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CNS & Neurological Disorders - Drug Targets, 2015, 14, 000-000
1
Antenatal Maternal Antidepressants Drugs Affect S100B Concentrations
in Fetal-Maternal Biological Fluids
Valentina Bellissima1, Gerard H.A. Visser2, Tessa F. Ververs1, Frank van Bel2,
Jacqueline U.M. Termote2, Marja van der Heide2 and Diego Gazzolo*1
1
Cesare Arrigo Children’s Hospital, Alessandria, Italy
2
Department of Perinatal Medicine, Utrecht Medical Center, Utrecht, the Netherlands
Abstract:
Introduction. Antidepressant treatment during pregnancy is speedily increasing in developed
countries and this phenomenon has occurred without firm evidence on safety and/or efficacy.
Aims. The present study investigated from mid-trimester of pregnancy up to 24 hours after birth
the pattern of a brain damage marker, namely S100B, in maternal fetal and neonatal biological
fluids of pregnant women and their newborns antenatally treated by antidepressant drugs such
as selective serotonin re-uptake inhibitors (SSRI).
Methods: we conducted an observational study on 75 pregnant women treated in the mid –third
trimester by antidepressant drugs and 231 healthy pregnancies. S100B concentrations were
measured at 7 predetermined monitoring time-points before, during and after treatment in maternal, fetal and neonatal
biological fluids and correlated with neurological follow-up at 7 days from birth.
Results: In SSRI group S100B concentrations were significantly higher in SSRI than controls (P<0.001, for all) in
maternal blood, in amniotic fluid, in arterial and venous cord blood and at 24-h from birth. Highest (P<0.05) S100B levels
were found in SSRI infants showing major neurological symptoms at 7-d follow-up.
Conclusion: The present data on increased S100B levels in maternal, fetal and neonatal biological fluids suggest that
SSRI administration although beneficial to the mother, presents some risks for the infant.
Keywords: SSRI, maternal depression, S100B, teratology, fetal brain, brain injury.
INTRODUCTION
The administration of antidepressant drugs during
pregnancy, such as selective serotonin reuptake inhibitors
(SSRI), has raised about 2-3% of European women and up to
8% in USA Countries [1]. This phenomenon has occurred
without firm evidence on safety and or efficacy.
Data on animal studies showed the occurrence of
abortion, birth defects and enduring behavioral alterations
due to antidepressants treatment [2]. In humans, neural tube
defects, cardiovascular malformations, persistent pulmonary
hypertension, preterm birth, neonatal respiratory distress and
withdrawal syndrome (i.e. seizures, hyper-excitability
syndrome), and neurodevelopment abnormalities have been
reported [3-8]. The overall risk of antidepressants related
poor neonatal adaptation is estimated at 30% for all
antidepressant drugs, except for paroxetine that has a higher
risk [9]. Risk identification is indispensable for development
of efficient strategies on neonatal management of newborns
prenatally exposed to antidepressants. In this respect, the
measurement of brain constituents in biological fluids could
*Address correspondence to this author at the Department of Maternal, Fetal
and Neonatal Medicine, C. Arrigo Children’s Hospital, Spalto Marengo 46,
15100 Alessandria, Italy; Tel: +39 0131 207241; Fax: +39 0131 207268;
E-mail: [email protected]
1871-5273/15 $58.00+.00
be useful for the early identification of cases at risk for drug
side-effects.
Among consolidated brain damage markers, S100B, an
acidic calcium binding protein highly specific for central
nervous tissue (CNS) warrants consideration [10]. The
protein has a half-life of about 1-hour and it is mainly
eliminated by the kidney [11, 12]. Elevated S100B levels in
biological fluids (i.e. cerebrospinal, blood, urine, amniotic
and saliva) are consolidated marker of brain damage and
hypoxia in adult, children, newborns and fetuses [13-23].
S100B, in maternal blood of growth restricted fetuses, has
been shown to be a promising diagnostic tool of postnatal
cerebral hemorrhage [24]. Several functions, to date still
matter of investigation, have been assigned to S100B, among
which it has been reported that at physiological
concentrations (nanomolar) the protein, as a cytokine, acts as
neurotrophic factor [25], whilst at high concentrations
(micromolar), is neurotoxic leading to cell death trough
necrosis and apoptosis mechanisms [26]. Therefore, S100B
has been recently used to monitor, in the perinatal period,
drugs side-effect on fetal/neonatal CNS after maternal
cocaine and alcohol exposure or after antenatal nitric oxide
donors, glucocorticoids and allopurinol administration [2731].
