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Pharmacological aspects of neonatal antidepressant withdrawal
ter Horst, Peter G. J.; Jansman, Frank G. A.; van Lingen, Richard A.; Smit, Jan-Pieter; van
den Berg, Lolkje; Brouwers, Jacobus
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ter Horst, P. G. J., Jansman, F. G. A., van Lingen, R. A., Smit, J-P., de Jong-van den Berg, L. T. W., &
Brouwers, J. R. B. J. (2008). Pharmacological aspects of neonatal antidepressant withdrawal. Obstetrical &
Gynecological Survey, 63(4), 267-279.
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Volume 63, Number 4
OBSTETRICAL AND GYNECOLOGICAL SURVEY
Copyright © 2008
by Lippincott Williams & Wilkins
CME REVIEWARTICLE
12
CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total
of 36 AMA/PRA Category 1 CreditsTM can be earned in 2008. Instructions for how CME credits can be earned appear on the
last page of the Table of Contents.
Pharmacological Aspects of Neonatal
Antidepressant Withdrawal
Peter G. J. ter Horst, PharmD,* Frank G. A. Jansman, PhD, PharmD,†
Richard A. van Lingen, MD, PhD,‡ Jan-Pieter Smit, MD,§
Lolkje T. W. de Jong-van den Berg, PhD, PharmD,¶
and Jacobus R. B. J. Brouwers, PhD, PharmD储
*Hospital Pharmacist, Department of Clinical Pharmacy, Isala Clinics, Zwolle, The Netherlands; †Hospital
Pharmacist and Clinical Pharmacologist, Department of Clinical Pharmacy, Isala Clinics, Zwolle, and
University of Groningen, Groningen Research Institute for Pharmacy, Department of Pharmacotherapy and
Pharmaceutical Care, Groningen, The Netherlands; ‡Pediatrician, Princess Amalia Department of
Paediatrics, Division of Neonatology, Isala Clinics, Zwolle, The Netherlands; §Psychiatrist, ¶Professor in
Social Pharmacy and Pharmaco-Epidemiology, University of Groningen, Groningen Research Institute for
Pharmacy, Department of Social Pharmacy and Pharmacoepidemiology, Groningen, The Netherlands; and
储Hospital Pharmacist, Clinical Pharmacologist, and Professor in Pharmacotherapy and Clinical Pharmacy,
University of Groningen, Groningen Research Institute for Pharmacy, Department of Pharmacotherapy and
Pharmaceutical Care, Groningen, The Netherlands
Depression is common in reproductive age women, and continued pharmacologic treatment of
depression during pregnancy may be necessary to prevent relapse, which could be harmful for
both the fetus and the mother. Although data on drug safety are imperfect and incomplete, the
benefits of antidepressant therapy during pregnancy generally outweigh the risks. Neonates who
are exposed to antidepressant medications during gestation are at increased risk to have neonatal
withdrawal syndrome, although the exact incidence of this complication is unknown because the
definition of the syndrome is not clear and withdrawal reactions are probably underreported.
Tricyclic antidepressant withdrawal syndrome is most likely related to muscarinergic activity and
individual drug half-lives, and selective serotonin reuptake inhibitor withdrawal may be due to a
decrease in available synaptic serotonin in the face of down-regulated serotonin receptors, the
secondary effects of other neurotransmitters, and biological or cognitive sensitivity. Other factors
that influence neonatal toxicity or withdrawal include the normal physiologic changes of pregnancy, the altered activity of CYP450 enzymes during pregnancy, drug-drug transporter (PgP and
OCT3) interaction, and the presence of genetic polymorphisms in genes influencing drug metabolism. Further research is necessary.
Target Audience: Obstetricians & Gynecologists, Family Physicians
Learning Objectives: After completion of this article, the reader should be able to explain the
importance of antidepressant therapy during pregnancy and postpartum, summarize the important
neonatal effects of antidepressants, and describe the potential teratogenic effects of antidepressants.
It has been estimated that up to 70% of pregnant
women experience symptoms of depression, with
10% to 16% of pregnant women fulfilling diagnostic
criteria for a major depressive disorder (1–3).
Women with depression have significantly lower
health-related quality of life scores (4), and untreated
maternal depression has been associated with obstetrical complications such as preterm birth and low
birth weight, spontaneous abortion, preeclampsia,
and substance abuse (5,6). Women with prenatal
267
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Obstetrical and Gynecological Survey
depressive disorders are less willing to initiate breast
feeding, and untreated symptoms may also precipitate behavioral changes in the offspring (3).
Continued treatment of depression during pregnancy may be necessary to prevent relapses and
postpartum depression. This was demonstrated by
Cohen et al, who found that relapse of depression
occurs in 68% to 75% of women who stop antidepressant therapy before conception or during the first
trimester (7,8), and that nearly half of all pregnant
women who stop antidepressant therapy before conception need to restart it during pregnancy to control
depressive symptoms (9). This kind of relapse has
not been reported for other psychiatric conditions
(10). A review by Viguera showed that, compared
with discontinuation of antidepressant therapy, continuous therapy for major depression during pregnancy is associated with a 30% lower rate of relapse
per month (11). The factors which predict relapse of
depression have not yet been fully identified.
