitivity mediated
the association between PLES and NA (effect = 0.042; SE = 0.018; 95%CIs (0.011;
0.080)). Greater PLES was associated with greater CATS neglect/negative atmosphere
and higher scores on CATS neglect/negative atmosphere were associated with greater
BIS sensitivity which, in turn, was positively associated with NA. CATS
neglect/negative atmosphere was also positively associated with NA but the
association between PLES and NA was not significant. Jointly, PLES, CATS NAA, and
BIS sensitivity accounted for 52% of the variance in NA (Table 3). Indirect effect 1 was (effect = 0.096;
SE = 0.042; 95%CIs (0.017; 0.180)), but Indirect effect 2 was not (effect = 0.029;
SE = 0.014; 95%CIs (0.007; 0.062)) supported.
Table 3
Model coefficients for serial mediation models testing
effects of prenatal maternal stress on the prenatal life events scale
(PLES) through childhood neglect/negative atmosphere and adolescent
BIS sensitivity to adolescent affective outcomes
Consequent
M1 (CATS NNA)
M2 (BIS)
Y (NA)
Antecedent
B
b
SE
B
b
SE
B
b
SE
X
(PLES)
0.143
0.934*
0.380
0.041
0.422
0.575
0.024
0.126
0.237
M1 (CATS NNA)
–
–
–
0.503
0.789***
0.091
0.205
0.163***
0.045
M2 (BIS)
–
–
–
–
–
–
0.588
0.298***
0.026
Constant
–
9.453***
0.619
–
43.034***
1.116
–
− 1.829§
1.074
R2 = 0.02, F(1, 266) = 6.022*
R2 = 0.26, F(2, 265) = 40.851***
R2 = 0.52, F(3, 264) = 100.479***
M1 (CATS NNA)
M2 (BIS)
Y (ED)
Antecedent
B
b
SE
B
b
SE
B
b
SE
X
(PLES)
0.143
0.934*
0.380
0.041
0.422
0.575
0.043
0.712
0.791
M1 (CATS NNA)
–
–
–
0.503
0.789***
0.091
0.195
0.492***
0.145
M2 (BIS)
–
–
–
–
–
–
0.598
0.962***
0.083
Constant
–
9.453***
0.619
–
43.034***
1.116
–
23.890***
3.386
R2 = 0.02, F(1, 266) = 6.021*
R2 = 0.36, F(2, 265) = 40.851***
R2 = 0.52, F(3, 264) = 102.234***
M1 (CATS NNA)
M2 (BIS)
Y
(aggression)
Antecedent
B
b
SE
B
b
SE
B
b
SE
X
(PLES)
0.140
0.943*408
0.051
0.538
0.612
− 0.053
− 0.695
0.789
M1 (CATS NNA)
–
–
–
0.506
0.799***
0.093
0.239
0.471*
0.197
M2 (BIS)
–
–
–
–
–
–
0.238
0.297***
0.105
Constant
–
9.401***
0.626
–
42.897***
1.131
–
41.038***
4.648
R2 = 0.2 F(1, 266) = 5.351*
R2 = 0.27, F(2, 265) = 40.602***
R2 = 0.17, F(3, 264) = 12.675***
B standardized regression
coefficients, b unstandardized
coefficients, SE
heteroscedasticity-consistent standard error estimator
CATS neglect/negative atmosphere and BIS sensitivity mediated the
association between PLES and DERS (effect = 0.043; SE = 0.017; 95%CIs (0.012;
0.079)). Greater PLES was associated with greater CATS neglect/negative atmosphere
and higher scores on CATS neglect/negative atmosphere was associated with greater
BIS sensitivity which, in turn, was positively associated with greater ED. CATS
neglect/negative atmosphere was also associated with greater ED but the
associations between PLES and BIS and PLES and ED were not significant. Jointly,
PLES, CATS neglect/negative atmosphere, and BIS sensitivity accounted for 52% of
the variance in ED (Table 3). Indirect
effect 1 was (effect = 0.028; SE = 0.014; 95%CIs (0.006; 0.060)), but Indirect
effect 2 was not (effect = 0.025; SE = 0.033; 95%CIs (− 0.038; 0.095))
supported.
