Salivary cortisol reactivity in 6-month-old infants of mothers with severe psychiatric disorders: Preliminary findings from the face-to-Face Still-Face paradigm

Abstract

Background.
Maternal psychopathology is associated with altered HPA axis functioning in offspring. Most studies have focused on mildly affected populations, but less is known about the effect of severe maternal psychopathology. In our explorative study we investigated in a heterogenic sample of mothers with severe and long-lasting psychiatric disorders, if a diagnosis of depression and severity of general maternal psychiatric symptomatology were associated with infant salivary cortisol reactivity to the Face-to-Face Still-Face (FFSF) paradigm at 6 months of age.
Methods.
A clinical sample of 36 mother-infant dyads was explored. All mothers fulfilled criteria for a severe psychiatric disorder and had psychiatric complaints for the last two consecutive years. Maternal diagnosis was established during pregnancy using a diagnostic interview and general maternal psychiatric symptom severity was established by self-report at the time of the FFSF procedure. The FFSF paradigm was used to assess infants’ response to social stress at the age of 6 months. Infant saliva samples were collected at three time points: 5 minutes before and 15 and 30 minutes after the social stressor. Cortisol reactivity was operationalized as incremental Area Under the Curve (AUCi). Potential confounders were identified and adjusted for.
Results.
In regression analyses, a negative relationship was found between infant cortisol reactivity (AUCi) during the FFSF paradigm at 6 months and general maternal symptom severity at time of the FFSF paradigm (unadjusted n = 36, ß = −0.331, B = −9.758, SE 4.8, p = .048; adjusted n = 36, ß = −0.335, B = −9.868, SE 4.5, p = .039) and for diagnosis of perinatal depression at trend level (unadjusted n = 36, ß = −0.293, B = −8.640, SE 4.8, p = .083; adjusted n = 36, ß = −0.317, B = −9.347, SE 4.6, p = .052). Analyses were adjusted for gestational age.
Conclusions.
Preliminary results on cortisol reactivity in 6-month-old infants of mothers with severe and long-lasting psychiatric disorders show a significant reduction in the group of mothers who experienced a high level of psychiatric symptoms in the post-partum period, compared to mothers with lower levels of psychiatric symptomatology. The same trend was found for mothers with and without a diagnosis of perinatal depression. Since these infants are considered to be at increased risk for later psychopathology, our study suggests that future longitudinal studies should investigate whether reduced cortisol reactivity in babies could be a marker for any adverse outcomes, besides other possible risk factors (e.g. (epi)genetic phenomena).

Full text

Comprehensive Psychoneuroendocrinology 7 (2021) 100078
Available online 3 August 2021
2666-4976/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Salivary cortisol reactivity in 6-month-old infants of mothers with severe
psychiatric disorders: ndings from the face-to-Face Still-Face paradigm
Carlinde W. Broeks
a
,
b
,
d
, Rianne Kok
c
, Vandhana Choenni
a
, Rien Van
d
, Witte Hoogendijk
b
,
Manon Hillegers
a
, Astrid Kamperman
b
,
e
, Mijke P. Lambregtse-Van den Berg
a
,
b
,
*
a
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, the Netherlands
b
Department of Psychiatry, Erasmus MC, University Medical Center Rotterdam, the Netherlands
c
Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, the Netherlands
d
Arkin Institute for Mental Health, Amsterdam, the Netherlands
e
Epidemiological and Social Psychiatric Research Institute, Erasmus MC, Rotterdam, the Netherlands
ARTICLE INFO
Keywords:
Maternal psychopathology
Infant stress reactivity
Cortisol
HPA-Axis
Face-to-face still face paradigm
ABSTRACT
Background.
Maternal psychopathology is associated with altered HPA axis functioning in offspring. Most studies have
focused on mildly affected populations, but less is known about the effect of severe maternal psychopathology. In
our explorative study we investigated in a heterogenic sample of mothers with severe and long-lasting psychiatric
disorders, if a diagnosis of depression and severity of general maternal psychiatric symptomatology were asso-
ciated with infant salivary cortisol reactivity to the Face-to-Face Still-Face (FFSF) paradigm at 6 months of age.