The present study investigated in pregnancies exposed to
SSRI whether S100B concentrations are: i) changed in
© 2015 Bentham Science Publishers
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CNS & Neurological Disorders - Drug Targets, 2015, Vol. 14, No. 1
maternal bloodstream assessed during the during the midthird trimester of pregnancy; ii) modified in arterial and
peripheral cord blood, and iii) correlated with severe/mild
neurological sequelae.
MATERIALS AND METHODS
Population
We conducted an observational study in 75 pregnant
women, complicated by mood disorders and other
psychiatric illnesses requiring antenatal treatment with SSRI,
admitted to our III level centres for obstetrics and neonatal
care from February 2010 to March 2011. All women had
been treated by paroxetine (seroxat, 20 mg daily per os) for
at least 6 months. Psychiatric diagnosis and decisions about
SSRI dose, management and drug discontinuation were at
discretion of the treating physician. Diagnosis comprised
major depression (n=29), panic disorders (n=7), a combination of both (n=35), generalized anxiety disorder (n=2),
obsessive compulsive disorder (n=1) and bulimia (n=1).
At eight predetermined monitoring time-points (T1: 16-20
wks; T2: 27-30 wks; T3: 35-40 wks; T4: at delivery; T5:
amniotic fluid; T6: venous cord blood, T7: arterial cord blood;
T8: at 24-h after birth) maternal, fetal and neonatal biological
fluids were collected for standard laboratory assessment and for
S100B assessment. Control group was composed by 231
physiological pregnancies whose deliveries were between 37
and 42 weeks’ gestation. In control infants, clinical and
laboratory parameters were recorded at birth and at 24 hrs from
birth for the standard assessment (i.e., red blood cell count,
glycemia, urea, creatinine, and ion concentrations).
Gestational age was determined by clinical data and by first
trimester ultrasound scan. Appropriate growth was defined by
the presence of ultrasonographic signs (when biparietal diameter
and abdominal circumference were between the 10th and the
90th centiles) according to the normograms of Campbell and
Thoms and by postnatal confirmation of a birth weight between
the 10th and 90th centiles according to our population standards
after corrections for the mother’s height, weight and parity and
the sex of the newborn [32].
All infants admitted to the study fulfilled all the following
criteria: no maternal illness, no signs of fetal distress, pH more
than 7.2 in cord blood or venous blood, Apgar scores at 1 and 5
minutes >7. All newborns were in normal clinical condition
showing no overt neurological syndrome at the discharge from
the hospital.
The study protocol was approved by the local Ethics
Committees and the parents of the subjects examined gave
informed consent.
Exclusion criteria were: multiple pregnancies, fetal
malformations, chromosomal abnormalities, perinatal asphyxia,
and distocia.
Cranial Assessment
Cerebral ultrasound scanning was performed routinely in
newborns within the first 72-h and at day 7 after birth by use
of a real-time ultrasound instrument (Acuson; 128SP5,
Bellissima et al.
Mountain View CA), with a transducer frequency emission
of 3.5 MHz.
In the controls, cerebral ultrasound patterns were
evaluated before discharge from the hospital.
Neurodevelopmental Outcome
Neurologic examinations were performed daily, and
neonatal neurologic conditions were classified as described
by Prechtl [33], with each infant assigned to one of three
diagnostic groups: normal, abnormal (when one or more of
the following neurologic syndromes were present: hyper- or
hypokinesia, hyper- or hypotonia, hemisyndrome, apathy
syndrome, hyperexcitability syndrome), or suspect (if only
isolated symptoms were present but no defined syndrome
was evident).
Laboratory Measurements
Laboratory values in SSRIs infants were recorded at
admission to neonatal intensive care units for the standard
assessment (i.e., erythrocyte count; glucose, urea, creatinine,
hemoglobin, and ion concentrations; hematocrit; venous
blood pH; venous carbon dioxide and oxygen partial
pressures; base excess). In controls, clinical and laboratory
indexes were recorded at birth.
S100B Measurements
At the indicated time-points fetal and maternal biological
fluids were collected. Samples were centrifuged at 900 g for
ten minutes and resulting sera were stored at –70°C before
measurements. The S100B protein concentrations was
measured in all samples, using a commercially available
immunoluminometric assay (Lia-mat Sangtec 100, AB
Sangtec Medical, Bromma, Sweden). According to the
manufacturer’s instructions, this assay is specific for the β
subunit of the S100 protein and measures the β subunit as
defined by the three monoclonal antibodies SMST 12,
SMSK 25, and SMSK 28. The β subunit of the S100 protein
is known to be predominant (80% to 96%) in the human
brain [23]. Each measurement was performed in duplicate
according to the manufacturer’s recommendations, and the
averages were reported. According to the manufacturer’s
instructions, the sensitivity of the assay (B0 ± 3SD) was 0.02
µg/L; the within-assay coefficient of variability was ≤5.5 %,
and interassay coefficient of variability was ≤10.1% for
concentrations ranging between 0.28 and 4.17 µg/L.
