The Effect of Prenatal Antidepressant Exposure On Neonatal Adaptation A Systematic Review and Metanalysis

2013 COPYRIGHT PHYSICIANS POSTGRADUATE PRESS, INC. NOT FOR DISTRIBUTION, DISPLAY, OR COMMERCIAL PURPOSES.
e309 J Clin Psychiatry 74:4, April 2013

Focus on Womens Mental Health
Meta-Analysis
The Effect of Prenatal Antidepressant Exposure on
Neonatal Adaptation: A Systematic Review and Meta-Analysis
Sophie Grigoriadis, MD, PhD, FRCPC; Emily H. VonderPorten, MPH; Lana Mamisashvili, MSW;
Allison Eady, BA; George Tomlinson, PhD; Cindy-Lee Dennis, PhD; Gideon Koren, MD, FRCPC, FACMT;
Meir Steiner, MD, PhD, FRCPC; Patricia Mousmanis, MD, CCFP, FCFP; Amy Cheung, MD, MSc, FRCPC;
and Lori E. Ross, PhD
ABSTRACT
Objective: Conflicting reports on potential risks of
antidepressant exposure during gestation for the infant
have been reported in the literature. This systematic review
and meta-analysis on immediate neonatal outcomes were
conducted to clarify what, if any, risks are faced by infants
exposed to antidepressants in utero. Subanalyses address
known methodological limitations in the field.
Data Sources: MEDLINE, EMBASE, CINAHL, and PsycINFO
were searched from their start dates to June 2010. Various
combinations of keywords were utilized including, but not
limited to, depressive/mood disorder, pregnancy/pregnancy
trimesters, antidepressant drugs, and neonatal effects.
Study Selection: English language and cohort and case-
control studies reporting on a cluster of signs defined as
poor neonatal adaptation syndrome (PNAS) or individual
clinical signs (respiratory distress and tremors) associated with
pharmacologic treatment were selected. Of 3,074 abstracts
reviewed, 735 articles were retrieved and 12 were included
in this analysis.
Data Extraction: Two independent reviewers extracted
data and assessed the quality of the articles.
Results: Twelve studies were retrieved that examined PNAS
or the signs of respiratory distress and tremors in the infant.
There was a significant association between exposure to
antidepressants during pregnancy and overall occurrence
of PNAS (odds ratio [OR] = 5.07; 95% CI, 3.257.90; P < .0001).
Respiratory distress (OR = 2.20; 95% CI, 1.812.66; P < .0001)
and tremors (OR = 7.89; 95% CI, 3.3318.73; P < .0001) were also
significantly associated with antidepressant exposure. For the
respiratory outcome, studies using convenience samples had
significantly higher ORs (Q
1
= 5.4, P = .020). No differences
were found in any other moderator analyses.
Conclusions: An increased risk of PNAS exists in infants exposed
to antidepressant medication during pregnancy; respiratory
distress and tremors also show associations. Neonatologists
need to be prepared and updated in their management, and
clinicians must inform their patients of this risk.
J Clin Psychiatry 2013;74(4):e309e320
Copyright 2013 Physicians Postgraduate Press, Inc.
Submitted: June 21, 2012; accepted October 4, 2012
(doi:10.4088/JCP.12r07967).
Corresponding author: Sophie Grigoriadis, MD, PhD, Womens Mood and
Anxiety Clinic: Reproductive Transitions, Department of Psychiatry, FG 29,
Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, ON M4N
3M5, Canada (Sophie.Grigoriadis@sunnybrook.ca).
M
ajor depressive disorder (MDD) during pregnancy
is a serious condition that can be life threatening,
1,2

