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766 • J Clin Pharmacol 2012;52:766-770
BACKGROUND
Many more women than men suffer from depression,
with up to 20% of women of childbearing age diag-
nosed with the condition, most prevalent between
ages 25 and 44 years.1 Approximately 10% to 15% of
these women experience depression during pregnancy
and the postpartum period.2 Therefore, a substantial
number of women are likely to be taking antidepres-
sants when they become pregnant, and deciding
whether to take a medication during pregnancy is a
complex decision. It is known that at least 50% of
pregnancies are unplanned,3 so it is likely that a rela-
tively large number of women will use an antidepres-
sant in pregnancy, especially during the organogenesis
period.
Use of antidepressants during pregnancy has
increased substantially in the past several years, as
reported by a US group from the National Birth Defects
Prevention Study, an ongoing case control study of
risk factors for birth defects covering 10 US states.
Among 6582 mothers included in the study, 298 (4.5%)
reported use of an antidepressant in the 3 months
before and to the end of pregnancy. Use of selective
serotonin reuptake inhibitors (SSRIs) was reported
most often (3.8%), followed by bupropion (0.7%). The
authors noted an increase in reported antidepressant
use, from 2.5% in 1998 to 8.1% in 2005, and the num-
bers have likely increased since these data were ana-
lyzed 5 years ago.4 Although these numbers are from
the United States, it is likely that they reflect prevalence
Escitalopram is a serotonin reuptake inhibitor prescribed for
depression and anxiety. There is a paucity of information
regarding safety in pregnancy. The objective of this study was
to determine whether escitalopram is associated with an
increased risk for major malformations or other adverse out-
comes following use in pregnancy. The authors analyzed preg-
nancy outcomes in women exposed to escitalopram (n = 212)
versus other antidepressants (n = 212) versus nonteratogenic
exposures (n = 212) and compared the outcomes. Among the
escitalopram exposures were 172 (81%) live births, 32 (15%)
spontaneous abortions, 6 (2.8%) therapeutic abortions, 3 still-
births (1.7%), and 3 major malformations (1.7%). The only
significant differences among groups was the rate of low birth
weight (<2500 g) and overall mean birth weight (P = .225).
However, spontaneous abortion rates were higher in both
antidepressant groups (15% and 16%) compared with controls
(8.5%; P = .066). There were lower rates of live births (P = .006),
lower overall birth weight (P < .001), and increased rates of
low birth weight (<2500 g; P = .009) with escitalopram. Spon-
taneous abortion rates were nearly double in both antidepres-
sant groups (15% and 16%) compared with controls (8.5%)
but not significant (P = .066). Escitalopram does not appear
to be associated with an increased risk for major malforma-
tions but appears to increase the risk for low birth weight,
which was correlated with the increase in infants weighing
<2500 g. In addition, the higher rates of spontaneous abortions
in both antidepressant groups confirmed previous findings.
Keywords: Clinical pharmacology; clinical research; drug
information; epidemiology; psychopharmacology
Journal of Clinical Pharmacology, 2012;52:766-770
© 2012 The Author(s)
From the Motherisk Program, The Hospital for Sick Children, Toronto, Ontario,
Canada (Dr Klieger-Grossmann, Dr Weitzner, Dr Koren, Ms Einarson); S wiss
Teratogen Information Service, Lausanne, Switzerland (Dr Panchaud);
Florence Teratogen Information Service, Florence, Italy (Dr Pistelli); and
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON,
Canada (Dr Einarson). Submitted for publication October 25, 2010;
revised version accepted March 2, 2011. Address for correspondence:
Adrienne Einarson, RN, The Motherisk Program, The Hospital for Sick
Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; e-mail:
einarson@sickkids.ca.