Aggression as the Outcome
CATS neglect/negative atmosphere and BIS sensitivity mediated the
association between PLES and aggression (effect = 0.017; SE = 0.010; 95%CIs
(0.002; 0.042)). Greater PLES was associated with greater CATS neglect/negative
atmosphere and higher scores on CATS neglect/negative atmosphere was associated
with greater BIS sensitivity which, in turn, was positively associated with
aggression. CATS neglect/negative atmosphere was also positively associated with
aggression but the associations between PLES and BIS and PLES and aggression were
not significant. Jointly, PLES, CATS neglect/negative atmosphere, and BIS
sensitivity accounted for 17% of the variance in aggression (Table 3). Indirect effect 1 was (effect = 0.034;
SE = 0.020; 95%CIs (0.004; 0.081)), but Indirect effect 2 was not (effect = 0.012;
SE = 0.014; 95%CIs (− 0.016; 0.039)) supported.
Mediation Analyses with the PSS as the Predictor
Negative Affectivity as the Outcome
CATS neglect/negative atmosphere and BIS sensitivity mediated the
association between PSS and NA (effect = 0.070; SE = 0.020; 95%CIs (0.031;
0.112)). Greater PSS was associated with greater CATS neglect/negative atmosphere
and CATS neglect/negative atmosphere was positively associated with BIS
sensitivity (the association between PSS and BIS sensitivity was not significant)
which, in turn, was positively associated with NA (the association between PSS and
NA was not significant but CATS neglect/negative atmosphere was positively
associated with NA). Jointly, PSS, CATS neglect/negative atmosphere, and BIS
sensitivity accounted for 52% of the variance in NA (Table 4). Indirect effect 1 was (effect = 0.049;
SE = 0.020; 95%CIs (0.016; 0.091)) but Indirect effect 2 was not (effect = 0.024;
SE = 0.032; 95%CIs (− 0.036; 0.088)) supported.
Table 4
Model coefficients for serial mediation models testing
effects of prenatal maternal stress on the perceived stress scale
(PSS) through childhood neglect/negative atmosphere and adolescent BIS
sensitivity to adolescent affective outcomes
Consequent
M1 (CATS NNA)
M2 (BIS)
Y (NA)
Antecedent
B
b
SE
B
b
SE
B
b
SE
X (PSS)
0.242
0.224***
0.058
0.041
0.060
0.080
0.034
0.026
0.035
M1 (CATS NNA)
–
–
–
0.496
0.780***
0.097
0.201
0.159***
0.047
M2 (BIS)
–
–
–
–
–
–
0.587
0.294***
0.026
Constant
–
3.262§
1.820
–
41.702***
2.388
–
1.376
1.395
R2 = 0.24, F(1, 262) = 15.038***
R2 = 0.28, F(2, 261) = 41.879***
R2 = 0.52, F(3, 260) = 93.879***
M1 (CATS NNA)
M2 (BIS)
Y (ED)
Antecedent
B
b
SE
B
b
SE
B
b
SE
X (PSS)
0.242
0.224***
0.058
0.041
0.060
0.080
0.125
0.292*
0.118
M1 (CATS NNA)
–
–
–
0.496
0.780***
0.097
0.169
0.426**
0.147
M2 (BIS)
–
–
–
–
–
–
0.598
0.959***
0.080
Constant
–
3.262§
1.820
–
41.702***
2.388
–
15.974***
4.480
R2 = 0.06, F(1, 262) = 15.038***
R2 = 0.26, F(2, 261) = 41.879***
R2 = 0.54, F(3, 260) = 101.171***
M1 (CATS NNA)
M2 (BIS)
Y
(aggression)
Antecedent
B
b
SE
B
b
SE
B
b
SE
X (PSS)
0.238
0.224***
0.060
0.054
0.081
0.081
− 0.081
− 0.150
0.113
M1 (CATS NNA)
–
–
–
0.497
0.786**
0.100
0.249
0.491*
0.200
M2 (BIS)
–
–
–
–
–
–
0.237
0.296**
0.106
Constant
–
3.243§
1.860
–
41.039***
2.420
–
45.060***
5.602
R2 = 0.06, F(1, 262) = 14.131***
R2 = 0.26, F(2, 261) = 42.219***
R2 = 0.16, F(3, 260) = 12.504***
B standardized regression
coefficients, b unstandardized
coefficients, SE
heteroscedasticity-consistent standard error estimator
CATS neglect/negative atmosphere and BIS sensitivity mediated the
association between PSS and DERS (effect = 0.072; SE = 0.021; 95%CIs (0.034;
0.114)). Greater PLES was associated with greater CATS neglect/negative atmosphere
and higher scores on both were associated with greater BIS sensitivity which, in
turn, was positively associated with ED (the associations between PLES and ED and
CATS neglect/negative atmosphere and ED were not significant). Jointly, PLES, CATS
neglect/negative atmosphere, and BIS sensitivity accounted for 54% of the variance
in ED (Table 4). Indirect effect was 1
(effect = 0.041; SE = 0.018; 95%CIs (0.010; 0.081)) but Indirect effect 2 was not
(effect = 0.024; SE = 0.032; 95%CIs (−0.035; 0.089)) supported.