Drug exposure registries reveal that antidepressants are used in 0.1% to 1.8% of pregnant women
from the first trimester to delivery (12–20). In addition to depression, antidepressants are used to treat
panic and stress disorders, major depressive disorders, obsessive compulsive disorders, phobias, anxiety disorders, and borderline personality disorders.
Selective serotonin reuptake inhibitors (SSRIs) are
the antidepressant drugs most commonly prescribed
during pregnancy. However, concerns have recently
been raised regarding paroxetine exposure during the
first trimester, which may be associated with an
increased risk of cardiovascular malformations in
exposed fetuses (21).
In this systematic review, we summarize the current literature on the teratogenesis of antidepressant
medications, and describe neonatal withdrawal from
tricyclic antidepressants (TCAs) and SSRIs. We also
discuss the possible pharmacological background,
such as maternal pharmacokinetics, pharmacogenetics, and placental transporter mechanisms.
The authors have disclosed that they have no financial relationships with or interests in any commercial companies pertaining to
this educational activity.
The Faculty and Staff in a position to control the content of this
CME activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies
pertaining to this educational activity.
Lippincott CME Institute, Inc. has identified and resolved all
faculty and staff conflicts of interest regarding this educational
activity.
Reprint requests to: P. G. J. ter Horst, MSc, PharmD, Department of Clinical Pharmacy, Isala Clinics, P.O. Box 10400, 8000 GK
Zwolle, The Netherlands. E-mail: [email protected].
LITERATURE SEARCH STRATEGY
Relevant articles for inclusion in this review were
systematically selected by performing a literature
search of publications, using PubMed (from 1968
until November 2006), the Excerpta Medica database
EMBASE (1974 until November 2006), and Medline
(1966 until November 2006), for the subheadings
“neonatology,” “neonatal abstinence syndrome,” “antidepressive agents,” TCA, SSRI, “substance withdrawal
syndrome,” pharmacogenetics, pharmacokinetics, placenta, pregnancy, polymorphism, and transporter. Crossreferences from relevant articles were also screened
for inclusion. Because human placentas are morphologically and functionally different than those of animals, animal data were not included. No reports from
randomized controlled clinical trials (RCTs) were available, so the best evidence from case reports or case
series or review articles was used. The absence of RCT
results from major ethical considerations which prevent
the study of drug effects in pregnant women.
PLACENTAL TRANSFER OF
ANTIDEPRESSANTS
The human placenta consists of 10 to 40 cotyledons containing chorionic villi. The chorionic villus
is the functional unit of the human placenta, and is
the site for exchange between the maternal and fetal
circulations. The villus consists of a central fetal
capillary, stroma, and an outer trophoblast layer.
Trophoblastic cells are present as mononuclear cells
called cytotrophoblasts and multinucleate cells called
syncytiotrophoblasts. The composition of the trophoblast layer in the human placenta changes during
pregnancy. During the first trimester, the villi have a
nearly complete cytotrophoblast layer underneath the
syncytiotrophoblast layer. Later in pregnancy, the cytotrophoblast layer becomes discontinuous. In addition
to the trophoblast layer, the fetal and maternal circulations are separated by a trophoblast basement membrane, connective tissue space, an endothelial basement
membrane, and fetal capillary endothelium (22).
Solutes in the maternal circulation can reach the
fetal circulation by passing through the apical brushborder (maternal facing) and basolateral or basal
(fetal facing) membranes of the syncytiotrophoblast
(23). Parameters which influence the rate of passage
include the maternal-fetal concentration gradient of
the unbound fraction of the drug, the surface and
thickness of the placental membranes, and the biochemical characteristics of the diffusing molecules
(lipid solubility, polarity, molecular weight, and pKa
Neonatal Antidepressant Withdrawal Y CME Review Article
value) (23). Ion-trapping of drugs that are weak bases
may occur because the fetal pH (pH ⫽ 7.3) is different from the maternal pH (pH ⫽ 7.4). The human
placenta contains multiple enzyme systems, including those responsible for drug oxidation, reduction,
hydrolysis, and conjugation (24). Cytochrome P-450
enzymes important for oxidative metabolism are
designated CYP1A1, 1A2, 2C, 2D6, 2E1, 2F1,
3A4, 3A5, 3A7, and CYP34B1 (24,25). CYP2D6
is an important enzyme in antidepressant drug
metabolism; the existing genetic polymorphisms
of CYP2D6 make drug response and toxicity
sometime unpredictable at first exposure.
Changes in drug permeability during pregnancy
result from placental changes such as decreasing
membrane thickness and increasing placental blood
flow, the expression of active CYP-enzymes (1A1,
2D6, 2E1, 3A4) (26), and the regulation of different
transporters.
