Review

Antidepressant use in pregnancy: a critical

review focused on risks and controversies
Byatt N, Deligiannidis KM, Freeman MP. Antidepressant use in
pregnancy: a critical review focused on risks and controversies.
Objective: Conicting data have led to controversy regarding
antidepressant use during pregnancy. The objectives of this study are to
i) review the risks of untreated depression and anxiety, ii) review the
literature on risks of exposure to antidepressants during pregnancy, iii)
discuss the strengths and weaknesses of the dierent study designs used
to evaluate those risks, and iv) provide clinical recommendations.
Method: MEDLINE/PubMed was searched for reports and studies on
the risk of rst-trimester teratogenicity, postnatal adaptation syndrome
(PNAS), and persistent pulmonary hypertension (PPHN) with in utero
antidepressant exposure.
Results: While some individual studies suggest associations between
some specic major malformations, the ndings are inconsistent.
Therefore, the absolute risks appear small. PNAS occurs in up to 30%
of neonates exposed to antidepressants. In some studies, PPHN has
been weakly associated with in utero antidepressant exposure, while in
other studies, there has been no association.
Conclusion: Exposures of concern include that of untreated maternal
illness as well as medication exposure. It is vital to have a careful
discussion, tailored to each patient, which incorporates the evidence to
date and considers methodological and statistical limitations. Past
medication trials, previous success with symptom remission, and
womens preference should guide treatment decisions.
N. Byatt
1
, K. M. Deligiannidis
2
,
M. P. Freeman
3
1
Psychiatry and Obstetrics & Gynecology, Psychosomatic
Medicine, Womens Mental Health, University of
Massachusetts Medical School/UMass Memorial
Medical Center, Worcester, MA, USA,
2
Psychiatry and
Obstetrics & Gynecology, Depression Specialty Clinic,
Womens Mental Health Specialty Clinic, Center for
Psychopharmacologic Research and Treatment,
University of Massachusetts Medical School/UMass
Memorial Medical Center, Worcester, MA, USA and
3
Psychiatry, Perinatal and Reproductive Psychiatry
Program, Harvard Medical School/Massachusetts
General Hospital, Boston, MA, USA
Key words: antidepressant; in utero; teratogenicity;
postnatal adaptation syndrome; persistent pulmonary
hypertension
Nancy Byatt, Psychiatry and Obstetrics & Gynecology,
Psychosomatic Medicine, Womens Mental Health,
University of Massachusetts Medical School/UMass
Memorial Medical Center, 55 Lake Avenue North,
Worcester, MA 01655, USA.
E-mail: nancy.byatt@umassmemorial.org
Accepted for publication October 10, 2012
Summations

No single type of malformation has been consistently observed across studies with any commonly
used antidepressant. Some individual studies suggest associations between particular selective seroto-
nin reuptake inhibitors (SSRIs) and specic birth defects.

Postnatal adaptation syndrome (PNAS) occurs in up to 30% of neonates exposed to antidepressants

in late pregnancy.

Some studies nd a small association between persistent pulmonary hypertension of the newborn
(PPHN) and SSRI use, although other studies do not.
Considerations

SSRIs remain the most studied antidepressants in pregnancy. Less data are available for serotonin
norepinephrine reuptake inhibitors (SNRIs), mirtazapine, nefazodone, trazodone and vilazodone.

The current evidence base is limited by data that do not i) systematically assess infants, ii) use appro-
priate control groups, iii) use blind raters of the neonates and iv) take into account maternal diagno-
sis or symptoms or other confounding variables.

The evidence regarding the risk of PPHN because of in utero antidepressant exposure is inconclusive.
94
Acta Psychiatr Scand 2013: 127: 94114 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd
All rights reserved
DOI: 10.1111/acps.12042
ACTA PSYCHIATRICA SCANDINAVICA
Introduction
During the reproductive years, a signicant pro-
portion of women experienced depressive and anx-
iety disorders (1). Approximately 18.4% of women
suer from antenatal depression, and as many as
19.2% of mothers develop a depressive disorder
within several weeks of delivery (2). Anxiety disor-
ders are also common, with a prevalence rate of
21.7% during the 3rd trimester of pregnancy, and
11.1% during the rst 3 postpartum months (3, 4).
Untreated depression and anxiety during preg-
nancy negatively impacts mother and fetus/child.
Women are more likely to experience inadequate
maternal weight gain (5) and abuse substances (6).
Depression in pregnancy is also associated with
preeclampsia, preterm birth (710), increased risk
for delivery of a low birth weight infant (11), elec-
tive termination of the pregnancy (12), postpartum
depression (13), and anxiety. Depression is associ-
ated with fetal distress (14) and an increased risk
of neonatal care unit admission and caesarian
delivery (15).
Postpartum depression can negatively impact
child development and has been associated with
dicult infant and childhood temperament (16,
17) and attachment insecurity (16). Maternal
depression may also lead to emotional and func-
tional disability in children including cognitive
delays (18), behavioural problems (16), and di-
culties with social interaction (19). Children of
depressed mothers are at increased risk of develop-
mental delay, impaired language development, and
lower IQ scores (20, 21). The impact of maternal
depression has eects beyond infancy, as one-third
of school-aged children of depressed mothers suf-
fer from depressive, anxiety, or disruptive disor-
ders (22). Eective treatment of maternal
depression mitigates this negative impact (23).
Perinatal depression can also be fatal; maternal
suicide accounts for up to 20% of postpartum
deaths in depressed women (24).
Stress and anxiety during pregnancy inuence
maternal behaviour and birth outcomes: maternal
tobacco smoking, caeine consumption, poor
nutrition and exercise, preterm labor, preterm
birth, and low birth weight are associated with pre-
natal anxiety (25). Antenatal anxiety may increase
the risk of childhood developmental and psychiat-
ric disorders. It may adversely aect infant emo-
tional development (26) and has been associated
with reductions in gray matter density in young
children (27). Treatment of perinatal depressive
and anxiety disorders is of paramount importance
to mitigate these risks. Despite the risk of relapse
to depressive episodes and anxiety and associated
adverse eects, women are likely to stop antide-
pressant treatment during attempts to conceive or
pregnancy (28, 29).
Due to conicting reports in the literature on the
risk of rst-trimester teratogenicity, postnatal
adaptation syndrome (PNAS), and persistent pul-
monary hypertension (PPHN) with in utero anti-
depressant exposure, a review of these topics is of
great clinical importance. In this review, selected
topics of controversy regarding antidepressant use
in pregnancy are presented, to provide clarication
during clinical decision-making and risk/benet
assessment and discussion. A review of all possible
outcomes is beyond the scope of this study.
Although not reviewed in this article, there are
associations between antidepressant in utero expo-
sure and measures of birth outcome, including an
increased rate of spontaneous abortion (3035)
(3639), low birth weight (35, 40, 41), and reduced
gestational age or preterm birth (35, 40, 4244) in
depressed women exposed to antidepressants.