Methods.
A clinical sample of 36 mother-infant dyads was explored. All mothers fullled criteria for a severe psychiatric
disorder and had psychiatric complaints for the last two consecutive years. Maternal diagnosis was established
during pregnancy using a diagnostic interview and general maternal psychiatric symptom severity was estab-
lished by self-report at the time of the FFSF procedure. The FFSF paradigm was used to assess infants’ response to
social stress at the age of 6 months. Infant saliva samples were collected at three time points: 5 min before and 15
and 30 min after the social stressor. Cortisol reactivity was operationalized as incremental Area Under the Curve
(AUCi). Potential confounders were identied and adjusted for.
Results.
In regression analyses, a negative relationship was found between infant cortisol reactivity (AUCi) during the
FFSF paradigm at 6 months and general maternal symptom severity at time of the FFSF paradigm (unadjusted n
=36, ß = − 0.331, B = − 9.758, SE 4.8, p =.048; adjusted n =36, ß = − 0.335, B = − 9.868, SE 4.5, p =.039) and
for diagnosis of perinatal depression at trend level (unadjusted n =36, ß = − 0.293, B = − 8.640, SE 4.8, p =.083;
adjusted n =36, ß = − 0.317, B = − 9.347, SE 4.6, p =.052). Analyses were adjusted for gestational age.
Conclusions.
Preliminary results on cortisol reactivity in 6-month-old infants of mothers with severe and long-lasting
psychiatric disorders show a signicant reduction in the group of mothers who experienced a high level of
psychiatric symptoms in the post-partum period, compared to mothers with lower levels of psychiatric symp-
tomatology. The same trend was found for mothers with and without a diagnosis of perinatal depression. Since
these infants are considered to be at increased risk for later psychopathology, our study suggests that future
longitudinal studies should investigate whether reduced cortisol reactivity in babies could be a marker for any
adverse outcomes, besides other possible risk factors (e.g. (epi)genetic phenomena).
* Corresponding author. PhD Address: P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
E-mail address: mijke.vandenberg@erasmusmc.nl (M.P. Lambregtse-Van den Berg).
Contents lists available at ScienceDirect
Comprehensive Psychoneuroendocrinology
journal homepage: www.sciencedirect.com/journal/comprehensive-psychoneuroendocrinology
https://doi.org/10.1016/j.cpnec.2021.100078
Received 22 March 2021; Received in revised form 10 July 2021; Accepted 2 August 2021

Comprehensive Psychoneuroendocrinology 7 (2021) 100078
2
1. Introduction
Severe maternal psychopathology may deeply impact child out-
comes. Previous studies have shown that infants affected by maternal
depression have reduced resilience and higher risks for psychiatric dis-
orders and other health issues [1]. More specically, previous literature
suggests that maternal psychopathology can cause early disturbance of
infant HPA-axis functioning. This disturbance might be a mechanism
that explains the higher vulnerability to both mental and physical dis-
ease [2]. Most research on HPA-axis functioning in infants of mothers
with mild psychopathology has reported mixed results, with both hyper-
and hypo-activation of the infant stress system [3]. However studies
found that under extremely stressful conditions children showed
reduced rather than increased cortisol responses to stressors [4,5]. A
recent study showed this might be transmitted by genetic factors as well,
as a history of maternal childhood maltreatment was associated with
downregulation of cortisol in newborns [6]. Thus, both over- and
under-activation should be considered as a form of dysregulation and as
potential outcomes of the impact of maternal psychopathology on child
mental and physical development.