but, nonetheless, often remains undertreated.
3
Concerns
over the possible association of adverse effects on the
infant partially impede the use of antidepressant medica-
tion during pregnancy.
4
Indeed, there have been a variety
of reports regarding transient short-term adverse neonatal
or neurobehavioral effects observed in the neonate, which
have been referred to collectively as poor neonatal adap-
tation syndrome (PNAS).
5,6
Although the mechanism of
PNAS is not completely understood, it most likely represents
a withdrawal or discontinuation syndrome
7,8
or is second-
ary to serotonin toxicity.
9
Symptoms can include respiratory
distress, tremors, shaking or jitteriness, irritability, sleep
disturbances, poor muscle tone, weak or absent cry, hypogly-
cemia, and seizures among others. The syndrome has been
described to occur in up to 30% of infants that have had
serotonergic antidepressant exposure in utero.
6,10
Lattimore
et al
11
completed a meta-analysis
11
that pooled the results
from studies of various designs reporting on this syndrome
following third trimester exposure. The researchers did not
find a significant association between poor neonatal adapta-
tion and exposure to selective serotonin reuptake inhibitors
(SSRIs) in their primary analysis but did in a secondary anal-
ysis (OR = 1.99; 95% CI, 1.432.77; P = .003), which included
a study
12
that was initially excluded because it reported SSRI
exposure in the first trimester as well as the third. This meta-
analysis, however, was published over 6 years ago, and since
then several new studies have been published on this syn-
drome. Moreover, the Lattimore
11
meta-analysis included
studies without a control group, making interpretation
problematic.
The aim of the present study was to perform a sys-
tematic review and rigorous, up-to-date meta-analysis
examining what, if any, relationship exists between pre-
natal antidepressant exposure at any point in pregnancy
and immediate neonatal outcomes. We examined PNAS
(as defined by the authors in each study) in addition to 2
individual clinical signs, namely, respiratory distress and
tremors. In order to address the methodological limitations
of the available research, we also examined whether the
effect on PNAS or on individual signs differed in subgroups
of studies formed by each of the following potentially effect-
modifying variables: the effect of study type, study quality,
timing of exposure, and the use of adjusted data.
Grigoriadis et al
C
l
i
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i
c
a
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P
o
i
n
t
s
Antidepressant exposure during pregnancy may be
associated with poor neonatal adaptation syndrome (PNAS)
in the infant.
Antidepressant exposure during pregnancy may be
associated with respiratory distress and tremors in the infant.
Clinicians must inform and prepare women taking
antidepressants during pregnancy that their infant may
show signs of PNAS and, in case they occur, how they
will be managed.
DATA SOURCES AND STUDY SELECTION
This study is part of a larger program of research exam-
ining the effect of perinatal antidepressant medication use
as well as depression itself on outcomes; the methods have
been described in detail elsewhere.
13
Briefly, 2 professional
librarians, with expertise in the areas of psychiatry and
psychopharmacology, completed the literature searches
independently. Various combinations of keywords were
utilized, including but not limited to depressive/mood
disorder, pregnancy/pregnancy trimesters, antidepressant
drugs, and neonatal effects (full list of keywords provided
in supplementary material). The databases and vendors
used included MEDLINE (Ovid), MEDLINE In-Process
(Ovid) to access current literature (keyword searching only),
PsycINFO (American Psychological Association; Ovid),
CINAHL (Nursing; Allied Health), EMBASE (Exerpta
Medica, Elsevier; Ovid), and Scopus (Elsevier) to access
current literature (keyword searching only). Each database
was searched from its start date to June 30, 2010. Reference
lists in reviews and meta-analyses were searched but did not
produce any further references.
Inclusion and Exclusion Criteria
Cohort and case-control studies were included in the
meta-analysis if they (1) were published in the English lan-
guage; (2) reported original data; (3) reported on neonatal
effects following any antidepressant exposure, including
(but not limited to) selective serotonin reuptake inhibitors,
tricyclic antidepressants, and monoamine oxidase inhibi-
tors; (4) included a comparison group of pregnant women
not exposed to the antidepressant examined; and (5) pro-
vided sufficient data to calculate an effect size if it was not
provided. Because of the volume of potentially eligible
studies, we excluded abstracts and conference proceedings
and did not search for unpublished data. The following
outcomes were included in this meta-analysis: PNAS, respi-
ratory distress, and tremors as defined by the authors of the
original publication. During the review of the literature, it
became clear that many definitions are used for the clus-
ter of signs identified as PNAS and that the wide variety
of signs included in studies of PNAS makes it difficult to
pool studies for a meta-analysis. We included all studies that
defined PNAS as the presence of 1 or more of the following
signs: tremors or shaking, jitteriness, shivering, agitation,
irritability, increased or decreased muscle tone, poor feed-
ing, excessive weight loss, seizures, tachypnea or respiratory
distress, hypothermia, or hypoglycemia. We specifically
selected signs of respiratory distress (respiratory distress or
tachypnea when respiratory distress was not listed as a sign)
and tremors (or shaking if tremors was not listed as a sign)
for further examination, as these signs were deemed the most
important clinically, based on feedback by our advisory com-
mittee of key stakeholders (including representatives from
psychiatry, family medicine, obstetrics, neonatology, public
health, patient advocacy, and policy) that was assembled for
this program of research.
DATA EXTRACTION
The data extraction and quality assessment processes
employed in this research program have been described in
detail elsewhere.
13
In brief, 2 independent research assistants
screened the titles and abstracts of articles, relevant abstracts
were reviewed, and those articles meeting inclusion criteria
were retrieved. Data extraction forms were modeled after
the Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) statement
14
to record relevant data
from all eligible studies. The extracted data included source,
study design, participants (sample, control, demographics
and clinical characteristics), inclusion/exclusion criteria,
antidepressants examined, dosage, duration of exposure,
primary and secondary outcomes, outcome assessment
methods, and loss to follow-up. For publications in which
not all data were provided, we contacted the authors with
requests for raw data. We extracted adjusted estimates and
their variances where they were available. If no adjusted
estimates were provided, crude ORs or differences in means
(and sample variances) were computed from the published
data. We added 0.5 to all cells in studies with a 0 cell count
when calculating the OR.
Quality Assessment
The quality assessment tool used for this investigation
has been described in detail elsewhere.
13
In brief, the Sys-
tematic Assessment of Quality in Observational Research
(SAQOR) was based on existing quality assessment instru-
ments, including the checklist developed by Downs and
Black
15
and the Newcastle-Ottawa Scale,
16
and adapted to
assess the specific criteria necessary for evaluation of data
presented in this area of research. Research staff evaluated
a total of 19 criteria under the following categories for each
study by outcome: (1) sample, (2) control group, (3) quality
of exposure/outcome measure, (4) follow-up, and (5) dis-
torting influences. The last category specifically included
assessment as to whether analyses controlled for depres-
sion, other psychotropic medications, and other potentially
relevant confounders, such as smoking, alcohol, and illicit
drug use. On the basis of scores on the quality criteria evalu-
ated, a final quality rating (high, moderate, low, very low)
was assigned by using a modification of the Grading of Rec-
ommendations Assessment, Development and Evaluation
(GRADE) system.
17
High, moderate, and low were deemed
Neonatal Adaptation Following Prenatal Antidepressants
above quality threshold, whereas the very low were below
quality threshold. Data extraction and quality assessment
results for each study were compared between raters, with
any differences discussed with the principal investigators
until consensus was reached.
Statistical Analyses
In the few cases in which adjusted hazard ratios or rela-
tive risks were reported, we treated these as estimated odds
ratios. The DerSimonian and Laird random-effects model
was used to obtain pooled estimates of the OR for binary
outcomes and the weighted mean difference for continu-
ous outcomes.
18
When only 2 studies published data on an
outcome, we used a fixed-effects pooled estimate. Publica-
tion bias was assessed by visual inspection of funnel plots
depicting the individual study estimates (on the log scale
for ORs) against their standard error. Further, the number
of unpublished studies (k) was estimated by using the
L estimator developed by Duval and Tweedie.
19
In brief, if
k was 1 or more, then k studies were imputed by reflection
of the k largest effects around the summary estimate. The
standard errors of the k reflected studies were used for the
k imputed ones and the summary OR was reestimated in
this expanded dataset. If k was estimated to be 0, then there
was no evidence for publication bias. For studies with pub-
lication bias, Duval and Tweedies trim-and-fill method
19

