History and

Introduction
In 1894, Copeman, then president of the
British Medical Association, was called to
consult on a pregnant woman with intractable
vomiting !er condition was so severe that
Copeman decided to terminate the preg"
nanc# !is onl# available instrument was a
rubber probe, which he inserted into the
cervi$ in an unsuccessful attempt to rupture
the membranes Much to his astonishment,
the patient immediatel# stopped vomiting
and continued with s#mptom relief
throughout the rest of the night Copeman
promptl# announced the discover# of a new
treatment for h#peremesis in pregnanc#%
dilatation of the cervi$ uteri &or the ne$t
'uarter of a centur#, this was the standard of
care in obstetrics, although some authors
contended that dilatation of the anus
produced the same e(ect )1* +ractitioners at
the time would not have viewed this as a
ps#chosomatic intervention, but the results
certainl# seem to attest to the power of the
mind,bod# relationship
-he .rst true advance came in 19//, when 0
1 2ead described an approach he called
3natural childbirth,4 in which h#pnotic
suggestion was used to help women achieve
a rela$ed and relativel# painless state during
labor and deliver# !is wor5 received almost
no attention until the mid"1967s%perhaps
because h#pnosis in the earl# 1977s had
man# enemies in the medical setting )8*
9bstetrics was still not addressing the
emotional state of the patient as a ma:or
concern during pregnanc# and deliver#
-he modern era of obstetrics began in 1949,
with the advent of 3ps#choproph#la$is4
;elvovs5i )8* developed this program in
2ussia, which prepared women for childbirth
through education, social support, and
e$ercises in breathing and rela$ation &ernard
<ama=e and +ierre ;ella# were ma:or
proponents of the >oviet
approach, wor5ing from 1968 onward to
foster its development in &rance and other
countries in ?urope and >outh America In
19@1, Cherto5 attributed their success to 3a
remar5able convergence of the inAuence
from the left"wing political parties and the
2oman Catholic Church4 )1* !ow these
usuall# antithetical groups united to embrace
ps#choproph#la$is is a matter of speculation
-he emergence of childbirth classes did,
however, emphasi=e the centralit# of the
famil# and challenge the traditional,
authoritarian structure of medicine
?li=abeth Bing )/* pla#ed a 5e# role in
bringing the techni'ues of <ama=e and 2ead
to the general public in the Bnited >tates
Chat developed subse'uentl# were not onl#
the <ama=e classes that are now so common"
place, but also 3famil#4 involvement in
hospital deliveries &athers were brought into
the classes as active participants, learning
how to support and coach their wives during
the birthing process Initiall#, as Bing noted in
19@8, 3-he vast ma:orit# of the medical pro"
fessions raised their hands in horrorD here
were .rst do=ens, then hundreds, then
thousands of #oung couples demanding to be
together in labor and deliver#4 9bstetrics,
against considerable resistance, had become
a 3famil#"centered maternit#4 )/*
-he movement, .rst toward 3natural
childbirth4 and then to 3ps#choproph#la$is,4
highlighted a growing concern about the
motherEs sense of well"being during
pregnanc# and deliver# 1uring a similar time
period, American ps#chiatr# was embracing
the theories and practice of ps#choanal#sis
)4*, and clinicians were interested in its
application to medical diagnosis and
treatment +s#chiatrists were searching for
the hidden desires and impulses behind a
broad range of adverse events, including
spontaneous abortion, miscarriage,
h#peremesis gravidarum, and pre"eclampsia
-heir hope was that ps#chod#namic
interventions
603 Cop#right F 877G b# <ippincott Cilliams H Cil5ins Psychosomatic Medicine, b# Michael Blumen.eld and Iames
I >train
could improve the course of medical
diseases in ob
stetrics
;omiting during pregnanc# was the ob:ect of
a great deal of theoretical speculation In
19@8, Cherto5 )6* wrote 3It is ta5en to have
the general meaning of s#mbolic re:ection, an
oral attempt at abortion4 !owever, he was
inclined toward a more moderate viewJ
3!elen 1eutsch has pointed out the rather
ambivalent attitude in such cases in the
mother,child relationship the woman who
vomits has chosen to vomit and not to
miscarr#4 !is research involved ps#chological
interviews to uncover this 3ambivalence4 in
vomiting women In a similar vein, 2ingrose
)G* tal5ed about 3a pre"e$isting concealed
personalit# abnormalit#4 in to$emic patients
Bnfortunatel#, most of the ps#choanal#tic
studies featured small sample si=es, big
assumptions, methodologic Aaws, and no
random control trials -here was also a failure
to establish whether an emotional condition
was the cause or e(ect of an associated
disease >hortcomings aside, however, these
investigators often provided their sub:ects
with various ps#chosocial supports, and the
women often reported improvements in their
condition Mann )@*, for e$ample, studied
women who had su(ered from at least three
or more consecutive abortions All sub:ects
were o(ered wee5l# discussion sessions with
their obstetrician for the entire course of their
ne$t pregnanc# 9f the 1@6 women who
completed the stud# after screening for
identi.able g#necologic abnormalities, 81K
carried to term
?ventuall#, ps#chod#namic formulations
about the etiolog# of medical illness fell out of
favor as research focused more rigorousl# on
biological processes )4* In the 1987s, new
ps#choactive medications were entering the
mar5et in e$ponential numbers, and the .eld
of ps#chiatr# turned toward genetic research
and laborator# testing for answers about
mental illness &or a time, well"being during
pregnanc# was described in terms of ph#sical
status, hormones, and medications Mood
disorders such as postpartum depression
were investigated as the products of hor"
monal shifts occurring at deliver#
Interventions tended to be framed around
medications that could be prescribed
Currentl#, ps#chiatric research is emphasi=ing
a biops#chosocial model that balances
ps#chod#namic and biological thin5ing about
medical illness A growing bod# of literature is
showing the ph#siological effects of stress
and loss )4* >tudies have shown that life
events can a(ect the immune response, as
well as the release of hormones a(ecting
m#riad ph#siological responses, including
labor and deliver# -here is also growing
concern that untreated depression and
an$iet# ma# a(ect pregnanc# outcome )8*
-hus, ps#chosomatic medicine in obstetrics
now must address how a womanEs inner
d#namics interact with her environment
to relieve or worsen stress, which in turn can
a(ect her health and pregnanc#
Stress and Its Efects on
Pregnancy
-here is no doubt that a pregnant motherEs
health has far"reaching e(ects on her future
child Babies e$posed to drugs in utero are
more li5el# to have neural, cognitive, and
behavioral problems )8,9* Maternal nutrition
and smo5ing have 5nown e(ects on fetal
growth, whereas folic acid supplementation
can reduce the incidence of neural tube
defects )8* More recentl#, however,
researchers have been stud#ing the e(ects of
maternal ps#chosocial stress on the
pregnanc# and fetus
Bsing the crucible of medical training as their
model for stress during pregnanc#, +inhas"
!amiel et al )17* conducted a cross"sectional
surve# of female ph#sicians at the three
largest universit# hospitals in Israel &our
hundred 'uestionnaires were sent out, with a
68K response rate -he data were then
compared with base rates for the general
population According to the results, 1 in /8
respondents was estimated to have a still"
birth related to being a ph#sician
Appro$imatel# 1 in 8 had a premature
deliver# associated with residenc# training
At the time of 'uestioning, these women
faced not onl# the usual rigors of training, but
also additional coverage responsibilities for
male colleagues on militar# dut# -his stud#
was limited b# lac5 of controls for other ris5
factors a(ecting preterm birth !owever, the
numbers certainl# point to the importance of
loo5ing more closel# at stress during preg"
nanc# According to &inch )11*, female
ph#sicians in the Bnited >tates show a similar
trend toward increased ris5 for adverse
events during late pregnanc#%especiall#
preterm labor
9f course, stress in the wor5place ta5es
man# forms and is not limited to medical
training Mo=ur5ewich et al )18* conducted a meta"anal#sis of 89 studies
from ?nglish Medline from 19GG to August
1999 -he# found that ph#sicall# demanding
wor5 during pregnanc# could increase the ris5
of h#pertension or pre"eclampsia b# G8K -he
ris5 of delivering a small for gestational age
neonate was increased b# 68K +rolonged
standing at wor5 and shift or night wor5
increased the ris5 of a preterm birth b# 66K
Another stud# )1/* followed 4,869 women
who wor5ed past the thirtieth wee5 of
pregnanc#, assessing them at 1G and /7
wee5sE gestation Comen whose :obs
re'uired long periods )more than .ve hours
per da#* of both standing and wal5ing were
found to be at signi.cantl# increased ris5 for
preterm deliver# -he# tended to be child
caregivers, shop5eepers, cleaners, nurses,
and nursesE aides Because neither prolonged
wal5ing nor prolonged standing alone was
associated with preterm birth in this stud#, it
was suggested that other
variables speci.c to these particular
occupations might have been involved
1ata from the 1anish Lational Birth Cohort
)including //,G94 pregnancies of da#time
wor5ers and 8,7@6 pregnancies of shift
wor5ers* revealed an association between
.$ed night wor5 and fetal loss )14*
Cadhwa et al )16* cited evidence that
pregnant women under high levels of
ps#chological or social stress are at increased
ris5 for shorter gestation, earlier onset of
spontaneous labor, and preterm deliver#%
even after ad:ustments were made for other
biomedical, sociodemographic, and
behavioral ris5 factors In 1enmar5,
Lordentoft et al )1G* assessed 8,4/8 women
at 87 wee5sE gestation for stressful life
events Controlling for age, education, and
cohabitation, the# found an association
between severit# of life events and preterm
deliver# !edegaard et al )1@* prospectivel#
studied 6,8@/ 1anish women and found that
one or more highl# stressful life events
increased the ris5 for preterm deliver#
-he motherEs perceptions appear to be
almost as crucial as the stress itself In one
multicenter stud#, 8,69/ women were
assessed at appro$imatel# 8G wee5sE ges"
tation )18* Comen who answered 3#es4 to
the following items were at signi.cantl#
greater ris5 for preterm deliver# than the
control groupJ 3-here is a great deal of
nervous strain associated with m# dail#
activities4 and 3In general, I am ver# tense
and nervous4 -he groups were matched for
race, age, marital status, insurance,
education, and substance abuse In 199/,
Cadhwa et al
)19* found a signi.cant association between
pregnanc# an$iet# )as measured b# a .ve"
item inde$ focusing speci.call# on concerns
about the pregnanc#* and earl# labor and
deliver# -hese results were replicated 6
#ears later )87* 2ini et al )81* demonstrated
that levels of an$iet# could predict the length
of gestation in 8/7 women matched for
obstetric and sociodemographic ris5 factors
>tress was associated with length of gesta"
tion, whereas personal resources )master#,
self"esteem, and optimism* correlated with
birth weight
>urel#, not all women with high levels of
stress deliver prematurel# Multiple factors,
including the onset and course of the stress,
appear to determine its impact 2ui= and
+earson )88* found that stress appeared to
inAuence gestation the most when it
occurred between wee5s 88 and 84 of
pregnanc# !edegaard et al
)8/* demonstrated a correlation between the
ris5 for preterm birth and severit# of
ps#chological distress at /7 wee5sE gestation
In contrast, !erbert and Cohen found that
long"term e$posure to stress appeared to
shorten gestation more than acute stress
)84*
Stress and the
pathophysiology of
preterm birth Investigators are now loo5ing at how
stress directl# inAuences the biological
processes involved in normal
and preterm birth 2esearch reveals that
neuroendocrine, immune, inAammator#, and
vascular processes are involved in both the
stress response and the ph#siolog# )or
pathoph#siolog#* of labor )86* >tress a(ects pregnanc# on a neuroendocrine
level b# stimulating the production of
placental corticotrophin"releasing hormone
)C2!*, which appears to pla# a central role in
orchestrating labor )8G,8@* Comen in
preterm labor have signi.cantl# elevated
levels of C2! compared with gestational age"
matched controls -hese elevations precede
the onset of preterm birth b# several wee5s
At birth, C2! appears to increase at a signi."