Assessment of salivary cortisol response to the Face-to-Face Still-Face
(FFSF) paradigm is a widely adopted experimental procedure to assess
infants’ response to social stress during the rst months of life [7]. The
FFSF paradigm consists of a three-step interaction of infant and adult, in
which there is [1] a normal interaction episode [2], the episode of the
‘still-face’ in which the adult becomes unresponsive maintaining a
neutral facial expression, and [3] a reunion episode with normal inter-
action. Most studies on the FFSF paradigm have demonstrated that in-
fants respond by showing an increase of distress from baseline to
still-face and a decrease of distress during the reunion phase [8].
Research in clinical populations on infant response to the FFSF
paradigm has mainly focused on the impact of maternal depression,
because maternal depression has frequently been associated with
diminished emotional sensitivity and responsivity in both mother and
child [9,10]. Previous studies on cortisol reactivity following the FFSF
paradigm in clinical samples have shown inconsistent results. Two
studies showed an increased infant cortisol response in infants of
mothers experiencing depression and anxiety [11,12]. Another study
did not nd a relationship between maternal psychopathology and in-
fant cortisol response [13].
To our knowledge, no studies to date have examined cortisol reac-
tivity in response to the FFSF paradigm in infants of mothers with severe
and long-lasting psychiatric disorders. Parental emotional sensitivity
and behavioral responsivity are assumed to be crucial in the develop-
ment of adequate stress regulation in infants [14]. A pattern of inade-
quate caregiving and/or emotional unavailability in the post-partum
period is an important source of stress also for infants of mothers with
broader psychopathology. Especially in the case of severe and
long-lasting psychiatric disorders, mothers might be unable to
adequately adjust focus to their infants’ needs [15]. Considering this, the
FFSF paradigm might not evoke a similar marked reaction – both
emotionally, behavioral and biologically - in these infants as it would in
infants of a less or unaffected mother, because of habituation of the
infant to generally diminished responsivity of the mother. We hypoth-
esized both persistence of higher symptom severity postpartum as well
as depression might be associated with diminished cortisol reactivity in
6-month old infants. To explore these hypotheses, we assessed the in-
uence of psychiatric symptom severity and an established diagnosis of
depression in a high-risk psychiatric population of new mothers.
2. Methods
2.1. Study design and sample
The current study was embedded in an observational study on
parenting capacity of mothers with severe psychiatric disorders and
their infant’s development during the rst year of life (INCAS study
NL42662.078.12). For this purpose, multiple measurements were con-
ducted in the patient group; the control group only participated at 6
weeks post-partum. It was approved by the Erasmus MC medical
research ethics committee. Mothers were recruited in the third trimester
of pregnancy from specialized Psychiatry-Obstetrics-Pediatric (POP)
secondary and tertiary outpatient clinics and other specialized mental
health care institutions where pregnant women who suffer from psy-
chiatric disorders are treated. All fullled criteria for a current severe
psychiatric disorder established with a validated instrument (SCID I
[16], with at least two previous years of treatment, together with
dysfunction, as indicated by lower scores (<65) on the Global Assess-
ment of Functioning (GAF) scale [17]. The GAF scale rates impairment
of social, occupational and psychological functioning, ranging from 100
(extremely high functioning) to 1 (severely impaired). Infant salivary
cortisol was available for 43 mother-infant pairs during the FFSF para-
digm when the infant was 6 months old. Mother-infant pairs (n =7)
were excluded from analysis based on the following predened criteria
[1]: use of locally administered or systemic corticosteroids by infant (n
=0) [2], insufcient amount of saliva for cortisol assay (n =1) [3],
perinatal complications including prematurity (<37 weeks) (n =3) and
[4] missing information on maternal symptom severity (n =3). The nal
sample for analyses existed of 36 mother-infant pairs with salivary
cortisol measurements during the FFSF paradigm and information on
maternal symptom severity.
2.2. Measures
2.2.1. Dependent variable
Salivary cortisol was obtained in a standardized amount of 100
μ
l
from infants 5 min before the FFSF paradigm and 15 and 30 min
thereafter, using Salimetric Child Swabs (Salimetrics, State College PA)
[18]. The duration of sampling was at least 60 s, but if the swab was not
visibly saturated sampling was prolonged until (visible) saturation, or as
long as the infant would allow the researcher. Samples were centrifuged
for 10 min at 3000 rpm to extract the saliva and frozen at −80 ◦C.