Recent studies have raised questions about possi-
ble associations with antidepressant use in
pregnancy, including autism (45) and eects on
long-term neurocognitive development (46). While
all associations with in utero exposure are impor-
tant, we limited our review to topics that have
become the main controversies in antidepressant
use during pregnancy in recent years.
Aims of the study
The purposes of this review are to i) review the
risks of untreated depression and anxiety, ii)
review the literature on risks of exposure to com-
monly used antidepressants during pregnancy, iii)
discuss the strengths and weaknesses of the dier-
ent study designs used to evaluate those risks, and
iv) provide clinical recommendations.
Material and methods
A search was performed for the English language
literature indexed on MEDLINE/PubMed for the
period between 1966 and 2012 using the following
key terms: antidepressant, selective serotonin reup-
take inhibitor (SSRI), serotonin-norepinephrine
reuptake inhibitor (SNRI), noradrenergic and spe-
cic serotonin antidepressant (NaSSA), norepi-
nephrine reuptake inhibitor (NRI), uoxetine,
paroxetine, sertraline, citalopram, escitalopram,
uvoxamine, venlafaxine, mirtazapine, reboxetine,
duloxetine, bupropion, trazodone, nefazodone,
and vilazodone in association with antenatal
depression, maternal, pregnancy, prenatal expo-
sure, malformation, in utero exposure, neonatal
95
Antidepressant use in pregnancy
complications, gestational, neonatal health, neona-
tal outcome, birth outcome, PPHN, birth defects,
and congenital heart defect. To determine whether
other relevant articles were not identied in the ini-
tial search, all articles were cross-referenced. Origi-
nal observational studies, case reports, and case
series were included.
Results
First-trimester exposure: is there evidence of teratogenicity?
In the USA, approximately 1 in every 33 infants
(3%) is born with a major birth defect (47). Major
birth defects or malformations typically require
medical or surgical intervention for a structural or
functional abnormality. Antidepressants that aect
serotonergic tone could putatively increase the
incidence of congenital malformations because
serotonin is important in aspects of early embry-
onic development that impact development of the
neural tube, branchial arch, and heart.
Despite the high prevalence of birth defects
overall in the population, each specic type of
major birth defect is generally rare, and studies
that are inadequately powered or controlled may
overestimate risk and association. For example, of
the major birth defects studied in association with
antidepressant use, omphalocele occurs in 1 per
5386 births, gastroschisis occurs in 1 per 2229,
anencephaly 1 in every 4859, and craniosynostosis
in 410 per 10 000 births in the general population
(47). While congenital heart disease is relatively
common (48, 49), studies examining the eects of
drug exposure should ideally use the rate of unex-
posed infants with identical ascertainment methods
as a comparison rate for the malformation(s)
under study, rather than the 1% incidence of con-
genital heart disease (48, 49) in the general popula-
tion, which makes interpretation of ndings
dicult.
Dierent methodologies have been used to study
the risks of teratogenicity with antidepressant use
in pregnancy. Some use retrospective casecontrol
studies, which carry the risk of recall bias and large
non-response rates. Other prospective controlled
studies, often performed in teratology information
centers, use detailed drug use information in a
small number of women. A nal type of study uses
data from drug registries and administrative data-
bases, which carry the risk of exposure misclassi-
cation given that it is not clear whether women
who purchased the drug took it as prescribed.
When they recently compared interview data with
data from a prescription registry, Kallen et al.
found the most valid results are obtained through
prospective interview data on drug use. For pre-
scription data, they recommended avoiding the use
of prescriptions given earlier than 1 month before
the last menstrual period because of the increased
percentage of women who did not use the medica-
tion in pregnancy (50).
Across all study types, the risks of the underly-
ing untreated disorder and other associated con-
founding factors are rarely taken into account.
The strategy of using depressed women without
drug treatment as a comparison may not be ade-
quate given the likelihood that illness severity cov-
aries with medication use. Comparisons of
dierent SSRI eects may also be complicated by
the fact that this class of medications is used for
many conditions other than depression, including
anxiety disorders (51). SSRI preference may also
dier according to indication, and prescribing pat-
terns may dier between populations. To control
for maternal illness severity, Oberlander et al. used
a propensity score method that allowed them to
control for maternal illness severity and other
characteristics that impact neonatal outcomes.
Unfortunately, even with their large population
level data set, propensity score matching led to a
reduced sample size for comparison groups (52).
The use of dierent study designs and limita-
tions of each may explain why ndings of malfor-
mations are inconsistent. The data presented in
Table 1 are dicult to interpret because it is di-
cult to dierentiate whether adverse outcome is
associated with underlying illness, the medication
itself, or other unknown factors associated with
either or both.
Selective serotonin reuptake inhibitors. Prior to
2005, studies had not suggested an increased risk
of major congenital malformations with in utero
exposure to SSRIs (35, 36, 43, 5359). These stud-
ies, as well as those since, were generally limited by
insucient power, confounding variables, con-
cerns with the method of birth outcome classica-
tion, and limited exposure information (60). Over
the past several years, a number of studies have
found associations between specic SSRIs and
malformations, although the ndings are inconsis-
tent across studies, making their interpretation dif-
cult. A teratogen would be expected to cause a
similar type of malformation consistently across
studies. While this has not been the case with
SSRIs, sporadic reports have generated concerns.
Since 2005, the data have been conicting and
inconsistent (61) with regard to whether individual
SSRIs are associated with an increased risk of con-
genital malformations. Discrepant ndings have
fueled confusion, and it is unclear whether un-rep-
96
Byatt et al.
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99
Antidepressant use in pregnancy
licated results represent true associations. One
example of conicting ndings is the retrospective
casecontrol studies by Alwan et al. and Louik
et al. that linked the use of SSRI drugs with rare
malformations. Both studies carry a risk for recall
bias and have a high rate of non-responders (60,
62). Other studies have other methodological limi-
tations, for example, Wogelius et al. (63) identied
malformations from discharge diagnoses in women
with and without intrauterine SSRI exposure.
Examining physicians were aware of SSRI expo-
sure, which may have increased vigilance during
examinations, and led to surveillance bias and
overestimation of risks because of the identica-
tion of less serious malformations, for example,
mild cardiac defects that would not otherwise have
been identied. Other studies are so small that they
lack statistical power to detect anything, but
extreme risk increases that are unlikely to occur
with SSRI exposure.
A small increased absolute risk of rare defects
such as omphalocele, anencephaly, craniosynosto-
sis (60), cystic kidney, and congenital heart defects
(51, 6466) has also been reported. Importantly,
specic patterns of congenital malformations have
not been demonstrated with SSRIs across studies,
and teratogenicity is usually determined by a con-
sistent risk and pattern of malformation. Among
the SSRIs, paroxetine has become the most com-
plicated in terms of reported risks and recommen-
dations for use in pregnancy.