Aggression as the Outcome
CATS neglect/negative atmosphere and BIS sensitivity mediated the
association between PSS and DERS (effect = 0.028; SE = 0.015; 95%CIs (0.006;
0.062)). Greater PSS was associated with greater CATS neglect/negative atmosphere
and higher scores on CATS neglect/negative atmosphere were associated with greater
BIS sensitivity (the association between PSS and BIS sensitivity was not
significant) which, in turn, was positively associated with aggression. CATS
neglect/negative atmosphere was also positively associated with aggression but the
associations between PSS and aggression was not significant). Jointly, PSS, CATS
neglect/negative atmosphere, and BIS sensitivity accounted for 17% of the variance
in aggression (Table 4). Indirect effect 1
was (effect = 0.059; SE = 0.025; 95%CIs (0.016; 0.112)), but Indirect effect 2 was
not (effect = 0.013; SE = 0.014; 95%CIs (− 0.013; 0.041)) supported.
For a visual summary of mediation results, see Fig. 1.
Fig. 1
Visual summary of serial mediation results with childhood
neglect/ negative atmosphere (NNA) and adolescent behavioral
inhibition system (BIS) sensitivity operating in serial and mediating
the association between prenatal maternal stress and adolescent
affective outcomes, with A the
prenatal life events scale (PLES) and B the perceived stress scale (PSS) as indices of
prenatal stress. Solid lines indicate models with indirect effects
supported (indirect effects 1 and 3, across models) and dashed lines
indicate models with indirect effects not supported (indirect effect
2, across models). Coefficients are standardized regression weights.
NA negative affectivity, ED emotion dysregulation, AGG aggression.
***p < 0.001; **p < 0.01; *p < 0.05; 0.1 > p < 0.05
×
Follow-up Moderated Mediation Analyses
Adolescent ADHD status did not moderate the direct or indirect effect
(through CATS neglect/negative atmosphere) of PLES
on BIS (index = − 1.205; SE = 0.702; 95%CIs (− 2.599; 0.153)), on NA
(index = − 0.592; SE = 0.360; 95%CIs (− 1.326; 0.114)), on ED (index = 1.855;
SE = 1.124; 95%CIs (− 4.134; 0.404)), or on aggression (index = 1.007; SE = 0.700;
95%CIs [− 2.256; 0.567)). Maternal internalizing symptoms also did not moderate the
direct or indirect effect (through CATS neglect/negative atmosphere) of PSS on BIS
(index = − 0.081; SE = 0.106; 95%CIs (−0.287; 0.130)) on NA (index = − 0.040;
SE = 0.053; 95%CIs (−0.143; 0.071)), on ED (index = − 0.040; SE = 0.109; 95%CIs
(−0.261; 0.177)), or on aggression (index = − 0.040; SE = 0.109; 95%CIs (− 0.261;
0.177)).
Maternal internalizing symptoms did not moderate the direct or indirect
effect (through CATS neglect/negative atmosphere) of
PLES on BIS (index = − 0.042; SE = 0.032; 95%CIs (− 0.112; 0.017)), on NA
(index = − 0.021; SE = 0.017; 95%CIs (− 0.060; 0.008)), on ED (index = − 0.065;
SE = 0.052; 95%CIs (− 0.182; 0.025)), or on aggression (index = − 0.025; SE = 0.041;
95%CIs (− 0.111; 0.052)). Maternal internalizing symptoms also did not moderate the
direct or indirect effect (through CATS neglect/negative atmosphere) of PSS on BIS
(index = − 0.006; SE = 0.004; 95%CIs (− 0.014; 0.001)) on NA (index = − 0.003;
SE = 0.002; 95%CIs (− 0.007; 0.001)), on ED (index = − 0.009; SE = 0.006; 95%CIs
(− 0.021; 0.002)), or on aggression (index = − 0.004; SE = 0.004; 95%CIs
(− 0.014;0.004)).