Cortisol concentrations were quantied by solid phase extraction (SPE)
liquid chromatography – tandem mass spectrometry (LC-MS/MS) (Wa-
ters XEVO-TQ-S system, Waters Corporation, Milford, MA, USA).
Labeled glucocorticoids were present as internal standard. The Limit of
Quantication (LOQ) in LC-MS/MS for salivary cortisol was 1.0 nmol/L.
LLOQ were set where the precision was <20 % and the signal to noise
ratio >10. Day-to-day precision was determined on two levels (low-
–high, resp. 0.98 and 17.0 nmol/L). The coefcient of variation (CV) was
6 % for both levels. For details on the LC-MS/MS procedure in our
laboratory we refer to Noppe et al. [19].
Cortisol values at all three time points (C1 =baseline, C2 =15 min
after and C3 =30 min after) were checked for outlying values (>3 SD
above or below the mean). Outlying values (C1 n =4, C2 n =0, C3 n =2)
were winsorized using a conservative approach, by replacing the
outlying value with the next highest (but not outlying) value in the
dataset [7]. Measurements were log-transformed (10log) to approach
normality. Missing data (C1 n =6, C2 n =9, C3 n =12; 25 % (27/108) of
data points; mainly caused by an insufcient volume of salivary for
cortisol measurement) were imputed by multiple imputation (using 5
imputed data sets), using all suitable variables in our dataset. Both
unimputed and imputed data were described. Repeated analyses
including all outlying values resulted in similar results (results not
shown). Uncertainty regarding the selection of the most suitable cortisol
indices to measure reactivity has long been subject to debate. Pruessner
and colleagues [20] recommend to use the area under the curve for
analyses on datasets containing repeated measures of cortisol. The area
under the curve with respect to increase (AUCi) best captures cortisol
change over time [21] and was used as the dependent variable in our
analyses.
C.W. Broeks et al.

Comprehensive Psychoneuroendocrinology 7 (2021) 100078
3
2.2.2. Primary independent variable
Maternal psychiatric diagnosis was assessed in the third trimester of
pregnancy with the Structured Clinical Interview for the Diagnostic and
Statistical Manual of Mental Disorders-IV (SCID-IV) for all axis I psy-
chiatric disorders (SCID I) [16]. Interviews were administered by a
trained interviewer. Maternal diagnosis established with the SCID
(depressive disorder y/n) was used as an independent variable.
Maternal symptom severity was evaluated with the Brief Symptom
Inventory (BSI), which consists of 53 items on nine symptom dimensions
(Somatization, Obsession-Compulsion, Interpersonal Sensitivity,
Depression, Anxiety, Hostility, Phobic anxiety, Paranoid ideation, and
Psychoticism) [22]. The General Severity Index (GSI) represents the
mean BSI score. BSI data were collected 6 weeks and 6 months post-
partum; the GSI on both time points was highly correlated (β =0.857,
SE =0.09, p <.001) suggesting stability of symptom severity over time.
Normative data are available for clinical and non-clinical samples.
Regarding maternal current symptom severity, mothers were classied
as either higher or lower in symptom severity based on split of the GSI at
the group median (=0.83), which is just below the cut-off score for
Dutch outpatient clinical females (=0.93) closely resembling the healthy
population [23].
2.2.3. Potential confounders
Potential confounders were explored based on theoretical and
empirical grounds. The primary measure for reactivity of infant cortisol
during the FFSF paradigm (AUCi) was checked for associations with all
potential confounding variables available in our data (infant and
maternal age, marital status, parity, maternal education level, maternal
ethnicity (European or Non-European origin), maternal psychotropic
medication use, smoking during pregnancy (yes or no), gestational age,
birthweight, infant gender and feeding type (breastfeeding or formula
feeding). Only gestational age was associated with infant cortisol reac-
tivity at trend level (p =.06). Consequently, we included gestational age
as a potential confounder in the analyses.