was used to estimate exposure effects after adjusting for
potential publication bias. Between-study heterogeneity was
assessed by Cochrane Q and visual inspection of forest plots
and quantified by I
2
.
A nonsignificant Q and small I
2
suggest a common
underlying effect and that variations in estimated study
effects are due only to random variation and not true study-
to-study variation (heterogeneity). I
2
can be interpreted as
the proportion of the total variance due to heterogeneity.
In one interpretation, I
2
= 25% represents a low degree of
heterogeneity; 50%, a moderate degree; and 75%, a high
degree.
20
Subgroup analyses were run (regardless of whether
Q was significant) to explore sources of heterogeneity by
examining within-group effects and between-group differ-
ences in pooled effects based on several study characteristics
chosen a priori: whether a convenience sample was used (ie,
not consecutive or random sample), study quality (ie, those
above threshold compared with those below), timing of
exposure, and the use of adjusted data. The metafor pack-
age
21
in R (2.14.2)
22
was used for the statistical analyses.
RESULTS
Of the 3,074 abstracts reviewed, 2,339 were excluded based
on title and abstract. In total, 735 articles were retrieved and
assessed for eligibility and 15 articles met the inclusion crite-
ria (Figure 1).
23
Of these, 3 articles were excluded because 1
did not have a control group without antidepressant use for
this outcome,
5
1 did not report on the necessary outcomes,
24

and 1 did not have a comparable outcome measure,
25
leaving
12 studies for inclusion in the quantitative analysis (Table
1).
8,10,12,2634
Most studies reported data on more than 1 out-
come (8 reported on neonatal adaptation syndrome overall,
9 on respiratory signs, and 4 on tremors or shaking). Seven
studies used a convenience sample, while 5 studies used
either a population- or hospital-based sample. Eleven of the
12 studies were above our quality threshold. Seven studies
confirmed third trimester or late exposure. Three studies
provided adjusted data.
Figure 1. Identification of Independent Studies for Inclusion in Meta-Analysis (adapted from
PRISMA 2009 flow diagram
23
)
3,073 Records identified through
database searching
1 Additional record identified
through other sources
2,339 Records excluded 3,074 Records screened
12 Studies included in
quantitative synthesis
(meta-analysis)
735 Full-text articles
assessed for eligibility
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75 Nonpharmacologic interventions
178 Risk factors for antenatal depression
242 Impact of maternal depression
120 Postpartum treatment
47 Case reports/series
39 Other outcomes of interest
20 Insufficient data
2 PNAS but not an outcome of interest or
outcome measure not adequate

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Grigoriadis et al
Poor Neonatal Adaptation Syndrome
Overall, we pooled results from 8
studies; the OR for PNAS and exposure
to any antidepressant was 5.07 (95% CI,
3.257.90; P < .0001; Figure 2). While the
ORs for each subanalysis were significant,
there were no group differences based on
the following modifying variables deter-
mined a priori: (1) pooled results from
studies with convenience samples versus
nonconvenience samples (the latter
having a nonsignificantly different higher
OR than the first), (2) studies below qual-
ity threshold versus those above threshold
(with the better quality studies having a
lower OR), (3) studies with the use of
antidepressants late in pregnancy versus
those that did not have exclusive late
exposure (with the ORs being similar in
magnitude), and (4) studies that reported
adjusted data versus those with unad-
justed data (with the unadjusted studies
pooling to a higher OR) (Table 2).
Respiratory Distress
Nine studies reported on signs of
respiratory distress (including respiratory
distress or tachypnea). The pooled esti-
mate demonstrated a significant associa-
tion between exposure to antidepressants
and immediate neonatal respiratory signs
(OR = 2.20; 95% CI, 1.812.66; P < .0001;
Supplementary eFigure 1). The modera-
tor variable of study type was significant.
Although pooled estimates from stud-
ies using both convenience and non-
convenience samples were significant,
the studies using convenience samples
had significantly higher ORs (Q
1
= 5.4,
P = .020). No group differences were found
in any of the other subanalyses (Table 2),
although higher pooled ORs were found
in studies that were below quality thresh-
old, had subjects with late exposure, and
had results with unadjusted data.
Tremors
Lastly, with regard to tremors (or shak-
ing) in infants as the outcome, 4 studies
were pooled, with an OR of 7.89 (95%
CI, 3.3318.73; P < .0001; see Supple-
mentary eFigure 2). It was only possible
to compare studies with convenience
samples versus those without and stud-
ies above the quality threshold with those
below. No significant differences were
found (Table 2) for the moderator with
T
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Strengths and Limitations
The strength of our work rests on the attention paid to
potential confounding factors and consideration of meth-
odology. The research examining the potential effects of
prenatal antidepressant exposure has been criticized for
weak methodology in general
37
and for neglecting to account
for potential confounders known to affect pregnancy out-
comes. In response, we pooled estimates for all studies, using
adjusted data where possible, and then examined the effect of
moderator variables that we identified a priori. We assessed
the studies for the effect of using convenience samples (ie,
those that were not recruited using consecutive or random
sampling strategies) and whether study quality affected
interpretation. Moreover, we contrasted results by using
pooled estimates for studies that did and did not adjust for
confounders the authors of the original publication deemed
important. We examined the data for a potential effect for
timing of exposure,
38
as it has been suggested that third tri-
mester exposure may be an important factor in whether the
neonate displays PNAS.
10
Most of the moderator variables
did not appear to affect the significance of the results, a find-
ing that suggests a genuine effect of the antidepressants, as
almost all subanalyses remained significant and not sig-
nificantly different from one another, except one. The use
of convenience samples did appear to result in statistically
higher OR for respiratory distress than the studies that did
not use convenience samples. Given that the convenience
samples were ones that were not based on random or con-
secutive sampling, they may have been biased in favor of the
infant displaying respiratory distress and inflating the OR.
Regardless, the analysis with nonconvenience samples was
also statistically significant. Overall, the data exhibit a robust
effect, with consistently elevated ORs over 2 suggesting the
results are clinically significant as well.
39
The robustness of
the OR is reassuring, as it is unethical to conduct the gold
standard of randomized controlled trials with pregnant and
Figure 2. Exposure to Any Antidepressant and the Risk of Poor Neonatal Adaptation Syndrome
a
Study
Odds
Ratio 95% CI
Weight
(fixed), %
Weight
(random), %
Costei et al,
26
2002 7.26 0.8959.09 4.5 4.5
Laine et al,
27
2003 6.93 1.5331.38 8.6 8.6
Oberlander et al,
10
2004 4.59 0.9522.31 7.9 7.9
Levinson-Castiel et al,
8
2006 52.67 3.09898.14 2.5 2.5
Ferreira et al,
30
2007 3.10 1.337.24 27.4 27.4
Maschi et al,
32
2008 3.67 1.1611.58 14.9 14.9
Boucher et al,
31
2008 7.00 3.2015.31 32.2 32.2
Rampono et al,
34
2009 2.53 0.1255.55 2.1 2.1
Fixed-effects model 5.07 3.257.90 100
Random-effects model 5.07 3.257.90 100
Heterogeneity: I
2
= 0%,
2
= 0, P = .6174