Adolescent sex status did not moderate the direct or indirect effect
(through CATS neglect/negative atmosphere (NNA)) of
PLES on BIS (index = 0.677; SE = 0.653; 95%CIs (− 0.528; 2.018)), on NA
(index = 0.373; SE = 0.369; 95%CIs (− 0.309; 1.146)), on ED (index = 1.150;
SE = 1.159; 95%CIs (− 1.001;3.560)), or on aggression (index = 1.145; SE = 0.852;
95%CIs (− 0.317; 3.002)). Adolescent sex also did not moderate the direct or indirect
effect (through CATS neglect/negative atmosphere (NNA)) of PSS on BIS (index = 0.068;
SE = 0.085; 95%CIs (− 0.096; 0.242)), on NA (index = 0.037; SE = 0.047; 95%CIs
(− 0.052; 0.136)), on ED (index = 0.109; SE = 0.138; 95%CIs (− 0.140; 0.400)), or on
aggression (index = 0.101; SE = 0.100; 95%CIs (− 0.087; 0.295)).
Discussion
Our goals in this study were to assess, in middle-late adolescents,
whether prenatal maternal stress—conceptualized and measured as both relatively minor,
daily stressors and as relatively major, life events stressors—is associated with
indices of affective processing, specifically, affectivity, aggression, and emotion
dysregulation and whether these associations are mediated, serially, by differences in
the childhood home environment and adolescent BIS sensitivity. We also examined whether
adolescent ADHD diagnosis or maternal internalizing symptoms moderated any of the
mediational effects.
This study is one of a handful of examinations of transdiagnostic outcomes
of prenatal maternal stress, with findings applicable across the general and clinical
populations. To the best of our knowledge, this was the first evaluation of a serial
mediational effect and of the mediational effect of adolescent BIS sensitivity.
Findings of bivariate correlation analyses were generally as expected,
with a positive association of PLES scores with BIS sensitivity [110] and with NA [110, 111]. These
findings are not only consistent with earlier results, but extend those to the
transdiagnostic characteristics of negative affectivity, aggression, and emotion
dysregulation, in a relatively understudied developmental group, middle-late
adolescents. Interestingly, there was a differential pattern, where prenatal maternal
stress caused by major life events was associated with all measured adolescent outcomes
but ED whereas prenatal maternal stress caused by minor daily stressors was not
associated with any of the adolescent outcomes but ED. All of these relations
corresponded to small effects, perhaps because several third variables influence such
relations (including the ones assessed here) and/ or because prenatal maternal stress
was mother-reported whereas adolescent outcomes were self-reported.
Also as expected, the hypothesized mediators, CATS neglect/negative
atmosphere and BIS sensitivity were positively correlated with each other [85] and also with all assessed outcomes [40, 112‐116]. These relations corresponded to medium to
large effects, likely driven by their relative phenomenological and temporal proximity
and/ or partly due to shared method variance. In line with what is known about age and
sex differences, older age was associated with greater BIS sensitivity [117, 118] and girls reported greater BIS sensitivity. Others have
previously found a curvilinear relation between age and aggression, where aggression
increased until early-middle adolescence and declined by late adolescence [119, 120] and no sex-difference with regard to emotional neglect and abuse
[121] whereas here, we wound older age
was associated with greater aggression and girls reported greater CATS neglect/negative
atmosphere. Perhaps most importantly, prenatal maternal stress caused by major life
events was positively associated with prenatal maternal stress caused by minor daily
stressors but with the correlation coefficient corresponded to a small effect,
indicating that although the two variables are associated, they are not isomorphic (or
redundant) and thus represent related but distinct phenomena.