2.3. Analytic strategy
We used the Statistical Package for Social Sciences version 24 for all
analyses conducted in this study (IBM, New York, USA). A sensitivity
power analysis showed that within a sample size of 36 women we would
be able to detect a medium to large effect size of psychiatric symptom-
atology including gestational age as a confounder (f2 =0.23) with 80 %
power and a signicance level of 5 % in a two-sided test (G*Power v3
[10,11]. In our study we found a medium effect size; f2 was 0.12.
Therefore we underline the fact this is an exploratory study and results
have to be interpreted with caution. Multiple linear regression analyses
were conducted using the imputed dataset. Assumptions of multiple
linear regression (linearity, multivariate normality, absence of multi-
collinearity and homoscedascity) were checked visually (scatterplots,
histograms, Q-Q plots, P–P plots) and statistically (Mardia’s test, toler-
ance, >.2 VIF<10, Durbin-Watson between −2 and 2). The area under
the curve with respect to increase (or change) (AUCi) was calculated
based on imputed infant cortisol data, using the following formula:
{[(15 min value +baseline value)/2] x time in minutes} +{[(30 min
value +15 min value)/2] x time in minutes} - [baseline value* (time +
time)]. Missing at random (MAR) assumption was tested. No signicant
differences were found when cases with and without missing data points
were compared with regard to demographic, psychiatric and cortisol
indices. Maternal symptom severity (lower/higher) and maternal
depression (y/n) were regressed on infant AUCi, and adjusted for
gestational age at birth. Imputed results are reported. We reported
standardized beta (ß) and unstandardized B (B) with accompanying
standard error (SE). Analysis was repeated using the unimputed dataset,
by means of a sensitivity analysis.
3. Results
Table 1 presents the descriptive characteristics of the sample.
Depressive and anxiety disorders were most common (resp. 47 and 56
%) and psychiatric comorbidity was substantial (41 %). Approximately
half of the patient group used psychotropic medication during preg-
nancy, mostly antidepressants. Median General Severity Index (GSI) of
the BSI was 0.83 (0.4–2.75).
The analysis based on imputed data revealed a negative association
between general maternal psychiatric symptom severity and infant AUCi
(unadjusted n =36, ß = − 0.331, B = − 9.758, SE 4.8, p =.048; adjusted
for gestational age n =36, ß = − 0.335, B = − 9.868, SE 4.5, p =.039).
Unimputed data showed a similar result at trend level (unadjusted n =
24, ß = − 0.421, B = − 11.142, SE =5.4, p =.051; adjusted for gesta-
tional age n =24, ß = − 0.397, B = − 10.487, SE =5.4, p =.068).
Diagnosis of depression showed a negative association at trend level in
imputed data (unadjusted n =36, ß = − 0.293, B = − 8.640, SE 4.8, p =
.083; adjusted n =36, ß = − 0.317, B = − 9.347, SE 4.6, p =.052).
Unimputed data in 24 infants with availability of three subsequent
cortisol measurements, showed a negative trend although not signicant
(unadjusted n =24, ß = − 0.155, B = − 4.038, SE =5.5, p-value =.470;
adjusted n =24, ß = − 0.174, B = − 4.521, SE =5.4, p-value =.415). A
regression table of all analyses is available as supplementary material.
No signicant differences were found between subgroups of mothers
(lower vs. higher symptom severity and depression y/n) with regard to
baseline characteristics (e.g. maternal age, ethnicity, education level,
Table 1
Descriptive characteristics of mothers and infants (n =36).