Known placental transporters of antidepressants
include P-glycoprotein (PgP), OCT3, and SERT
transporters. The localization of the PgP efflux transporter determines the direction of the transport. If the
transporter is located on the apical membrane, it will
efflux into the maternal circulation. If it is located on
the basolateral membrane, it will efflux into the fetal
circulation (23). The role of the placenta as an efflux
transporter has been established, and Molsa et al
found that PgP is also involved in the transport of
drugs from the placenta to the maternal circulation
(27). Most drugs transported by PgP are basic, uncharged, hydrophobic, and contain multiple hydrogen bonds (28). An overview of drugs that interact
with PgP has been presented by Balayssac et al (29).
Of all antidepressants, desipramine, venlafaxine, and
paroxetine are known to interact with PgP (30).
Some herb extracts (curcumin, ginsenosides, piperine, green tea, and silymarin from milk thistle) inhibit
or accelerate the PgP-transporter mechanism, which
hypothetically could be harmful to the fetus (31).
Different polymorphisms for PgP have been found
with no apparent clinical relevance (28). A 2-fold
increase in PgP expression at the end of pregnancy
compared to early pregnancy has been reported, but
not yet confirmed in larger studies (32). Increased
PgP expression may protect the fetus from xenobiotics (33). In contrast, a small study in mice showed
that PgP-blocking drugs (digoxin, saquinavir) increase fetal exposure to these drugs (34).
The OCT3 transporter system, located in the basal
syncytiotrophoblast, serves as the placental transporter
for serotonin, dopamine, norepinephrine, histamine,
amphetamines, clonidine, cimetidine, imipramine, and
269
desipramine (23,24,26,35). Other TCAs may also be
transported by the OCT3 transporter. Although OCT3
has been shown to transport imipramine, a recent study
showed that imipramine may actually inhibit the
OCT3-transporter (36). Fluoxetine has been shown to
prevent serotonin from crossing the human placenta by
blocking the serotonin transporter (37); the clinical relevance of this finding is not yet understood.
TERATOLOGY
Studies of the possible association between maternal drug use and adverse or teratogenic fetal effects
are frequently complicated by methodological issues.
These include the lack of appropriate controls, incomplete ascertainment of cases, imprecise information about the timing of drug use in relation to
pregnancy, small numbers of reported cases with
insufficient power, suboptimal study design (cohort
or case-control), and the fact that most studies focus
on the overall incidence of major malformations instead
of specific birth defects. In addition, because most studies do not specify whether antidepressant use was
started because of maternal depression about an existing pregnancy complication or whether the complication occurred after drug therapy was initiated for other
reasons, it is difficult to ascribe cause and effect.
Not surprisingly, therefore, reports of the teratogenic risk of maternal TCA use have contradictory
results. Although one Swedish study identified an
association between maternal clomipramine use and
congenital cardiovascular anomalies such as ventricular or atrial septal defects (38), other studies have
found no teratogenic effects of TCA use during pregnancy or before conception (39–42). In addition,
TCA exposure has not been associated with an increased incidence of perinatal complications (43). In
general, the use of TCAs during pregnancy is considered safe, although the statistical power of published studies is low (44).
Several cohort studies that examined the use of
SSRIs in pregnancy found no increased risk of major
congenital malformations (45–49), whereas other cohort studies have reported an association between
SSRI use and adverse pregnancy outcomes such as
lower birth weight (but not low birth weight or intrauterine growth restriction), earlier gestational age
at delivery, and an increased incidence of minor
congenital anomalies (47,50). A recent meta-analysis
suggested that spontaneous abortion is more common
among women using antidepressants than among
women not using any drugs (51), but the analysis
270
Obstetrical and Gynecological Survey
could not determine whether this was associated with
the medication or with maternal depression itself.
One recent case-control study found a possible
relationship between maternal use of SSRIs (particularly paroxetine) during early pregnancy and an
increased risk of congenital cardiac defects (52),
whereas another case-control study reported an association between third-trimester use of SSRIs and
persistent fetal circulation (pulmonary hypertension)
(53). However, many studies evaluating a variety of
antidepressant medications have reported no teratogenic effects for TCAs, SSRIs, or any other antidepressant (45,46,49,52,54–58).
PHARMACOKINETICS OF
ANTIDEPRESSANTS IN PREGNANCY
The pharmacokinetics of most drugs are altered by
pregnancy, such that the doses of most drugs have to
be increased to maintain therapeutic levels (59). The
doses of nortriptyline and desipramine have to be increased during pregnancy (60), and Hostetter et al
found that 70% of pregnant paroxetine, sertraline, and
fluoxetine users needed to increase their daily dose to
control depressive symptoms (61). The responsible
pregnancy-related pharmacokinetic changes include
substantial first-pass metabolism in the gut, changes in
protein binding, a large volume of distribution, altered
hepatic clearance, and elimination half-lives up to 3
days (62–65). On the other hand, there is enhanced
absorption related to progesterone-related slowed intestinal transport (62,63). Another factor may be the effects of fetal drug metabolism. Although neonatal drug
metabolism is unpredictable, resulting in fluctuations in
blood concentrations (44,66–68), it is unknown whether
this occurs during prenatal life.