cantl# accelerated pace in women who are
delivering prematurel# compared with those
going to term
>tress also elevates plasma cortisol levels
through activation of the h#pothalamic"
pituitar#"adrenal a$is Cortisol inAuences
labor b# stimulating the production of
placental C2! )88* and b# suppressing the
immune s#stem )88*
Compromised immune function is another
possible conse'uence of stress that
predisposes women to preterm labor >tress
elevates cortisol levels and correlates with
signi.cant depression of l#mphoc#te activit#
)89*, which also predisposes the individual to
infection Bacterial vaginosis, the most
common lower genital tract infection in
women of reproductive age, increases b#
twofold the chances of preterm labor and
premature rupture of membranes )/7,/8*
-his appears to be at least partl# due to
proinAammator# c#to5ines, secreted as part
of the maternal or fetal response to microbial
invasion )//,/4* -hese c#to5ines have been
shown to promote spontaneous labor and
rupture of membranes b# stimulating multiple
processes, including the s#nthesis of
prostaglandinsD the release of
metalloproteases in the gestational tissuesD
and the production and release of fetal
cortisol, fetal deh#droepiandrosterone sulfate,
and placental C2! )/6*
Maternal cardiovascular disorders, including
pregnanc#"induced h#pertension and pre"
eclampsia, are among the ma:or indications
for elective preterm deliver# )/G* 2esearch is
beginning to demonstrate that stress, a
5nown ris5 factor for other cardiovascular dis"
orders, also a(ects h#pertensive disorders in
pregnanc# Mur5i et al )/@* assessed G8/
pregnant women at 17 to 1@ wee5sE
gestation and then at deliver# -he# found
that depression andNor an$iet# during earl#
pregnanc# could as much as triple the
subse'uent ris5 for preeclampsia -his ris5
was further increased b# bacterial vaginosis
>:ostrom et al )/8* showed a signi.cant cor"
relation between high"level maternal trait
an$iet# and hemod#namic processes with
h#po$ia and compensator# redistribution of
blood Aow to the fetal brain !errera et al
)/9* found that measuring biops#chosocial
ris5 factors doubled the possibilit# of
identif#ing patients that would subse'uentl#
develop arterial h#pertension and
preeclampsia McCubbin et al )47*
were able to signi.cantl# predict length of
gestation and infant birth weight b#
measuring the reactivit
# of diastolic blood pressure in pregnant
mothers who were otherwise at low ris5 for
preterm deliver#
PSYCHSCI!" I#$E%&E#$I#S
-he role of ps#chosocial intervention for
pregnant women at ris5 is not #et clear, and
research is still in the beginning stages -he
Cochrane +regnanc# and Childbirth 0roup
)41* reviewed 1G randomi=ed trials of ad"
ditional support given during at"ris5
pregnancies involving 1/,G61 women
>upport was de.ned as some form of
emotional support occurring during home vis"
its, clinic appointments, andNor via phone
Additional information and advice ma# also
have been given -here was not a signi.cant
improvement found in perinatal outcomes for
these women, but there was a reduction in
the li5elihood of cesarean birth
S'((!%Y
>tudies are indicating that pregnant women
under stress are vulnerable to adverse
outcomes such as preterm labor, which is the
most common .nal pathwa# of pregnanc#
complications -he ph#siological response to
stress is multidimensional, and labor ma# be
hastened through numerous di(erent
mechanisms If preterm labor is to be more
e(ectivel# prevented, it is crucial that we
more full# understand and implement
measures to alleviate the e(ects of stress on
pregnanc#
Pregnancy
Complications
Iust as stress complicates pregnanc#, so can
pregnanc# create its own stress, as stated b#
a neonatal intensive care unit )LICB* nurse
who found herself hospitali=ed for preterm
laborJ 3-here are times when #ou canEt stand
it and all #ou want to do is to get out Oou
5now what it would do to #our bab#, but for a
moment, it doesnEt matter4 -he following
section describes a few of the ordeals
e$pectant mothers ma# have to face
)E* %ES$
>ome mothers su(er conditions that re'uire
bed rest and admission to the hospital%that
is, preterm labor at less than 88 wee5s with
bulging or ruptured membranes, severe
h#pertension, pre"eclampsia, placenta
previa, or placenta accreta -his often means
being in the patient role, far from home,
famil#, friends, and other supports
-here is growing debate regarding the
bene.ts of bed rest for pregnanc#
complications such as preterm labor and
h#pertension 2esearch is limited, and the
studies are generall# inconclusive )48,44*
!owever, bed rest is still
widel# recommended b# obstetricians for
various conditions As a result, a woman with
a high"ris5 pregnanc# ma# .nd herself
con.ned to a prison the si=e of a bed Be"
cause she is immobili=ed, the rest of her
famil# will have to perform her usual duties,
including care of other children ?$hausted,
the# ma# have diPcult# understanding the
iron# of :ust how grueling bed rest can be
?speciall# painful can be the ambiguit# of the
womanEs situation Although she is doing
ever#thing in her power to have a health#
bab#, there is no guaranteed outcome >he
ma# .nd herself cr#ing more, arguing more,
panic5ing more, and sleeping less Medica"
tions that slow or inhibit the uterine
contractions ma# magnif# her discomfort,
causing :itteriness, irritabilit#, or palpitations
Magnesium sulfate can produce a muscle
rela$ation so profound that one patient
described feeling paral#=ed
Chen a ps#chiatric consult is called, it is
often because the woman has reached the
point of wanting to Aee the hospital At these
times, the most important service the
clinician can provide is to listen to her frus"
tration and validate the sacri.ces she is
ma5ing for her bab# Comfort measures such
as free access to television and telephone,
assistance with long distance calls, or
providing a window view can also help
C!SE E+!(P"E A 86"#ear"old <atino patient
was hospitali=ed on a high"ris5 9B unit for
preterm labor at 8G wee5s gestation >he cried
in despair over being so far awa# from home
that her famil# could onl# visit on select
wee5ends >he had a /"#earold daughter who
was constantl# begging her to come home >he
was torn between the needs of this child and
fears for her unborn bab# At times, she was
overwhelmed with an$iet# and the impulse to
get up and run -he language barrier often
made it impossible for her to communicate her
da#"to"da# needs, deepening her sense of
isolation and helplessness
As soon as the consultant presented her
dilemma, the sta( moved this patient ne$t to a
>panish"spea5ing roommate !er mood almost
immediatel# lifted, and she was able to
complete her hospital sta#
Chen mar5ed an$iet# and sleeplessness are part
of the picture, the ps#chiatrist should consider
sleeping aids and low"dose ben=odia=epines, given
on an as needed basis In the authorsE e$perience,
patients tend to use these sparingl#, and
complications are rare At most, one bab# had a
temporar# decrease in reactivit# on monitoring,
with a normal ultrasound -his ris5 must be
weighed against the conse'uences of not
intervening,
which could include severe distress in the mother,
noncompliance with treatment, or even a
discharge against medical advice Medication is
discussed in more detail later
HYPE%E(ESIS ,%!&I*!%'(
!#peremesis gravidarum is a condition of
intractable vomiting during pregnanc# that
can result in electrol#te imbalance, weight
loss, 5etosis, acetonuria, andNor organ
damage if untreated Although mild nausea
and vomiting are e$perienced in most normal
pregnancies, h#peremesis gravidarum is
relativel# rare, occurring in less than 1K of
all pregnancies )46*
-o date, the onl# 5nown cause of this
condition is pregnanc# 2esearchers have
e$amined numerous biological factors that
ma# pla# a contributing role -hese include
elevated levels of human chorionic
gonadotropin hormone, h#perth#roidism, and
alterations in gastric p! and motilit# )4G*
+s#chological factors have also been studied,
including increased vulnerabilit# to stress and
decreased social supports, immaturit# and
e$cessive dependence on the mother, and,
.nall# )as noted previousl#*, s#mbolic
re:ection of pregnanc# )4G* !owever,
evidence"based data are limited, and much of
h#peremesis gravidarum remains a m#ster#
Chat is not enigmatic is the level of stress
resulting from this condition -here is no
aspect of life that is not severel# derailed
9ne woman statedJ 3I had to 'uit wor5, 'uit
law school, and sta# home all da# M#
QnewR husband gives me an allowance I
went shopping with m# mother and
vomited in the changing room4 Another
tal5ed about the e(ects on her self"imageJ
3ItEs hard to feel se$# when #ouEve got this
terrible breath all the time and #ouEre
surrounded b# cups of #our own spit4
9ccasionall#, patients welcome ps#chiatric
intervention 9ne woman became clinicall#
depressed, partl# in reaction to the isolating
e(ect of this illness >he improved with a
serotonergic antidepressant and visiting
nurse referral In most cases, however, the
overwhelming concern is the vomiting itself
and the desire for relief A receptive and
non:udgmental attitude on the part of sta( is
crucial, especiall# given earlier punitive
notions about h#peremesis being an 3oral
attempt at abortion4 )6*
*E!$H - -E$'S % #E.)%#
3?ver#thing #ou do for parents who have had
a loss will be remembered ?ver# single
nuance Because this is the onl#, onl# time
the# will get to spend with their bab#, the#
will remember ever#thing4 )from M>, whose
bab# died of cardiac malformations a few
da#s after birth* 2egardless of whether we
li5e it, it is at times of loss that our patients
are most aware of us
Medicine has shifted dramaticall# since the
mid19@7s in its approach to perinatal loss
and grief Bntil
the 19@7s, contact with the dead bab# was
3virtuall# unthin5able4 )4@*, and tran'uili=ers
were prescribed to dull the distress of the
parents -he loss was not viewed as
e'uivalent to the loss of a more mature child,
and parents were encouraged to get
pregnant again as soon as the# were
ph#sicall# able >C spo5e about her bab#
daughter, who lived onl# / da#s after being
born in the late 19G7s with severe ano$ic
brain damageJ 3-he nurse held her up behind
the nurser# glass, but we never got to touch
her -here was no closure -o this da# I
cannot visit m# husbandEs grave because it is
ne$t to her grave the pain is too raw4
-oda#, the standard of care is the e$act
opposite )4@* -he obstetric sta( encourage,
but do not push, parents to see, hold, and
name the bab#, no matter how premature or
damaged, to help them e$perience this
bab#Es life and death as real -he# often help
mothers put together a memor# bo$
containing pictures, clothing, a loc5 of hair,
and other ob:ects associated with the bab# A
nurse is available throughout this time to pro"
vide support +arents are advised to give
themselves time to grieve before attempting
another pregnanc# -he# are o(ered
information about supports in the
communit#, including bereavement
organi=ations and groups -he famil# or the
sta( ma# call the ps#chiatrist for an
evaluation or to provide additional support,
especiall# if there is concern about
depression in the mother 0rieving mothers
have repeatedl# emphasi=ed the importance
of being recogni=ed as parentsJ 3-hat was a
fact even though some cannot imagine it,4
said
M> >uch statements as 3IEm never going to
be the same4 need to be validated as
e$pressions of a basic truth, as well as
con.rmation of the bab#Es impact on this
parentEs life Mothers also value doctors 3who
seemed to feel responsible for us without
impl#ing something went wrong4 )M>*
Clinicians must be aware of their patientsE
obstetric histories &or the mother who has
lived through a previous miscarriage or
stillbirth, memories of her lost bab# ma# be
particularl# powerful during subse'uent
pregnancies 3Chen a mom gets near the
gestational age of the loss, ta5e care
?ver#one 5nows the e$act gestational age of
the babies the# lost that da# was one of
the hardest da#s of m# life4 )M>*
In conclusion, it is crucial that the clinician
honor the deep attachment of parents to
their babies, especiall# when there is a loss
As one parent stated, 3Imagine a love so
strong that sa#ing hello and goodb#e in the
same da# was worth the sorrow4
*(ES$IC !)'SE
More than 16K of pregnant women
report ph#sical and se$ual abuse
during pregnanc# )48* +regnanc# does
not protect women from abuse, and
there has been some controvers# over
whether pregnanc# itself is a
ris5 factor for abuse
In:uries place women at greater ris5 for
preterm labor and fetal loss Clinicians
must speci.call# as5 women about
whether the# are e$peri
encing abuse or fear being hurt b# their
partners be
cause the# are not li5el# to volunteer this
information 9rgani
=ations and toll"free crisis lines are available,
and sometimes provide information on small
cards that can be easil# hidden Meep in mind
that battered women are at greater ris5 for
death when the# attempt to leave the
relationship )49* A safet# plan mu
s
t be in place before this step is ta5en Most
organi=ations for survivors of domestic abuse
emphasi=e the importance of support and
education, cautioning against pushing women
to ta5e a particular action
*I--IC'"$IES .I$H )%E!S$-EE*I#,
2esearch has repeatedl# con.rmed the
bene.ts of breastfeeding for both babies and
mothers, and man# medications appear to be
relativel# safe during nursing )67* -his does
not mean, however, that breastfeeding is for
ever#one, or that ever#one who nurses feels
better &ar from being a purel# instinctual
behavior, it is a s5ill that must be learned b#
both mother and bab# >ome .nd the process
relativel# carefree, but others do not Man#
mothers initiall# .nd themselves e$hausted
and sore, with crac5ed or bleeding nipples
and hungr#, inconsolable babies Bnless
support is available, this state of a(airs can
lead to deh#dration for the babies and de"
spair for the mothers It is crucial that new
mothers anticipate the need for closer
monitoring of their babies during the initial
wee5s of lactation If the# have a mood
disorder, the# ma# need additional supports
to help prevent re"emergence of s#mptoms
due to disrupted sleep and other demands of
breastfeeding -he# should also be informed
about communit# supports, including <a
<eche <eague and local lactation consultants
Mothers who decide to switch to bottle"
feeding ma# e$perience needless guilt and a
sense of failure Clinicians should be read# to
provide additional reassurance and validation
for women in this situation
Psychiatric
*isorders
$HE !#$EP!%$'( PE%I*
In the past, clinicians maintained that
pregnanc# was a time of relative well"
being for women, including those with
ps#chiatric disorders )61* <ife would
be much easier if this were true
because man# women with mental
illness choose to discontinue their
ps#chotropic medications on learning that
the# are pregnant%fre'uentl# with
encouragement b# ph#sicians -he
motivation of ever#one concerned is to
protect the fetus from e$posure to drugs
Bnfortunatel#, studies show that this
practice ma# actuall# increase the ris5 to
mother and bab# )68,6/*
According to most statistics, pregnanc# does