a
Meta-analysis results for all studies.
0.01 0.1 1 10 100
higher ORs for the convenience samples and studies below
quality threshold.
Publication Bias
We did not find evidence for the presence of publication
bias in our main PNAS analysis; heterogeneity was not sig-
nificant, the funnel plot appeared symmetric around 5, and,
when the L estimator of Duval and Tweedie was used,
19
there
did not appear to be missing studies. There did appear to
be publication bias for the individual symptoms analyses,
although the impact was minor on the estimates. For the
respiratory distress analysis, the adjusted OR, which was
derived from the trim-and-fill procedure,
19
was 2.00 (95%
CI, 1.592.52; P < .0001). The trim-and-fill procedure yielded
an adjusted OR of 5.17 (95% CI, 2.1112.73; P < .003) for the
tremors outcome.
DISCUSSION
The objective of this study was to determine if any rela-
tionship exists between prenatal antidepressant exposure
and poor immediate neonatal outcomes. The results of our
meta-analysis suggest that there is a genuine increased risk
for PNAS. Moreover, as this syndrome appears not to be
uniformly defined, we further examined 2 specific clinical
signs, namely, respiratory distress and tremors; a significant
association was also shown for the aforementioned signs and
the infant having been exposed to antidepressants in utero.
To our knowledge, ours is the first meta-analysis to examine
PNAS as a syndrome as well as individual signs with anti-
depressant exposure at any point in pregnancy. Our results are
similar to those of Lattimore and colleagues,
11
despite their
inclusion of only 3 studies (Hendrick et al,
35
Chambers et al,
5

and Goldstein et al
36
) of their pooled 6 that did not provide
unexposed control group data. We did not include Zeskind
et al,
25
which was included in the Lattimore et al analysis,
11

because the frequency of tremors was not provided.
Grigoriadis et al
depressed women to definitively determine any potential
adverse effects of these medications, and we are still cur-
rently limited to observational research.
It is important to note that not all of the studies included
in this meta-analysis defined PNAS in the same way; 2 used
an objective scoring system to measure it, although each
applied the system slightly differently, and 1 used a scale
(ie, Levinson-Castiel,
8
Rampono,
32
and Laine
25
). Several
researchers have identified different clusters of signs that
they found to be associated with antidepressant exposure
during pregnancy. The studies included in this meta-analysis
had significant overlap in the clinical signs they identified,
but they were also diverse. We also assessed the presence of
2 individual signs that experts in our advisory committee
agreed are highly specific to this syndrome, at least clini-
cally, and they were also significant. Although we analyzed
the 2 individual signs to circumvent the diversity in the way
the syndrome was operationalized at the time the original
studies were conducted, this method can also be considered
a limitation of our meta-analysis, as the signs we chose may
not be universally accepted as always occurring in this syn-
drome. Although we grouped studies according to timing of
exposure, we were able to segregate only those that did and
did not report third trimester exposure. Thus, the studies
in the not confirmed category had infants exposed from
any trimester of pregnancy, which could have included the
third.
It is important that future studies specify timing of expo-
sure by trimesters of pregnancy to definitively determine
whether timing is an important factor for the emergence
of PNAS. Moreover, future studies should objectively mea-
sure PNAS, preferably with a validated assessment measure.
Table 2. Exposure to Any Antidepressant and Risk of Poor Neonatal Adaptation Syndrome (PNAS) or Signs: Meta-Analyses
Results
Total
Sample
Size
Within Group
No. of
Studies
No. of
Cases
Heterogeneity Effect of Moderator
Analysis OR (95% CI)
a
P Value
Q
(df)
Within P Value I
2
(%)
Q
(df)