When examined in greater complexity, i.e., in a serial mediation model,
both indices of prenatal maternal stress were associated with adolescent affective
outcomes, through the serial effects of differences in the early childhood home
atmosphere/environment and in adolescent BIS sensitivity. Of import, the effect of
prenatal stress on the herein assessed adolescent affective outcomes was only
significant in the presence of a mediational effect of childhood neglect/ negative
atmosphere and BIS sensitivity (i.e., full mediation). The mediational effect of
childhood neglect/ negative atmosphere (indirect effect 1) was significant even in the
absence of the subsequent mediational effect of BIS sensitivity. This is consistent with
earlier findings indicating an association between prenatal maternal stress and
subsequent difficulties with parenting [122] and child maltreatment [71]. Our finding further extends these prior results insofar as it
suggests an effect of these variables on adolescent affective outcomes. The mediational
effect of BIS sensitivity (indirect effect 2) was only significant in the presence of a
preceding mediational effect of childhood neglect/ negative atmosphere. This set of
results have both conceptual and clinical implications.
Regarding conceptual implications, first, these findings underscore the importance of examining the effect
of mechanisms—when examined in the context of mediators, the direct path between
prenatal maternal stress and outcomes was not significant, indicating the observed
relation was fully mediated by the assessed mechanisms. This finding is consistent with
contemporary thinking about the complexity of relations between variables indexing human
development and psychology; that accounting for relevant mechanisms and influences may
reveal small or otherwise undetected effects [123].
Second, as noted, although the
mechanisms via which gestational stress is associated with neurodevelopment and
increases risk for offspring behavioral problems have yet to be elucidated [19], a leading hypothesis is that prenatal maternal
stress impacts, via fetal exposure to elevated cortisol, offspring brain systems related
to stress processing and regulation, such as the septohippocampal system. Our results
are consistent with this hypothesis insofar as they show that prenatal maternal stress
is associated with adolescent offspring affective problems through greater BIS
sensitivity, with the septohippocampal system, and its monoaminergic brainstem afferents
hypothesized to be implicated in BIS sensitivity [124].
Regarding clinical implications, establishing that an early-emerging
characteristic may be a protective or risk factor for later functional impairments,
behavioral problems, or psychopathology enhances conceptualization of developmental
trajectories to such outcomes. Arguably, however, the practical significance of such a
characteristic and its role is closely linked to the degree to which it is a promising
intervention—prevention or treatment—target and that is largely determined by the degree
to which it is malleable [125]. It is
against this backdrop that we discuss the relevance of the current set of results for
prevention of adolescent affective problems such as negative affectivity, aggression,
and ED and the sequalea of such problems, including diagnosable psychopathology
[126‐128]. In the context
of the variables examined here, the first point of intervention would need to be during
the prenatal period and focus on decreasing maternal stress. Such preventions and
treatments are available and include cognitive-behavioral, interpersonal, and
psychoeducational strategies, with data indicating short-term efficacy of cognitive and
psychoeducational techniques for reducing prenatal maternal stress [129‐131]. Early evidence shows Both mindfulness-based
interventions and yoga may also effectively decrease prenatal maternal stress, but
methodologically rigorous studies are needed to confirm observed effects [131‐134]. Virtual reality, although also promising, is
less available than these approaches and more research is needed to establish its
efficacy [135]. In case of children for
whom prenatal maternal stress had already occurred (e.g., who present to clinical care
during early childhood or later), consistent with a differential susceptibility
framework, an alternative point of intervention would be during childhood and focus on
decreasing neglect/ negative atmosphere and improving the early childhood home
atmosphere/environment (e.g., through parent training; [136]. In terms of scientific rigor, studies on parenting programs are
heterogeneous, with some methodologically sound designs assessing efficacy of e.g.,
Group Family Nurse Partnership [137], REAL
Fathers Initiative [138], and SOS Help for
Parents [139]. In case of children for
whom both the prenatal maternal stress and the negative childhood home
atmosphere/environment had occurred (e.g., who present to clinical care during early
adolescence or later), there is yet an alternative point and focus of intervention. In
such cases, intervention would be indicated during adolescence and to aim at attenuating
BIS sensitivity. Data show the BIS may be malleable as environmental (vs. genetic)
effects contribute to changes in BIS sensitivity [140]. Although to our knowledge, no interventions explicitly target
BIS sensitivity, certain interventions target and have been observed to alter
reinforcement sensitivity (e.g., Cognitive Remediation Therapy targets punishment
sensitivity and Transcranial Magnetic Stimulation targets reward sensitivity)
[141, 142]. Other interventions do not target reinforcement sensitivity but
have been shown to reduce BIS sensitivity (e.g., Behavioral Activation Therapy and
certain mindfulness types) [143,
144]. Pharmacological treatments, e.g.,
anxiolytic drugs also reduce BIS sensitivity [36]. Of note, BIS sensitivity is not to be conflated with anxiety.