Paroxetine. In 2005, a small study performed by
GlaxoSmithKline suggested an increase in cardiac
malformations in infants exposed to paroxetine in
utero compared with controls. As a result, Glaxo-
SmithKline modied the prescribing information
to include a warning regarding the risk of cardiac
malformations with antenatal paroxetine exposure.
This study was not peer-reviewed or published, but
was presented to the US FDA and cited elsewhere
(67). As this recommendation was based on non-
peer-reviewed, unpublished data, and a relatively
small sample size, its ndings are dicult to inter-
pret (68). Since then, multiple studies (41, 51, 60,
66, 6973), although not all (65, 74), have found
an association between prenatal paroxetine expo-
sure and an increased risk of congenital malforma-
tions, yet the causality and magnitude of that risk
are unclear.
A recent meta-analysis based on research prior
to 2006 found that paroxetine was associated with
1.7-fold risk increase of cardiac malformation (71).
A later review, however, concluded that it is not
practical to use a meta-analysis to examine the
safety of paroxetine in pregnancy given the limita- T
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100
Byatt et al.
tions in the methodology of the published studies
(75). Another meta-analysis that examined 37
studies from January of 1992 through September
2008 provides further evidence of an increased risk
of major congenital malformations with paroxetine
exposure. The authors concluded that rst-trimes-
ter paroxetine exposure is associated with an
increased prevalence of combined cardiac defects
[prevalence odds ratio (POR) = 1.46%; 95% CI
1.171.82] and aggregated defects (POR = 1.24;
95% CI 1.081.43) (70).
Other SSRIs. Specic individual studies have
found malformations associated with specic
SSRIs as isolated reports. These include hypertro-
phic stenosis (76), congenital heart defects, and
other major abnormalities (41, 65, 73, 77) with u-
oxetine, omphalocele (62, 7779) and cardiac sep-
tal defects (62, 77, 79) with sertraline, and
omphalocele (62, 7779), congenital heart defects
(62, 77, 79), and neural tube defects (73) with cita-
lopram. Other studies, however, have not sug-
gested an association between uoxetine (62, 64,
69, 7784), sertraline (41, 51, 69, 73, 8084), or cit-
alopram (41, 8082, 84) and major congenital
abnormalities. While the data are very limited,
escitalopram has not been associated with risk of
major malformation (62, 73, 81, 85).
Meta-analyses. When interpreting this data, it is
imperative to consider meta-analyses, because the
power of individual studies may not be adequate
and large numbers of subjects are needed to dem-
onstrate association with congenital malforma-
tions. Five meta-analyses have investigated the risk
for major malformations in association with anti-
depressant use during pregnancy. Four of these
studies found no statistically signicant increased
risk of major malformations in the rst trimester
of pregnancy (31, 8688). The fth meta-analysis
found an increased risk of cardiac malformations
in infants exposed to paroxetine in the rst
trimester (71).
In summary, paroxetine and other SSRIs have
not consistently been demonstrated to be associ-
ated with particular birth defects. Paroxetine use
during early pregnancy has been the most contro-
versial, as it has been associated with an increased
risk of overall major malformations, particularly
atrial and ventricular septal defects in several
studies (51, 60, 66, 69, 72), but assessments of
large databases have not supported this nding
(65, 74).
Serotoninnorepinephrine reuptake inhibitors (SNRIs),
norepinephrine reuptake inhibitors (NRI), and other
antidepressants. Compared with the SSRIs, there
are fewer reports on the reproductive safety pro-
les of other antidepressants. While the available
evidence is extremely limited, studies examining
venlafaxine, duloxetine, nefazodone, and mirtaza-
pine do not suggest an increased risk of congenital
malformations (32, 39, 81, 89, 90). An increased
risk of left outow tract heart defects has been
inconsistently demonstrated in association with
bupropion. Overall, the limited studies have shown
reassuring, but not denitive data regarding the
reproductive safety of venlafaxine, trazodone,
mirtazapine, and bupropion.
Bupropion. Bupropion has ecacy for smoking
cessation, and tobacco use is associated with birth
complications. Understanding the safety of bupro-
pion in pregnancy is important as it may be a
potential treatment option for women with depres-
sion and nicotine dependence. In 1997, Glaxo-
SmithKline established a Bupropion Pregnancy
Registry and by March 2008, 3.6% and 1.3% of
infants exposed to bupropion were reported to
have congenital abnormalities and congenital heart
defects, respectively. Congenital heart defects were
found in both retrospective and prospective
reports (91), raising concern that rst-trimester bu-
propion exposure might increase the risk of con-
genital heart defects. The rst prospective study on
bupropion use in pregnancy did not demonstrate
an increased risk of major malformation with bu-
propion exposure; however, the sample was small
with only enough power to detect a ve-fold
increased risk (37). A retrospective casecontrol
study that examined the risk of bupropion expo-
sure 1 month prior to conception until 3 months
after conception found that exposed infants were
more likely to have left outow tract heart defects,
but not other defects (OR = 2.6; 95% CI 1.25.7)
(92). Another casecontrol study did not nd an
increased risk of congenital malformations when
they compared rst-trimester bupropion exposure
to (1) rst-trimester exposure to other antidepres-
sants and (2) bupropion exposure outside the rst
trimester (93). Other studies (37) (92) are reassur-
ing as they do not demonstrate an increased risk of
congenital malformations following exposure to
bupropion during pregnancy. Even with the possi-
ble increased risk of congenital heart defects (91,
92), the absolute risk of a congenital heart defect
remains low at 2.1/1000 births in exposed infants
(92) when compared with the estimated prevalence
of 0.82/1000 births in the general population (49).
SNRIs and other non-SSRI antidepressants. There
are a very limited number of studies examining
101
Antidepressant use in pregnancy
SNRIs (such as venlafaxine and duloxetine).
A large prospective cohort study that included the
SNRI venlafaxine and other non-SSRI antidepres-
sants mirtazapine, nefazadone, bupropion, and
trazodone found that the prevalence of cardiac
malformations was well below the prevalence rate
at 0.6% in the antidepressants as a group (81).
Data obtained from the Swedish Medical Birth
Registry also do not suggest an increased risk of
congenital malformations after exposure to SNRI/
NRIs. However, because of small sample size, it
only would have detected a marked teratogenic
eect (89).
Mirtazapine. A prospective, comparative study
that examined whether exposure to mirtazapine
during organogenesis increased the rate of major
malformations found that mirtazapine was
not associated with an increased risk of major mal-
formation (39).
Trazodone/nefazodone/vilazodone. Data on trazo-
done and nefazodone are limited with the excep-
tion of a multicenter prospective controlled study,
which found that trazodone and nefazadone did
not increase the rates of major malformation
above the baseline (90). A literature review did not
reveal any data on vilazodone.