DOI: 10.1177/0091270011405524
Pregnancy Outcomes Following
Use of Escitalopram: A Prospective
Comparative Cohort Study
Chagit Klieger-Grossmann, MD, Brenda Weitzner, MD, Alice Panchaud, PhD, Alessandra
Pistelli, MD, Thomas Einarson, PhD, Gideon Koren, MD, and Adrienne Einarson, RN
Pharmacovigilance
PREGNANCY OUTCOMES FOLLOWING USE OF ESCITALOPRAM
PHARMACOVIGILANCE 767
throughout the world. The World Health Organization
(WHO) ranks depression as the leading cause of dis-
ability worldwide and estimates that it affects approxi-
mately 120 million people.5
Escitalopram is an antidepressant belonging to the
SSRI class. It is marketed under the trade names
Lexapro, Cipralex, Seroplex, and Lexamil for treatment
of adults with major depressive disorder, generalized
anxiety disorder, social anxiety disorder, or panic
disorder. Its name derives from the fact that it is the
S-stereoisomer (enantiomer) of the earlier drug citalo-
pram. As well, the pharmacological profiles of the
2 drugs are very similar. It is noted for its high selec-
tivity of serotonin reuptake inhibition and has side
effects typical of the SSRI class.6 There have been
2 studies published on the safety of citalopram use
during pregnancy that reported no serious adverse out-
comes
7,8
; however, a third study reported an increased
risk for cardiovascular birth defects (odds ratio [OR],
2.52; 95% confidence interval [CI], 1.04-6.10). It must
be noted that the latter study was based on data
obtained from a prescription database, where it is not
known whether the woman actually took the drug,
only that she redeemed the prescription.9
Escitalopram has been introduced into the market
relatively recently in Canada, with the first sales on
February 14, 2005.10 At The Motherisk Program, we
have subsequently experienced an increasing number
of calls from women concerning the safety of this drug.
However, there is little information regarding its safety
during pregnancy. There were no adverse outcomes
reported in 21 exposures to escitalopram that were part
of a larger prospective database study from Motherisk
(excluded from this current study).11 Similarly, the
Swedish Medical Birth register reported no adverse
outcomes among 56 exposed infants.8
The objectives of this study were 3-fold: (1) to deter-
mine whether the use of escitalopram during preg-
nancy is associated with an increased risk for major
malformations above the baseline of 1% to 3%; (2) to
determine the rates of spontaneous abortions, thera-
peutic abortions, stillbirths, and mean birth weight
and gestational age at delivery; and (3) to determine
if the neonate required admission to the neonatal
intensive care unit (NICU).
METHODS
This was an observational multicenter cohort study
with 2 comparison groups, using prospectively col-
lected data. The Motherisk Program in Toronto, the
Swiss Teratogen Information Service, and the Flor-
ence Teratogen Information Service provide
evidence-based information regarding the safety and
risks associated with exposures to drugs, chemicals,
radiation, and infectious diseases during pregnancy
and lactation to pregnant and lactating women and
their health care providers in a similar fashion.
Women call us for information regarding the safety
of a drug, usually early in pregnancy. Those request-
ing information regarding the use of escitalopram in
pregnancy were asked if they would be interested in
participating in the study. During the initial telephone
contact, demographics, medical and obstetrical his-
tories, and details of exposure and concurrent expo-
sures were recorded using a standardized questionnaire.
Details regarding the exposure included duration and
timing in pregnancy, as well as dose, frequency, and
indication for drug use.
Approximately 2 to 3 months following expected
date of delivery (EDD), researchers telephoned each
woman, confirmed participation, and obtained oral
consent to participate. It was verified that the caller
was exposed to escitalopram in pregnancy, and subse-
quently the researcher completed the questionnaire.
Information was recorded regarding details of any fur-
ther exposures or changes since the initial call. Out-
comes of interest included outcome of the pregnancy,
defined as spontaneous or therapeutic abortion, still-
birth or live birth, presence or absence of a major
anomaly (structural or functional dysgenesis of fetal
organs and/or skeletal structures), birth weight, gesta-
tional age at delivery, method of delivery, and presence
or absence of neonatal distress in the newborn period
and up to 2 weeks after delivery. Malformations were
counted only if exposure took place in the first trimes-
ter, during organogenesis, and neonatal adverse effects
were only counted if the drug was taken close to deliv-
ery (within 1 week). Following completion of the ques-
tionnaire, the researcher sent a letter to the caller’s
physician if there were a live birth, asking for verifica-
tion of the information obtained from the mother
regarding the baby’s health. Each woman was matched
to a woman who subsequently contacted the teratogen
information services with exposure to (1) other anti-
depressants (SSRIs, venlafaxine, bupropion, trazodone/
nefazodone, and mirtazapine) and (2) nonteratogenic
exposures such as acetaminophen, antibiotics, anti-
histamines, and so on (drugs or other exposures that
have been studied in pregnancy and found not to cause
adverse pregnancy outcomes). They were matched for
maternal age ±2 years, alcohol consumption and smok-
ing, and gestational age at time of call ±2 weeks.