Phase 1 Metabolism (Cytochrome P-450)
A main factor influencing the pharmacokinetics of
antidepressants during pregnancy is the cytochrome
P-450 isoenzyme system (69). A study of drug metabolism by CYP1A2, CYP2D6, and CYP3A4 during pregnancy showed that the metabolism of drugs
during pregnancy may be altered (70). Anderson
reviewed CYP1A2 activity during pregnancy (59),
and showed the activity of CYP1A2 is reduced about
65% to 70% at the end of pregnancy, compared with
the postpartum period (59,71). This finding may be
relevant for antidepressants that are metabolized by
CYP1A2, such as amitriptyline, clomipramine, desmethylimipramine, fluvoxamine, and imipramine.
Although data are lacking, blood concentrations of
these antidepressants may be altered.
CYP2C19 is involved in demethylation reactions
which occur during the metabolism of amitriptyline,
clomipramine, desmethylimipramine, fluvoxamine,
and imipramine (72).
CYP2D6 also regulates the hydroxylation of antidepressants, which are generally lipophilic bases with a
protonable nitrogen atom (73), and this contributes to
their therapeutic and adverse effects (72). CYP2D6
activity is increased by 47.8% at the end of pregnancy
compared to the postpartum period (74,75). It is likely
that blood concentration levels of antidepressants (except trazodon and nefazodon) are lowered by this mechanism, which could result in a relapse of depression
during pregnancy.
Pharmacogenetic Variations in Phase 1
Metabolism
Phase I metabolism is also subject to genetic
variability. Much of the available information relevant to antidepressants regards the CYP2D6 subenzyme. The activity of CYP families, as well as
several drug transporters, is regulated by a variety
of nuclear receptors: pregnan X (PXR), constitutive androstane receptor (CAR), hepatic nuclear
factors, and the aromatic hydrocarbon receptor
(AhR) (76,77). The CYP2D6 gene is highly polymorphic, with over 70 known variants. It has been
estimated that 36% of the world population has a
variant gene, with relevant clinical consequences
(78). Homozygosity of the null alleles of CYP2D6
is associated with poor metabolism (debrisoquine).
Null allele heterozygosity, or homozygosity for
intermediate metabolic alleles, gives rise to intermediate enzyme activity, whereas CYP2D6 gene
duplications give rise to ultrarapid metabolic activity (78). Although the different allelic forms of
CYP2D6 have not been associated with depression
during pregnancy and in the postpartum period
(79), they may result in a 2-fold difference in the
required clomipramine and imipramine doses, a
8-fold difference in the desipramine doses, a 3-fold
difference in the required nortriptyline doses, a
10-fold difference in the trimipramine doses, a
2-fold difference in the fluoxetine and paroxetine
doses, a 5-fold difference in the mianserin doses,
and a 4-fold difference in the venlafaxine doses
(78). The C/C genotype of the CYP2D6 enzyme,
5-ht2aT102C CY2D6, has been associated with
severe paroxetine side effects (80), although it is
not known whether plasma levels are increased.
Neonatal Antidepressant Withdrawal Y CME Review Article
Wadelius et al found that in extensive metabolizers
of CYP2D6, the metabolism was decreased by
53% during pregnancy, whereas for poor metabolizers the metabolism was increased by 63% (75).
Genetic variability in the activity of the CYP2C19
enzyme may result in a 2-fold difference in amitriptyline, clomipramine, imipramine, citalopram,
and moclobemide doses and a 3-fold difference in
fluoxetine doses (78).
Phase 2 Metabolism
Uridine diphosphate glucuronyltransferases (UGT)
are extensively involved in the phase 2 metabolism
of TCAs and SSRIs. Fluctuations in activity may
occur, due to high interindividual expression of some
UGT isoforms and their activity (81), the activity of
promoter genes of UGT expression genes, and decreasing enzyme activity during pregnancy (62).
Receptor Polymorphism
Polymorphisms of serotonin (5-hydroxytryptamine,
5-HT) receptors and variations in 5-HT synthesis,
5-HT storage, and 5-HT membrane uptake may lead
to variations in drug response (82). Of all serotonin
receptors, 5-HT, 5-HT1, and 5-HT2a are of particular
interest. Polymorphisms of the 5-HT1a receptor gene
have been reported, although their clinical relevance
has not yet been established yet. The A50V polymorphic variant has been shown to result in loss of a
detectable 5-HT response (83). Polymorphisms of
variable number tandem repeats (VNTRs) have been
associated with altered responses to fluvoxamine
therapy and an altered prolactin response to clomipramine therapy (83).
Murphy and coworkers showed that the C/C genotype of the 5-HT2a receptor (HTR2A) has been associated with both paroxetine withdrawal symptoms
and the severity of paroxetine side effects in adults
(80). This relevant finding should be explored in
neonates.