Summary. Recently, the safety of SSRIs in preg-
nancy has been challenged by data from large pop-
ulation-based studies. Reports are dicult to
interpret because of the lack of consistent ndings
and the inability to assess cause and eect from
association studies. Most reports do not take into
account the underlying psychiatric condition and
variables that may not be controlled for that would
dier between groups being compared. While some
individual studies suggest associations between
SSRIs and some specic major malformations, the
ndings are inconsistently observed; therefore, the
absolute risks appear small. While the limited avail-
able data suggest a possible association between bu-
propion and congenital heart defects (91, 92), the
absolute risk appears low. Although the very lim-
ited studies examining SNRIs have been reassuring,
further investigation is needed before the risks
associated with their use may be fully understood.
Later pregnancy controversies
Postnatal adaptation syndrome (PNAS). All SSRIs
cross the placenta, carrying the potential to
increase serotonin concentrations in the developing
fetus. Increased serotonin concentrations may
impact fetal cardiovascular, respiratory, and neu-
rological development, which all involve serotonin.
Premature neonates may be more susceptible to
PNAS given their immature lung and central ner-
vous systems.
Since PNAS was rst noted in 1973 (94), expo-
sure to antidepressants during late pregnancy has
been associated with infant irritability, abnormal
crying, tremor, lethargy, hypoactivity, decreased
feeding, tachypnea, and respiratory distress (95
99). As data emerge, this cluster of symptoms is
increasingly referred to as PNAS. It has also been
referred to as neonatal behavioural syndrome or
poor neonatal adaptation syndrome with studies
focusing on a collection of symptoms including
irritability, tachypnea, hypothermia, and hypogly-
cemia (96, 100102). Clinical signs and symptoms
usually develop from birth to days after delivery
and are time limited. While they usually resolve
within days or weeks of delivery (95), symptoms
have been reported to last as long as 6 weeks
(103). Severity and length are impacted by multiple
factors including dose, timing and duration of
exposure, and SSRI pharmacology including half-
life, presence of active metabolites, and maternal
and infant hepatic cytochrome P450 isoenzyme
genotype, among others (104).
As shown in Table 2, Dierent methodologies
have been used to examine the relationship
between PNAS and antidepressants. Databases of
adverse drug event reports have the advantage of
being able to detect eects too rare to be detected
in clinical trials. Similar to case reports, however,
databases of adverse drug reaction reports are lim-
ited by lack of incidence rate determination, und-
erreporting and reporter bias (95). The
identication of PNAS symptoms related to anti-
depressant exposure is also complicated by the
challenge of determining whether the symptoms
are due to maternal illness or medication exposure
(105). Important considerations in evaluating the
data include the following: i) whether systematic
assessments of infant were conducted, ii) whether
appropriate control groups were included in the
study, iii) whether raters of the infants were
blinded to antidepressant exposure, iv) whether
maternal diagnosis or symptoms were taken into
consideration, and v) whether other confounding
variables may contribute to neonatal symptoms.
Numerous mechanisms have been proposed for
PNAS including serotonin toxicity (104), oversti-
mulation of serotonin (101), and infant genotype
(106). Many PNAS symptoms overlap those found
in adult SSRI discontinuation syndrome, choliner-
gic overdrive, and serotonin syndrome. Several
case reports note infant toxicity after in utero
exposure to paroxetine (106) and uoxetine (97,
102
Byatt et al.
Table 2. Maternal use of antidepressants and the risk of postnatal adaptation syndrome (PNAS)
Study Design Antidepressant studied N Findings
Chambers et al. (1996) (35) Prospective, controlled Fluoxetine 73 infants with
third-trimester
antidepressant
exposure vs. 101
infants with first- and
second-trimester
antidepressant
exposure
PNAS associated with late
exposure only compared
with early exposure
(aRR = 8.7)
Late pregnancy exposure
associated with NICU
admission (RR = 2.6)
Oberlander, et al. (2004) (104) Prospective, controlled
follow-up
Paroxetine, fluoxetine, sertraline
or citalopram alone or in
combination with clonazepam
28 infants with late
pregnancy SSRI
exposure vs. 18
infants with SSRI
and clonazepam
exposure vs. 23
non-exposed infants
PNAS symptoms in 39%
of infants with SSRI and
clonazepam exposure vs.
25% exposed to SSRI and
9% of controls
(unadjusted RR = 3.5)
Costei, et al. (2002) (102) Prospective, controlled Paroxetine 55 with late exposure
to paroxetine, 27
infants with early
exposure, and 27
with no exposure
Third-trimester paroxetine
exposure was associated
with PNAs symptoms in
22% of exposed compared
with 11% controls
(unadjusted RR = 4.0)
Zeskind and Stephens (2004) (156) Prospective, controlled Fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine
17 SSRI-exposed vs.
17 non-exposed
infants
SSRI-exposed infants
exhibited a wide range
of neurobehavioural
outcomes (p>0.05)
Laine, et al. (2003) (101) Prospective, controlled Citalopram, fluoxetine 20 mothers and infants
with late pregnancy
antidepressant
exposure vs. 20
mothers and infants
without exposure
Exposed infants had lower
Apgar scores and a four-fold
increase in serotonergic
symptom score in first 4
days of life (P = 0.008)
As serotonergic symptoms
increased, cord blood
5-H1AA levels decreased
(P = 0.007)
Galbally, et al. (2009) (118) Prospective, controlled Fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, mianserin,
mirtazapine, escitalopram
27 women exposed
to medication vs
matched controls
Third-trimester antidepressant
exposure associated with
increased risk of PNAS,
increased rate of admission
to the special care nursery
and higher rates of jaundice
no difference between
specific antidepressants
Maschi, et al. (2008) (120) Prospective, controlled Fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine
200 neonates with
antidepressant
exposure vs. 1200
controls
No difference between
antidepressant exposure
and PNAS
Levinson-Castiel, et al. (2006) (116) Matched control SSRIs, venlafaxine 120 infants; 60 with
prolonged
antidepressant
exposure vs. 60
controls
PNAS occurred in 30% of
infants with SSRI exposure
vs. none in non-exposed
group
13% met criteria for severe
neonatal doseresponse
effect.
Cohen, et al. (115) Retrospective, cohort study Fluoxetine 64 motherinfant
pairs
Increased risk of special
care nursery admissions
after exposure to fluoxetine
in late trimester when
compared with early trimester
exposure (18.9% vs. 9.1%)
103
Antidepressant use in pregnancy
Table 2. (Continued)
Study Design Antidepressant studied N Findings
Rampono, et al. (2009) (157) Prospective, observational Fluoxetine, citalopram, paroxetine,
sertraline, escitalopram,
fluvoxamine, venlafaxine
56 motherinfant
pairs; 27 exposed
to SSRI vs. 11 to
venlafaxine vs.