There is certainly overlap between BIS hyperactivity and excessive anxiety, as BIS
hyperactivity may result in excessive focus on environmental threat and, as an indirect consequence, on threatening associations with
previous stimuli [36]. Nonclinical and
clinically anxious individuals exhibit an automatic, preferential attention to threat
(i.e., attentional bias) [145]. Despite
this overlap, the response of the defense system of which the BIS is part is context- or state-dependent. In contrast, individuals with
elevated levels of anxiety stably perceive the
environment as dangerous; as such, elevated trait anxiety is associated with negative
schema, hyper-vigilance to threatening information, and at the memory level,
hyper-recall of threatening information [146].
Limitations and Future Directions
Prenatal maternal stress was assessed via retrospective report, which
is associated with potential biases, including, but not limited to biases resulting
from current psychological disorders or functioning. Three lines of evidence lend
credence to the validity of assessing prenatal maternal stress via retrospective
report.
First, although past 6 months maternal internalizing symptoms were
positively associated with both measures of prenatal maternal stress (prenatal stress
caused by major life events and prenatal stress caused by minor daily stressors) and
these two measures of prenatal stress were also positively associated with each
other, the magnitude of these relations were mostly small. This arguably indicates,
on one hand, that current maternal internalizing symptoms did not to a confounding
extent influence maternal report of prenatal stress. Further, that mothers
differentiated between the two types of stressors suggests absence of a systematic
bias.
Second, earlier data evince the accuracy of retrospective report of
relevant characteristics and information, such as descriptions of the family
environment 25 years ago validated against prospective measures of such environment
(moderate correlations of 0.30–0.45 [147]; maternal report of breastfeeding history from 20 years ago
validated against clinic charts (strong correlations of 0.86) [148]; maternal report about a range of pre and
peri-natal factors (e.g., infant birth weight, infant admission to special care baby
unit, method of delivery, smoking during pregnancy, high blood pressure/oedema during
pregnancy) from four to nine years ago validated against antenatal records
[149] and against maternal report
6 months postpartum [150]; or parental
report of child birth information from 12 years ago validated against hospital
records [151].
Third, we repeated our analyses conducted with the “mean prenatal life
events distress score” using “the number of prenatal life events” as the PLES
predictor and replicated our findings (see Supplement). This is meaningful as the
former score comprises items assessing the extent to which one was negatively
affected by events that occurred whereas the latter comprises items assessing whether
or not such events occurred. Arguably, the former is considerably more subject to
recall bias than the latter. Although these data lend credence to the herein obtained
retrospective report of prenatal stress, a recall bias cannot be completely ruled
out. As such, our data are best conceptualized as preliminary indication that the
herein observed relations are worthy of examination in considerably more
resource-consuming longitudinal, prospective designs.
Given poor internal consistency of the other CATS subscales, only one
aspect of the early childhood home atmosphere/environment was examined in our
research (i.e., neglect/negative atmosphere), future research may examine whether our
findings generalize to other aspects of the childhood home environment, such as
physical abuse and neglect or sexual abuse. Similarly, only one aspect of
reinforcement sensitivity was tested in this study (i.e., BIS sensitivity). Evidence
shows prenatal maternal nutrition and stress affect offspring mesocorticolimbic
system [152], and such prenatal
programming of offspring mesocorticolimbic system appears to play a role in the
development of traits related to behavioral activation system (BAS) sensitivity, such
as attention toward salient stimuli, reward sensitivity as well as extraversion,
novelty seeking, and impulsivity [153].
Accordingly, future research may examine whether the herein obtained results
generalize to other aspects of reinforcement sensitivity, such as BAS
sensitivity.
Mediation can be demonstrated in cross-sectional research [154], but only via statistical criteria
[123, 155‐158].
Accordingly, we established atemporal mediation, mathematically/ statistically. As we
tested but did not find support for reversed models—as recommended e.g., in
cross-sectional designs, where temporal precedence is not definitively established
[159‐163], our
findings evince unidirectionality of observed effects and indicate additional
research is warranted, e.g., experimental or prospective studies to establish
temporal mediation and thus causation [161, 164].