Alterations in the SERTPR gene may lead to alterations in the response to fluvoxamine, paroxetine,
citalopram, and fluoxetine (10). The A/A and A/C
genotypes of TPH A218C gene have been associated
with a slowed response to paroxetine (10).
DeVane et al tried to predict the effects of the PgP
C3435T genotype on fetal exposure to substrate
drugs (84). Of particular interest are the TT genotypes
of both maternal and fetal/placental PgP receptors. This
combination is suspect for high exposure to antidepressants (imipramine, desipramine, venlafaxine, parox-
271
etine) and may be a key factor in the explanation of
antidepressant withdrawal.
NEONATAL SYMPTOMS AFTER
PRENATAL EXPOSURE TO
ANTIDEPRESSANTS
The most important neonatal morbidity associated
with maternal antidepressant use is the occurrence of
neonatal withdrawal symptoms. The increasing prevalence of the neonatal withdrawal syndrome is not
surprising, in light of the increase in maternal antidepressant use and the high frequency of the corresponding syndrome in adults. According to Haddad,
the criteria that define withdrawal syndrome include
onset shortly after the drug is discontinued or the
dosage is reduced, short duration, rapid reversal on
restarting the original drug, symptoms distinct from a
reappearance of the underlying disease for which the
drug was prescribed, and symptoms not attributable
to other causes (85). The definition proposed by
Desmond also includes central nervous excitation
and respiratory and gastrointestinal dysfunction (86).
Prevention of withdrawal symptoms in adults by
tapering the medication dose instead of abruptly discontinuing it has been recommended, but data from
randomized controlled trials are lacking. The British
National Formulary recommends that antidepressants
administered for 8 weeks or more should be reduced
over a 4 week period (85). It has also been suggested
that discontinuing the drug over the course of a year,
by reducing the dose by 25% every 3 months, is
optimal (85), but this would be inappropriate for
pregnant women who wish to prevent withdrawal
symptoms in their offspring. No data are available on
the prevention of neonatal withdrawal signs by tapering the maternal antidepressant dose during the
last weeks of pregnancy or treating the newborn with
low doses of the maternal medication. Recently, in a
study by Abdel-Latif of mothers using opioids during
pregnancy, it was found that neonates that were
breastfed by mothers who continued their antidepressants showed significantly fewer withdrawal symptoms than those who were bottle-fed (87). These
results may be the starting point for preventing neonatal withdrawal from other pharmacological agents,
including antidepressants.
A prospective study showed that both maternal
TCA and SSRI use significantly increased the risk of
neonatal respiratory distress, hypoglycemia, and neonatal convulsions (88). No statistically significant
differences were found between both groups. This
study also showed that women using antidepressants
272
Obstetrical and Gynecological Survey
often use other medications as well during pregnancy, making the interpretation of antidepressant
withdrawal symptoms difficult (88).
Maternal depression is a major confounding factor
in determining whether neonatal symptoms are due
to withdrawal from in utero exposure to antidepressants. Oberlander and colleagues showed that only
neonatal respiratory distress was a symptom of antidepressant withdrawal, whereas other neonatal symptoms such as feeding problems, jaundice, and even
convulsions were found in both medication exposed
and nonexposed neonates of depressed mothers (89).
(100,102). Although the nature of the data (case
reports and small series) makes it hard to draw conclusions, it is interesting that withdrawal from SSRIs
is associated with more cardiac problems and abnormal crying and aberrant stool than withdrawal from
other agents. At the present time, only one case
report has described the use of phenelzine (MAO
inhibitor) during pregnancy, but no abnormalities
were observed in the neonate (103). Specific findings
for each TCA are given below.
Neonatal Symptoms After Maternal TCA
Exposure
A case report describing neonatal withdrawal from
antenatal desmethylimipramine exposure described
breathlessness, tachypnea, tachycardia, and cyanosis
(104). Symptoms related to withdrawal from imipramine include irritability, weight loss, breathlessness,
cyanosis, tachypnea, and profuse sweating (104,105).
One neonate who was exposed to imipramine required hospitalization for 30 days, but was discharged in good health (105).
It is estimated that, overall, 50% of adults exhibit
withdrawal symptoms after discontinuing TCA use
(90). It is hypothesized that short half-lives, high
doses, long-term use, and abrupt discontinuation of
TCA therapy increase the likelihood of withdrawal
symptoms (91). TCA withdrawal syndromes in neonates have been described and include jitteriness,
irritability, convulsions, bowel obstruction, and urinary retention (92–96). It has been estimated that
20% to 50% of neonates might develop TCA withdrawal reactions as a result of maternal use (97–99).
Two theories regarding the development of TCA
withdrawal are described: the cholinergic theory and
the adrenergic theory (100,101). The cholinergic theory is based on the fact that TCAs bind to peripheral
and central muscarinic receptors, and this binding—
essentially cholinergic blockade—eventually produces muscarinic up-regulation (which incidentally
is one explanation for the tolerance of side effects).