Statistical Analysis
S100B concentrations are expressed as mean and 25-75th
centiles. Data were analyzed by Kruskal-Wallis one-way
analysis of variance and Mann-Whitney U test when not
normally distributed. Comparison between proportions was
performed with Fisher’s exact test. Statistical significance
was set at P<0.05.
RESULTS
Perinatal characteristics in the studied groups are shown
in Table 1. Maternal age, gestational age and weight at birth,
Antenatal SSRI Administration and S100B
CNS & Neurological Disorders - Drug Targets, 2015, Vol. 14, No. 1
the incidence of vaginal and caesarean section delivery,
gender, Apgar score at 1st and 5th minutes did not differ
(P>0.05, for all) between SSRI and controls, whilst the
incidence of deliveries before 37 wks was significantly
higher (P<0.001) in SSRI group. Indeed, no significant
differences (P>0.05, for all) regarding gestational age at
sampling time-points T1 and T2 have been found, whilst at
T3 and T4 gestational age was at sampling was lower
(P<0.01, for both) in SSRI group.
Table 1.
Perinatal characteristics in mothers and infants
antenatally treated by selective serotonin re-uptake
inhibitors (SSRI) and controls.
different monitoring time-points (T1-T4) showed a flat trend
and did not differ (P>0.05, for all) from baseline to delivery
time-points. In SSRI pregnant women, S100B started to
increase from T1 onwards, remaining at higher level at T2T3 and reaching its highest peak at delivery (T4) (P<0.01,
for all).
Table 2.
Severe and mild neonatal symptoms in infants
antenatally treated by selective serotonin re-uptake
inhibitors (SSRI) and controls.
Neonatal Outcomes
SSRI
(n=75)
Controls
(n=231)
P
Severe Neonatal Symptoms
SSRI
(n=75)
Controls
(n=231)
P
Maternal Age
30 ± 5
26 ± 4
0.59
Grade I (N°/total)
18/75
57/231
0.95
Gestational age at delivery (wk)
39 ± 2
40 ± 1
0.63
Grade II (N°/total)
0/75
0/231
100
8/75
0/231
<0.001
Grade III (N°/total)
1/75
0/231
0.56
Parameters
Delivery <37 wk (N°/total)
Vaginal (N°/total)
RDS
CNS
Mode of Delivery
Cesarean section (N°/total)
3
10/75
65/75
52/231
179/231
0.09
Hypotonia (N°/total)
4/75
0/231
0.004
0.09
Seizures (N°/total)
3/75
0/231
0.02
Gastrointestinal Tract
Gender
Male (N°/total)
42/75
121/231
0.6
Feeding difficulty (N°/total)
19/75
0/231
<0.0001
Female(N°/total)
33/75
110/231
0.9
Vomiting (N°/total)
4/75
0/231
0.004
Birth Weight
Mild Neonatal Symptoms
<10th centile (N°/total)
0/75
0/231
1.00
Excessive crying (N°/total)
12/75
0/231
<0.001
10-90th centiles (N°/total)
75/75
231/231
1.00
Tremors (N°/total)
18/75
0/231
<0.001
Sleep alteration (N°/total)
25/75
0/231
<0.001
Hypo/Hyperthermia (N°/total)
2/75
0/231
0.10
Apgar Score >7
Apgar 1 min (N°/total)
59/75
231/231
0.26
Apgar 5 min (N°/total)
73/75
231/231
0.96
Gestational Age at Sampling
T1 (wks)
26 ± 1
26 ± 1
1.00
T2 (wks)
31 ± 1
31 ± 1
1.00
T3 (wks)
37 ± 1
38 ± 1
<0.01
T4 (delivery)
38 ± 2
40 ± 1
<0.01
In Table 2 mild and severe clinical patterns at 7th day
follow-up are reported. No significant differences (P>0.05,
for all) in different RDS grades were found between groups.
Newborns antenatally exposed to SSRI showed a higher
incidence (P<0.01, for both) of major CNS patterns
characterized by hypotonia syndrome and seizures.
Furthermore, infants complicated by feeding difficulties and
vomiting were significantly higher in SSRI group (P<0.001,
for both). Among mild symptoms no differences (P>0.05)
between groups in hypo/hyperthermia occurrence has been
reported whilst the detection of CNS patterns characterized
by excessive crying, tremors and sleep alterations were
significantly higher (P<0.001, for all) in SSRI group.