18 controls
Neonatal abstinence scores
were higher (p < 0.05) on day
1 in exposed infants compared
with controls
Exposed infants had higher
serotonin scores and Brazelton
Neonatal Behavioral Assessment
Scale (BNBAS) scores for motor and
autonomic clusters, habituation,
and social interactive (P<0.05)
Suri, et al. (2007) (44) Prospective, naturalistic
study
Sertraline, fluoxetine, paroxetine,
bupropion, nortriptyline
90 women comprised
of 49 with MDD
taking antidepressant
vs. 22 with MDD
either not taking
antidepressant or
limited exposure
vs. 19 healthy controls
Infants of women with MDD
and exposed to
antidepressants had
greater rates of admission
to the special care nursery
then women with MDD who
were not treated with
antidepressants and
healthy women
(21%, 9%, and 0%,
respectively)
Suri et al. (2011) (158) Prospective, naturalistic
study
Sertraline, fluoxetine, paroxetine,
bupropion, nortriptyline
64 women; 33 with MDD
and antidepressants vs.
16 with a history of
MDD who were either
not treated with
antidepressant or had
limited exposure vs. 15
healthy controls
No differences between
groups regarding Apgar
scores, special nursery
admissions or on the
BNBAS
Hendrick et al. (2003) (55) Prospective case series Fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, venlafaxine
131 infants exposed
to SSRIs
10.5% of infants
exhibited PNAS
Sit et al. (2011) (159) Prospective case series Fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, nortriptyline
21 motherinfant pairs
with antidepressant
exposure
No association between
cord-to-maternal
concentration ratios
and perinatal events
Ferreira et al. (2007) (117) Retrospective chart review Fluoxetine, citalopram, paroxetine,
sertraline
66 neonates with SSRI
exposure vs. 90 without
exposure
Behavioural signs in 77.6%
of SSRI-exposed neonates
compared with 41%
non-exposed
Tremors, agitation,
spasms, hypotonia,
irritability, and
sleep disturbances were
reported in 63.2% of
exposed infants and
respiratory effects in 40.8%
Kallen (2004) (40) Prospective Swedish Birth
Registry
Paroxetine, fluoxetine, sertraline,
citalopram
555 infants with late
SSRI exposure vs. 728
controls
Increased risk for respiratory
distress (OR = 2.21),
hypoglycemia (OR = 1.62),
convulsions (OR = 1.9)
low Apgar score (OR = 2.33)
with maternal use of
antidepressants
Effects were not specific to any SSRI
Warburton et al. (2010) (52) Retrospective register study Fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine
Infants exposed to
antidepressants in
the last 14 days of
pregnancy vs. infants
exposed earlier in
pregnancy
No difference in neonatal
symptoms among women
exposed to antidepressant
in the last 14 days of
pregnancy when compared
with those who were not
Sanz et al. (2005) (100) WHO database case series
review
Paroxetine, fluoxetine, sertraline,
citalopram
93 infants with late
SSRI exposure
69% of cases with neonatal
behavioural symptoms
were associated with
paroxetine (n = 64), 14 with
fluoxetine, 9 with sertraline,
and 7 with citalopram
104
Byatt et al.
107109). Several of those reports note elevated
infant serum levels, supporting toxicity as the
cause (97, 107, 108, 110). Other reports document
discontinuation symptoms following in utero anti-
depressant exposure (110), specically with sertra-
line (111), paroxetine (98100, 112, 113), and
venlafaxine (114).
In 1996, Chambers et al. (35) published the rst
cohort study examining PNAS and found that late
pregnancy exposure to uoxetine was associated
with an increased special care nursery admission
rate when compared with exposure earlier in preg-
nancy. A similar study that retrospectively com-
pared exposure with uoxetine early and late in
pregnancy found an increased risk of special care
nursery admissions after late pregnancy exposure
to uoxetine (115).
Another study that prospectively compared neo-
natal complications in infants found that third-tri-
mester paroxetine exposure had a high rate of
neonatal complications compared with controls
(22% vs. 5.5%, respectively) (102). Using the same
denition as Chambers et al., Oberlander et al.
found that thirty per cent of infants exposed to
SSRI alone or in combination with clonazepam
showed symptoms of poor neonatal adaptation,
25% and 39%, respectively (104). Another hospi-
tal-based cohort study found PNAS in 30% of
infants exposed to SSRIs (116). This rate of 30% is
higher than found by Costei et al. (22%) (102) and
Hendrick et al. (10.5%) (55), but very similar to
that found by Chambers et al. (31.5%) (35) and
Oberlander et al. (30%) (104). The data collected
by Costei may not represent the true rate as data
were collected later after delivery and cases may
have been missed. A retrospective chart review
study reported a higher rate of behavioural signs
(77.6%) in SSRI-exposed infants compared with
41% of the non-exposed (117).
In a prospective comparison study, using cord
blood levels of 5-hydroxyindoleacetic acid
(5-H1AA) and a modied Serotonin Syndrome
Scale, infants exposed to citalopram or uoxetine
in late pregnancy had lower Apgar scores and
more serotonergic symptoms than infants not
exposed (101). Other prospective studies have also
found that third-trimester exposure to antidepres-
sants is associated with PNAS symptoms (118) and
greater special care nursery admission rates (119).
While it lacked statistical signicance, a prospec-
tive controlled cohort noted a trend for increased
risk of PNAS symptoms in infants exposed to an-
tidepressants in the second and third trimester.
Mild symptoms may have been underreported
because of recall bias during data collection inter-
views with mothers (120).
SSRIs and SNRIs may both cause PNAS symp-
toms. A prospective observational study compar-
ing placental transfer and neonatal eects of SSRI
and SNRI (venlafaxine) exposure in pregnancy to
non-exposed matched controls found that both
SSRIs and venlafaxine transferred across the pla-
centa and were associated with PNAS symptoms
(121). An analysis of the World Health Organiza-
tion adverse events database reported 94 cases of
PNAS after in utero exposure to SSRIs and venla-
faxine. PNAS symptoms in infants were noted
after maternal uoxetine, citalopram, or paroxe-
tine exposure (100). However, the total number of
women using these medications was not reported,
so the incidence of neonatal symptoms was not
possible to ascertain.
In 2004, the FDA suggested (122) that providers
consider tapering antidepressants in the third tri-
mester. While discontinuation is intuitive if antide-
pressants are associated with neonatal symptoms,
this recommendation did not receive formal clini-
cal study prior to its release. Since this recommen-
dation, Warburton (2010) and colleagues assessed
babies of mothers who were not exposed to antide-
pressants in the last 14 days of pregnancy com-
pared with those who were not exposed and
factored in maternal psychiatric symptoms and
other possible cofounding variables into their anal-
ysis. After accounting for confounding variables,
there was no dierence in PNAS among women
exposed to antidepressant in the last 14 days of
pregnancy when compared with those who were
not. However, the total number of women using
these medications was not reported, so the inci-
dence of neonatal symptoms was not possible to
ascertain (52). This study was also limited by the
inclusion of subjects on uoxetine, which may have
been in the subjects system given its long half-life
of 2 weeks.