not protect women from mental illness,
particularl# when there is a pre"e$isting
condition -he ris5 of depression appears to
be 17K to 1GK in women of childbearing age,
regardless of gestation In fact, one stud#
showed women scoring higher on measures
of depressive s#mptoms at /8 wee5sE
gestation than at 8 wee5sE postpartum )64*
-he impact of pregnanc# on bipolar disorder
is not clear, but recurrence of illness is not
uncommon, and the ris5 of relapse in treated
bipolar patients appears to escalate mar5edl#
with abruptl# discontinuing medication )64*
In one isolated e$ception, 0rof et al )66*
studied bipolar women with sustained well"
being o( lithium and found that the# did
better during pregnanc# than the 9"month
periods before and after
Man# schi=ophrenic women report a
worsening of their mental status during
pregnanc# )6G* 9bsessive"compulsive
disorder )9C1* appears to worsen with
pregnanc#, whereas the course of an$iet#
disorders during pregnanc# is variable, with
some women improving and others reporting
an increase in s#mptoms
$HE PS$P!%$'( PE%I*
Bnli5e pregnanc#, the postpartum period is
uniforml# considered a time of high ris5 for
women with ps#chiatric histories, especiall#
bipolar disorder ;iguera et al
)68* studied 171 bipolar women who had
discontinued lithium during pregnanc#,
comparing them with age"matched controls
Among those sub:ects who had maintained
stabilit# for the .rst 47 wee5s o( lithium, the
rate of recurrence during wee5s 41 to G4 was
@7K in postpartum sub:ects compared with
84K in nonpregnant controls
Comen with other ps#chiatric disorders are
also at substantiall# increased ris5 during the
postpartum period -hose who have su(ered
ma:or depression in the past have a /7K ris5
for postpartum depression )6@,68* -ri$ler et
al )69* studied 919 schi=ophrenic women
during pregnanc# and afterward -he# found
that 179 women )119K* decompensated
within G months after deliver#, compared
with onl# / )7/8K* during pregnanc#
Chen reviewing the literature, readers should
5eep in mind that there is no standard
de.nition of 3postpartum4 Investigators
stud#ing hormonal shifts immediatel# after
deliver# will probabl# be writing about
postpartum da#s -hose reAecting on the
stresses uni'ue to caring for a newborn will
be referring to months In 19G1, +a(enberger
)G7* noted that a woman was more li5el# to
be hospitali=ed ps#chiatricall# during the .rst
/7 da#s after childbirth than at an# other
time in her life 1>M"I; similarl# identi.ed 4
wee5s as
the time span for
3
postpartum onset
4
9
E
!ara and Se5ows5i )G
1* viewed 9 wee5s as the critical period for
postpartum depression when comparing
a(ected women with controls 2obinson and
>tewart )G8* described postnatal depression
as usuall#
3
within 1 to G months after deliver#
4
McLeil )G/* categori=ed postpartum p
s
#chosis as either
3
earl# onset
4
)within / wee5s* or
3
late onset
4
)up to G months* >ome authors have
considered an event postpartum if it occurred
within 1 #ear of deliver#
-here is also diversit# of opinion regarding
the inAuence of biological factors on
postpartum disorders -hus far, e(orts to
correlate the occurrence of postpartum mood
s#mptoms with hormone levels )estrogen,
progesterone, cortisol, or th#roid* have been
unsuccessful )G8* -here has also been no
conclusive evidence regarding
neurotransmitter s#stems or tr#ptophan
levels -here has onl# been a minor
association between depression and th#roid
d#sfunction in th#roid antibod#"positive
women )G8* Lumerous investigators insist
that mood must be a(ected b# the powerful
hormonal and ph#siological shifts that occur
with deliver#, predicting that improvement in
research techni'ue will ultimatel# elucidate
that relationship 9thers maintain that it is
the life changes occurring with birth and the
'ualit# of supports that determine the
motherEs emotional state
*EP%ESSI#
!ntepartum *epression
Clinicians fre'uentl# fail to recogni=e
antepartum depression because of its overlap
with normal s#mptoms of pregnanc#
)including insomnia, decreased energ# and
concentration, and appetite changes* -his
highlights the importance of in'uiring
speci.call# about low mood and loss of
pleasure or interest Man# obstetric programs
are advocating for more formal screening as
well
-o date, there are no oPcial standards for
ps#chosocial screening of pregnant women It
is also not clear whether screening actuall#
accomplishes its goals of identif#ing
individuals at ris5 and ma5ing them more
available for treatment +riest et al )G4*, in
collaboration with the Cochrane +regnanc#
and Childbirth 0roup, will be evaluating the
e(ectiveness of ps#chosocial screening with
the methods currentl# in use -he most
commonl# used tools are 3s#mptom"based4
self"report measures of maternal distress,
such as the ?dinburgh 1epression >cale,
andNor 3ris5"based4 indices for mental illness
during pregnanc#, such as the Antenatal 2is5
Tuestionnaire developed in Australia Both
tools appear to be most valuable when
combined with a clinical interview of the
women scoring as high"ris5 for depression
and an$iet# )G4*
2is5 factors for antenatal depression include
personal or famil# histor# of mood disorder,
marital d#sfunction and lac5 of spousal
support, increased number of children,
#ounger age of the mother, and low level of
education )G6,GG*
1epression during pregnanc# imposes
signi.cant ris5s on both mother and bab# It
is one of the strongest predictors of
postpartum depression, and man# depressed
mothers report that their s#mptoms began
well before deliver# )GG* A(ected women are
more li5el# to have poor nutritional status
and use drugs or alcohol, while being less
li5el# to obtain ade'uate prenatal care -heir
babies tend to be more withdrawn and
irritable )GG*
-here are currentl# no guidelines for the
treatment of depression during pregnanc#
)GG*%perhaps because the diagnosis is so
fre'uentl# missed, and perhaps because of a
general reluctance to prescribe an#
medications that might a(ect the fetus
Comen with mild to moderate s#mptoms
fre'uentl# bene.t from supportive
ps#chotherap#, cognitive therap#, or inter"
personal therap# )61* >pinelli and ?ndicott
)G@* found that interpersonal ps#chotherap#
appeared signi.cantl# more bene.cial on
measures of mood than the control
intervention )a parenting education program*
+s#chotherap# is therefore generall#
considered a .rst"line treatment for
antepartum depression
It is important to remember that man#
women have become debilitated b#
s#mptoms )eg, being unable to eat or sleep,
get out of bed, or ta5e care of other children*
before even admitting the# were depressed
9ne woman re'uired intravenous Auids
multiple times for vomiting related to severe
an$iet# and depression -his .nall# resolved
when she resumed the antidepressant she
had been ta5ing before pregnanc# Chen the
motherEs abilit# to manage her health and
her pregnanc# becomes :eopardi=ed,
medications and even hospitali=ation should
be considered in addition to ps#chotherap#
C!SE E+!(P"E A 86"#ear"old woman,
admitted for rupture of membranes with her
si$th child at /8 wee5s, later informed the sta(
that she had persuaded her spouse to brea5 her
water with a tool stolen from her midwife
Because her last bab# had been born
prematurel# and done well, she had assumed%
at least on a conscious level%that this bab#
would have a similar outcome Bnable to care
for her home and other children as well as she
thought she should, she could see no other wa#
to deal with her constant ph#sical discomfort
and fatigue >he had hoped that after deliver#
she would immediatel# regain her strength and
resume her regular chores 9n interview, she
described feeling overwhelmed, depressed, and
an$ious during most of this pregnanc#
-his patient was diagnosed
with ma:or depres
sion and generali=ed an$iet# >he denied
suicidalit# and e$pressed a sense of remorse
for the harm she could have caused her bab#
>he was treated with antidepressant
medication and referred for outpa
tient treatment >he and her husband

were evalu
ated b# Child +rotective >ervices )C+>* and
visiting nurse services with the intent of
monitoring their parenting and the safet# of the
children at home -he# were also referred to
communit# supports, in
cluding visiting nurse services and poss
i
bl# a home health care wor5er -his patient
E
s mood disorder ma# have been considered
both antepartum and post
partum because her .fth child was onl# 17
months old In these and other cases, it is
crucial that clini
cians help patients accept supports, in
c
luding ps#
chotherap#, and realisticall# e$plore the option
of medications during pregnanc#
Postpartum *epression
After birth, the health of mother and bab#
continue to be intertwined ine$tricabl#
+ostpartum depression interferes with the
mother,bab# relationship, thus placing the
entire famil# at ris5 )GG* 1epressed mothers
appear to have more diPcult# responding to
infant cues, fostering insecure attachment
behavior -heir children are more li5el# to
have signi.cant behavioral problems, such as
sleep and eating disorders, fre'uent temper
tantrums, and dela#ed language
development Maternal depression is also
associated with increased rates of accidental
in:ur#, child abuse, and child neglect )GG*
-he di(erential for postpartum depression
includes bipolar disorder, in which depressive
or mi$ed episodes are common )68*, baby
blues, and bereavement Bipolar disorder is
discussed in a later section
Baby blues is 'uite common, reported in
about 67K of women It is characteri=ed b#
mood s#mptoms, but lac5s the severit#,
persistence, or pervasive 'ualit# of
postpartum depression -he cardinal feature
is labilit#% women ma# describe cr#ing 3at
the drop of a hat4 or 3when something comes
on the television4 )G8* Clinicians should
consider a more serious diagnosis when there
is sleeplessness, persistent d#sphoria and
anhedonia, disturbance in realit# testing, or
loss of self"esteem
Bereavement after a loss )whether from a
miscarriage, stillbirth, traumatic pregnanc#
or deliver#, severe disabilit# in the infant, or
famil# strife* is characteri=ed b# depressive
s#mptoms, but there should be intervals in
which the mother e$periences some relief
from her pain After the initial shoc5 of loss,
grief tends to 3come in waves4 If it is
relentless, a diagnosis of depression should
be considered
Clinicall#, postpartum depression often
presents with prominent an$iet# and
obsessive thoughts or behavior 1epressed
mothers ma# worr# e$cessivel# about their
bab#Es safet# or feeding habits, interpreting
an# diPculties as evidence of their
inade'uac# )G8* Chen the# come for
treatment, the# often refer to themselves as
3cra=#4 or 3out of control4 9ne woman
e$pressed a sense of despair over her
husbandEs ease with their bab#, immediatel#
concluding that she was inept and ancillar#
Another woman attac5ed herself over her in"
abilit# to feel the happiness she was
e$pected to feel with 3such a good bab#4
Lumerous women report intrusive thoughts
and fears of causing some sort of harm to the
infant, either through loss of control or negli"
gence Although the incidence of actual
ph#sical harm to newborns is low, the
distress of the mother is 'uite high, and
famil# members ma# be alarmed as well 9n"
going support and monitoring are crucial to
preserving the motherEs self"esteem and
preventing a worsening of these s#mptoms
?ven if postpartum depression is not so
di(erent from other depressive episodes in
its biochemistr#, it is distinct in its crippling
e(ect on the womanEs self"image as a
mother, as well as its impact on the famil# at
a vulnerable stage
Although the general prevalence of
depression in postpartum women )1/K* does
not di(er substantiall# from that of age"
matched controls )17K*, certain subgroups
are at much higher ris5 for this disorder As
stated previousl#, women with a past histor#
of depression are at a /7K ris5 for
developing postpartum depression -hose
who have su(ered from a previous episode of
postpartum depression have a 67K ris5 )68*
+s#chiatrists have debated whether
postpartum depression should have a speci.c
diagnostic categor# 9n the one hand, studies
have not shown this disorder to be
biochemicall# distinct from other episodes of
depression 9n the other hand, the high rates
of recurrence for postpartum depression, as
well as its characteristic s#mptoms, do
suggest that depression during this period is
at least e$perienced in a uni'ue wa# b# the
women who su(er from it 2egardless of
outcome, the active debate has 5ept the
spotlight on this disorder as a ma:or public
health concern
+ostpartum depression rarel# progresses to
ps#chosis, which occurs in about 1 to 8 per
1,777 pregnancies )G8* -his potential was
tragicall# illustrated in the case of Andrea
Oates, who reportedl# drowned her .ve
children in the belief that she was saving
them from eternal damnation )G8* According
to records that have been made public, she
had su(ered three episodes of postpartum
depression, each increasing in severit# and
dangerousness 1uring the second episode,
she had become suicidal over impulses to 5ill
her children, and one ps#chiatrist had
reportedl# warned her about the danger of
further pregnancies )G8*
In the authors
E
e$perience, postpartum depression tends to
respond well to treatment -he women, fright
ened b# their s#mptoms but determined to
improve their functioning as mothers, tend to
form strong al
liances with their therapists and ps#chiatrists
-he# are generall# compliant with and
responsive to medica
tions, and man# have reported feeling calmer
a
nd better able to sleep even before the
e$pected onset of thera
peutic antidepressant e(ects ;isiting nurse
services can be particularl# helpful, providing
much needed support and monitoring of new
mothers who are homebound &or
breastfeeding mothers, t
h
ere are a number of antidepressants )to be
discussed later* that appear reasonabl# safe
for the bab#, especiall# with careful
monitoring )67*
2ecentl#, there has been interest in
proph#lactic antidepressant treatment for
women who have had at least one previous
episode of postpartum depression In one
stud# of 8/ such women )G9*, those who
chose to start antidepressant treatment
immediatel# after birth had a much lower
relapse rate )G@K* than those who elected to
have monitoring alone )G86K*
!#+IE$Y *IS%*E%S !#*
)SESSI&E/C(P'"SI&E
*IS%*E%
-he course of an$iet# disorders during
pregnanc# is variable In one stud#, the
ma:orit# )@@K* of women with panic disorder
had reported improvement during pregnanc#,
but the# also tended to have milder s#mp"
toms than the group )87K* that reported
worsening with pregnanc# )@7*
An$iet# is fre'uentl# prominent during
episodes of mood disorder, and reportedl#
accompanies pre" and postpartum depression
in up to 67K of cases )@1* It also can be part
of the prodrome for worsening a(ective
illness or even ps#chosis A complicated or
diPcult pregnanc# ma# cause high levels of
an$iet#, progressing to generali=ed an$iet#
or panic disorder as a result 9ne woman,
who had previousl# miscarried at 8/ wee5s,
began having panic attac5s as her ne$t bab#
approached this gestational age
As stated in a previous section, there is