All cases and controls were analyzed to determine
the rates of live births, spontaneous abortions, thera-
peutic abortions, stillbirths, major malformations,
768 • J Clin Pharmacol 2012;52:766-770
KLIEGER-GROSSMANN ET AL
gestational age at birth, and mean birth weights. Out-
comes of interest (categorical) were compared between
the exposed and comparison groups using chi-squared
analysis; continuous data (gestational age at birth and
birth weight) were contrasted using analysis of vari-
ance (ANOVA) with Scheffé post hoc test when
significant.
This study was approved by the Research Ethics
Board at The Hospital for Sick Children in Toronto,
Canada.
RESULTS
There were no differences in any of the maternal
characteristics in the women from the 3 teratogen
information services. The mean ± SD age of the women
was 33.1 ± 2.3 years. The women were matched for
age, smoking, and alcohol use; 10% were smokers,
2% used alcohol, and none used drugs of abuse,
with the mean ± SD age 33.1 ± 2.3 years. All women
were similar in education and socioeconomic (SES)
background, which was higher than average in the
population. All the women in the cohort were taking
escitalopram prior to becoming pregnant. Following
exclusion of spontaneous and therapeutic abortions,
116 of 180 (64%) took the medication throughout
pregnancy until delivery. Most of the remaining
women discontinued in the first trimester (n = 64;
35%), with 2 women discontinuing in the second
trimester.
Among 213 escitalopram infants (including one
pair of twins) born to the 212 mothers who took esci-
talopram, there were 172 (81%) live births, 32 (15%)
spontaneous abortions, 3 (1.8%) stillbirths, 19 (11%)
premature births, and 3 (1.7%) major malformations.
The mean ± SD birth weight of exposed infants was
3198 ± 594 g, and mean gestational age at delivery
was 38.6 weeks. The rate of low birth weight (<2500 g)
was higher in the escitalopram group (9.9%) compared
with those taking other antidepressants (3.6%, P =
.038) and nonteratogens (2.1%, P = .003). There were
no differences in the rates of major malformations or
premature births, stillbirths, or NICU admissions.
However, spontaneous abortion rates were nearly
double in both antidepressant groups (15% and 16%)
compared with controls (8.5%, P = .066) although
statistically nonsignificant (see Table I).
DISCUSSION
To our knowledge, this is the first prospective com-
parative study to examine the safety of escitalopram
use during pregnancy. Exposure to this drug does
not appear to be associated with an increase in the
rate of major malformations above baseline (1%-3%)
in the general population. It should also be noted
that the rates of malformations in 2 of the groups
were within this expected range, but that of the anti-
depressant comparison group (0.6%, based on a single
case) was lower than expected. That finding could
Table I Pregnancy Outcomes
Outcome
Escitalopram
(n = 213a)
Other
Antidepressants
(n = 212)
Nonteratogens
(n = 212) P Valueb
Live births, No. (%) 172 (80.8) 167 (78.8) 191 (90.1) .006c
Major malformation, No. (% of live births) 3 (1.7) 1 (0.6) 2 (1.0) .830
Spontaneous abortion, No. (% of all exposures) 32 (15.0) 34 (16.0) 18 (8.5) .066
Therapeutic abortion, No. (% of all exposures) 6 (2.8) 8 (3.8) 1 (0.5) .222
Stillbirth, No. (% of all births) 3 (1.7) 3 (1.8) 2 (1.0) .984
Premature birth,d No. (% of all live births) 19 (11.0) 10 (6.0) 9 (4.7) .097
Neonatal intensive care unit admission,
No. (% of live births)
14 (8.1) 15 (9.0) 12 (6.3) .989
Low birth weight (<2500 g), No. (%) 17 (9.9) 6 (3.6) 4 (2.1) .009e
Birth weight, mean ± SD 3198 ± 594 3470 ± 540 3458 ± 540 <.001e
Average gestational age at birth, mean ± SD 38.6 ± 2.2 39.1 ± 1.7 38.9 ± 3.6 .225
aIncludes 1 pair of twins.
bChi-squared tests were used for all outcomes except birth weight and gestational age, for which analysis of variance was used, followed by Scheffé test.
cBoth antidepressant groups differed significantly from nonteratogens but not each other.
dLess than 37 weeks’ gestation.
eEscitalopram differs significantly from both other groups; the other 2 groups do not differ.