S100B concentrations were measurable in all samples
drawn from different fetal-maternal biological fluids.
In controls, maternal blood proteins’ concentrations at
Maternal S100B in SSRI group was significantly higher
(P<0.001, for all) than controls at all monitoring time-points.
Identically, S100B amniotic fluid concentrations were
significantly higher (P<0.001) in SSRI than control group.
At birth arterial and venous cord blood S100B
concentrations were significantly higher (P<0.001, for all) in
SSRI newborns.
At 24-h from birth, higher (P<0.001) S100B levels were
detectable in SSRI group than controls. However, when
SSRI infants were sub-grouped according to the occurrence
of severe CNS symptoms at 7 days follow-up the following
protein’ patterns have been shown: no significant differences
(P>0.05, for all) in maternal blood concentrations at T1-T4,
whilst S100B concentrations were significantly higher
(P<0.05, for all) in fetal/maternal (T6, T7) and neonatal (T8)
biological fluids (Figure 1 and Table 3).
DISCUSSION
There is growing evidence that women are prone to
depression and about 20% have a lifetime chance of being
diagnosed with a depressive disorder [34]. Pregnancy seems
a risk factor since during and directly after pregnancy 10%
of women will develop a major depressive disorder [35].
4
CNS & Neurological Disorders - Drug Targets, 2015, Vol. 14, No. 1
Thus, the use of antidepressants (i.e. selective serotonin reuptake inhibitors) during pregnancy is speedily increasing up
to 2-3% of pregnant women in Europe and 8-10% in the
USA countries [1]. Administration has happened in absence
of solid evidence on safety or efficacy as well as no
conclusive data on their potential side-effects on
fetal/neonatal function and development have been
documented.
18
P<0.05
P<0.05
P<0.05
16
S100B ( g/L)
14
12
10
8
6
4
2
0
C
SSRI N SSRI P
C
SSRI N SSRI P
T5
C
T6
SSRI N SSRI P
T7
Figure 1. S100B concentrations (µg/L) expressed as median and
5-95 centiles assessed in arterial (T5) and venous (T6) cord
blood and at 24-h from birth in peripheral blood (T7) in
healthy infants (C) and in those antenatally treated by selective
serotonin re-uptake inhibitors (SSRI) with normal (N) and
abnormal (P) 7-d neurological follow-up.
Table 3.
S100B concentrations (µg/L) expressed as median
and 25th-75th centiles in different maternal, fetal and
neonatal biological fluids in SSRI and control
groups. *P<0.001 vs controls.
Biological Fluid
SSRI (N=75)
Controls (N=231)
Median
25th
75th
Median
25th
75th
16-20 wks
0.20*
0.10
0.54
0.06
0.04
0.08
27-30 wks
0.16*
0.10
0.56
0.05
0.04
0.07
35-40 wks
0.18*
0.11
0.61
0.07
0.03
0.13
delivery
1.83*
0.82
3.01
0.12
0.06
0.27
Amniotic Fluid
0.44*
0.39
0.51
0.20
0.14
0.36
arterial
3.83*
1.83
4.50
1.33
0.80
1.89
venous
2.91*
2.12
3.59
0.75
0.47
1.23
5.23
7.49
0.59
0.47
0.95
Maternal Blood
Cord Blood
Neonatal Peripheral Blood
At 24-h
5.48*
The present study shows that concentrations, in maternal,
fetal and neonatal biological fluids, of a consolidated brain
damage marker, namely S100B, significantly increased after
SSRI
administration.
Furthermore,
higher
S100B
concentrations were detectable up to 24 hours from birth
Bellissima et al.
especially in infants showing severe neurological symptoms.
Data on S100B in maternal, fetal and neonatal biological
fluids are in agreement with previous observations
suggesting the presence of a clinical/subclinical CNS
damage in SSRI fetuses/infants [12-24].