growing concern about the e(ects of stress
and untreated an$iet# during pregnanc#,
especiall# in relationship to the
cardiovascular status of the mother )/G,/9*
and the mechanisms of preterm labor )86*
+anic attac5s can even be confused with pre"
eclampsia )@8*
+regnanc# and the postpartum period appear
to worsen the course of 9C1, and man#
women report that their s#mptoms .rst
began during pregnanc# )@/* +regnanc#"
associated 9C1 is often characteri=ed b#
comorbid ma:or depression, intrusive violent
thoughts, contamination obsessions, and a
good response to treatment with serotonin
reupta5e inhibitors As stated previousl#,
although the violent thoughts tend to be
distressing to the mother, the# are rarel#
associated with harm to the bab# !owever,
e$aggerated fears, rituals, procrastination, or
avoidance behaviors could cause harm b#
interfering with the motherEs self"care during
pregnanc# or bonding with the bab#
afterward )@/* Comen with 9C1 should be
aware of the possible e(ects of pregnanc#
and childbirth on their condition so the# can
ta5e measures to protect themselves
accordingl#
)IP"!% *IS%*E%
&or a bipolar woman, treatment planning for
pregnanc# should ideall# begin when she
reaches childbearing age In fact, it has
become the standard of care to test for
pregnanc# and provide contraception coun"
seling before beginning certain mood
stabili=ers, such as valproic acid );+A*, which
is associated with increased ris5 for neural
tube defects )@4*
Bipolar women who choose to become
pregnant )or .nd themselves pregnant* need
to be informed that the ris5 of relapse is high
when their medications are suddenl#
discontinued%about 67K with lithium )68*
-here is evidence that gradual taper
attenuates that ris5 and lengthens the time
period before recurrence )68* +atients who
have maintained long periods of stabilit# ma#
choose to attempt medication taper prior to
conception, with the plan of resuming
medications if necessar# after the .rst
trimester If the patient has dif.cult#
conceiving, however, this approach becomes
impractical
-reatment of bipolar patients during
pregnanc# is inherentl# complicated because
the 3.rst line4 mood"stabili=ing medications
all carr# some ris5 for congenital anomalies,
as is discussed later At the same time, the
untreated mood disorder imposes its own
ris5s, including conse'uences of depression
mentioned earlier Manic patients are more
li5el# to abuse substances or engage in high"
ris5 se$ual behavior, and ma# be more
vulnerable to altercations ending in violence
)G6* -he# ma# also have more diPcult#
compl#ing with prenatal care and measures
such as diabetic diet or bed rest to address
complications of pregnanc#, as described in
the following case
C!SE E+!(P"E A /8"#ear"old woman
admitted for preterm labor complained of
mar5ed an$iet#, sleeplessness, and being
unable to 3sit still4 for bed rest 0enerall#
gregarious, pressured, and highl# active, she
tried to occup# herself with paperwor5 and
3chores4 in bed 1espite clona=epam given on
an as needed basis and intensive support, her
sleeplessness continued, and she constantl#
felt compelled to get up, ma5e her bed,
organi=e and decorate her
room, or leave the ward for
3
one cigarette a da#
4
Chen not in motion, she found herself over
whelmed with cr#ing spells, as well as
memories of childhood trauma and a past
miscarriage -his patient became distressed
whenever sta( tried to discuss the po
s
sibilit# that she might have a mood disorder
>he refused to consider an# medications e$cept
for clona=epam, which she discontinued after
deliver# of her bab#
In the authorsE e$perience, man# e$pectant
mothers, especiall# those with bipolar
disorder, have their own ideas about
treatment In fact, the scenario of a woman
announcing she is pregnant and stopping all
her medications is probabl# more common
than that of one re'uesting help with an
anticipated pregnanc# -he clinicianEs .rst
challenge is to persuade patients to accept
ps#chiatric treatment and fre'uent
monitoring during pregnanc#%with or
without medications -he ne$t challenge is an
honest and realistic discussion about the
ris5s and bene.ts of medications >ome pa"
tients will insist on going through at least the
.rst trimester o( all medications, accepting
the ris5 of sudden discontinuation 9thers
ma# insist that the# will decompensate if an#
of their medications are changed, accepting
the potential teratogenic ris5 A third group
will report not 5nowing that the# are
pregnant until well into the second trimester
It is not uncommon for a clinician to research
and carefull# deliberate over a treatment
recommendation, onl# to .nd that the patient
has alread# ta5en the decision out of his or
her hands
-he individual treatment contract re'uires
both patient and clinician to openl# accept
ris5s%in one direction or the other%that
involve a developing fetus +atients who
become ps#chotic o( their medications or
who have a histor# of multiple
hospitali=ations should be encouraged to
continue their medications through the
pregnanc# If anticonvulsants are used for
mood stabili=ation, then folic acid should be
prescribed 9ne ma# consider graduall#
changing from ;+A to a mood stabili=er with
lower teratogenic ris5 )5eeping in mind that
the critical period for neural tube defects is
during the .rst 6 wee5s of gestation Q@4R*
An# modi.cations should be accompanied b#
more fre'uent appointments and monitoring
Consultation with a perinatologist or genetic
counselor ma# also be helpful +atients who
have had longer periods of stabilit# ma# want
to graduall# wean certain medications before
attempting to conceive -he# should be
encouraged to pursue fertilit# counseling to
shorten as much as possible the re'uired
time o( medications Active and informed
participation in treatment is crucial for both
patients and clinicians
&or pregnant women re'uiring maintenance
therap#, lithium has been considered a
treatment of choice )@4*, although there is
also growing interest in lamotrigine )@6,@@*
?stimates of lithiumEs teratogenic ris5 are
variable and are discussed in a later section
-here appears to be a small increase in the
rate of congenital anomalies, including
cardiac malformations, with maternal use of
lithium during the .rst trimester !owever,
lithium is considered safer than ;+A and
carbama=epine, which are associated with
increased ris5 for spina bi.da among other
anomalies &re'uent monitoring of mother,
bab#, and lithium levels are important,
particularl# near the time of deliver#, when
there are mar5ed shifts in the motherEs Auid
and electrol#te balance >ome researchers
have suggested that lithium be given in / to
6 dail# doses in order to avoid high pea5s of
serum concentration )@4* -here is
controvers# over whether the lithium dose
should be partiall# tapered during the last 17
da#s before deliver# )68,@4* >ome authors
maintain that this will help prevent neonatal
to$icit#, whereas others e$press concerns
about the high ris5 for relapse in the
postpartum period
<amotrigine is now being prescribed as a
mood stabili=er and appears particularl#
e(ective in preventing depressive episodes in
bipolar patients )@6,@G* -his ma# be
especiall# relevant for pregnant bipolar
women, who appear to have more depressive
or d#sphoric"mi$ed episodes than
nonpregnant controls%G/K versus /8K of
recurrences according to ;iguera et al )68*
-hus far, data from the <amotrigine
+regnanc# 2egistr#
)@@* suggest that the overall incidence of
ma:or malformations with .rst trimester use
of lamotrigine in monotherap# is not
signi.cantl# di(erent from that of the general
population !owever, the registr# is not de"
signed to detect increases in speci.c
malformations -he teratogenic ris5 increases
substantiall# when lamotrigine is mi$ed with
other anticonvulsants in combination therap#
)@@* <amotrigine rapidl# and easil# crosses
into the placenta )@8* !owever, there appear
to be onl# isolated case reports on adverse
neonatal effects Clearance appears to
progressivel# increase during pregnanc# until
/8 wee5sE gestational age, reaching a pea5 of
more than three times baseline, and then be"
gins to decline )@9* -his ma# have
implications for the dosage re'uirement of
the mother
Clinicians have also treated patients with
alternative agents, such as high"potenc#
neuroleptics or ben=odia=epines, given in
small dail# doses or on an as needed basis
-he ePcac# of this approach is not 5nown,
but the intent is to minimi=e the total
e$posure to medications In addition )as is
discussed later*, certain ben=odia=epines and
classical antips#chotics are considered to
have relativel# low teratogenic potential
1uring the postpartum period, bipolar
patients are at particularl# high ris5%it has
alread# been noted that relapse rates are as
high as @7K for those who are untreated
)68*, and postpartum ps#chosis reaches a
rate of /7K for bipolar mothers )A C
;iguera, personal communi
cation, April 9, 8776*
Lumerous investigators are recommending
proph#lactic treatment, which might include
resuming mood stabili=ers during the wee5
before or immediatel# after deliver# )87*
Clinicians must balance the ris5 of neonatal
to$icit# or withdrawal against the ris5 of an
untreated postpartum mood disorder
PSYCH$IC *IS%*E%S
&or schi=ophrenic women, both pregnanc#
and the postpartum period impose ma:or
hardships -o begin with, there is a relativel#
high incidence of povert# in this population,
and social supports are fre'uentl# in"
ade'uate Man# women lose their housing
arrangements when the# become pregnant
and have diPcult# obtaining ade'uate
mental health and prenatal care )G6* -he
babies are at greater ris5 for pregnanc# and
birth complications, low birth weight, preterm
birth, and perinatal death )81,88*%primaril#
because of increased incidence of maternal
smo5ing, substance abuse, and man# other
general ris5 factors for obstetric
complications
>chi=ophrenic patients and an# woman with a
histor# of ps#chotic s#mptoms should be
closel# monitored during pregnanc# and the
postpartum period because ps#chosis can be
particularl# dangerous during this period of
time 9ne patient presented to +lanned
+arenthood at /G wee5sE gestation,
demanding an abortion Another stabbed
herself in the abdomen during her si$th
month of pregnanc#, after .rst stabbing her
older child >he later claimed she was tr#ing
to save both children from traumas she had
su(ered in her own life
-he postpartum period appears to be the
time of greatest ris5 for ps#chosis in women
-he actual incidence is 1 to 8 per 1,777
postpartum women, but the relative ris5 of a
hospitali=ation for ps#chosis is about
81@ during the .rst /7 da#s after giving
birth and 18@ during the .rst 97 postpartum
da#s )8/* >ome authors have viewed
postpartum ps#chosis as a uni'ue phe"
nomenon, with its own etiolog# and clinical
presentation )84* !owever, most see this
disorder as similar to other ps#chotic
episodes, but triggered b# the stresses of
pregnanc# and deliver# )8/*
+ostpartum ps#chosis is generall# viewed as
an affective disorder )8/*, and ;iguera
recommends that it be treated as a variant of
bipolar disorder >he estimates that about
G7K of postpartum women who become
ps#chotic have a bipolar course Bipolar
women have a 87K to /7K ris5 for this
disorder, and women who have had a
previous episode are at @6K to 97K ris5 for a
recurrence with subse'uent births )A C
;iguera, personal communication, April 9,
8776*
&re'uentl#, there is an as#mptomatic period
of 8 to / da#s after deliver#, followed b# a
prodrome of worsening insomnia and
agitation )84* >#mptoms of postpartum
ps#chosis often include labilit# and mar5ed
disorgani=ation of thoughts and behavior,
bewilderment, and poor memor# even in the
face of normal cognitive testing )84*
C!SE E+!(P"E A /8"#ear"old woman
presented a wee5 before deliver# with a
complaint of an$iet# and sleeplessness >he did
not share her histor# of a brief manic episode 4
#ears previousl# >he reported feeling calmer in
the hospital and was discharged with referrals
Cithin 1 wee5, she was brought to the hospital
in an agitated and disorgani=ed state, thrashing
and stri5ing out at an#one who came near >he
later reported that she had been having
Aashbac5s of childhood se$ual abuse, hearing
the voice of her perpetrator telling her that if
she told an#one about him she would be put in
an insane as#lum >he gave birth and
responded 'uic5l# to low"dose antips#chotic
medication >he and her famil# agreed to have
her observed at home on a 84"hour basis with
intensive outpatient treatment and visiting
nurse services 1a#s later, her famil# brought
her bac5, again combative and frightened,
hallucinating, and sleepless >he was
hospitali=ed ps#chiatricall# for about 8 months,
in a severel# mi$ed depressive state 3It was
li5e a dar5 hole,4 she stated 3Oou 5now #ou
shouldnEt 5ill #ourself but #ou canEt see an#
wa# out4 >he ultimatel# recovered on lithium
and an at#pical antips#chotic, and remained
stable on lithium for more than 8 #ears before
moving to a di(erent area
-his patient initiall# presented as an$ious but
ver# reserved and deliberate in her personal
st#le -here was no irritabilit#, pressured
speech, or elation It was onl# when she was
readmitted in a ps#chotic state that her mother
described an episode of sleeplessness and
ps#chosis 4 #ears previousl# -he patient
improved so 'uic5l# on low"dose antips#chotic
medication that she was initiall# diagnosed with
a brief reactive ps#chosis )aggravated b#
possible posttraumatic stress disorder* due to
the stress of imminent deliver# After she gave
birth, however, her course was classic for a
bipolar variant of postpartum ps#chosis, in
which there was the initial brief period of well"
being followed b# a mar5edl# disorgani=ed
state -his patientEs case highlights the
importance of diagnosing an underl#ing mood
disorder, as well as maintaining a high level of
vigilance for s#mptoms during the postpartum
period
+erhaps the most daunting tas5 facing a
clinician is determin
ing which infants might be at ris5 for harm
from their mothers As a rule, women who
murder newborns within 84 hours after birth
have not been found to be ps#chotic at the
time )86* !owever, moth
ers who 5ill after this point are often
responding to delu
s
ions or hallucinations, tr#ing to save children
from what the# perceive as an evil destin#, or
the# are suicidal )G8* -he# ma# also have
violent outbursts leading to accidental death
(aternal
Capacity
-here are times when a ps#chiatrist will be
re'uired to evaluate a motherEs capacit# to
ensure the care and safet# of her newborn
bab# outside the hospital 0enerall#, the
mother has a histor# of mental illness or ad"
diction )9ther red Aags for the obstetric
team include lac5 of prenatal care,
homelessness, isolation from supports, lac5
of preparation for the bab#, or unusual
behavior with the bab# or sta( after birth*
-his is not an eas# tas5, and if one e$pects to
provide an absolute answer, it becomes
impossible 9ver the #ears, the authors have
arrived at certain guidelines to structure this
wor5 more realisticall#
&irst, the most important mission here is not
to predict the future based on a diagnostic
evaluation, but rather to assist the mother,