PREGNANCY OUTCOMES FOLLOWING USE OF ESCITALOPRAM
PHARMACOVIGILANCE 769
well have been due to chance, as the sample size was
modest.
This is the first time in any of our antidepressant
studies that we have documented an increased risk
for low birth weight. Recently, we published a large
prospective comparative study including 11 different
antidepressants (N = 928) where we compared the
rates of low birth weight, preterm delivery, and small
for gestational age among infants who were exposed
and not exposed to antidepressants during pregnancy.
We did not find a significant difference between the
2 groups in birth weights,
12
which confirmed the find-
ings of a previous study.
13
Conversely, other groups
have reported that infants exposed to antidepressants
during pregnancy were significantly smaller.14,15 In
the current study, the lower birth weight is because
2 significant outcomes are related, with more infants
born weighing <2500 g lowering the overall mean birth
weight. If we removed the infants weighing <2500 g
from the analysis, the overall mean birth weight would
be similar to the other 2 groups.
However, the higher (but nonsignificant) number
of spontaneous abortions in both antidepressant
groups is similar to previous findings reported in other
studies. Recently, 2 large studies were published using
different methodologies, one a prospective compara-
tive cohort study and the other a nested case control
study. Both studies reported an increased risk for spon-
taneous abortion with the same odds ratio of 1.6.16,17
Currently, it is not possible to conclude whether this
increase is due to the drug or maternal depression as
these studies did not have a comparison group of
women with untreated depression.
The strengths of this type of study include a per-
sonal interview with the individual, which involved
detailed history taking and included documentation
of actual consumption of the drug during pregnancy.
In addition, details were verified with the child’s phy-
sician. Using prospective comparative groups is con-
sidered level 2 evidence because it allows comparisons
between exposed and nonexposed groups. Because
randomized controlled studies are unlikely to be con-
ducted, this level of evidence is likely to be the highest
level available for physicians caring for pregnant
women with depression.
There were 2 main limitations; we had a relatively
small sample size, which can detect only common
occurrences with an 80% power to detect approxi-
mately a 3.5-fold increased risk for malformations
above a baseline risk of 3%, with an α of 0.05. Typi-
cally, approximately 750 participants in each group
would be required to detect a 2-fold increase in major
malformations, and thousands would be required to
detect rare defects. The lack of a comparison group of
women diagnosed with depression and not taking an
antidepressant makes it difficult to determine whether
other adverse effects were due to the depression or the
drug. At teratogen information services, women call
us only for information regarding a drug, so we were
unable to compile such a group using this model.
Women who have been diagnosed with depression
prior to becoming pregnant should weigh the benefits
and risks carefully with their health care provider
before making a decision about continuing an antide-
pressant during pregnancy. If they do decide to discon-
tinue, the medication should be tapered off slowly to
avoid abrupt discontinuation syndrome.
18
Failure to
treat depression during pregnancy can have adverse
effects on both the mother and child—most notably, it
can be the biggest predictor of postpartum depression.
A woman who is depressed may also make other poor
decisions during her pregnancy, such as drinking alco-
hol, smoking cigarettes, and not attending appoint-
ments with her obstetrician. Finally, a woman who is
depressed may also have difficulty bonding with her
child after birth and may experience other adverse
attachment behaviors.19
Escitalopram does not appear to be associated with
an increased risk for major malformations, but it
appears to increase the risk for low birth weight, which
was correlated with an increase in infants born weigh-
ing <2500 g. In addition, the higher rates of spontane-
ous abortions were similar to previous findings.
Financial disclosure: A Einarson received an educational unre-
stricted grant from Eli Lilly Canada to study the safety of Cymbalta
during pregnancy.
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