Although there is a tendency to
avoid psychiatric medications
during pregnancy, the high
prevalence of psychiatric disorders in pregnant women—15% to 25%, according to recent epidemiologic studies1-3—means that women and their physicians
often face impromptu decisions regarding
the initiation or continuation of
drug therapy during pregnancy.4
The management of psychiatric
problems and pharmacologic treatment
in pregnancy is complex and burdened
with many biologic and personal
factors.5 Psychiatrists need to consider
the impact of untreated illness on the
mother and the fetus, as well as the
possibility of increased risk for obstetric
complications and congenital malformations
associated with pharmacologic
treatment. It should be stressed that
untreated psychiatric illnesses pose a
tremendous threat to the fetus because of maternal behavior and that discontinuing
effective psychotropic treatments
may exacerbate maternal mental
illness and cause secondary effects on
All currently available psychopharmacologic
agents and their metabolites cross the placenta,6 and in some cases,
intrauterine exposure to psychiatric
drugs may lead to neonatal withdrawal
syndrome (NWS), also called neonatal
NWS occurs in newborns going
through withdrawal symptoms as a
result of the mother's use of psychoactive
drugs during pregnancy. It is characterized
by signs and symptoms of
CNS hyper-irritability, GI dysfunction, and respiratory distress; and by vague
autonomic signs and symptoms that
include yawning, sneezing, mottling,
and fever. This syndrome usually begins
within 72 hours but may appear up to
2 weeks after birth.6,7 The clinical
presentation of neonatal drug with withdrawal
varies depending on the drug(s),
timing, and amount of the last maternal
use, maternal and infant metabolism
and excretion, and other unidentified
Psychotropic medications given to
the mother cause pharmacologic effects
on the fetus. These effects are related
to the mechanism of action and therapeutic
objectives of the treatment (for
the mother) and can produce symptoms and signs in the newborn that are distinct
from those of NWS. In many cases, the
clinical picture is very similar and,
thus, difficult to differentiate.
This is probably the case with the
effects of antipsychotics, which have
been associated with tachycardia, GI
dysfunction, sedation, and hypotension.
In addition, extrapyramidal symptoms
may include hyperactivity,
hyperactive deep tendon reflexes, motor
restlessness, and abnormal movements,
which can persist for several weeks,9
as well as tremors, posturing and flapping
of the hands, increased muscle
tone, vigorous rooting and suckling,
arching of the back, and shrill crying.10
NWS seems to be related to the pharmacologic
effects of the drug, and once
the drug is excreted, the symptoms
resolve. Nevertheless, it is difficult to
conclude that there is no withdrawal
effect associated with the use of antipsy-chotics, because the clinical presentations
are not exclusive. Despite this
controversy, antipsychotics have not
usually been associated with withdrawal
symptoms but with pharmacologic
effects in the newborn. For that reason,
they have been excluded from further
analysis in this review.
The adverse effects of prenatal antidepressant
exposure in the newborn may
be secondary both to the effects of the
drug and to its withdrawal. Both tricyclic
antidepressants (TCAs) and selective
serotonin reuptake inhibitors (SSRIs)
are known to cause neonatal withdrawal
symptoms when used during the third
trimester of pregnancy and especially
when nearing time of delivery.
Symptoms associated with antidepressant
withdrawal are collectively called
NWS or neonatal discontinuation.11,12
Withdrawal effects of TCAs have been
characterized since at least 1979.13-16 The
most common withdrawal symptoms
include irritability, tremulousness, diarrhea,
poor feeding, respiratory distress,
and seizures (convulsions). These symptoms can occur in newborns whose
mothers were taking either therapeutic
or larger doses. Withdrawal can begin
within 72 hours postpartum and last for
NWS associated with the use of
SSRIs has been under discussion for several years and the concept is now
well established, although it is still
underresearched; its incidence is estimated
to be around 30% of exposed
neonates.17 NWS seems to be a classrelated
problem because it has been
described with almost every SSRI;
however, there is speculation that some
agents in this class are more prone to
induce this problem than others.