Between P Value I
2
(%)
PNAS overall
All studies 8 270 959 5.07 (3.257.90) < .0001 5.35
7
.617 0.0
Study type
Convenience sample 6 167 693 3.96 (2.286.85) < .0001 1.30
5
.935 0.0 1.4
1
.237 26.0
Not convenience sample 2 103 266 11.89 (2.0967.76) .005 1.81
1
.179 45.0
Study quality
Above quality threshold 7 185 813 4.34 (2.537.45) < .0001 4.38
6
.625 0.0 0.97
1
.325 18.0
Below quality threshold 1 85 146 7.00 (3.2015.31)
b
< .0001
Timing of exposure
Exposed late 5 226 794 5.13 (2.869.21) < .0001 4.98
4
.290 20.0 0.00053
1
.982 0.0
Unsure/not exposed late 3 44 165 5.20 (1.8614.57) .002 0.37
2
.831 0.0
Confounders
Adjusted findings 2 181 312 4.74 (2.1410.52) < .0001 1.91
1
.167 48.0 0.07
1
.794 1.0
Unadjusted findings 6 89 647 5.46 (2.7210.97) < .0001 3.36
5
.644 0.0
Respiratory distress
All studies 9 23,224 676,186 2.20 (1.812.66) < .0001 12.9
8
.116 38.0
Study type
Convenience sample 4 78 349 4.18 (2.297.60) < .0001 2.40
3
.493 0.0 5.4
1
.020 42.0
Not convenience sample 5 23,146 675,837 2.01 (1.762.30) < .0001 4.84
4
.304 17.0
Study quality
Above quality threshold 8 23,174 676,040 2.20 (1.792.72) < .0001 12.6
7
.081 45.0 0.0
1
> .999 0.0
b
.022
Timing of exposure
Exposed late 6 5,536 76,657 2.64 (1.694.14) < .0001 7.94
5
.160 37.0 0.6
1
.440 5.0
Unsure/not exposed late 3 17,688 599,529 2.14 (1.602.86) < .0001 4.85
2
.089 59.0
Confounders
Adjusted findings 2 16,410 583,939 2.24 (1.752.86) < .0001 0.09
1
.770 0.0 0.02
1
.880 0.0
Unadjusted findings 7 6,814 92,247 2.30 (1.723.08) < .0001 12.15
6
.059 51.0
Tremors
All studies 4 106 482 7.89 (3.3318.73) < .0001 5.41
3
.144 44.5
Study type
Convenience sample 2 34 216 11.31 (0.63204.37) .100 3.70
1
.054 73.0 0.03
1
.857 1.0
Not convenience sample 2 72 266 8.59 (4.1417.81) < .0001 0.76
1
.384 0.0
Study quality
Above quality threshold 3 82 336 6.74 (2.3919.03) .0003 4.11
2
.128 51.0 0.78
1
.376 14.0
b
.0003
Timing of exposure
Exposed late 4 106 482 7.89 (3.3318.73) < .0001 5.41
3
.144 44.5
Unsure/not exposed late 0 0 0
Confounders
Adjusted findings 0 0 0
Unadjusted findings 4 106 482 7.89 (3.3318.73) < .0001 5.41
3
.144 44.5
a
Pooled effect size estimated using random-effects model.
b
Pooled effect size estimated using fixed-effects model.
Although the 2 studies that did employ an objective measure
used the Finnegan score,
40
which is used to assess neonatal
withdrawal symptoms following exposure to opioid drugs
to determine the need for intervention, it has not been
validated for antidepressant exposure as far as we are aware.
One of the most important limitations, however, stems from
the original studies that did not commonly control for the
potential effects of depression itself. As we do not completely
understand the pathophysiology of depression, we cannot be
confident about what adverse effects can be present in the
infant. With the emerging data on how maternal mood can
affect fetal development,
41
future studies must account for
the role of maternal depression.
Implications
A review
42
of the various studies that examined immedi-
ate neonatal symptoms in infants exposed to antidepressants
in utero concluded that infants exposed to all classes of anti-
depressants displayed a spectrum of symptoms similar to
those that may be seen in adults exposed to the same drugs.
Since up to 85% of adults may suffer from withdrawal
symptoms after abrupt discontinuation of antidepressant
medication, it seems likely that infants who are no longer
being exposed to antidepressants through their mothers
would experience similar symptoms, although PNAS does
not universally occur, as approximately one-third of exposed
infants display it.
42(p177)
The issue is that most adult studies
report on subjective symptoms, which cannot be elicited from
infants. The debate continues though regarding this phenom-
enon being secondary to overstimulation,
9
as it is difficult
to differentiate withdrawal reactions from toxicity leading
to overstimulation symptoms in infants because such pat-
terns of antidepressant-induced complications are clinically
similar in the neonate.
42(p181)
Some argue that withdrawal
reactions and symptoms of serotonergic toxicity occur along
a continuum.
42
Serotoninergic antidepressants with a short
half-life may be present in adequate concentrations at birth
to induce toxicity and decrease over time at rates sufficient to
induce withdrawal signs.
42(p181)
The third causal explanation
postulates that the signs of PNAS may result from changes
in early formation of the lungs or brain that are sustained
but become evident with the novel demands during neonatal
adaptation.
43
However, given that a constellation of signs has
been reported for PNAS, it is possible that different signs may
result from varying mechanisms.
28
Tremors, for example,
can be typical of withdrawal.
7,8
Respiratory signs may result
from serotonergic stimulation, as serotonin is known to have
a role in the development and modulation of the lungs
31
; in
more severe cases, signs may present as respiratory distress
and, some suggest, as mild persistent pulmonary hyperten-
sion, although this hypothesis remains to be determined.
44

It might also be possible that the mechanism differs among
patients and specific drugs.
45
Those with a shorter half-life,
for example, may be more likely to cause PNAS, as is the case
with discontinuation syndrome in adults following the cessa-
tion of a short-acting antidepressant. It is not known at this
time if the phenomenon is dose related and there can be an
interaction with maternal metabolism and perhaps genetic
susceptibility or predisposition.
46
Some clinicians argue the
antidepressant dose should be reduced prior to delivery to
reduce the incidence of PNAS. This is likely related to the
US Food and Drug Administration
47
and Health Canada
48

issuing advisories in 2004. However, this approach will put
the mother at risk of undertreatment during a critical time.
Only with future research will the mechanism or mecha-
nisms be clearly understood and their implications. Specific
drug effects as opposed to pooling various antidepressants
also need more attention.
Encouragingly, the signs associated with exposure to anti-
depressants in utero are believed to be most commonly mild,
have a limited course, can begin within hours after birth, and
typically resolve within days to 2 weeks.
8,10,49
However, more
work is necessary to fully understand this syndrome. The
studies pooled in this meta-analysis varied in their reporting
of the clinical features listed above. For example, the timing
of signs was not always reported. Onset of signs was noted
as within the first 24 hours following birth by 3 studies
10,30,34

and within the first 48 hours by 2 studies.
8,31
Duration of
signs was documented to be most commonly up to the first
48 hours post delivery in 2 studies,
10,31
although a median of
3 days duration was reported by another study,
30
and signs
still noted at 4 days by another.
8
Not all studies reported on
the effect of the signs on the length of hospital stay, but of
those that did, 4 documented longer or prolonged hospi-
tal stays,
26,2830
whereas 2 studies
10,31
reported the signs had
no significant effect on hospital stay. As described above, the
type of signs reported for PNAS vary, including among the
pooled studies. For example, although respiratory distress
was not significant in one study
33
and another reported no
treatment was necessary for any infant,
8
others reported that
some infants did require intubation
26
(3 infants in total) and
ventilatory support (number of infants not provided).
30