her famil#, health care wor5ers, and agencies
such as C+> in planning for the care and
safet# of a bab# Ideall#, ever#one together
will be e$ploring supports and deciding on
the level of intervention re'uired for
accomplishing this goal -he 'uestions that
arise are then fairl# straightforwardJ Chat
5ind of da#"to"da# supervision does this
mother needU 1oes she have diPcult#
functioning alone or under stressU If so,
would regular therap# sessions and visits
from a nurse be suPcient, or would she
re'uire a case manager and an intensive da#
treatment programU Could a supportive
residence be appropriateU Is a spouse, group
of relatives, or partner prepared to assume
guardianship at times when she is unable to
parentU
>econd, the motherEs willingness to
ac5nowledge the need for support and
monitoring is generall# even more important
than the severit# of her condition 1enial and
isolation are problematic for an# mother,
child pair, but fran5l# dangerous when the
mother has a mental illness or addiction
+erhaps the most worrisome presentation is
of a mother who tests positive multiple times
for cocaine and claims the tests are wrong In
this case, there is generall# no opportunit#
for intervention or treatment planning, and
the mother is essentiall# unpredictable 9ne
can then onl# rel# on observation from
outside agencies, such as C+>
C!SE E+!(P"E A 89"#ear"old patient with a
histor# of bipolar disorder and borderline
personalit# traits presented to the obstetric
ward as articulate, well related, and a(ectionate
with her bab# >he described her mood as
stable on medications since her last
hospitali=ation for suicidal behavior about 8
months previousl# >he declared she would do
an#thing for her bab#, including accept 84"hour
supervision !owever, some behavior in the
past suggested otherwise >he had recentl#
become homeless after leaving a supervised
residence for mentall# ill mothers, stating 3I
couldnEt tolerate the structure4 According to
the sta( there, she had not been attending
treatment sessions or following house rules
>he was not viewed as being able to function in
their program, even if she applied for
readmission >he had no famil# supports and
had last been hospitali=ed about 8 months
previousl# for suicidal behavior
Appearing unable to cooperate with constant
supervision, this patient was assessed at the
time as being too unpredictable to care for her
bab# outside the hospital C+> placed the bab#
in foster care after consulting her regarding an#
preferences she might have for the bab#Es
temporar# guardian
C!SE E+!(P"E A /8"#ear"old woman with a
histor# of drug use and possible mood disorder
presented as guarded and irritable with the
obstetric sta(, becoming loud and oppositional
when frustrated >he fre'uentl# re'uired
reassurance and clari.cation of unit procedures,
and was initiall# indignant to be seen b# a
ps#chiatrist As time passed, she appeared
calmer and more approachable After she
delivered her bab#, she re'uested an increase
in her antips#chotic medications !er manner
with her bab#, who was admitted to the LICB,
was reportedl# an$ious but loving
-his patient had been sta#ing the last 4 months
at a supervised residence for mentall# ill
mothers and planned to return there after
discharge >he hoped to wor5 with the
residence sta( to obtain her 0?1 and ultimatel#
transition to her own home >ta( at the
residence described this patient as engaged in
her treatment program and helpful with the
other mothers !er urine drug screens were all
reportedl# negative during her sta#
-his patient was assessed as having the
capacit# to provide for the care and safet# of
her bab# with the support of her residential
program Although occasionall# guarded, she
had shown over a period of months that she
responded well to structure and appeared
highl# motivated to continue her treatment
C!SE E+!(P"E
9ne woman with cognitive im
pairment and previous C+> involvement was
'uite convincing in h
er description of how she would care for her
bab# in a famil# shelter >he also spo5e at some
length about how she maintained a relationship
with two other children, who reportedl# lived
awa# from her !er C+> wor5ers did not
'uestion this woman
E
s a(ecti
o
n for her children, but gave an account of an
older infant becoming severel# ill while living
with her, ultimatel# having to be placed -he#
had found her living 'uarters to be .lth#, and
the bab# bottles crusted over with la#ers of
dried, spoiled mil5
Collateral information is essential, especiall#
with regard to the patientEs parenting histor#
In the hospital, even severel# impaired
mothers become attached to their children,
and it is e$tremel# rare to encounter a
woman who does not appear loving with her
newborn )unless of course her mental status
is a(ected b# being sic5, in pain, andNor
recovering from surger#* A single diagnostic
interview, even when thorough, can be
deceptive
$HE .(!# .H
%E-'SES $%E!$(E#$
In some cases, the ps#chiatrist must assess
the capacit# of a woman before she gives
birth, especiall# when she is refusing
treatment and demanding to leave the hos"
pital against medical advice
A common scenario is the woman who
endures a long period of bed rest, then insists
on leaving the hospital 9ften, there is a crisis
at home or a toddler who needs her care -he
stress of such conAicting demands is severe,
but so is the ris5 to mother and bab# outside
the hospital Most of these patients decide to
sta# after venting their concerns and
receiving additional support from their
families and sta( In rare cases, however, a
woman will ac5nowledge her condition and
the ris5s involved, but remain determined to
leave% sometimes promising to return when
the crisis at home is resolved If she can
present an outpatient alternative for
treatment, she will probabl# be released
!owever, the sta( should ma5e ever#
reasonable e(ort to encourage her to sta# or
return as 'uic5l# as possible
9ccasionall#, a woman ma# demand to
leave, insisting there is no ris5 or that she
has no concerns in this area In this case, her
:udgment might be impaired, and she
re'uires a ps#chiatric evaluation
C!SE E+!(P"E A 8/"#ear"old woman with
poorl# controlled diabetes demanded to leave
despite high and widel# Auctuating blood
sugars >he
stated that her husband had left her so she did
not care what happened to her In fact, she had
stopped chec5ing her blood sugars or ta5ing
insulin for several wee5s >he admitted to
feeling hopeless and overwhelmed, with
fre'uent suicidal thoughts >he was diagnosed
with depression and placed on constant
observation in the hospital, where she sta#ed
until her blood sugars improved, her suicidal
thoughts lifted, and further wor5 was done with
her marital crisis
In this case, the patient had shown a pattern of
endangering herself and her pregnanc# in
reaction to her loss <eaving the hospital would
have simpl# been another warning )heard or
not* about the increasingl# lethal impact of this
separation on her
C!SE E+!(P"E A 19"#ear"old woman
demanded to leave, having ruptured
membranes with twins at 8/ wee5s >he
claimed that nothing would happen to her or
the twins as long as she was at home !er
mother implored the sta( not to release her,
claiming that her daughter had a long histor# of
impulsive behavior and reall# was not
processing what was being said to her -he
patient was placed temporaril# on constant
observation )which she did not resist* until her
mother convinced her to sta# >he was also
o(ered additional supports such as free
telephone service, and her .ancV was allowed
to sta# with her for additional hours >he
ultimatel# re'uested and received
antidepressant treatment and a ps#chiatric
referral
-his patient did not appear to process the infor"
mation presented to her about the
conse'uences of leaving the hospital >he was
totall# preoccupied with and focused on her
immediate frustration and demands for
discharge >he would not give lip service to an#
warnings regarding this action, even after being
told b# sta( that this would ma5e it easier for
her to leave !er :udgment appeared to be
seriousl# compromised b# the stress of this
crisis 9nce measures were ta5en to support
her sta# and prevent her from precipitousl#
leaving, this patient became less an$ious and
more engaged in treatment
-he evaluation of a pregnant patient who
refuses treatment is similar to that of a
mentall# ill mother preparing to be
discharged from the hospital In the former
case, a reasonable )although seldom optimal*
plan for the safet# of mother and bab# is a
5e# element of the assessment 2efusal or
inabilit# to participate in such a plan ma# be
evidence of impaired :udgment
Substance
Abuse
Caring for addicted patients during
pregnanc# is perhaps the most diPcult
challenge in all of medicine As soon as
clinicians are aware that drugs are an issue,
the# are bound to e$perience a sense of
helplessness and fear for the bab# !owever,
man# patients 5eep their use a secret, or
simpl# do not see5 prenatal care -he .rst
tas5 of the clinician is to accept that
substance abuse is a common problem and
routinel# in'uire about it -he second tas5 is
to create an alliance that 5eeps the patient
coming to appointments Mac0regor et al
)8G* observed that regular prenatal care was
the most important determinant of pregnanc#
outcome, regardless of whether substance
use was continued
-he third tas5 is to help the patient obtain
treatment 9nl# about 6K to 17K of pregnant
women in need of substance abuse
treatment actuall# receive it )8@* Clinicians
often fail to detect the addiction, and
patients ma# have a host of reasons to
conceal it, including fear of losing child
custod# or being prosecuted for child abuse
)88* +unitive measures, such as removal of
newborn infants from their mothers solel# on
the basis of a positive drug test, ma# serve
onl# to alienate patients from care and ma5e
clinicians reluctant to order to$icolog#
screens )88* An additional barrier is isolation
from supports and resources +atients
fre'uentl# report lac5 of programs,
transportation, or child care
-he following paragraphs review e(ects of
commonl# used substances on the
developing fetus Meep in mind that addicted
patients often simultaneousl# smo5e, abuse
multiple drugs and alcohol, and have poor
nutrition and health status )89* +s#chiatric
assessment is an important part of the care
of drug"abusing patients% an estimated G7K
have a comorbid ps#chiatric condition )97*
Clinicians need to be aware of resources in
the communit# because man# patients do
not 5now their options
!"CH"
It is estimated that 87K of pregnant women
consume some alcohol during pregnanc#
)91*, and that 8G million infants are born
each #ear in the Bnited >tates with
signi.cant alcohol e$posure and a wide range
of abnormalities )98* 9ne 199G surve# )9/*
indicated that about 67,777 children showed
signs of fetal alcohol e(ects, whereas 6,777
children were born with fetal alcohol
s#ndrome )&A>*, the leading 5nown cause of
mental retardation in the Bnited >tates )98*
Appro$imatel# 86K of &A> children have
some degree of mental retardation )98*
Alcohol persists in the amniotic Auid about
twice as long as in the maternal bloodstream
As a result, the fetus is e$posed to higher
levels of alcohol for longer
periods of time than the mother is e$posed
In addition, cigarette smo5ing ma#
e$acerbate the teratogenic e(ect of prenatal
drin5ing )94*
CC!I#E
According to a stud# b# >hi5les in 1997, 6
million Americans were estimated to use
cocaine dail#, while 87 million use it once per
month or moreD at least half of these are
women of childbearing age )96* -he .rst
nationwide surve# of /G hospitals found an
average of 11K of women using cocaine
during pregnanc#, with the percentage
ranging from 78K to 88K )9G*
Comen who use cocaine are at greater ris5
for no prenatal care, shorter gestation,
premature rupture of membranes, preterm
labor and deliver#, spontaneous abortion,
abruptio placentae, decreased uterine blood
Aow, and death -he babies are more li5el# to
su(er ma:or congenital anomalies involving
the brain, genitourinar# tract, bowel, heart,
limbs, and face -he incidence of intrauterine
growth retardation, fetal distress, and
mortalit# is also increased Cerebrovascular
accidents have been reported in both mother
and fetus )89*
HE%I#
!abitual use of opiates during pregnanc#
does not increase the ris5 of congenital
anomalies, but there are other potential
adverse outcomes +regnant heroin addicts
and their children often develop severe
infections related to intravenous drug use,
such as hepatitis, s#philis, and !I; Abruptio
placentae, neonatal withdrawal, preterm
birth, and fetal growth retardation are also
associated with maternal opiate use Children
with in utero e$posure di(er from nondrug"
e$posed children on measures of cognitive
abilities, motor development, and behavior
!owever, the postnatal environment appears
to inAuence the childrenEs developmental
progress more than prenatal e$posure to
heroin )89*
A number of authors have recommended that
withdrawal from heroin or methadone not be
attempted after /8 wee5sE gestation because
of the possible ris5 of abruptio placentae,
preterm labor, premature rupture of mem"
branes, or fetal death in more advanced
pregnanc# )89* Methadone is most
commonl# used as maintenance treatment
for pregnant, heroin"addicted mothers, but its
ePcac# is controversial Most infants )@7K,
97K* with chronic in utero e$posure to
methadone su(er from abstinence s#mptoms
)89*, generall# re'uiring e$tended
observation in the hospital !owever,
because of dail# dosing, man# methadone
programs provide structure and compulsor#
monitoring that is not possible in other
settings +atients are generall# e$pected to
give random urine samples for to$icolog# and
have regular sessions with their drug
counselors -his level of care would augment
and perhaps improve compliance with regular
prenatal care
C!##!)I#I*S !#* $)!CC
About /K of Americans use mari:uana dail#,
and 17K to 16K use it once or more per
month ?stimated rates of use during
pregnanc# var# from /K to about 87K )9@*
-hus far, mari:uana use during pregnanc#
appears to be associated with mild fetal
growth retardation and maternal lung
damage, but more research is needed to
evaluate long"term e(ects )89* Cigarette
smo5ing has been associated with increased
ris5 of spontaneous abortion, placenta
previa, and abruptio placentae )88*
Psychotropic
(edications
-he most critical period for the introduction of
congenital anomalies is the .rst trimester
)speci.call# the .rst 68 da#s postconception*,
a time when most women are unaware of
being pregnant )89* It follows that preven"
tion of birth defects should ideall# begin
before conception ever occurs%perhaps as
soon as a woman reaches childbearing age
because up to 67K of pregnancies are
unplanned )98* Comen are routinel# warned
to avoid radiographs, radioactive materials,
and to$ins such as mercur# or lead +ublic
service announcements also caution against
use of alcohol, drugs, and tobacco during
pregnanc# -he medical communit# is clear
regarding these ha=ards to unborn children
!owever, there is much more ambiguit# in
the area of medications, a huge arra# of