Mothers
Demographic characteristics range
Age, years
a
32.6
(5.51)
19–44
Ethnicity
•European origin 77%
•Non-European origin 19%
Married/partnered (yes) 81%
Education level (higher professional or university
education)
50%
Parity (multiparous) 61%
Smoking during pregnancy (yes)
b
22%
Psychotropic medication use during pregnancy
(yes)
b
53%
Clinical characteristics
Psychiatric disorder during pregnancy
•SCID diagnosis of depression or dysthymia 47%
•SCID diagnosis of anxiety 56%
•SCID diagnosis (other)
c
36%
•General Severity Index (BSI)
d
6 months pp 1.01 (.71)
Infants
Demographic characteristics range
Age (months)
e
5.7 (.53) 4–6
Gender (boy) 58%
Gestational age (weeks)
e
39.3
(1.70)
37–46
Birthweight (grams)
e
3336
(465)
2040–4225
Note: with regards to psychiatric characteristics there is some overlap because of
psychiatric comorbidity (i.e. depressive AND anxiety disorder).
Abbrev: The Structured Clinical Interview for the Diagnostic and Statistical
Manual of Mental Disorders-IV (DSM-IV) (SCID); Brief Symptom Inventory
(BSI).
a
Age at the moment of the Face-to-Face-Still-Face paradigm.
b
Psychotropic medication includes antidepressants (SSRI/nSRI/TCA), anti-
psychotics, and anxiolytics.
c
Including bipolar and psychotic disorder (n =8) and eating disorders (n =5);
diagnoses of addiction and PTSD were evaluated, but not present in this sample.
d
Mean reference range for Dutch outpatient clinical females: 0.93–1.32 and
for healthy females: 0.29–0.45.
e
Values are mean (SD).
C.W. Broeks et al.

Comprehensive Psychoneuroendocrinology 7 (2021) 100078
4
smoking or psychotropic medication use). Fig. 1 depicts infant salivary
cortisol reactivity before and during the FFSF paradigm within groups of
mothers with lower vs. higher symptom severity and mothers with
depressive disorders (y/n). Fig. 2 shows scatterplots of the correlation
between the infant cortisol AUCi during the FFSF paradigm and the
maternal GSI (left) and presence of a depressive disorder (y/n) (right).
4. Discussion
This explorative study is among the rst to examine the association
between severe maternal depression and general psychiatric symptom
severity and infant cortisol reactivity. We hypothesized both persistence
of depression and higher symptom severity postpartum in a group of
mothers with severe and long-lasting psychiatric disorders would be
associated with diminished infant cortisol reactivity. Our preliminary
results show diminished cortisol reactivity during the FFSF paradigm in
6-month-old infants of mothers with a high concurrent level of general
psychiatric symptoms. Generally, our ndings are in line with previous
studies in children living in high-risk environments, showing reduced
rather than elevated cortisol responses to new stressors when conditions
are chronically stressful [4,5]. Low cortisol levels and diminished
reactivity to stressors have been found in adults with prolonged or
recurrent depression or PTSD [24,25] as well as in infants of traumatized
mothers [26]. We hypothesize this pattern might already be present in
(very) early stages of life, as a subtype and early marker of HPA-axis
dysregulation.
With regards to HPA-axis functioning, it is known that both too high
and too low cortisol levels contribute to disease states; balance is critical,
particularly quick recovery following a perturbation [27]. Diminished
cortisol responses possibly reect lower responsivity to social stressors
associated with chronic maternal emotional unavailability. Different
studies, mostly in mothers with depression, have demonstrated that
these mothers behave less adequate toward their infants [8]. However,
this effect is not consistently reected in infants’ behavioral responses
during FFSF paradigm; some infants show less distressed behavior than
control infants [9], whereas other studies nd higher arousal and more
negative infant behavior (e.g. gaze aversion) [28,29]. Possibly, the same
pattern applies to infant cortisol reactivity during the FFSF paradigm,
with the addition that the most chronically deprived infants might show
diminished reactivity as opposed to a more clearly marked reaction in
their less or non-deprived counterparts. A possible explanation might be
a dose-response relationship between maternal “stress” (coming from
different sources, i.e. the severity of their psychiatric complaints, their
psychiatric and possible maltreatment history as well as from difcult
life circumstances) and more pronounced alterations (both higher and
lower) in the infants’ (cortisol) reactivity to maternal
non-responsiveness. This might be the reason other studies found
enhanced [11,12] or no [13] cortisol reactivity in relation to the FFSF
paradigm, as these samples consisted of low-risk or mildly affected
populations.