Two studies
12,29
documented significantly more convulsions
in infants exposed to antidepressants. Thus far, long-term
sequelae have not been reported for PNAS, but the long-
term outcomes have not been well studied. Longer term data
were provided by only one study
27
of those pooled in which
significant differences were not evident at 2 months post-
delivery between antidepressant-exposed versus unexposed
infants. Clearly, more systematic work is needed to charac-
terize PNAS and determine which infants are most at risk,
including those that will develop serious signs and any that
may experience long-term sequelae.
The effect of breastfeeding on PNAS is unknown. If this
syndrome results from a discontinuation phenomenon,
breastfeeding would seem advantageous as the infant would
continue to get some exposure through breast milk. Note,
however, that in 1 of the pooled studies in this meta-analysis,
all the infants were breastfed, yet the antidepressant-exposed
group still developed signs of PNAS.
33
Although this may be
related to a lower level of antidepressant exposure via lacta-
tion than during gestation, future research should examine
the impact of breastfeeding on the development and evolu-
tion of PNAS.
Grigoriadis et al
The decision of whether or not to use antidepressant
medication requires weighing the risks of the effects of
depression itself as well as the effects of the medication on
the fetus, neonate and child; beneficial effects on the mother
and risk of relapse if medication is discontinued must also be
reviewed. Both mother and baby must be considered in any
decision. Women who choose to use antidepressant medica-
tion while pregnant must be counseled that the infant may
develop PNAS, and that, to date, data suggest this syndrome is
usually transient, although more severe symptoms have been
reported. The woman and her family must be supported in
their decision regarding the use of antidepressant medica-
tion and assured that should complications arise, they will be
identified and treated immediately. This work highlights the
ongoing need to collaborate with the entire health care team
and in particular increase the awareness of neonatologists
of antidepressant exposure in the infant such that appropri-
ate care is expeditiously provided if necessary. Moreover, the
family may require ongoing support if a prolonged neona-
tal intensive care unit admission occurs; arrangements for
such can be more quickly arranged if clinicians have prior
knowledge.
Drug names: citalopram (Celexa and others), clonazepam (Klonopin and
others), fluoxetine (Prozac and others), fluvoxamine (Luvox and others),
mirtazapine (Remeron and others), paroxetine (Paxil, Pexeva, and others),
sertraline (Zoloft and others), trazodone (Oleptro and others), venlafaxine
(Effexor and others).
Author affiliations: Department of Psychiatry, Womens College Hospital,
Toronto (Dr Grigoriadis and Mss VonderPorten, Mamisashvili, and Eady);
Womens College Research Institute, Toronto, (Drs Grigoriadis and Dennis);
Department of Psychiatry, University Health Network, and Clinical Trials
Resource Center, Toronto General Research Institute (Dr Grigoriadis);
Department of Psychiatry, Sunnybrook Health Sciences Center, Toronto
(Drs Grigoriadis and Cheung and Mss VonderPorten and Mamisashvili);
Sunnybrook Research Institute, Toronto (Drs Grigoriadis and Cheung);
Department of Psychiatry (Drs Grigoriadis, Dennis, Cheung, and Ross),
Department of Medicine (Dr Tomlinson), Faculty of Nursing (Dr Dennis),
Departments of Pediatrics, Pharmacology, Pharmacy, and Medical Genetics
(Dr Koren), and Institute of Medical Sciences (Dr Steiner), University
of Toronto, Toronto; Center for Innovation in Complex Care, Toronto
General Hospital, Toronto (Dr Tomlinson); Division of Clinical Decision-
Making and Health Care, Toronto General Research Institute, Toronto
(Dr Tomlinson); Motherisk Program, The Hospital for Sick Children, Toronto;
and Departments of Medicine, Pediatrics and Physiology/Pharmacology,
University of Western Ontario, London (Dr Koren); Departments of
Psychiatry and Behavioural Neurosciences and Obstetrics and Gynecology,
McMaster University; Womens Health Concerns Clinic, St Josephs Hospital;
and St Josephs Healthcare, Hamilton (Dr Steiner); Healthy Child Development
Program, Ontario College of Family Physicians, Toronto; York Central
Hospital, Richmond Hill; and Markham Stouffville Hospital, Markham (Dr
Mousmanis); and Center for Addiction and Mental Health, Toronto (Dr Ross),
Ontario, Canada. Dr Grigoriadis is now with the Department of Psychiatry,
Sunnybrook Health Sciences Center, and Sunnybrook Research Institute,
Toronto. Mss VonderPorten and Mamisashvili are with the Department of
Psychiatry, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
Author contributions: Conception and design: Drs Grigoriadis and Ross; data
analysis and interpretation: Drs Grigoriadis, Tomlinson, Ross, Dennis, Koren,
Steiner, Mousmanis, and Cheung and Mss VonderPorten, Mamisashvili,
and Eady; drafting or revision of the manuscript: Drs Grigoriadis, Ross,
Tomlinson, Dennis, Koren, Steiner, Mousmanis, and Cheung and Mss
VonderPorten, Mamisashvili, and Eady; and approval of the final version
of the manuscript for publication: Drs Grigoriadis, Ross, Tomlinson,
Dennis, Koren, Steiner, Mousmanis, and Cheung and Mss VonderPorten,
Mamisashvili, and Eady. Drs Grigoriadis and Ross had full access to all of
the data in the study and take responsibility for the integrity of the data and
the accuracy of the data analysis.
Potential conflicts of interest: In the last 5 years, Dr Grigoriadis has received
honoraria as a consultant and a member of an advisory committee or for
lectures from Wyeth Pharmaceuticals, GlaxoSmithKline, Pfizer, Servier, Eli
Lilly Canada, and Lundbeck; and has received research grant support from
the Canadian Institutes of Health Research (CIHR), Ontario Ministry of
Health, Ontario Mental Health Foundation, and CR Younger Foundation.
Dr Steiner has been a consultant to AstraZeneca, Azevan, Servier, Bayer
Canada, and Lundbeck; has received grant/research support from CIHR,
Pfizer, Eli Lilly, and Lundbeck; and has received honoraria from the Society for
Womens Health Research and AstraZeneca. Drs Tomlinson, Dennis, Koren,
Mousmanis, Cheung, and Ross and Mss VonderPorten, Mamisashvili, and
Eady have no financial disclosures to report.
Funding/support: This research was funded by a Research Syntheses grant
from the CIHR, KRS-83127, and the Ontario Ministry of Health and
Long-Term Care through the Drug Innovation Fund, grant # 2008-005.
Dr Grigoriadis has a new investigator award in womens health research from
the CIHR in partnership with the Ontario Womens Health Council, award
NOW-88207. Dr Ross is supported by a new investigator award from CIHR
and the Ontario Womens Health Council, award NOW-84656. In addition,
support to the Center for Addiction and Mental Health for salary of scientists
and infrastructure has been provided by the Ontario Ministry of Health and
Long-Term Care.
Disclaimer: The views expressed here do not necessarily reflect those of the
Ministry of Health and Long-Term Care.
Previous presentations: Preliminary results of this study were presented
at the Motherisk Update 2012 (paper title: The effect of antidepressant
medications on mothers and babiesan updated systematic analysis);
May 23, 2012; Toronto Ontario, Canada Canadian Psychiatric Association
Conference (paper title: Evidence-based discussion guide for antidepressant
treatment in depressed pregnant and postpartum women); October 1315,
2011; Vancouver, British Columbia, Canada Canadian Institutes for Health
Research, Innovations in Gender, Sex and Health Research Conference (paper
titles: [1] Effects of in utero exposure to antidepressant medication during
pregnancy: a meta-analysis and [2] Short-term and long-term impact of
untreated maternal depression on the child); November 2223, 2010; Toronto,
Ontario, Canada Canadian Psychiatric Association Conference (paper title:
Outcomes associated with antidepressant medication use during pregnancy:
a meta-analysis); September 2326, 2010; Toronto, Ontario, Canada 36th
Annual Meeting of the North American Society for Psychosocial Obstetrics
and Gynecology (poster title: Preliminary results from the Reproductive Life
Stages Algorithm Project: use of antidepressant medication during pregnancy
and lactation: development of an evidence-based decision tool); February
1013, 2010; Richmond, Virginia Organization for the Study of Sex
Differences 3rd Annual Meeting (poster title: An evidence-based algorithm
to quantify risk-benefit decision-making for use of antidepressant medication
during pregnancy and lactation); June 46, 2009; Toronto, Ontario, Canada
35th Annual Meeting of the North American Society for Psychosocial
Obstetrics and Gynecology (poster title: Use of antidepressant medication
during pregnancy and lactation: development of an evidence-based decision
tool); February 47, 2009; New Haven, Connecticut Canadian College of
Neuropsychopharmacology Annual Meeting (poster title: An evidence-based
algorithm to quantify risk-benefit decision-making for use of antidepressant
medication during pregnancy and lactation. Research in progress: current
state of knowledge); June 69, 2008; Toronto, Ontario, Canada.
Acknowledgments: The authors thank their advisory committee members
for providing valuable input and lending their expertise to this project:
Hiltrud Dawson, RN (Health Nexus, Toronto, Canada); Michael Dunn, MD
(Sunnybrook Health Sciences Center, Toronto, Canada); Adrienne Einarson,
RN (The Hospital for Sick Children, Toronto, Canada); Alicja Fishell, MD
(Womens College Hospital, Toronto, Canada); Jasmine Gandhi, MD (Ottawa
Hospital, Ottawa, Canada); Jan Kasperski, RN, MHSc (Ontario College of
Family Physicians, Toronto, Canada); Sidney Kennedy, MD (University Health
Network, Toronto, Canada); Diane Meschino, MD (Womens College Hospital,
Toronto, Canada); Irena Nulman, MD, PhD (The Hospital for Sick Children,
Toronto, Canada); Sagar Parikh, MD (University Health Network, Toronto,
Canada); Paula Ravitz, MD (Mount Sinai Hospital, Toronto, Canada); Sarah
Romans, MD (University of Otago, Wellington, New Zealand); Simone Vigod,
MD (Womens College Hospital, Toronto, Canada); Jennifer Blake, MD
(Sunnybrook Health Sciences Center, Toronto, Canada); and Karen Wade, RN,
MScN (Toronto Public Health, Toronto, Canada). The authors would also like
to thank Lindsay Witton, MSW (Womens College Hospital, Toronto, Canada);
Maura OKeefe, MSW (Womens College Hospital, Toronto, Canada); and
Svetlana Emelianova, MD (North York General Hospital, North York, Canada)
for providing their feedback during many research meetings. Sheila Lacroix,
MLS (Center for Addiction and Mental Health, Toronto, Canada), and Ani
Orchanian-Cheff, MISt (University Health Network, Toronto, Ontario),
devised search strategies and completed literature search. The authors also
thank Alex Kiss, PhD (Sunnybrook Health Sciences Center, Toronto, Canada),
for performing preliminary meta-analyses and Jenna McKay, BA (Womens
College Hospital, Toronto, Canada), and Kimberly Radford, BA (Womens
College Hospital, Toronto, Canada), for assisting with data extraction and
quality assessment processes. Dr Kennedy has received research funding or
honoraria in the past from AstraZeneca, Biovail, Eli Lilly, GlaxoSmithKline,
Janssen-Ortho, Lundbeck, Pfizer, St Jude Medical, and Servier. Ms Einarson
has conducted research funded by an unrestricted grant from Eli Lilly
Canada. Dr Nulman has held a CIHR Collaborative grant with Duchesnay.
Dr Parikh has had education or research grants or served on advisory boards
or as a speaker for AstraZeneca, Apotex, Biovail, Bristol-Myers Squibb, CIHR,
Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric
Association, GlaxoSmithKline, Genpharm, Janssen, Eli Lilly, Lundbeck,
Novartis, Pfizer, and Wyeth. There were no conflicts of interest or relevant
financial disclosures reported by any of the other acknowledged individuals.
Additional information: This work was carried out at the Departments of
Psychiatry, Womens College Hospital, University Heath Network, Center for
Addiction and Mental Heath, and University of Toronto, Toronto, Ontario,
Canada.
Supplementary material: See accompanying pages.
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Editors Note: We encourage authors to submit papers for
con sideration as a part of our Focus on Womens Mental
Health section. Please contact Marlene P. Freeman, MD, at
mfreeman@psychiatrist.com.
Supplementary material follows this article.

