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The Newer SSRI Anti-Depressants and Pregnancy
Volume 12, No. 1, April 2005
The prevalence of clinical depression during pregnancy has been estimated to be 7-12% by a recent
meta-analysis. (Bennett et al., 2004). Additionally, in over 3000 obstetric patients screened, 20% had
high scores on Centre for Epidemiological Studies Depression Scale (Bonari et al., 2004).
Therefore, it is not surprising that the Illinois Teratogen Information Service receives many requests for
information regarding pharmacological treatment of depression during pregnancy.
The decision of whether or not to keep a woman on medication during pregnancy is complex. The
many possible adverse effects of untreated depression must be considered. There is a growing body of
literature on an association of obstetrical complications with untreated maternal depression. Women
with untreated depression are also more likely to use alcohol, tobacco, and illicit drugs (Zuckerman et
al., 1989). They may be less able to motivate themselves to attend prenatal appointments or follow
medical advice and have poor nutrition (Bonari et al., 2004). The risk of self injury and suicide is a real
concern. Thus, it is essential to consider each case individually prior to making medicine changes.
While past newsletters (March 1995 and 1999) have discussed the selective serotonin reuptake
inhibitors (SSRIs), Prozac, Zoloft, and Paxil, this newsletter reviews current literature regarding
prenatal exposure to the newer SSRIs, Lexapro and Celexa. NonSSRIs antidepressants,
Wellbutrin and Effexor, are also discussed.
Lexapro (escitalopram)
Escitalopram is an SSRI used in the treatment of depression. Escitalopram, marketed as Lexapro, is the
active isomer of citalopram, thus the two compounds are chemically similar.
Congenital anomalies
Unpublished animal studies examining the effects of prenatal exposure to escitalopram have been
conducted by the manufacturer (Forrest Labs). No increase in congenital anomalies was seen at doses
75X the maximum recommended human dose (MRHD) in rats. Decreased fetal body weights, delays in
ossification, slightly increased offspring mortality, and signs of maternal toxicity were observed at the
higher doses.
To date there have been no human studies examining the effects of prenatal exposure to escitalopram.
There is human data, however, about citalopram use in pregnancy, the results of which should have
some application to escitalopram.
Celexa (citalopram)
Citalopram, marketed as Celexa, is an SSRI used to treat depression. Due to the relatively recent
marketing of this medication (approved by the FDA in 1998), data examining the effects of prenatal
exposure, particularly long term development, is limited.
Congenital anomalies
Unpublished experimental animal studies examining the effects of prenatal exposure to citalopram have
been conducted by the manufacturer (Forrest Labs). Teratogenic effects (cardiovascular and skeletal
defects) were only observed at the highest doses when maternal toxicity symptoms were present.
Lowered birth weights and increased offspring mortality were also present at the higher doses. No
adverse effects were seen with rabbit studies with doses 5X MRHD.
Two small prospective human studies have been performed examining birth outcomes following
prenatal exposure to citalopram. One study prospectively followed a group of 10 women taking
citalopram 20-40mg/day throughout pregnancy and one woman taking citalopram starting in the second
trimester (Heikkinen et al., 2002). These women were being treated for either depression or panic
disorders. There were no major malformations present and no differences in the Apgar scores or
birthweight compared to a control group.
Additionally, a larger prospective study from a drug recording program of the Swedish Medical Birth
Registry reported the pregnancy outcomes of 531 infants prenatally exposed to SSRIs, 365 of which
were exposed to citalopram (Ericson et al., 1999). This registry identifies early pregnancy exposures,
but timing and dosing were poorly specified. Of those infants exposed to citalopram, there was no
increase in major malformations and no pattern to any of the birth defects.
The authors also noted that due to two reports to the FDA, they specifically checked but did not find
any cases of optic nerve hypoplasia, although the infants were evaluated only in the perinatal period.
They did find a small but significant increase in prematurity (OR 1.6) in women taking any SSRIs. It is
not clear what role the medicine, maternal condition, or life style factors associated with the maternal
condition played.
Neonatal withdrawal
Nordeng et al. (2001) described 5 possible cases of neonatal withdrawal with various SSRIs, including
one case of an infant whose mother took 20mg/day of citalopram from months 5-7 and an increased
dose of 30mg/day from months 7-9. The infant was born at term and had light abstinence symptoms
with increased tonus in his extremities and neck, and was jittery. All symptoms, with the exception of
tonus, resolved within seven days of birth (Nordeng et al., 2001). No medical treatment was needed.
Laine et al. (2003) prospectively followed 20 infants exposed to the SSRIs citalopram (N=10) and
Prozac (N=10) compared to control group of healthy women not receiving psychotropic medication.