It is often hypothesized deviations of cortisol measures (high or low)
directly point to impairment or ‘disease states’. But as the HPA axis is an
adaptive biological system, it might be more accurate to view changes in
activity and reactivity of cortisol markers as an adaptation to ‘non
average’ circumstances. In our population of infants, it could be hy-
pothesized the infant (and consequently the infant HPA axis) is not so
easily ‘impressed’ by a relatively minor trauma like the still-face pro-
cedure. This adaptation of the HPA axis could also be seen as a change
intended to promote resilience under these specic circumstances [30].
Our study has several strengths and limitations. Limitations include
the absence of a control group. As a result, we only assessed variations
within infants with a psychiatrically affected mother. Additionally, our
sample size was limited. Following our power calculation, we had an 80
% chance that a medium to large effect size would result in a signicant
result. We cannot rule out that our results, although signicant and
robust across analysis, might reect a spurious effect instead of a true
Fig. 1. Salivary cortisol log (nmol/L) 5 min before (‘baseline’) and 15 min (‘peak’) and 30 min (‘recovery’) after Face-to-Face Still-Face (FFSF) paradigm in 6 month
old infants in infants from mothers a) with (n =17) and without (n =19) a depressive disorder and b) with high (n =18) and low (n =18) general maternal
psychiatric symptom severity based on the Brief Symptom Inventory (BSI). Note: standard errors are reported.
Fig. 2. Scatterplot of the maternal General Severity Index (GSI) (left) and presence of a depressive disorder (right) and the incremental area under the curve (AUCi)
of three salivary cortisol measurements before and after Face-to-Face Still-Face (FFSF) paradigm in 6 month old infants in infants.
C.W. Broeks et al.

Comprehensive Psychoneuroendocrinology 7 (2021) 100078
5
effect. Furthermore, information on feeding and napping time was not
available, two factors that might affect cortisol reactivity in infants.
The foremost strength is our diverse sample, that brings into focus a
more severely affected clinical population. The fact we found between-
group differences in this sample might point to the potentially great
impact of symptom severity, with the caution of spurious effects. Further
strengths are the availability of detailed and reliable diagnostic infor-
mation in mothers. To date, most studies have focused on enhanced
stress reactivity in at-risk infants; our preliminary results show reduced
cortisol responses in infants from the most affected mothers (both in
relation to depression and general psychiatric symptom severity). This
nding highlights the need to elucidate the mechanisms of early HPA-
axis development (and the complex interplay of gene x environment
phenomena) in the subgroup of infants from mothers with severe and
long-lasting psychiatric disorders to better understand the trans-
generational transmission.
Conict of interest
None.
CRediT authorship contribution statement
Carlinde W. Broeks: Conceptualization, Data curation, Formal
analysis, Methodology, Writing – original draft, Writing – review &
editing. Rianne Kok: Conceptualization, Data curation, Funding
acquisition, Methodology, Writing – review & editing. Vandhana
Choenni: Conceptualization, Data curation, Funding acquisition,
Methodology, Writing – review & editing. Rien Van: Writing – review &
editing. Witte Hoogendijk: Writing – review & editing. Manon Hill-
egers: Writing – review & editing. Astrid Kamperman: Conceptuali-
zation, Formal analysis, Methodology, Writing – review & editing.
Mijke P. Lambregtse-Van den Berg: Conceptualization, Data curation,
Formal analysis, Funding acquisition, Methodology, Writing – review &
editing.
Acknowledgements
This study was supported by the Sophia Foundation for Scientic
Research (SSWO, grant number 570, 2012).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.cpnec.2021.100078.
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