Copyright 2013 Physicians Postgraduate Press, Inc.

Supplementary Material

Article Title: The Effect of Prenatal Antidepressant Exposure on Neonatal Adaptation: A Systematic
Review and Meta-Analysis
Author(s): Sophie Grigoriadis, MD, MA PhD, FRCPC; Emily H. VonderPorten, MPH; Lana
Mamisashvili, BSc (Hons); Allison Eady, BA; George Tomlinson, PhD; Cindy-Lee Dennis,
PhD; Gideon Koren, MD, FRCPC, FACMT; Meir Steiner, MD, PhD, FRCPC; Patricia
Mousmanis, MD, CCFP, FCFP; Amy Cheung, MD, MSc, FRCPC; and Lori E. Ross, PhD
DOI Number: 10.4088/J CP.12r07967

List of Supplementary Material for the article

1. Keywords Keywords
2. eFigure 1 Exposure to any antidepressant and the risk of respiratory distress in the neonate: meta-
analysis results for all studies
3. eFigure 2 Exposure to any antidepressant and the risk of tremors in the neonate: meta-analysis
results for all studies

Disclaimer
This Supplementary Material has been provided by the author(s) as an enhancement to the published article. It
has been approved by peer review; however, it has undergone neither editing nor formatting by in-house editorial
staff. The material is presented in the manner supplied by the author.