When TCAs are discontinued, the muscarinic receptor up-regulation results in “cholinergic overdrive” in
some patients (100). The adrenergic theory holds that
TCA therapy causes inhibition of norepinephrine reuptake, so that the synaptic concentration of norepinephrine increases. This leads to a decrease in both
the firing rate and norepinephrine turnover; with
prolonged use, there is a decrease in ␣2-receptor
sensitivity, leading to a further increase in norepinephrine release. With abrupt cessation of TCA
therapy, synaptic norepinephrine levels decrease.
Decreased norepinephrine levels and decreased receptor sensitivity lead to a sudden increase in
norepinephrine release and turnover, and an increase in the synaptic firing rate (101).
Table 1 lists all published antidepressant neonatal
withdrawal signs, classified by antidepressant and
category according to Dilsaver and Moses-Kolko
Desmethylimipramine and Imipramine
Nortriptyline
Symptoms of neonatal withdrawal from nortriptyline have included respiratory distress, cyanosis,
hyperhydrosis, lethargy, poor suck reflex, and tachycardia (105–107). Urinary retention has also been
described, but may have been due to nortriptyline
toxicity and not withdrawal; regardless, it resolved
within 40 hours after delivery (105,107).
Neonatal Symptoms After Maternal SSRI
Exposure
The neonatal SSRI withdrawal syndrome has been
described by Moses-Kolko (102) and appears to be
similar to the TCA withdrawal syndrome in adults
described earlier by Dilsaver (100). Often the term
“poor neonatal adaptation” (PNA) has been used to
describe these symptoms, which include convulsions,
jitteriness, poor muscle tone, weak or absent cry,
respiratory distress (within 3 days after birth), hypoglycemia, low Apgar score, and seizures (54,108).
Other symptoms of in utero exposure to SSRIs
include increased motor activity, fewer different behavioral states, lower neonatal platelet serotonin levels, and deviant neonatal sleep patterns (109,110).
The timing and intensity of neonatal SSRI discontinuation signs appear to be related to dose and duration
of treatment, enzymatic activity levels of serotonin
Neonatal Antidepressant Withdrawal Y CME Review Article
273
TABLE 1
Symptoms of the neonatal antidepressant syndrome, specified for SSRI and TCA
Category
Sleep/energy
Central nervous system
Symptoms
Somnolence
Irritability
SSRI
Sertraline (148)
Fluoxetine (44,150 –152)
Paroxetine (89,150,153,154)
Citalopram (89,150,153,154)
Convulsions
Fluoxetine (68,120,152,154)
Paroxetine (155,156)
Abnormal cry patterns
Fluoxetine (68,44)
Sertraline (148)
Paroxetine (44,128,153,154)
Citalopram (44,153)
Gastrointestinal
Aberrant stool
Fluoxetine (160)
Paroxetine (161)
Poor suck necessitating Fluoxetine (68,150,153)
tube feeding
Sertraline (148)
Paroxetine (150,154,156)
Motor
Agitation
Fluoxetine (44,68,150,152,154,160,164)
Sertraline (138,148)
Paroxetine (127,129,150,156,165)
Citalopram (154)
Tremors, jitteriness,
Fluoxetine (44,152)
shivering
Sertraline (148)
Paroxetine (127,154,161,165)
Decreased tone
Fluoxetine (68,89,121)
Sertraline (139)
Paroxetine (155)
Citalopram (89,153)
Increased tone rigidity
Fluoxetine (44,120,150,160,164)
Sertraline (121)
Paroxetine (44,112,127,129,153,154,
156,165)
Apathy
Fluoxetine (44,68,150,160)
Paroxetine (128,150,153)
Somatic
Temperature instability
Paroxetine (156)
Hypoglycemia
Fluoxetine (68,160)
Paroxetine (129,168)
Respiratory/cardiovascular Tachypnea
Fluoxetine (120,160)
Sertraline (138)
Paroxetine (44,151,153,154,165)
Dyspnea
Sertraline (121)
Paroxetine (155)
Respiratory distress
Fluoxetine (68,120,121,160)
Sertraline (89)
Paroxetine (168)
Arrhythmias
Fluoxetine (169,170)
Tachycardia
Fluoxetine (152)
Unstable blood
Fluoxetine (89)
pressure
Bradycardia
Paroxetine (155,156)
Cyanosis
Fluoxetine (44,89)
Preterm delivery
Fluoxetine (154)
Sertraline (121,153)
Paroxetine (89,150,153)
synthesis and metabolism, and the availability of
serotonin precursors (90).