While they found a 4-fold increase in serotonergic symptoms (tremor, restlessness and rigidity) in
SSRI-exposed infants ages 1-4 days, there were no significant differences in symptom scores when
only the citalopram group was compared to the controls. No differences were found in vital signs such
as blood pressure, heart rate and body temperature between the two groups, with the exception of a
statistically significant increase in heart rate in the SSRI group at 2 weeks of age. No specific medical
treatment was needed.
Long term development
Psychotropic medications alter neurotransmitter levels in the maternal brain, thus there is a theoretical
risk that they can also alter the developing fetal brain. These brain alterations could potentially lead to
behavioral or learning deficiencies.
In the study by Heikkinen et al. 2002 (discussed previously), 11 infants who were exposed to
citalopram in utero were followed until age 1 year. The body weights of all infants were normal at one
year, as was the neurological development. One child could not walk at the age of 1 year, but the
neurological status of this child was evaluated as normal 6 months later (Heikkinen et al., 2002). Due to
the limitation of the small sample size and limited follow up time, further investigation in this area is
necessary.
Wellbutrin/Zyban (bupropion) Bupropion is an aminoketone used both as an antidepressant
(Wellbutrin) and as an aid in smoking cessation (Zyban).
Congenital anomalies
One study in rabbits only saw an increase in skeletal anomalies and delayed ossification at the highest
dose when maternal toxicity was present (Tucker, 1983). This same study reported that high doses
given to pregnant rats produced maternal toxicity, but that no congenital anomalies were found in the
offspring.
The majority of human data on pregnancy exposure is available through a bupropion pregnancy
registry maintained by the manufacturer, GlaxoSmithKline. The registry prospectively collected
pregnancy exposure information and outcomes since September 1997. Controls were not used. The
current update of this registry (February 2004) indicated that 534 pregnancy outcomes have been
prospectively analyzed with 354 live births following first trimester exposure. Of these first trimester
exposures, there were 12 pregnancy outcomes resulting in birth defects (3.4%), which is not higher
than the general population.
However, of the 12 birth defects, 7 were isolated heart defects. Therefore there is continued study to
assess an association specifically with cardiac defects.
Additionally, a prospective controlled study found no increase in the rate of malformations in 136
women taking bupropion in the first trimester (Chun-Fai-Chan et al., 2005). Forty-five women took
bupropion throughout pregnancy. There were 72 livebirths and no major malformations reported. Due
to the small sample size this study had a 80% power to identify a 5-fold increase risk for
malformations.
There were also no differences in birth weight, gestational age at birth, or stillbirth compared to the
controls. There was a significant increase risk for miscarriage among women taking any antidepressant
or taking bupropion (12.3-15.4%) compared to a control group without depression (6.7%). In addition
to the medicines, this latter finding could reflect factors with the maternal depressive condition or
simply reflect an unusually low miscarriage rate in control women.
Neonatal withdrawal
No reports of neonatal withdrawal have been published.
Long term development
There are at present no published studies examining the long term effects on development in children
prenatally exposed to bupropion.
Effexor (venlafaxine)
Venlafaxine is a bicyclic antidepressant marketed as Effexor.
Congenital anomalies
Unpublished animal data available from the manufacturer (Wyeth) reported no increase in
malformations in the offspring of rats given up to 11 times and rabbits given up to 12X MHRD.
Decreased weight and viability were noted in offspring at 10X MHRD in rats. Another study by da-
Silva et al. produced similar results in rats prenatally exposed to venlafaxine (da-Silva et al., 1999).
They found no increased risk for congenital malformations, but did find a slight decrease in birth
weight of litters exposed to venlafaxine. Data obtained from the U.K. Drug Safety Research Unit
included pregnancy outcomes for 26 live births in women who took venlafaxine during pregnancy
(Einarson et al., 2001). No major malformations were reported.
A larger study by Einarson et al. (2001) prospectively collected information about birth outcomes of
150 women exposed to venlafaxine during pregnancy, 126 of which used the medication during the
first trimester and 34 throughout the pregnancy.
Seventy percent of the woman took 75mg venlafaxine (range: 37.5-300mg). The authors compared
pregnancy outcomes of this group to two control groups, women who used SSRI’s during pregnancy
and women who did not take antidepressants. Pregnancy outcomes such as the number of live births,
spontaneous abortions, preterm delivery, birth weight and major malformations were examined. The
pregnancy outcomes were not statistically different between the three groups for any of these factors.
The results from this study are promising, but are limited by the small sample size which provides only
an 80% power to detect a 4-fold increase in malformations.
Neonatal withdrawal
The WHO Collaborating Centre for International Drug Monitoring in Sweden described 17 reports of
neonatal withdrawal syndrome, of which only 6 were regarded as potentially related (Sanz et al., 2005).
An individual case report in a German journal described an infant with restlessness, hypertonia,
jitteriness, irritability and poor feeding (de Moor et al., 2003). The diagnosis of neonatal withdrawal
was further suspected when there was a temporary improvement after administration of low dose (1
mg) venlafaxine. After 8 days, with no further treatment, the infant’s symptoms resolved.