Study
Fixed effect modeI
Random effects modeI
Heterogeneity: Isquared=38%, tausquared=0.0232, p=0.1155
Costei et al,
26
2002
Klln,
12
2004
Oberlander et al,
10
2004
LevinsonCastiel et al,
8
2006
Oberlander et al,
28
2006
Davis et al,
29
2007
Ferreira et al,
30
2007
Boucher et al,
31
2008
Galbally et al,
33
2009
0.01 0.1 1 10 100
Odds Ratio
OR
2.04
2.20
11.24
2.21
10.50
31.19
1.91
1.94
3.74
2.50
2.22
95%CI
[1.83; 2.28]
[1.81; 2.66]
[0.63; 200.70]
[1.71; 2.86]
[2.06; 53.52]
[1.80; 540.12]
[1.63; 2.25]
[1.59; 2.37]
[1.80; 7.77]
[1.14; 5.49]
[0.47; 10.54]
W(fixed)
100%
0.1%
18.2%
0.5%
0.1%
46.5%
29.9%
2.2%
1.9%
0.5%
W(random)
100%
0.4%
23.9%
1.4%
0.5%
32.3%
28.8%
6.0%
5.3%
1.5%
Supplementary eFigure 1. Exposure to any antidepressant and the risk of respiratory distress in the
neonate: meta-analysis results for all studies. Abbreviations: see Figure 2.
Study
Fixed effect modeI
Random effects modeI
Heterogeneity: Isquared=44.5%, tausquared=0.3288, p=0.1442
LevinsonCastiel et al,
8
2006
Ferreira et al,
30
2007
Boucher et al,
31
2008
Galbally et al,
33
2009
0 0.1 1 10 1000
Odds Ratio
OR
6.89
7.89
7.17
3.44
15.31
70.71
95%CI
[3.87; 12.28]
[3.33; 18.73]
[3.11; 16.53]
[1.26; 9.38]
[3.45; 68.05]
[3.85; 1299.18]
W(fixed)
100%
47.8%
33.2%
15.0%
3.9%
W(random)
100%
38.0%
32.9%
21.4%
7.7%
Supplementary eFigure 2. Exposure to any antidepressant and the risk of tremors in the
neonate: meta-analysis results for all studies. Abbreviations: see Figure 2.
Keywords

Antenatal Antidepressant (search words: Major Depression; Depression; depressive disorder,
mood disorder, dysthymic disorder, pregnancy, trimester, pregnancy unplanned/unwanted, prenatal
care, pregnant women; antenatal/pregnant/prenatal/perinatal/puerperal; Neonatal withdrawal,
neonatal abstinence syndrome, poor adaptation syndrome, neonatal adaptation, prenatal
exposure/delayed effects, substance withdrawal symptoms, spontaneous abortion, miscarriage,
fetus, fetal, neonatal, newborn, infant, infant outcome; maternal outcome, suicide, maternal
suicide; premature birth, premature delivery, neurocognitive outcome or development, neurological
outcome or development, infant development/child development, abnormalities, drug induced;
attachment/mother/maternal, maternal behaviour; prenatal exposure, first trimester
pregnancy/second trimester pregnancy/third trimester pregnancy/pregnancy complication;
Tricyclic Antidepressant Drugs/Antidepressant Drugs/SSRIs/Monoamine Oxidase
Inhibitors/Pregnancy*)
Antenatal Non Drug (search words: Psychotherapy/ Brief Psychotherapy/Interpersonal
Psychotherapy; Support Groups; Counseling; Interpersonal Therapy or Interpersonal
Psychotherapy; Supportive Therapy or Narrative Therapy; Cognitive Therapy or Cognitive
Behavioral Therapy; Psychoeducational or Psychodynamic; Psychosocial Intervention or
Psychological Intervention; Psychosocial care, psychosocial rehabilitation, primary prevention,
social support, prevention, therapy; Motivational Interview; emotion-focused counseling, non-
directive counseling; Major Depression/Depression; Pregnancy/Prenatal or Antenatal)
Antenatal Risk Factors for Depression (search words: Major Depression; depressive disorders,
dysthymic disorders, Depression; Pregnancy; unwanted/unplanned pregnancy, adolescent
pregnancy, Prenatal or antenatal; Risk Assessment/ Risk Management/ At Risk Populations/ Risk
Factors; Protective Factors; psychosocial support, social support)
Postnatal Antidepressant (search words: depressive disorder/mood disorder, dysthymic disorder;
postpartum/postnatal; Major Depression; Depression; Tricyclic Antidepressant
Drugs/Antidepressant Drugs/SSRIs/Monoamine Oxidase Inhibitors)
Lactation / Breastfeeding: Postpartum Depression, Antidepressants, etc. (search words: Breast
milk, Breast Feeding/ Lactation/ Lactating, weaning; Depression, puerperal depression, postpartum
depression, dysthymic disorders, depressive disorders; breast milk and antidepressants,
Antidepressant Drugs/Antidepressants*)
Postnatal Non Drug (search words: Postpartum, postnatal; pregnancy, Psychotherapy/ Brief
Psychotherapy/Interpersonal Psychotherapy; Support Groups; Counseling; Interpersonal Therapy
or Interpersonal Psychotherapy; Supportive Therapy or Narrative Therapy; Cognitive Therapy or
Cognitive Behavioral Therapy; Psychoeducational or Psychodynamic; Psychosocial Intervention or
Psychological Intervention; psychological rehabilitation, social support, psychoeducational
support, Motivational Interview; non-directive counseling, emotion-focused counseling, cognitive
rehabilitation, psychotherapeutic techniques, Major Depression/Depression; Postnatal)
Risk Factors for Postpartum Depression (search words: Postpartum/postnatal, postpartum
period, prevention/control, therapy, psychosocial care, social support, psychosocial rehabilitation,
psychosocial intervention; risk assessment/risk management, at risk populations, risk factors,
primary mental health prevention, protective factors, unwanted/unplanned pregnancy, pregnancy;
depressive disorders, dysthymic disorders; Postpartum Depression/ Risk Assessment/At Risk
Populations/Risk Factors/Risk Management; Protective Factors; child development, attachment
behaviour, infant/child behaviour, maternal behaviour, untreated depression, neurocognitive
development, mother-child relations, infant care, neurological/neurocognitive development).

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