When administered in the third
trimester, fluoxetine increased the risk
of premature delivery, the need for
special-care nurseries, and the incidence
of lower birth weight and length.18
The most common symptoms associated
with SSRI deprivation in neonates
were respiratory difficulties, cyanosis on feeding, and jitteriness.19,20 Other
common neonatal withdrawal symptoms
included low Apgar scores, irritability,
constant crying, shivering,
increased tonus, eating and sleeping
difficulties, and convulsions.21 This
syndrome is usually self-limited and resolves quickly; in most cases, Apgar
scores reach 8 to 9 after 1 minute.
In the World Health Organization case
series,20 paroxetine was more frequently
associated with NWS than were other
SSRIs, but the methodology used can
neither confirm nor deny this difference.
Because of its pharmacokinetic and
pharmacodynamic properties, there may
be a higher risk of NWS with paroxetine.
Costei and associates22 followed up
55 neonates exposed to paroxetine in
the third trimester and found a significant
increase in respiratory distress,
hypoglycemia, and jaundice when compared
with neonates exposed to paroxetine
in the first 2 trimesters or those
who were not exposed.
The symptoms of NWS seem to be
associated with a serotonergic imbalance.
Laine and associates23 used a
prospective controlled study of 20 mothers
taking either fluoxetine or citalopram
during the third trimester to measure
neonatal withdrawal symptoms and
levels of monoamines in the umbilical
cord. Children exposed to an SSRI had
lower Apgar scores during the first 15
minutes and presented a 4-fold increase
in serotonin-related symptoms (myoclonus,
restlessness, tremors, shivering,
hyperreflexia, uncoordination, and rigidity)
during the first 4 days of life
compared with controls. Levels of monoamines
(serotonin, its metabolite 5-
hydroxyindole acetic acid, the dopamine
metabolite homovanillic acid, and noradrenalin)
in the umbilical cord were reduced
in newborns exposed to SSRIs.
The effects of anxiolytics, especially
benzodiazepines (BZDs), in the
newborn are a mixture of the pharmacologic
effects of the substance and
possible withdrawal symptomatology.
Even if some investigators have described
lower birth weights, shorter
birth length, and significantly more
perinatal complications than in their unexposed control groups,24 there are 2 different neurologic consequences in the
newborn: the floppy infant syndrome
and NWS. When diazepam and other
BZDs were administered close to delivery,
the neonates frequently presented
with floppy infant syndrome, which is
characterized by muscular hypotonia,
hypothermia, lethargy, respiratory problems,
and feeding difficulties. Although some investigators claim that infants
recover without long-lasting effects, it
is speculated that these effects cause
some types of neurocognitive developmental
Although it is difficult to ascribe
these effects to BZD action on the brain
or to sudden deprivation, NWS symptoms
after exposure have been well
documented for a variety of BZDs.25,26
NWS symptoms included low Apgar
scores, hypertonia, irritability, abnormal
sleep patterns, constant crying,
tremors, myoclonus, bradycardia,
cyanosis, suckling difficulties, apnea,
feeding aspirations, diarrhea, vomiting, and growth retardation.
Both pharmacologic effects and
NWS can be present at the same time,
making the clinical picture more bizarre.
The frequency and severity of NWS can
be related to the pharmacokinetic profile
of the particular BZD. Diazepam is longacting
and has a long half-life27; a longer
half-life can be associated with a prolonged
effect of the drug in the newborn,
whereas a shorter half-life can, more
frequently, be associated with deprivation
It has been hypothesized that there
is a relationship between long-term
effects of BZD and brain development
involving neurocognitive function. The
topic is highly controversial, but studies
have only been conducted in animal
models, which showed that BZD exposure
produced immediate and long-lasting
effects. Rats prenatally exposed to
diazepam had significant deficits in
acquisition and retention of spatial
discrimination tasks.28 Another investigated
substance, alprazolam, given
prenatally to mice29 and rats30 produced
significant increases in anxiety in
offspring that were tested as either juveniles
or adults. These long-lasting effects
may be related to the desensitization of
the γ-aminobutyric acid (GABA) receptor. A recent study showed that male
rats exposed to BZD had behavioral
deficits and were hypersensitive to pentylenetetrazol,
a GABA antagonist.31
This effect seemed to be less pronounced
in female rats, but the gender differences
have to be more thoroughly explored.
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