Mid-third trimester elevated S100B blood levels in
pregnant women SSRI-treated constitutes, to our knowledge,
the first observation warranting further consideration in
terms of protein’s source. In detail: (i) recent meta-analysis
reported that S100B concentrations in cerebrospinal, blood
fluids of drug free-depressive patients were higher when
compared with euthymic patients [36]; (ii) increased S100B
is suggestive of glial alterations in mood disorders either due
to brain damage [12-14] or due to functional secretion by
glial cells or due to changes in brain blood barrier (BBB)
permeability increasing protein’s release into systemic
circulation [37], and (iii) anti-depressive drugs, acting on
astrocytes secretion of S100B via the serotonergic system,
decrease protein’s concentration in systemic circulation as
expression of response to treatment [10]. Altogether, bearing
in mind that treatment was successful in all pregnant women,
it is reasonable to infer that the source of persistently high
S100B levels could reasonably be maternal CNS although
the possibility that part of the protein measured in the
maternal bloodstream could have a fetal origin can be
consistent. In this regard, it has been previously suggested
that during intrauterine conditions at highest risk for brain
stress/damage (i.e. acute and chronic hypoxia, drug sideeffects) an excessive release of the protein from fetal CNS
can occur and part of the protein can pass through placenta
into the maternal district [24]. The mechanisms through
which S100B is transported from fetus to mother is still
unknown although several hypothesis (passive/active
transport) have been proposed [10, 12-14]. In this respect,
Sannia et al. showed that S100B concentrations are
pregnancy-dependent and higher (5–6 times) in fetal than in
maternal districts [38]. The explanations reside: i) in
hemodilution regarding different blood volume ratio (about
1:20-25) between fetal–maternal bloodstreams, ii) to S100B
transfer modalities trough placenta regulated by a gradient of
concentration mechanism and, iii) to fetal CNS development
requiring an higher amount of protein. It is noteworthy in
this respect, that in SSRI infants fetal-maternal gradient (data
not shown) were significantly different from controls. The
finding warrants further consideration. It has been suggested
a Janus’s face behaviour of the protein: at physiological
concentration (nanomolar) S100B acts as a cytokine with a
neurotrophic effect [25], whilst at elevated concentrations
(micromolar) is neurotoxic participating in a cascade of
events leading to cell death or apoptosis. Thus, the
significant decrease in fetal-maternal gradient opens-up to
the possibility of an increased maternal protein’s
concentration due to fetal CNS stress/damage [26] or,
interestingly, to a fetal compensatory mechanism in order to
avoid protein’s neurotoxic effects. The findings of no
differences in S100B concentrations between arterial and
venous cord and the higher amniotic fluid levels in SSRI
offer additional support to the latter point. However, the
highest S100B values detected in severe cases support the
notion that long-term SSRI treatment may trigger the
cascade of events responsible for CNS stress and damage.
Antenatal SSRI Administration and S100B
In the present study we also found that in infants
antenatally treated by SSRI S100B blood levels remained
higher up to 24 hours from birth especially in those with
severe CNS symptoms. Data fit in part a recent observation
from Pawlusky et al. showing significant differences
between SSRI exposed and non exposed newborns in
maternal and cord blood [39].
The finding of elevated S100B concentrations in the
post-natal period deserves further consideration. In
particular, bearing in mind that: i) half-live of paroxetine
(about 20-h) [40] and S100B (about 1-h) [10]; ii) all women
stopped treatment 24-h before delivery, and iii) higher
S100B were detectable in infants with mild/absent
symptoms; altogether it is reasonable to suggest that high
S100B is due to exaggerated release from glial cell SSRImediated reasonably responsible of CNS stress/damage at a
clinical/subclinical stage. Another explanation may reside in
protein release due to SSRI complication such as withdrawal
syndrome [40].
Finally, the potential role of S100B as a tool for
therapeutic strategy monitoring has to be taken into account.
It has been previously reported that S100B can be useful for
evaluating the effectiveness/side-effect of perinatal treatment
such as antenatal glucocorticoids and nitric oxide donors and
to investigate maternal addiction to cocaine and alcohol on
fetal/neonatal brain development [27-31].
In conclusion, the present study strenghtens the notion
that fetal/neonatal well-being monitoring is becoming
possible: SSRI administration alters S100B release triggering
a cascade of events reasonably leading to CNS damage at a
clinical/subclinical stage. However, further investigations on
a wider study population investigating CNS development at
long-term follow-up (2-6 years) are needed.
CNS & Neurological Disorders - Drug Targets, 2015, Vol. 14, No. 1
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
LIST OF ABBREVIATIONS
BBB = Brain Blood Barrier
[16]
CNS = Central Nervous Tissue
SSRI = Selective Serotonin Reuptake Inhibitors
[17]
[18]
CONFLICT OF INTEREST
The funding sources had no role in the study design, data
collection, data interpretation, data analysis, or writing of
this manuscript.
ACKNOWLEDGEMENTS
This study is part of the I.O. PhD International Program,
under the auspices of the Italian Society of Neonatology and
of the Neonatal Clinical Biochemistry Research Group and I
Colori della Vita Foundation, Italy.
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Revised: February 1, 2014
Accepted: February 18, 2014