potentiall# dangerous chemicals that some
women need to ta5e ever# da# An# decision
in this area re'uires a realistic assessment
and careful weighing of ris5s and bene.ts
$YPES - %IS0 I# P%E,#!#CY
Chen evaluating medications, clinicians and
researchers are generall# loo5ing at the
following t#pes of ris5J )a* organ
malformation or teratogenesis, )b* fetal
e(ects,
)c* neonatal e(ects, and )d* long"term
neurobehavioral se'uelae )99* It is important
to remember that damage associated with a
particular medication ma# actuall# be caused
b# the condition being treated, rather than
drug to$icit# )177* &or e$ample, neonatal
irritabilit# and decreased activit# are
associated with both e$posure to certain
antidepressants and maternal depression
itself )171*
+atients tend to overestimate the potential
dangers of medications, as indicated b# one
stud# of women presenting to a teratogen
information service )-I>* for consultation
Chen as5ed about the possibilit# of mal"
formations with the medications in 'uestion,
the women gave a mean response of 84K, a
high rate, even for agents 5nown to be
nonteratogenic )178* -his mind"set could
lead to unnecessar# fear and even a sense of
pressure to terminate a pregnanc# 1uring
therapeutic trials of
Auo$etine, the elective abortion rate was as
high as /7K )17/* -his .nding highlights the
need for prenatal counseling in pregnant
women on medications
$eratogenicity
A teratogen is de.ned as an# agent that can
produce a permanent abnormalit# of
structure or function in an organism e$posed
during embr#onic life )177* &or e$ample,
;+A, which is associated with increased inci"
dence of neural tube defects )1K,8K*, as
well as fetal valproate s#ndrome, is
considered teratogenic )174* -?2I>, a -I>
organi=ation that provides a database as well
as other information, also includes in this
de.nition agents that produce permanent
abnormalities through to$icit# to the fetus
)177*
Before implantation in the uterus, which
occurs about 1 wee5 postconception, the
blastoc#st is separate from the mother and is
essentiall# protected from substances
transported through maternal circulation -he
period of the embr#o starts with implantation
and e$tends through the .rst 68 to G7 da#s
postconception -he organs and tissues of the
unborn bab# are being formed during this
period, which is also called organogenesis
<ethal malformations present as spontaneous
abortion, which often occurs before
recognition of the pregnanc# )99* Congenital
anomalies are detected in appro$imatel#
/6K to 6K of newborns )176* -he true
fre'uenc# of anomalies is believed to be
almost twice this .gure because 177K
detection is not usuall# achieved until about 6
#ears of age Anomalies are more fre'uent in
miscarriages and stillbirths, particularl# .rst"
trimester miscarriages )99*
Animal studies are traditionall# used to
assess the teratogenic potential of
medications, and are part of the B> &ood
and 1rug Administration )&1A* approval
process !owever, the most fre'uentl# used
animal models are rodents, resulting in G7K
speci.cit# and sensitivit# of the studies
)17G* Investigations of nonhuman primates
#ield much better prediction of the human
response, with
97K sensitivit# and speci.cit#, but are orders
of magnitude more e$pensive In addition, a
lac5 of malformations in e$posed animals
does not guarantee that a drug is safe in
humans -his was tragicall# illustrated in the
case of thalidomide, responsible for a
generation of babies with severe limb
malformations, among other anomalies
)17@* Lumerous animal models with in utero
e$posure to thalidomide did not show birth
defects )178*
-he onl# true assessment of medication
safet# comes from human studies, and even
these must be constantl# updated &or
e$ample, until 1981, ;+A was considered
relativel# safe for use in pregnanc# 9nl# one
uncon.rmed case of birth defects from ;+A
was reported between 19G9 and 19@G It was
not until the 1987s that clinicians began to
identif# babies with clusters of anomalies
)fetal valproate s#ndrome* and neural tube
defects )174* Bnfortunatel#, teratogens
continue to be discovered onl# aft
er numerous children have alread# been born
with malformations )99*
-etoto1ity
1uring the fetal stage, growth through cell
multiplication is the predominant event,
accompanied b# some cell migration
&etoto$ic agents most commonl# cause
growth retardation 1isrupted histogenesis,
fetal death, or stillbirth can also occur
>ome agents, including warfarin and cocaine,
ma# attac5 normall# developed organs b#
interrupting blood Aow or otherwise causing
cell necrosis )99* -he result could be an
abnormalit# mimic5ing an organ malfor"
mation occurring earlier in development
-hus, there are rare conditions in which
medications cause serious congenital
anomalies during the second trimester -?2I>
would consider warfarin and Coumadin to be
teratogens, even though the damage
occurred after the period of organogenesis
9thers might, more strictl# spea5ing,
categori=e these agents as fetoto$ic
#eonatal $o1icity
-he fetus has a lower hepatic e$cretion rate
than the mother and has more diPcult#
tolerating pharmacologic compounds )179*
Leonatal to$icit#, or perinatal s#ndrome, can
result from e$posure to certain medications
during the third trimester or at the time of
deliver# -he s#mptoms are variable and
generall# time limited, lasting from hours to
months after birth ?$amples of neonatal
to$icit# include transient metabolic abnor"
malities, h#pogl#cemia, withdrawal
s#ndromes, and h#potonia )3Aopp# bab#
s#ndrome4* )99*
1ata on fetal and neonatal e(ects of
medications are still limited, generall#
consisting of isolated case reports with
almost no case"controlled studies Cause,
e(ect relationships are largel# unclear%what
is described as to$icit# in one report ma# be
named withdrawal in another ?ven less clear
are the magnitude of ris5s involved and the
e(ects of medication dosage
9ne e$ception, however, is the e(ects of
methadone, which are relativel# well
understood and predictable Comen treated
with methadone late in pregnanc# usuall#
give birth to babies with neonatal narcotic
withdrawal s#mptoms -he presentation ma#
var# but tends to include h#pertonicit#,
tremor, irritabilit#, diarrhea, and vomiting
)117* >#mptoms are usuall# observed in the
.rst da#s after birth, but the onset ma# be
dela#ed for 8 to 4 wee5s -hese e(ects,
although prolonged, are still time limited #eurobeha2ioral Se3uelae
-here is growing concern about the long"
term e(ects of prenatal e$posure to
medications, particularl# the
neurobehavioral se'uelae -he
developing brain is shaped through
comple$ mechanisms of cell migration,
di(erentiation, and programmed cell
reduction or 3pruning,4 which continue
throughout intrauterine development and
long afterward )111* <ittle is 5nown about
what happens to these processes when a
pregnant mother ta5es medications that alter
neurotransmitter levels In a similar vein,
'uestions are being raised about the e(ects
of maternal illnesses, including mood disor"
ders, which also a(ect neurotransmitter
levels )99* <ongitudinal studies of prenatall#
e$posed children are the onl# wa# to begin to
address these 'uestions
Mnowledge in this area is still in the 3infant4
stage, given the challenges inherent to
longitudinal studies >o far, however, the
results of the longer"term studies appear to
follow trends suggested b# e$amination of in"
fants at birth Medications associated with
higher teratogenic ris5, such as ;+A, are also
associated with more adverse outcomes
#ears later 1ata seem to be more reassuring
with medications carr#ing little or no
teratogenic ris5 SPECI-IC C"!SSES -
(E*IC!$I#S I# P%E,#!#CY
-his subsection describes ongoing research
on some of the more widel# used
ps#chotropic medications Because the data
are constantl# evolving, the goal here can
onl# be to give readers a starting point for
their own in'uiries in this .eld
!ntidepressants
Teratogenicity
-o date, the antidepressants, especiall#
selective serotonin reupta5e inhibitors )>>2Is*
and tric#clic antidepressants )-CAs*, have not
been associated with an overall increased
incidence of ma:or malformations in babies
e$posed during the .rst trimester &luo$etine
is the best studied of the >>2Is, with multiple
case"controlled studies and registr# data
)64,118,11G* 9nl# one stud# showed a
mi$ed result regarding minor malformations
)118*
1ata are less e$tensive for the other >>2Is
but show similar results )11@,119* 9ne more
recent e$ception, however, is a retrospective
stud# b# 0la$o>mithMline loo5ing at ma:or
congenital malformations in infants born to
/,@74 women ta5ing antidepressants during
the .rst trimester of pregnanc# )187,181*
-he .nal anal#sis is pending, but thus far, the
prevalence of congenital malformations in the
paro$etine group was found to be 8/ of 68@
infants with .rst"trimester e$posure )4/GK*
-his represented an increased ris5 as
compared with other antidepressants )odds
ratio Q92R 887D 96K con.dence interval QCIR
1/4,/G/* -here was also an increased
prevalence of cardiovascular
mal
formations for paro$etine compared with
other an
tidepressantsJ 14 of @74 e$posed infants, or
19K )92 878D 96K CI 17/
,
48/* ;entricular septal defect oc
curred in 17 of these 14 infants )187,181*
9ne must 5eep in mind that in the
Bnited >tates
the ov
e
rall prevalence of congenital malformations is
estimated at /K &or cardiovascular
malformations alone, the overall estimated
prevalence is 1K )188* In this stud#, there
were other antidepressants with an increased
92, but the numbers were too small for
a
96K CI
!allberg and >:oblom )18/* performed an
e$tensive review of studies on >>2Is during
pregnanc# and lactation up to 877/ Included
were .ndings of the >wedish Birth 2egistr#
)1996,>eptember 877/*, in which the rate of
congenital anomalies for children e$posed to
>>2Is during the .rst trimester was 89K
)18/ a(ected among a total of 4,891* -his
did not di(er from the e$pected rate among
none$posed children Lo particular t#pe of
malformation was overrepresented &or indi"
vidual >>2Is, n 6@4 for Auo$etine )//K
malformations*, n 1,G9G for citalopram )/1K
malformations*, n @78 for paro$etine )/4K
malformations*, and n 1,7G@ for sertraline
)87K malformations*
-here is some concern regarding a
nonsigni.cant increase in the rate of
spontaneous abortions in >>2I"treated
women )eg, 1/6K vs 89K in one
teratogen information services Q-I>R stud#*
)11@* Mc?lhatton et al )184* found similar
rates in one uncontrolled stud# of women on
-CAs )11K for those e$posed to -CAs alone,
and 1/8K for those e$posed to -CAs plus
other drugs*
?$tensive data from pregnanc# registries and
-I> services have shown no increase in
malformations in babies with .rst"trimester
e$posure to -CAs )186* Imipramine and
amitript#line are the most e$tensivel#
studied -CAs
Fetal and neonatal efects
More recentl#, the &1A and drug
manufacturers agreed to a class labeling
change for >>2Is and serotonin and
norepinephrine reupta5e inhibitors )>L2Is*%
grouped together under the term 3>2Is4
<abeling now includes a statement regarding
potential adverse e(ects on newborns
e$posed during late pregnanc# -here is still
debate in this area because studies are
limited in si=e with variable results
Moses"Mol5o et al )18G* reviewed the
literature on neonatal outcome after
e$posure to >2Is for at least the third
trimester of pregnanc# through deliver# -he#
found that late >2I e$posure carries an
overall ris5 ratio of /7 )96K CI, 87,44* for a
neonatal behavioral s#ndrome, when
compared with earl# gestational e$posure or
no e$posure Most case reports involved
Auo$etine and paro$etine, and a(ected
newborns demonstrated some of the
following signsJ central nervous s#stem
)most commonl#,
:itterinessNtremorsNshivering or irri"
tabilit#Nagitation*D motor )usuall# increased
muscle tone*D respirator# )usuall# mild upper
airwa# congestion andNor transient
tach#pnea*D or gastrointestinal )feeding or
digestive diPculties* -hese were usuall#
mild, disappearing b# 8 wee5s of age
Medical management consisted primaril# of
supportive care in special care nurseries
-here was one intubation among /1/ term
infants described in suPcient detail for
'uanti.cation Lo deaths were reported as
resulting from neonatal >2I e$posure -he
onset of s#mptoms varied from birth to /
wee5s ?arlier onset appeared consistent with
>>2I to$icit#, whereas late onset was
considered a sign of withdrawal &urther
stud# is needed to determine whether
pharmacologic properties or simpl# fre'uenc#
of use resulted in paro$etine and Auo$etine
being most commonl# associated with
neonatal s#ndromes -hese studies did not
control for maternal depression, which is also
associated with neonatal fussiness,
irritabilit#, inconsolabilit#, decreased motor
tone, decreased activit# level, and letharg#
)171*
Cith the >>2Is, there is some suggestion that
higher doses of Auo$etine could be
associated with lower birth weight and
gestational age )119*, but other studies are
inconsistent
!uman placental passage has been studied
for most of the >>2Is In one of the more
comprehensive studies, the ratios between
cord vein and maternal venous serum
concentrations were 789 for sertraline )n
17*, 748 for paro$etine )n G*, 7G4 for
Auo$etine )n 16*, and
7@7 for citalopram )n 4* 9ther >>2Is that
have not been studied would be considered
li5el# to cross the placenta due to their low
molecular weights )18@*
-here have been reports suggesting an
association between third"trimester e$posure
to -CAs and anticholinergic e(ects
)irritabilit#N:itteriness, h#poactivit#, colon
bloc5age, andNor urinar# retention* in
newborns -hese s#mptoms tend to occur
within the time interval re'uired for
eliminating these drugs, which is e$tended in
neonates )186*
Mc?lhatton et al )184* followed 88/ women
ta5ing -CAs in monotherap# beginning in the
.rst trimester and another 1@4 women on
-CAs plus other prescription drugs -here was
no increase in malformation rates compared
with historical controls !owever, the authors
did .nd what the# considered to be a high in"
cidence of neonatal disorders, such as
drowsiness and withdrawal s#mptoms )eg
h#pothermia, c#anosis*% 9GK of neonates
e$posed to -CAs plus other medications and
4GK of those e$posed to -CAs alone
>ei=ures that were believed to be secondar#
to drug withdrawal have also been reported in
two cases with clomipramine )188*
9verall, the neonatal e(ects of
antidepressants appear to be limited in
occurrence, scope, and time !owever, this
does present both clinician and mother
wit
h the tas5 of weighing the ris5s and bene.ts
of anti
depressant treatment in the third trimester
%
most par
ticularl# when one is considering starting
medications during this period versus waiting
until after deliver# !allberg and >:oblom
)18/* have reco
m
mended using the minimum e(ective dose of
>>2Is during late preg
nanc# because of the possibilit# of premature
birth and adverse drug e(ects in the
newborn
Neurobehavioral efects
Lulman et al )11/* evaluated the e(ects of
prenatal antidepressant e$posure over
periods of up to @ #ears -he# started with
comparing three groups of pregnant womenJ
those treated from the .rst trimester with tri"