We examined relations across a set of a priori chosen variables,
selected based on theory and prior empirical data. Certainly, the relations between
prenatal maternal stress and adolescent outcomes is complex, with several additional
variables also influencing such relations. Although we aimed to assess some of these
variables, including maternal smoking or drug use during pregnancy, only a small
number of mothers reported they smoked or used alcohol or drugs, indicating there may
be need in the future to oversample mothers who engage in substance use. Examples of
pertinent variables not assessed here include child genetic predisposition or life
events, and parental emotion regulation or parenting style. In support, there is
evidence that prenatal maternal stress may have greatest impact on areas of
functioning in which the offspring has a genetic vulnerability; in one study,
prenatal maternal anxiety was associated with adolescent offspring ADHD outcome at
age 15 years only in children with a specific variation of the COMT gene
[60].
In intending to assess the moderational effect of maternal
internalizing symptomology, we assessed maternal anxiety and depressive symptoms as
experienced during the past 6 months. Current and past 6 months internalizing
symptoms may not be related to maternal internalizing symptomology during pregnancy
or after, however, it is a good proxy for the likelihood of maternal anxiety or
depression as well as for genetic predisposition to offspring psychopathology
[87]. Nevertheless, to be able to
make stronger claims about the moderational effect of maternal psychopathology, it
will be important to collect data on this variable during and after pregnancy.
As noted, we found outcomes were differentially associated with
prenatal maternal stress caused by major life events vs. daily stressors; the former
was associated NA and aggression whereas the latter was only associated with ED. It
would be premature to speculate on this pattern based on the current findings, but
whether these differential effects replicate (and what might be driving them) may be
conceptually relevant to explore in the future.
We defined adolescence based on chronological age without accounting
for biological age or pubertal status, though these may not necessarily correspond.
It thus remains an outstanding question whether these findings replicate if
adolescence is defined based on biological maturity.
Finally, the current sample was a community-based sample, with the
majority of youth White. It will be important to examine whether results generalize
to clinical populations, ethnic minorities and other racial groups as well as to
collect data on symptoms, beyond children and parents, from teachers. Related, as
described in Methods, adolescents were oversampled
for ADHD. As such, sampling was not random and findings may not correspond to what
would be observed in a randomly selected group of adolescents. Although we assessed
and did not find evidence for a moderational effect of ADHD status, there are
associated features of ADHD (e.g., at the group level, differences in IQ or SES) that
were not evaluated in this manner but may have a bearing on the results.
Summary
In this first study assessing the serial mediational effect of differences
in the childhood home environment and adolescent behavioral inhibition system
sensitivity on the association between prenatal maternal stress and adolescent affective
outcomes, we found that the relation between prenatal maternal stress and adolescent
affective outcomes is mediated by both childhood neglect/negative atmosphere and
adolescent behavioral inhibition system sensitivity. These relations held across types
of maternal stress, i.e., across stress caused by major, life events stressors and
stress caused by minor, daily stressors and were not moderated by adolescent ADHD
diagnosis or by current/recent maternal internalizing symptomology. On its own, neither
childhood neglect/negative atmosphere nor adolescent behavioral inhibition system
sensitivity exerted a mediational effect, indicating it is in the modeled and tested
serial order that they account for the relation between prenatal maternal stress and
adolescent negative affectivity, aggression, and ED. Prevention and intervention efforts
aimed at reducing negative adolescent affective outcomes and the potential psychiatric
sequelae of such outcomes are to be tailored, with regard to their focus and target, to
the developmental phase during which the intervention occurs.
Declarations
Conflict of interest
None of the Authors have any biomedical or financial conflicts of
interest.
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The macros provide a 95% CI around the indirect effect. When zero
is not in the 95% CI, the indirect effect is different from zero at p < 0.05 (two tailed).
The Association Between Prenatal Maternal Stress and Adolescent Affective Outcomes is Mediated by Childhood Maltreatment and Adolescent Behavioral Inhibition System Sensitivity
Auteurs
T. Sebők-Welker E. Posta K. Ágrez A. Rádosi E. A. Zubovics M. J. Réthelyi I. Ulbert B. Pászthy N. Bunford