There are at least 3 possible mechanisms explaining SSRI withdrawal. These include: 1) a decrease in
TCA
Clomipramine (149)
Clomipramine (93)
Clomipramine (93,93,149,157–159)
Clomipramine (93,162,163)
Clomipramine (93,149,158,163,166)
Clomipramine (158,159,162,163,167)
Clomipramine (159,162,163,167)
Clomipramine (157,159,162,166,167)
Clomipramine (162)
Clomipramine (162,166,167)
Clomipramine (162)
Clomipramine (93,159,162,163,167)
Clomipramine (93,162,167)
available synaptic serotonin in the face of downregulated serotonin receptors, 2) the secondary effects of other neurotransmitters (e.g., dopamine) or
biological or cognitive sensitivity in individual pa-
274
Obstetrical and Gynecological Survey
tients, or 3) cholinergic rebound (seen in withdrawal
from paroxetine), comparable to the postulated
mechanism of symptoms of withdrawal from TCA
(111). It is hypothesized that the frequency of the
SSRI withdrawal syndrome is determined by antagonist potency at the serotonin reuptake site (111).
Several clinical studies indicate the relative frequency of neonatal withdrawal symptoms. Oberlander et al prospectively studied 46 women taking
SSRIs over a 4-year period and found that 30% of the
exposed neonates (14 of 46) experienced perinatal
complications, such as transient respiratory distress
and cardiac arrhythmias, which required continued
hospital admission for observation, compared to 9%
(2 of 23) of an unexposed group (44). Another study
by the same group that included nearly 16,000 pregnancies found that 13.9% of SSRI exposed neonates
experienced respiratory distress compared to only
7.8% of nonexposed neonates, as well as a higher
incidence of feeding problems and jaundice (89).
Laine et al reported that neonates who were prenatally exposed to SSRIs had a 4-fold higher serotonergic symptom score than unexposed neonates (121
vs. 30), of which the most prominent symptoms were
tremor, restlessness, and rigidity (112). These results
suggested that SSRI withdrawal symptoms may reflect serotonin overstimulation or toxicity rather than
withdrawal (112–114).
An overview of all case reports, cohort studies,
unpublished FDA databases, and case series describing SSRI withdrawal symptoms was recently presented by Moses-Kolko et al (102). In 2005, Sanz et
al published the results of an analysis of the WHO
database of adverse drug reactions regarding the neonatal effects of withdrawal from prenatal SSRI exposure (115). Although it is difficult to compare
these 2 reports because of differences in datasets and
reporting systems, these data indicate an overall risk
ratio of 3 (95% CI, 2.0–4.4) for relatively mild and
transient neonatal SSRI withdrawal symptoms (CNS,
motor, respiratory, and gastrointestinal symptoms)
(102). The Sanz study, which included data from 102
cases, concluded that prenatal exposures to paroxetine and fluoxetine were most likely to result in
signs of neonatal withdrawal such as convulsions. An
accompanying editorial comment by Ruchkin suggested that a higher threshold be used for prescribing
SSRIs during pregnancy (116). This warning indicated concern not only about neonatal withdrawal
symptoms, but also referred to studies reporting
longer-lasting effects, such as an attenuated pain
response or changes in physiological reactivity and
behavioral activations. However, other studies, such
as those of Nulman and Gentile, have found that
prenatal SSRI exposure has no long-term effects on
neurodevelopment (41,117,118). Of all SSRIs, paroxetine appears to be the drug with the highest risk of
causing neonatal withdrawal, although this finding is
hard to interpret because paroxetine is the most
widely prescribed SSRI. Other SSRIs associated with
newborn withdrawal include citalopram, fluoxetine,
and venlafaxine.
The symptoms of withdrawal from 8 specific SSRI
antidepressants are listed below.
Fluoxetine
Case reports have described neonatal problems associated with prenatal fluoxetine exposure, including
abnormal white blood cell counts and reduced pain
response (119), erythematous rash and petechiae
(120), neonatal encephalopathy (121), hypertonia,
restlessness, and jitteriness (122). However, there
have also been reports documenting no signs of neonatal withdrawal or any associated morbidities after
prenatal fluoxetine exposure, possibly because these
studies controlled for confounding factors. For example, Suri et al (123) presented a study of 62
patients in which women with a history of smoking,
marijuana use, prenatal stress, or anxiety were excluded, because these factors have been independently associated with low birth weight, decreased
gestational age, and risk of preterm birth (124–126).
They found that obstetrical complications and abnormal pregnancy outcomes were not more frequent
after prenatal exposure to fluoxetine.
Paroxetine
Reported neonatal problems associated with in
utero exposure to paroxetine include elevated creatinine kinase levels, respiratory distress, convulsions,
jitteriness and hyperreflexia (127), reduced pain response (128), hypertonia, irritability, feeding problems, myoclonic activity, and hypothermia (122).
Profuse neonatal salivation has also been reported,
but the mother was also taking olanzapine (129).
Although there is one case report of a neonate prenatally exposed to paroxetine who suffered a severe
intraventricular hemorrhage (130), other reports have
failed to demonstrate abnormal platelet counts in
exposed neonates (130).