c#clic antidepressants )n 87* or Auo$etine )n
66*, and an untreated control group )n 84*
After these women gave birth, the
researchers found no increase in ma:or
malformations or perinatal complications in
babies e$posed to antidepressants Children
between 1G months and @ #ears old were
then e$amined for IT and language
development, and no di(erences were found
between e$posed and une$posed groups
In another series, partiall# overlapping with
the previous stud#, there were 47 children,
ages 16 to @1 months, whose mothers had
ta5en Auo$etine throughout pregnanc# )64*
-he# did not di(er from controls on measures
of intellectual development, language de"
velopment, or behavior Mattson et al )189*
performed comprehensive
neurops#chological evaluations on GG
children, ages 4 to G, with prenatal e$posure
to Auo$etine -here were no signi.cant
di(erences between these children and
controls
Caspar et al )1/7* found lower A+0A2 scores
at birth )84 vs 97 at 6 minutes* in /1
infants of mothers who too5 sertraline or
another >>2I during pregnanc# >ertraline
was the antidepressant for about half the
mothers in the stud# -he controls were
infants of depressed women who did not ta5e
medication during pregnanc# At ages G to 47
months, these children scored lower than 1/
controls on the Ba#le# ps#chomotor
development inde$ and testing for behavioral
motor 'ualit# -he Ba#le# mental
developmental inde$es were similar in both
groups Lo signi.cant difference between the
two groups of children was found on
morpholog# e$amination -he authors have
postulated that these subtle motor .ndings
are consistent with the pharmacologic
properties of the drugs !owever, the#
caution readers that this stud# is limited b#
its sample si=e, use of di(erent >>2Is,
depression ratings based on self"reports, and
di(erences in mean age between the two
groups studied In addition, the age range of
the children studied was wide )G,47 months*,
but the average age was #ounger than 18
months in both groups It is not clear what
happens to the motor .ndings described as
the e$posed children develop further
Electrocon2ulsi2e $herapy
Teratogenicity
?lectroconvulsive therap# )?C-* involves
limited e$posure to medications, and it is
possible to minimi=e transfer of substances
into the fetoplacental s#stem b# the choice of
anesthetic agents ?C- ma# be the treatment
of choice for ps#chotic depression during
pregnanc#, given the largel# un5nown ris5 of
combining antidepressant, antips#chotic, and
sedative medications )186*
Miller )1/1* reviewed the literature on /77
cases of ?C- during pregnanc# &ive cases of
congenital abnormalities )1G@K* were
reported%an incidence lower than the 88K
seen in an historical control population )1/8*
-here was no clustering of speci.c
abnormalities
Fetal and neonatal efects
In this case review )1/1*, 9/K of the women
treated during pregnanc# su(ered
complications during the course of ?C-
administration &re'uentl#, there was no
apparent causal relationship with the
treatment -here were cases of transient
benign fetal arrh#thmias ).ve cases*, vaginal
bleeding ).ve cases*, and uterine
contractions or abdominal pain )four cases*
observed soon after ?C- administration
!owever, there were no apparent adverse
e(ects on these infants after deliver# -here
have been four reported cases of premature
labor with ?C-, but none of these episodes
immediatel# followed a treatment, so other
causes are not ruled out
Neurobehavioral efects
-he authors have not found formal data on
the long"term e(ects of prenatal e$posure to
?C-
)en4odia4epines
Teratogenicity
?pidemiologic data on the benzodiazepines
has been plentiful but not entirel# consistent
>ome studies show no increase in
malformations among infants with .rst"
trimester e$posure, whereas others show a
small but signi.cant increase Anal#sis of
case"control studies alone revealed a
signi.cantl# increased ris5 for either ma:or
malformations or oral cleft, but pooled )case"
control and cohort* studies showed no such
association )1//* -o date, the available data
have suggested that ben=odia=epine
e$posure during the .rst trimester increases
the ris5 for congenital anomalies )ie, from
77GK for oral cleft to 7@K*, but the absolute
ris5 remains low )1/4* 1ia=epam is the best
studied of the ben=odia=epines, followed b#
chlordia=epo$ide
Fetal and neonatal efects
-here has been some concern regarding the
fetal and neonatal e(ects of
ben=odia=epines, especiall# with larger doses
in continuous use Most of the reports in this
area are on dia=epam, and the e(ects appear
to be transient Minimi=ing the dosage ma#
be one wa# to mitigate adverse e(ects on
the fetus 9ne advantage of ben=odia=epines
is that the# can be given on an as"needed
basis for acute s#mptom relief
Chen pregnant women are treated with
dia=epam, loss of beat"to"beat heart rate
variabilit# and decreased fetal movement
ma# occur )1/6,1/G* &etal monitoring and
periodic ultrasound e$ams are important
when this occurs 1ia=epam use during the
third trimester or at the time of deliver# ma#
lead to apnea, h#potonia, or h#pothermia in
the newborn Conversel#, tremors, irritabilit#,
and h#pertonia, similar to neonatal narcotic
withdrawal, can occur in some babies whose
mothers were treated chronicall# with
dia=epam through the third trimester )1/@*
In one report, however, clona=epam was
given in doses ranging from 76 to /6 mg
dail# to women with panic disorder during
labor and deliver#, and there were no
apparent perinatal adverse e(ects )1/8*
C=ei=el and -oth )1/9* found that /,G78
infants with prenatal e$posure to dia=epam
weighed, on average, 116 g less than
une$posed infants 2eports are inconsistent
regarding head circumference )147,141*
Neurobehavioral efects
In one stud#, 1@ children with prenatal
e$posure to dia=epam or other
ben=odia=epines were observed to have
dela#ed gross motor development at G to 17
months of age !owever, few di(erences
from controls were apparent at 18 months
)148,14/* Be#ond 18 months, the previous
di(erences appeared to normali=e
Mc?lhatton )144* studied 667 e$posed
children for various times up to the age of 4
#ears and found no increase in malformation
rate or adverse e(ects on either
neurobehavioral development or IT It was
not possible to establish a direct cause,e(ect
relationship with prenatal ben=odia=epine
e$posure for children in whom developmental
de.cits persisted
>ti5a et al )146* anal#=ed the statistical
relationships between prescription data of
pregnant mothers and evaluations of their
childrenEs subse'uent behavior in school Lo
signi.cant di(erence was found between the
two groups and their controls
!ntipsychotics
Teratogenicity
>tudies of neuroleptic use during pregnanc#
are complicated b# multiple confounding
variables, including ris5 factors associated
with ps#chotic illness itself >till,
animal studies and reviews of human
pregnancies have failed to clearl#
demonstrate an# speci.c organ malformation
with use of chlorproma=ine, haloperidol, or
perphena=ine )14G* In 199G, Altshuler et al
)14@* performed a meta"anal#sis of reports
on phenothia=ines given in the .rst trimester
to nonps#chotic women -he# found a 84K
incidence of anomalies, with a baseline rate
of 87K, and concluded that the additional
ris5 was 74K 2eports on haloperidol and
perphena=ine have some variabilit#, but an#
increase in ris5 for congenital anomalies
appears to be small )178,148,161*
1ata are still limited with the at#pical
antips#chotics McMenna et al )168* reviewed
data from a cohort of pregnant women who
had contacted the Motheris5 +rogram in
Canada, the Israeli -eratogen Information
>ervice, or the 1rug >afet# 2esearch Bnit
database in ?ngland Comen who had been
e$posed to at#pical antips#chotics during
pregnanc# were matched to a comparison
group of pregnant women without such
e$posure -here were 161 pregnanc#
outcomes with e$posure to olan=apine )n
G7*, risperidone )n 49*, 'uetiapine )n /G*,
and clo=apine )n G* -here were no
statisticall# signi.cant di(erences in an# of
the pregnanc# outcomes of interest between
the e$posed and comparison groups, with the
e$ception of low birth weight )17K in the
e$posed babies compared to 8K in the
comparison groupD p 776* and the rate of
therapeutic abortions )p 777/*
Fetal and neonatal efects
!igh"potenc# antips#chotics given in the
third trimester have been associated with
e$trap#ramidal s#mptoms )?+>* in the
newborn -hese s#mptoms reportedl# began
1 to / da#s after birth if the mother was
treated orall#, and / to 4 wee5s later if depot
in:ections were used -here have been
reports of ?+> persisting in babies for up to G
to 17 months )69,16/* 9ther potential neu"
roleptic e(ects on the neonate include
increased cr#ing and suc5ing, sluggish
primitive reAe$es, vasomotor instabilit#,
wea5ness, h#pertonicit#, and increased
cr#ing )164* -hese reports tend to be older,
raising such issues as dosage and
confounding maternal factors -he# do point
to the importance of limiting the dosage and
avoiding depot in:ections as much as
possible
Neurobehavioral efects
2eports on the long"term e(ects of prenatal
e$posure to neuroleptics are largel# limited to
older studies of women being treated for
h#peremesis In one such stud# )166*, there
were 68 babies whose mothers had ta5en
chlorproma=ine 67 to 177 mg per da# during
pregnanc# -he# were followed for 4 to 6
#ears after birth and found to be health#, with
no behavioral or mental abnormalities -he
mode of assessment was not described
>lone )16G* followed 161 babies with prenatal
e$po
sur
e to unspeci.ed phenothia=ines for up to 4
#ears -he ITs of these children were e'ual to
those of con
trols and children who were irregularl#
e$posed in utero to phenothia=ines
&inall#, >ti5a et al )16@* found that children
e$posed to classical antips#chotics in utero
during the second half of pregnanc# showed
no di(erence in school behavior compared
with the matched controls
9ddl# enough, +latt et al )168* reported
signi.cantl# increased height andNor weight
in children with prenatal e$posure to the
classical antips#chotic drugs -hese
di(erences were noted at di(erent points in
development between 4 months and @ #ears
of age, and the si=e of the e(ect was
positivel# correlated with the duration of
e$posure
1ata appear to be still pending on the
neurobehavioral e(ects of at#pical
antips#chotics given during pregnanc#
(*/S$!)I"I5I#, (E*IC!$I#S
-his class includes lithium and anticonvulsant
medications )also called antiepileptic drugs
QA?1R* -he teratogenic potential of these
medications is highl# variable, and the data
on speci.c drugs have changed dramaticall#
over the #ears &or e$ample, ;+A and carba"
ma=epine, formerl# considered drugs of
choice for pregnant epileptic women, are now
viewed as ris5 factors for neural tube defects
2eports on lithium, however, are more
favorable than in the past !nticon2ulsants
Assessment of the e(ects of anticonvulsant
)A?1* treatment is confounded b# multiple
factors )169* &irst, it is not clear how the
presence of a maternal sei=ure disorder
a(ects the developing fetus At one time, it
was believed that children of epileptic
mothers, independent of A?1 use, were
about three times more li5el# to have malfor"
mations than the general population )@4*
!owever, !olmes et al )1G7* e$amined 98
infants whose mothers had a histor# of
epileps# but too5 no anticonvulsant drugs
during pregnanc# -he fre'uenc# of
congenital abnormalities did not di(er from
that of the control population +ol#drug
therap# tended to increase the rate of
malformations 9f course, one might e$pect
that women treated with multiple agents
would have more severe epileps# or mood
disorder%another confounding factor
Teratogenicity
VPA is one of the most problematic
ps#chotropic medications in the .rst
trimester +ooled data from .ve prospective
?uropean studies )1G1* showed an increased
incidence of ma:or congenital anomalies
among 184 children with prenatal e$posure
to ;+A )relative
ris5 49, with 96K CI 1G,167* -he
estimated ris5 of spina bi.da among children
whose mothers were treated with ;+A during
the .rst trimester of pregnanc# is 8K in
populations with a bac5ground rate of
1N1,777 -he ris5 ma# be greater in
populations with a higher bac5ground rate
)169* A fetal valproate s#ndrome )&;>* has
been described as characteri=ed b# neural
tube defects, craniofacial anomalies, digit
and limb defects, urogenital malformations,
retarded ps#chomotor development, and low
birth weight )1G8* In one series, 9 of 1@
babies e$posed in utero to valproate had
features of &;> )1G/* -he mother of one
a(ected infant had not started treatment
until the second trimester of pregnanc#
arbamazepine )CBS* was the drug of choice
for epileps# during pregnanc# for decades
)@4* !owever, in the 1987s, it was found to
be associated with increased ris5 of spina
bi.da )76K,17K* and other congenital
anomalies -he teratogenic ris5 increased
when carbama=epine was combined with
other agents, especiall# ;+A In three large
series )1G4,1GG*, the malformation rate in
babies with prenatal e$posure to CBS varied
from /@K to GGK -he lowest rate, /@K,
was for CBS given onl# in monotherap#
A fetal CBS s#ndrome has been described
that includes growth and developmental
dela#, along with minor facial and other
anomalies similar to those seen with other
anticonvulsants &eatures of this s#ndrome
were seen in most of /6 children whose
mothers were treated with CBS monotherap#
in one series )1G@*, and G of 4@ such children
in another )1G8*
-hus far, the data suggest that lamotrigine
monotherap# is safer than ;+A or
carbama=epine during the .rst trimester of
pregnanc# According to the Iul# 8776 report
of the <amotrigine +regnanc# 2egistr# )@@*,
there were 696 outcomes )including live
births and induced abortions* e$posed to
lamotrigine monotherap# during the .rst
trimester Ma:or malformations were found in
1@ cases or 89K )96K CIJ 1@K,4GK* -here
was one outcome with a ma:or defect among
89 outcomes following a second"trimester
monotherap# e$posure -here were 111 total
outcomes involving .rst trimester e$posure
to lamotrigine plus ;+A, with or without ad"
ditional A?1s -he incidence of ma:or
malformations was 11@K )96K CIJ GGK,
196K* Among 88@ outcomes with .rst"
trimester e$posure to lamotrigine plus one or
more other A?1s )not including ;+A*, the inci"
dence of ma:or malformations was /1K )96K
CIJ 14K,G6K* -here was no consistent
pattern of birth defects reported
prospectivel# to the registr# but, as stated
previousl#, the registr# is not designed to
detect increases in speci.c malformations
Fetal and neonatal efects
VPA use during the third trimester has been
associated with perinatal distress, transient
neonatal h#pogl#cemia,
and unusual neonatal behavior )169* <iver
to$icit# was also reported in three newborns
e$posed to ;+A )174* -here was one report
of &;> in a bab# who was .rst e$
posed in the second trimester )1G/*
arbamazepine has been associated with
decreased head circumference at birth in
multiple studies -he signi.cance of this
.nding is not clear%one stud# suggests that
this normali=es as children reach 66 #ears of
age )1G9* -here are case reports of transient