PNAS appears to be multifactorial in nature,
with late pregnancy antidepressant use accounting,
in part, for neonatal symptoms. It is important to
consider that maternal anxiety has also been asso-
ciated with changes in infant behaviour and self-
regulation (123). Exposure to antidepressants in
pregnancy, regardless of timing, has been associ-
ated with PNAS. While the available evidence is
conicting, the overall data suggest that PNAS can
occur in neonates exposed to SSRIs and SNRIs,
yet have most often been reported after exposure to
paroxetine, uoxetine, and venlafaxine (84, 120).
Persistent pulmonary hypertension of the newborn
(PPHN). Pulmonary hypertension is a normal
and required state for the fetus in utero because
the placenta, as opposed to the lung, is responsible
105
Antidepressant use in pregnancy
for gas exchange. At birth, the lung replaces the
placenta as the primary site of gas exchange, and
there is a rapid drop in pulmonary vascular resis-
tance and a resultant increase in pulmonary blood
ow. Multiple chemical pathways are responsible
for this cardiopulmonary transition (124).
PPHN can result whenever cardiopulmonary
transition does not occur. PPHN is a rare disorder
that occurs in approximately 12 per 1000 births
(125). Reduced length of gestation and premature
birth has been associated with increased risk of
PPHN (121). Infants with PPHN present within
twelve hours of birth with cyanosis and mild respi-
ratory distress and can develop severe respiratory
failure requiring intubation and mechanical venti-
lation (126). Even with therapy, PPHN can be fatal
in approximately 1020% of cases (127), depend-
ing upon the etiology (128). Approximately 25%
of infants with moderate-to-severe PPHN will
demonstrate signicant neurodevelopmental
impairment at 1224 months (129).
Respiratory insuciency is one symptom of
PNAS and may represent the presence of a mild
form of PPHN and not PNAS, per se (130, 131). It
is not certain that SSRIs are associated with the
development of PPHN, but there is some evidence
that longer periods of in utero SSRI exposure may
be associated with increasing risk, and severity, of
neonatal respiratory complications (132). How
SSRIs may aect neonatal respiratory complica-
tions is under investigation. The accumulation of
SSRIs in the lungs may result in high circulating
levels of serotonin which, through its vasoconstric-
tive eects, increases pulmonary vascular
resistance and may cause proliferation of smooth
muscle cells in the fetal lung (133), but not all stud-
ies have found elevated serotonin levels (134).
Another possible mechanism may involve the
inhibitory eect of SSRIs on nitric oxide synthesis,
an essential vasodilator that regulates vascular
tone (135), but other studies do not support that
hypothesis (134). Importantly, through unidenti-
ed mechanisms, depression and the use of SSRIS
during pregnancy have been associated with a
reduced length of gestation and increased risk of
premature birth (84) that itself is associated with
an increased risk of PPHN. Additionally, genetic
factors contribute to the risk of developing PPHN
(128). Functional polymorphisms in the serotonin
transporter promoter region may modulate the
risk of PPHN in both adults (136) and infants with
in utero exposure to SSRIs (128, 137).
In 1996, Chambers et al. (35) rst reported that
late in utero exposure to uoxetine was associated
with an increased risk of PPHN when compared
with rst-trimester exposure (2.7% vs. 0%), espe-
cially when compared with the prevalence found in
the general population (0.070.10%). A subse-
quent casecontrol study found that SSRI use after
the 20th week of pregnancy was signicantly asso-
ciated with PPHN (adjusted odds ratio
(AOR) = 6.1), but use of SSRIs or other antide-
pressants prior to 20-week gestation was not (138).
A retrospective analysis of data from the Swedish
Medical Birth Register also found an association
between PPHN and maternal SSRI use during
early pregnancy [relative risk (RR) = 2.4] and late
pregnancy (RR = 3.6); though, the absolute risk
was small (139). This groups most recent analysis
that also included tricyclics, monoamine oxidase
inhibitors, SNRIs, and other antidepressants dem-
onstrated an increased RR of PPHN for antide-
pressant exposure in early pregnancy (RR = 2.30),
for later exposure (RR = 2.56), and for both early
and later exposure (RR = 3.44) (41).
Most of the aforementioned studies (41, 140,
141) restricted their analyses to infants delivered
after 34 completed weeks of gestation because
shorter gestation is associated with an increased
risk of PPHN. A recent population-based cohort
study used national health register data demon-
strated an increased risk of PPHN associated with
SSRI prescription after 20-week gestation and
before 8-week gestation (142). The risk of PPHN
associated with exposure to individual SSRIs was
of a similar magnitude, suggesting a class eect.
This study restricted their analyses to infants deliv-
ered after 33-week gestation and was the largest
completed study of the relationship between in ute-
ro SSRI exposure and PPHN.
As shown in Table 3, other studies have sug-
gested no association between antidepressant use
during pregnancy and PPHN. Two studies (143,
144) compared the prevalence of PPHN among
infants whose mothers were exposed to antidepres-
sants in the third trimester of pregnancy compared
with infants not exposed and did not nd any dif-
ference. The Wichman et al. study (144) is limited
by a lack of delineation between women treated in
late pregnancy and during the rst trimester.
Because late trimester use has been identied as a
possible risk factor for PPHN, the inclusion of
women who were treated in the rst trimester may
have contributed to the negative nding. Addition-
ally, the small size of both of these studies makes it
likely that a possible association would have been
missed. Most recently, a casecontrolled study of
11 923 births, including 20 cases of PPHN, demon-
strated an increased risk of PPHN with cesarean
delivery prior to the onset of labor (OR = 4.9) but
not with SSRI use during the second half of preg-
nancy (145).
106
Byatt et al.
In 2006, based on data from the Chambers
et al. study, the FDA published a Public Health
Advisory regarding an increased risk of PPHN
associated with the use of SSRIs after the 20th week
of pregnancy. This advisory resulted in changes to
drug labeling to include a risk of PPHN with the
use of antidepressants during late pregnancy. In
December 2011, the FDA released a Drug Safety
Table 3. Maternal use of antidepressants and the risk of persistent pulmonary hypertension of the newborn (PPHN)
Study Design Antidepressant studied N Findings
Chambers CD et al. (1996) (35) Prospective observational
cohort
Fluoxetine 228 exposed women vs.