Citalopram
In a pharmacokinetic study of maternal citalopram
therapy during pregnancy, delivery, and lactation in
Neonatal Antidepressant Withdrawal Y CME Review Article
11 women, no neonatal problems were reported
(131). Franssen et al described a case of severe
respiratory distress, sleep disorder, hypotonia, and
hypertonia in a neonate exposed to citalopram prenatally (66). Sivojelezova et al reported that 20 of 63
fetuses exposed to citalopram in utero had neonatal
problems, including pneumothorax (n ⫽ 2), fetal
distress (n ⫽ 10), decreased heart rate (n ⫽ 3), heart
rate variability (n ⫽ 1), breathing difficulties (n ⫽ 2),
and meconium staining/aspiration (n ⫽ 10) (132). In
the same study, exposed neonates were 4 times more
likely to require intensive care than infants who had
not been exposed.
Bupropion
In a study of in 136 women who took buproprion
during pregnancy, there were no differences in exposed versus nonexposed neonates, although significantly more spontaneous abortions were reported by
the exposed group (P ⫽ 0.009) (133). According to
the authors, the observed rate of spontaneous abortion was comparable to that associated with exposure
to other antidepressants (133).
Fluvoxamine
Evaluation in 92 pregnant women revealed no increased risk of adverse neonatal events (134).
Venlafaxine
No differences in maternal or neonatal outcomes
were observed in women who used venlafaxine
parentally compared to a matched control group of
non-SSRI users (47). A case report of de Moor et al
described a neonate with hypoglycemia, tremor, jitteriness, and feeding problems after prenatal venlafaxine
exposure. However, these symptoms disappeared
within 8 days (135). Data kept on file by the manufacturer of venlafaxine (Wyeth Pharmaceuticals, The
Netherlands) indicate that antenatally exposed infants
have displayed respiratory distress, feeding difficulties,
cyanosis, apnea, seizures, temperature instability, vomiting, hypotonia, hyperreflexia, irritability, and constant
crying (136).
Mirtazapine
One case report described a neonate with persistent
fetal circulation and pulmonary hypertension after
prenatal exposure to mirtazapine (137).
275
Sertraline
Enhanced startle response and reduced pain response (54), an exaggerated MORO-response (138),
and a case of nystagmus (139) have been reported
after prenatal exposure to sertraline. Bot et al described a prenatal exposed neonate with myoclonic
activity, lip smacking, irritability, jitteriness, opisthonus, and EEG abnormalities (122).
MEASUREMENT OF THE NEONATAL
ANTIDEPRESSANT WITHDRAWAL
SYNDROME
One problem with the published literature is that
there are currently no objective diagnostic criteria or
a validated scoring system for identifying and quantifying signs and symptoms of neonatal withdrawal
from prenatal exposure to antidepressants. Another
problem is that neonatal symptoms may not develop
until after the first week of life, when the infant has
been discharged from the hospital. Although monitoring for 1 week after birth has been recommended
(85), this is currently not part of standard neonatal
care. With no alternatives, the Committee on Drugs of
the American Academy of Pediatrics has stated that
neonatal withdrawal symptoms related to in utero exposure to clomipramine may be compared to symptoms
associated with withdrawal from exposure to maternal
narcotics (140). Several existing scoring systems are
described below, but none has been validated for the
evaluation of antidepressant withdrawal.
In the early 1970s, the Finnegan score was developed to evaluate neonates who had been parentally
exposed to opiates and cocaine (141). If the score
was higher than a specified threshold, treatment according to a standard protocol, which frequently included phenobarbital therapy, was recommended.
The Finnegan score has been widely used, but has
been validated only for opiates. The neonatal intensive care unit network neurobehavioral scale (the
NNNS scale) was developed for the Maternal Lifestyle Study (142–144). It assesses and scores the full
range of infant neurobehavioral performance, including infant stress, abstinence and withdrawal, and
neurological functioning. The scale has been validated for both low- and high-risk infants who have
been stabilized after withdrawal from prenatal exposure to opiates, cocaine, and nicotine (143). The
neonatal evaluation required for the NNNS scale is
labor intensive, and training is required for valid
testing. Other scoring systems, such as the Neonatal
Drug Withdrawal Scoring System (NDWSS), the
276
Obstetrical and Gynecological Survey
Neonatal Narcotic Withdrawal Index (NNWI), and
the Neonatal Withdrawal Inventory, were developed
for other pharmacologic classes of drugs and/or have
not been empirically validated (145). All of these
scoring systems were developed for drugs of abuse.
Serious methodological problems affecting the
score’s validity may rise if these scoring systems are
used to assess antidepressant drug withdrawal (146).
Laine et al (112) used a nonvalidated scoring system (the serotonergic symptom score), based on the
definition of the serotonin syndrome (147). The evaluation includes assessment of blood pressure, heart
rate, and body temperature, and examination for myoclonus, restlessness, tremor, shivering, hyperreflexia, incoordination, and rigidity (112). Compared
to the other scoring systems described above, this
method seems more suitable for evaluating neonatal
withdrawal from serotonergic/antidepressant drugs.
However, this method has not been validated (yet). As
these data make obvious, a scoring system specifically
for neonates with in utero exposure to maternal antidepressants is needed and is being developed (112).
13.
14.
15.
16.
17.
18.
19.
20.
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