Long term development
The long term effects on development in children prenatally exposed to venlafaxine has not been
studied.
Summary
Reproductive studies to do not suggest an increase in congenital anomalies for any of the four
medications discussed, although the studies are still limited by their small sample sizes. Studies with
sample sizes less than 150 women allow at most a 4 fold detection of increased risk (Einarson and
Einarson, in press). Further evaluation of a possible association with bupropion and cardiac defects is
still needed.
Exposure to antidepressants which inhibit serotonin reuptake during the third trimester of pregnancy
carries the risk of a neonatal withdrawal/serotonergic syndrome. Reported symptoms are non specific
and typically self limiting. Symptoms most commonly reported include agitation, irritability,
hypotonia, hypertonia, hyperreflexia, drowsiness, persistent crying, and sucking problems
(Prescrire International, 2004). Small nonblinded case series suggest such findings occur in 20-30% of
infants with third trimester exposure to the older SSRIs (Prozac, Paxil, and Zoloft) compared to 6-9%
of control infants (Prescrire International, 2004).
Individual case reports of withdrawal-like symptoms also exist for Celexa and Effexor. However,
discontinuing antidepressants near delivery is controversial due to maternal and infant adverse effects
with postpartum depression. Longterm studies on whether there are any effects on neurobehavioral
outcomes are absent. Currently there only studies on early childhood development for Prozac and the
tricyclic antidepressants.
It should be noted that stopping medication is not a “no risk” option since there are concerns to a
pregnancy with untreated maternal depression. The severity of maternal symptoms should help dictate
medicine use during pregnancy.
References
Bennett, et al. (2004) Prevalence of depression during pregnancy: systematic review. Obstet Gynecol
103(6):698-709.
Bolton HL, et al. (1998) Incidence and demographic correlates of depressive symptoms during
pregnancy in an inner London population. J Psychosom Obstet Gynaecol 19(4):202-9.
Bonari L, et al. (2004) Perinatal risks of untreated depression during pregnancy. Can J Psychiatry
49(11)726-735.
Chun-Fai-Chan, et al. (2005) Pregnancy outcome of women exposed to bupropion during pregnancy: A
prospective comparative study. Am J Obstet Gynecol 192(3):932-936.
da-Silva et al. (1999) Postnatal development of rats exposed to fluoxetine or venlafaxine during the
third week of pregnancy. Braz J Med Biol Res 32(1):93-8.
de Moor RA, et al. (2003) [Withdrawal symptoms in a neonate following exposure to venlafaxine
during pregnancy] Ned Tijdschr Geneeskd. 12;147(28):1370-2.
Ericson A, et al. (1999) Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin
Pharmacol 55:503-508
Einaron TR and Einarson A (In press) Newer antidepressants in pregnancy and rates of major
malformations: a meta-analysis of prospective comparative studies Pharmacoepidemiology and Drug
Safety.
Einarson A, et al. (2001) Pregnancy outcome following gestation exposure to venlafaxine: a
multicenter prospective controlled study. Am J Psychiarty 158:1728-1730.
Forest Laboratories (2005) Product information.
GlaxoSmithKline Bupropion Pregnancy Registry (2004) Research Triangle Park, NC.
Heikkinen T, et al. (2002) Citalopram in pregnancy and lactation. Clin Pharmacol Ther 72(2):184-91.
Kessler R, et al. (1993) Sex and depression in the National Comorbidity Survey I: Lifetime prevalence,
chronicity and recurrence. Journal of Affective Disorders 29:85-96.
Laine K, et al. (2003) Effects of exposure to selective serotonin reuptake inhibitors during pregnancy
on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch
Gen Psychiarty 60:720-726.
Nordeng, et al. (2001) Neonatal withdrawal syndrome after in utero exposure to selective serotonin
reuptake inhibitors. Acta Paediatr 90:288-291.
Prescrire International (2004) Neonatal complications after intrauterine exposure to SSRI
antidepressants. 13(71)103-104.
Sanz EJ, et al. (2005) Selective serotonin reuptake inhibitors in pregnant women and neonatal
withdrawal syndrome: a database analysis. Lancet 365:482-487.
Tucker WE (1983) Preclinical toxicology of bupropion: An overview. J Clin Psychiatry 44:60-62.
Zuckerman, et al. (1989) Depressive symptoms during pregnancy: relationship to poor health
behaviors. Am J Obstet Gynecol 160:1107-1111.
Contributors
Michelle Martin, BS
Genetic Counseling Intern
Jennifer Sloan, PhD
Genetic Counseling Intern
Mara Gaudette, MS, CGCCoordinator, Illinois Teratogen Information ServiceEugene Pergament, MD, PhD, FACMGNorthwestern Reproductive Genetics, Inc.

Source: http://fetal-exposure.org/s/ssriantidepressants_apr2005.pdf