254 controls
Late in utero exposure
associated with increased
risk of PPHN as compared
with first-trimester
exposure (2.7% vs. 0%)
Chambers et al. (2006) (138) Multicenter case control Citalopram, fluoxetine,
paroxetine, sertraline,
TCA, bupropion, venlafaxine,
trazodone
377 women whose infants
had PPHN vs. 836 matched
controls
After the 20th week of
pregnancy, antidepressant
use was associated with
PPHN (AOR = 6.1), but use
of antidepressants prior to
20-week gestation was not
Kallen and Olausson (2008) (139) Population-based retrospective
cohort
Citalopram, sertraline,
fluoxetine, mirtazapine,
paroxetine
504 infants with PPHN of
831 324 births; 11 of which
had antidepressant exposure
Early pregnancy SSRI use
(RR = 2.4) and late
pregnancy use (after 34 weeks)
(RR = 3.6) associated
with PPHN
Andrade et al. (2009) (143) Retrospective review SSRI, TCA, miscellaneous 1104 exposed infants vs.
1104 matched controls
Prevalence of PPHN among
infants with any
third-trimester antidepressant
exposure = 1.81 per 1000
infants
No association among those
infants exposed to SSRIs in
third trimester (2.14 per 1000)
vs. unexposed infants
(2.72 per 1000)
Wichman et al. (2009) (144) Retrospective review Citalopram, venlafaxine,
escitalopram, paroxetine,
fluoxetine, sertraline,
more than 1 SSRI
24 406 women with no SSRI
use vs. 808 women with SSRI
exposure
16 newborns diagnosed with
PPHN, but none of whom
had exposure to SSRI
(0.07% vs. 0.0% p>0.99)
Wilson, et al. (2010) (160) Prospective database case
control
SSRI 11 923 births Use of SSRIs in the second
half of pregnancy was
identified in 5% of the
controls but none of the
cases (OR = 0)
Reis and Kallen (2010) (41) Population-based, prospective
cohort
TCA, SSRIs, MAOIs,
SNRIs (other antidepressant)
12 914 women with early
exposure vs. 5987 with later
exposure vs. 4080 with both
early and late exposure vs.
1 062 190 women without
exposure
Increased relative risk of
PPHN for antidepressant
exposure in early pregnancy
(RR = 2.30), for later exposure
(RR = 2.56) and for both early
and later exposure (RR = 3.44)
Kieler et al. (2011) (142) Population-based, prospective
cohort; national health
registers
SSRIs, other antidepressant 28 067 women filled a
prescription for SSRI vs. 1 588
140 women without
Increased risk of PPHN for SSRI
prescription in late pregnancy
(AOR = 2.1; 3 per 1000 liveborn
infants compared with the
background incidence of 1.2
per 1000) and before 8-week
gestation (AOR = 1.4)
Women without SSRI use and
with prior hospitalization for
a psychiatric disorder were
at increased risk of having
infant with PPHN (AOR = 1.3)
Women with a prior
hospitalization for a psychiatric
disorder and late gestation
SSRI prescription were at
greater risk (AOR = 3.1)
TCA, tricyclic; AOR, adjusted odds ratio; SSRI, selective serotonin reuptake inhibitor; RR, relative risk; OR, odds ratio; MAOI, monoamine oxidase inhibitor; SNRI, serotonin
norepinephrine reuptake inhibitor.
107
Antidepressant use in pregnancy
Communication (146) which stated that there is
insucient evidence that antidepressant exposure
during pregnancy causes PPHN. This recent state-
ment is an accurate reection of the current litera-
ture that has reported either a small association
between PPHN and maternal antidepressant use
during pregnancy or no association.
Although studies have also reported an associa-
tion between mode of delivery and PPHN (140,
141, 147149), several were small and lacked con-
trol groups. Studies that have investigated the role
of cesarean delivery and the risk of PPHN are lim-
ited because it is not clear whether the risk of
PPHN is increased secondary to the mode of deliv-
ery or intrauterine fetal distress.
Clinical implications and discussion
The treatment of women during pregnancy is com-
plex, and clinical decisions should be based on the
risks, benets, and alternatives to psychopharma-
cological treatment. All risks need to be consid-
ered, including those of untreated maternal
psychiatric illness and the known and unknown
potential risks of psychotropic medication. To pro-
vide optimal clinical care to women and their
developing child, it is imperative to consider risks
of treatment in the context of illness severity, con-
sequences of no treatment and under-treatment
and individual treatment preferences.
Interpreting a conflicting evidence base
Clinicians face the challenge of interpreting an
expanding and sometimes controversial evidence
base that is summarized in Table 4. Comparing the
available studies is dicult because of methodo-
logical weaknesses and dierences in study design,
outcome measures, and exposure (72). This under-
lines the inherent and varying diculties conduct-
ing epidemiological studies of this nature. In such
a complicated area of study, no individual study is
denitive. Statistical signicance does not necessar-
ily translate into a valuable clinical or epidemio-
logical nding. For example, an OR of 1.2
compared with 1.7 may be statistically signicant,
yet not important from an epidemiological or clini-
cal perspective.
The current evidence for malformations is lim-
ited because of inconsistent ndings and limited
methodology of the published studies (150). Few
studies have controlled for maternal illness and
therefore do not take into account whether repro-
ductive outcomes are due to maternal illness or
antidepressant exposure. Many studies also group
malformation types together to detect a dierence
in risk. For example, some studies have grouped
together all septal defects or congenital heart dis-
ease, encompassing a variety of birth defects and
a range of severity. As a result, it is not known
whether or not the reported increased risk for car-
diac defects is for minor, moderate, or severe
forms, which each carries varying medical risks to
the infant. Larger sample sizes are required to
improve the identication of particular terato-
genic patterns, so that specic birth defects associ-
ated with antidepressants can be isolated
consistently and reproduced across studies. While
the large studies that do not show evidence of ter-
atogenicity are reassuring, the literature also con-
tains a number of studies that suggest concerns.
The current evidence base for PNAS also has
limitations in that it does not: i) systematically
assess infants, ii) use appropriate control groups,
iii) use blind raters of the neonates, and iv) take
into account maternal diagnosis or symptoms or
other confounding variables. Despite these limita-
tions, these study ndings vary less than those of
the teratogenicity or PPHN studies and therefore
more strongly suggest an association between
antidepressant use in pregnancy and PNAS.
Similarly, the PPHN literature is limited by
small and/or uncontrolled studies. There are other
reported risk factors, including race, method of
delivery, obesity, asthma, and diabetes (141) that
many studies do not take into account. While the
PPHN literature is inconclusive, the available evi-
dence reports either a small association between
PPHN and maternal antidepressant use during
pregnancy or no association.
Clinical importance of results
Given the inconclusive evidence, it is vital to have
a careful discussion tailored to each patient that
Table 4. Results summary
Teratogenicity
While individual studies suggest associations between selective serotonin
reuptake inhibitors (SSRIs) and some specific major malformations, the findings are
inconsistent; therefore, the absolute risks appear small
SSRIs remain one of the best-studied classes of medications used in pregnancy
Less data are available for serotoninnorepinephrine reuptake inhibitors,
mirtazapine, nefazadone, trazodone, and vilazodone
While an increased risk of left outflowtract heart defects has been inconsistently
demonstrated in association with bupropion, the absolute risk of a congenital
heart defect remains low
Postnatal Adaptation Syndrome (PNAS)
PNAS has been reported to occur in up to 30% of neonates exposed to
antidepressants in late pregnancy and has most often been reported after
exposure to paroxetine, fluoxetine, and venlafaxine
Persistent pulmonary hypertension (PPHN)
The available evidence reports either a small association between PPHN and
maternal antidepressant use during pregnancy or no association
108
Byatt et al.
incorporates the evidence to date on the risks and
benets of antidepressant use in pregnancy. We
recommend educating women about the risks of
exposure to antidepressants throughout preg-
nancy, which should include the US Food and
Drug Administration categorization. Unfortu-
nately, the US FDA antidepressant risk categori-
zation is limited and does not adequately inform
the decision-making process. The limitations of
this system include lack of a requirement for sys-
tematic human data, lack of clear dierentiation
between pregnancy categories, lack of incorpora-
tion of risks of the maternal illness, and potential
benets of the medication. Newer drugs are usually
much more poorly studied in human pregnancy, as
little human data are required before a drug comes
to market. Therefore, healthcare providers and
patients who rely on the US FDA categories may
receive an oversimplied and often inaccurate
assessment of the knowledge base regarding a spe-
cic medication in human pregnancy. Despite
numerous studies, information regarding possible
teratogenicity of antidepressants has not been
updated since an FDA public health advisory in
2005 was released concerning paroxetine and the
possible associated risk of increased cardiac mal-
formations. The FDA is currently working on risk
categorization that will include more meaningful
and useful information to clinicians (151). How-
ever, with the current limitations of the FDA cate-
gories, it is crucial to incorporate the current
research literature into the decision-making and
informed consent process.
Translating results into clinical practice
As summarized in Table 5, we recommend weigh-
ing the risks and benets of treatment with antide-
pressants during pregnancy while carefully
considering the risk of untreated illness. What
poses a greater risk: exposure to untreated illness
or the antidepressant? If the benets of treatment
outweigh the risks, then the medication should be
prescribed based on an individualized risk/benet
assessment and discussion. Past medication trials
and previous success with symptom remission and
womens preference should guide treatment deci-
sions. To avoid exposure to more than one antide-
pressant or under-treated illness, one should
choose a medication with known ecacy for indi-
vidual women. The goal of treatment should be to
maximize non-medication evidence-based treat-
ments, such as specic forms of psychotherapy,
and remission of the maternal symptoms, with
judicious use of pharmacotherapy when indicated.
Unless there is a reason to use another class of
antidepressant, SSRIs are generally considered
rst-line in pregnancy. SSRIs are well character-
ized, and even though risks have been reported,
the preponderance of data is reassuring. It makes
less sense to preferentially use a medication with
less available human data. When selecting an anti-
depressant for a pregnant woman who has not had
past medication trials, many providers prefer uo-
xetine because of the amount of data available and
lack of long-term developmental sequela in chil-
dren (152). A current response or history of a posi-
tive response to medication should help determine
which medication to continue or initiate. The bene-
ts of discontinuing an eective medication often
do not outweigh the risks of relapse or of exposing
mother and fetus to a second antidepressant medi-
cation during pregnancy.
To maximize the treatment of depression and
minimize risks of maternal and fetal exposure to
antidepressants and untreated depression, women
should receive the minimal eective dose of an
antidepressant. The increased dose requirements
across gestation (153, 154) should be considered
and weighed against the risks when determining
the minimal eective dose. It is also important to
avoid under-treatment as residual depression and
medication exposure represent dual exposures for
the fetus.
Polypharmacy with multiple psychotropic medi-
cations should also be avoided, unless there is a
clear indication for the use of multiple pharmaco-
therapies. Some studies suggest that the use of
SSRIs in combination with benzodiazepines may
increase the risk of congenital heart malformations
(77) and PNAS (104). Another study did not dem-
onstrate an increased risk of congenital malforma-
tions after exposure to multiple antidepressants
(82). It is important to consider that approximately
Table 5. Clinical points of emphasis
Unless there is a reason to use another class of antidepressant, selective serotonin
reuptake inhibitors are generally considered first-line in pregnancy
A current response or history of a positive response to medication should help
determine which medication to continue or initiate
Strongly consider using an antidepressant that the woman has responded to in the
past, to avoid unnecessary exposures during pregnancy
Maximize non-medication evidence-based treatments
To avoid exposure to both illness and medication, use lowest possible dose while
also avoiding under-treatment
Avoid polypharmacy with multiple psychotropic medications, unless there is a
clear indication for the use of multiple pharmacotherapies
Tapering antidepressants in the third trimester has not been shown the decrease
in the incidence of postnatal adaptation syndrome or improve infant outcomes,
and it carries the risk of precipitating relapse of depression
Exposure to untreated illness can be mitigated by preconception counseling,
psychoeducation regarding risks and benefits of treatment and no treatment,
close clinical monitoring, and a careful treatment plan tailored to the each
woman
109
Antidepressant use in pregnancy
50% of pregnancies are unplanned and many
women enter the rst trimester on several medica-
tions. For example, a positive response to taking
two antidepressants concurrently may indicate that
the risk of relapse with discontinuation of either
outweighs the risk of polypharmacy.
Despite the FDAs suggestion in 2004 (122) that
providers consider tapering antidepressants in the
third trimester, there is no evidence suggesting this
approach reduces the incidence of PNAS or
improves infant outcomes. It also carries the risk
of precipitating relapse or postpartum depression,
particularly in high-risk individuals (52, 95).
Individualized treatment recommendations or
plans should aim to diminish both the risk of
exposure to untreated illness and the antidepres-
sant. Exposure to untreated illness can be
mitigated by preconception counseling, psychoed-
ucation regarding risks and benets of treatment
and no treatment, close clinical monitoring, and a
careful treatment plan tailored to the each woman
(155). The risks associated with antidepressant use
can be mitigated using antidepressants with reas-
suring human data, using the minimal eective
dose, and avoidance of polypharmacy. Outcomes
for mother and child can be optimized by the utili-
zation of multidisciplinary approach that takes
into account risks of treatment and no treatment
and each womans preferences for treatment. This
can be accomplished by a careful discussion, tai-
lored to each patient, which incorporates the evi-
dence to date and considers methodological and
statistical limitations. Past medication trials, previ-
ous success with symptom remission, and womens
preference should guide treatment decisions.
Declaration of interests
The authors declare that they have no conict of interest.
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