abnormalities in vitamin M"dependent clotting
factors and h#pocalcemia with neurologic
d#sfunction in newborns e$posed to CBS
during the third trimester )1G9*
-here was one outcome with a ma:or defect
among 89 outcomes following second"
trimester e$posure to lamotrigine
monotherap# )@@* 1ata are limited regarding
neonatal e(ects -here is one case report of
respirator# distress and apnea"brad#cardia
following e$posure throughout pregnanc# to
lamotrigine and cloba=am, and one report of
respirator# distress and thromboc#topenia
following e$posure throughout pregnanc# to
lamotrigine )1@7*
Neurobehavioral efects
Bse of ;+A during pregnanc# appears to be
associated with neurologic abnormalities and
behavioral disturbances in e$posed children
Ardinger et al )1@1* found developmental
dela#s or abnormal neurologic signs in 16 of
18 children whose mothers too5 ;+A for
sei=ure disorders during pregnanc# In
another stud# )1@8*, there were eight
children, all G #ears old, with prenatal
e$posure to ;+A &our showed signs of
neurologic d#sfunction%mild in three cases
but correlating with the occurrence of
h#pere$citabilit# in the newborn period
Children whose mothers too5 ;+A for a
sei=ure disorder during pregnanc# often
re'uire special education interventions in
school )1@/* &;> is commonl# associated
with behavioral abnormalities, most often
h#peractivit#, poor concentration, or autistic
features )1@4*
In one stud#, prenatal e$posure to CBS
monotherap# was associated with decreased
performance in cognitive testing, but this
result was not duplicated in four other
investigations
9rno# and Cohen )1G8* tested 41 children, G
months to G #ears old, whose mothers had
been treated with CBS during pregnanc#
-hese children scored lower on average than
controls on the Ba#le# mental development
and McCarth# general cognitive e$amina"
tions !owever, Cide et al )1@6* tested /6 9"
month"old infants with prenatal CBS
e$posure, using the 0riPths test of
developmental performance -here was no
signi.cant di(erence between these infants
and controls In 0ail# et al )1@G*, /4
prenatall# e$posed children, age 66 #ears,
performed as well on IT testing as controls
Chen /7 of these children received more
detailed testing )1@@*, the fre'uenc# of
cognitive d#sfunction was
no more than e$pected >colni5 et al )1@8*
tested /G children with in utero CBS
e$posure, ages 16 to G #ears, for global IT
and language development -hese children
performed as well as controls -he fre'uenc#
of neurologic d#sfunction and school
problems was not greater than e$pected in
8/ children, ages G to 1/, with prenatal CBS
e$posure )1@9*
-he authors have not #et found reports on
the long"term neurobehavioral e(ects of
lamotrigine given during pregnanc#
"ithium
<ithium is one agent whose teratogenic
potential ma# be less than initiall# believed
-he earliest data had come from registr#
studies, which tend to be confounded b#
reporting bias )voluntar# case reporting*,
inclusion of pregnancies e$posed to pol#drug
therap# regimens, and lac5 of appropriate
control groups Teratogenicity
In the 19@G <ithium 2egistr# >tud#, there
were 886 cases of children e$posed to lithium
during the .rst trimester Congenital
anomalies were found in 111K, with
cardiovascular defects in 8K and ?bsteinEs
anomal# in 8/K )187* Clinical practice was
guided b# these results for the ne$t 86 #ears
Mallen and -andberg )181* studied 69 infants
born to women with manic"depressive illness
and ta5ing lithium during the .rst trimester
-he fre'uenc# of congenital anomalies )19K*
and heart defects )@K% none with ?bsteinEs
anomal#* were signi.cantl# greater than
among children of a matched cohort of
manic"depressive women who had not ta5en
lithium during pregnanc# In a later
prospective investigation, researchers from
four -I> services studied women reporting
lithium use during the .rst trimester of
pregnanc# )188* After these women gave
birth, 176 e$posed infants were e$amined
and matched against controls 9nl# 4K were
diagnosed with a ma:or congenital anomal#,
and 79K had a cardiac malformation
)speci.call#, ?bsteinEs anomal#* In the
control group, 8K had a ma:or malformation,
and 78K had a cardiac malformation, not
?bsteinEs Congenital anomalies occurred in
onl# /8K of G8 infants with .rst"trimester
e$posure to lithium in a record lin5age stud#
of Michigan Medicaid recipients )18/*, but
this stud# was not published in a form that
allows critical evaluation
<ithiumEs teratogenicit# appears limited, but
the si=e of its e(ect remains unclear -here
ma# be some ris5 for cardiovascular
malformations, but not the 477"fold
increased rate that was .rst reported )@4*
<ithium ma# be associated with increased
ris5 for ?bsteinEs anomal#, probabl# in the
range of 77K to 71K 1oppler Aow anal#sis
of the tricuspid valve has been suggested for
fetuses with .rst"trimester e$posure )@4*
<ithium still
appears safer in the .rst trimester than ;+A,
and there does not appear to be the
additional ris5 of neural tube defects
associated with ;+A and CBS
Fetal and neonatal efects
<ithium readil# crosses the placenta, and
serum concentrations rapidl# achieve
e'uilibrium in maternal and fetal circulation
)@4* &etal to$icit# appears to be related to
both cumulative dail# doses and transient
pea5s in concentration )184* In laborator#
animals, even transient pulses of high serum
lithium concentration can impair fetal
development Ceinstein recommended that
lithium be given in three to .ve e'ual doses
per da# of no more than /77 mg, and that
dosages be maintained at the lowest
e(ective level )186*
Leonatal to$icit# has been reported at
concentrations as low as 7/6 me' per < and
as high as 11 me' per < )184* -herefore,
serum lithium is not a reliable indicator of
neonatal to$icit# or safet# Clinical features of
lithium to$icit# are variable and ma# be
diagnosed as nonspeci.c transitor# neonatal
distress )184* &eatures can include c#anosis,
letharg#, h#potonia, poor gag and suc5
reAe$es, cardiac arrh#thmias, cardiomegal#,
transient h#poth#roidism and neonatal goiter,
impaired respiration, and transient
nephrogenic diabetes -he neonatal
elimination half"life is G8 to 9G hours -he ef"
fects of lithium to$icit# are generall# self"
limiting and resolve without complication
within 1 to 8 wee5s )18G* Cardiac
arrh#thmias and goiter can persist longer
)@4*
ConAicting reports have been published
regarding lithium e$posure and premature
deliveries or large for gestational age infants
)@4* In one case"controlled cohort stud#
)18@*, there was an increase in premature
births among mothers treated with lithium,
but no significant di(erence in birth weights
Another cohort stud# found no di(erence
between lithium"e$posed infants and
controls, e$cept for a small but statisticall#
signi.cant increase in birth weight in the
lithium group )188*
Neurobehavioral efects
-here is :ust one long"term stud# on the
neurobehavioral e(ects of prenatal lithium
e$posure >chou )188* conducted a postal
surve# of G7 >candinavian <ithium 2egistr#
children, all at least 6 #ears old, who had
been born without anomalies -heir mothers
reported no di(erence in development
between these children and 6@ une$posed
siblings, although both groups showed signs
of mild developmental dela# Cea5nesses of
this stud# include the developmental
assessment b# the mothers and the small
sample si=e )@4*
(E*IC!$I#S !#* "!C$!$I#
2esearchers are increasingl#
challenging the notion that medications
preclude breastfeeding !ale )67*
stated, 3Although there are man#
e$ceptions, a good rule is that less than
1K of the Wmaternal doseE of a drug will
ultimatel# .nd its wa# into the mil5 and
subse'uentl# into the infant the bene.ts
of breastfeeding often outweigh the ris5s to
the infantEs well"being4
9ne must still remember that the infant, with
an immature renal and hepatic s#stem, will
accumulate certain medications and be
vulnerable to to$icit# As a result, the
American Academ# of +ediatrics has recom"
mended against breastfeeding in mothers
ta5ing lithium Because of their long pediatric
half"lives, barbiturates, ben=odia=epines,
meperidine, and Auo$etine are also 5nown to
produce higher and occasionall# to$ic blood
levels in the infant Conversel#, medications
with shorter half"lives tend to pea5 more
rapidl# and are then removed from maternal
plasma, thus e$posing the mil5 and bab# to
reduced medication levels )67* Mothers can
further protect their infants b# timing their
feedings when plasma drug concentrations
are lower )ie, toward the end of the dosing
interval* 9f course, this ma# not be possible
with a newborn
1rugs with low protein"binding and high lipid
solubilit# tend to penetrate mil5 in higher
concentrations than other drugs -hus,
lipophilic CL>"active agents must be used
with particular caution in breastfeeding
mothers 1rug e(ects e$perienced b# the
mother, including sedation or depression,
might also appear in the bab# )67*
+remature infants or babies with unstable
gastrointestinal tracts tend to be the most
susceptible to drug e(ects in breast mil5
+h#sicians should therefore carefull# review
the lactation data on an# particular drug,
along with the medical condition and age of
the bab#, before advising a mother about
breastfeeding )67* ,'I*ES $ $HE
!SSESS(E#$ - %IS06
.HE%E $ "0
-he &1A has established pregnanc# ris5
categories for medications based on data
from human and animal studies -he# are
summari=ed as followsJ
A >tudies of pregnant women are ade'uate
and well controlled 2is5 is not demonstrated
with e$posure throughout pregnanc#
B Animal studies do not indicate a ris5 to the
fetus Lo ade'uate, well"controlled studies in
pregnant women
9r Animal studies show an adverse e(ect
2is5 is not demonstrated in ade'uate,
well"controlled studies of pregnant
women
C Animal studies show teratogenic or
embr#ocidal effects
Lo ade'uate, well"controlled studies in pregnant
women
9r
Lo studies are available in either animals or
preg nant women
1 ?vidence of human fetal ris5 Bene.ts ma#
at times :ustif# the ris5
X 2is5 clearl# outweighs the bene.t 1rug is
contraindicated
?ver# prescribed drug has an &1A pregnanc#
ris5 classi.cation, and the categories are
highl# familiar to clinicians in the Bnited
>tates !owever, this s#stem is often
ambiguous and can lead to unwarranted
conclusions )48* &or e$ample, depending on
the results of animal studies, the 3B4 ris5
categor# includes two 'uite di(erent groups
of drugs -he .rst group has reassuring
animal studies but is an un5nown entit# with
respect to e(ects on the developing human
-he second group has been widel# used b#
pregnant women with apparent safet# but
has some adverse e(ects on animals In
categories 3C4 and 31,4 no distinctions are
made between reversible and irreversible
e(ects, or mild and severe &or e$ample,
certain -CAs have been labeled as categor#
1 agents, but pooled data on human studies
have suggested that these drugs are safe for
use during pregnanc# )48*
9f course, no classi.cation s#stem can
provide a real measure of teratogenic ris5 for
an# one drug or patient Clinicians wanting to
perform a reasonable pregnanc# ris5
assessment should consult other information
sources, including publications, databases,
Ceb sites, and various organi=ations
Certain publications and databases such as
-?2I>, 2?+29-9X, and -9X<IL? provide
reviews of current studies in the literature
)8G* and can give the reader much needed
guidance in the interpretation of the data
-?2I> even rates the 'ualit# of the data as
3Lone, <imited, &air, 0ood, or ?$cellent,4 and
the estimated ris5 of teratogenic e(ects as
3Lone, Minimal, >mall, Moderate, !igh,
Bndetermined, or Bnli5el#4 2?+29-9X
provides information on lactation and
pregnanc# ?ven these reviews, however, are
onl# 3part of a comprehensive pregnanc# ris5
assessment that is necessar# to provide
counseling for such patients4 )8@*
-he +regnanc# 2is5 Letwor5 )1"877"@84"
8464* also provides clinicians with reviews of
the literature on an# given medication
+ersonnel are available to address individual
'uestions and concerns, and there is a
consulting ph#sician available to help further
clarif# the data
In addition, Massachusetts 0eneral !ospital
provides a Ceb site for patients and clinicians
see5ing information on womenEs issues,
including the reproductive safet# of
ps#chotropic medications )189* >imilar Ceb
sites are available throughout the Bnited
>tates and Canada
-he drug companies themselves can be
helpful, providing data from pregnanc#
registries and literature on their particular
medications It is important to remember,
however, that there are inherent di(erences
between pregnanc# registries and
population"based surveillance s#stems
!onein et al )188* studied reports from four
pregnanc# registries and compared their re"
sults with .ndings of the Metropolitan Atlanta
Congenital 1efects +rogram )MAC1+* -he
registriesE overall defect prevalence
)41N1,4@1 or 8@K* was slightl# lower than
that of MAC1+ )G,16@N196,G48 or /8K* 2eg"
istries were also less li5el# than MAC1+ to
ascertain internal and serious defects, and
identi.ed fewer defects per a(ected infant
than MAC1+, although these di(erences were
not statisticall# signi.cant <imitations of
registr# programs include relativel# small
numbers of e$posed individuals and,
fre'uentl#, lac5 of information about the
e$posed infant be#ond gestation and a few
da#s after birth
In the authorsE e$perience, companies have
been forthcoming with both positive and
negative .ndings in this area &or e$ample,
0la$o>mithMline more recentl# posted a
cautionar# statement about +a$il, based on
an investigation that is still in progress )187*
!ale )67* provides a comprehensive review of
medications during lactation, and rates their
safet# on a scale of <1 to <4 Included in this
review is the estimated relative infant dose,
which is the infant dose )mgN5gNda#* divided
b# the maternal dose )mgN5gNda#* &or man#
drugs, a relative infant dose of 17K or less is
considered safe !aleEs boo5 is updated
ever# 8 #ears, and the following numbers are
available for boo5 orders and in'uiriesJ
phoneJ )87G* /@G"9977 or )877* /@8"1/1@D
fa$J
)87G* /@G"9971 2?+29-9X and other
databases are also a good source of data on
lactation
Conclusion6 .here *o
.e ,o -rom Here
9ne of the great challenges in medicine is
helping women during pregnanc#, especiall#
those who are at ris5 because of ma:or
ps#chosocial stresses, mental illness, or
substance abuse Clinicians face the tas5 of
.nding mothers at ris5 earl# enough to
intervene e(ectivel# +s#chosocial screening
is not #et a standard of practice%researchers
are :ust beginning to stud# the e(ectiveness
of various approaches in this area 9nce
these mothers are found, the ne$t tas5 will
be safe, effective, and available treatment,
preferabl# ps#chosocial interventions that
include ps#chotherap# Chen medications are
used, the issue of safet# to mother and fetus
is ongoing and ever evolving
It is impossible to trul# measure the ris5 of
an# given medication In fact, the more a
medication is studied, the more ambiguit#
one will .nd Congenital anomalies occur with
or without teratogens, so malformations
should be e$pected in an# large enough
population
ta5
ing the medication -he longer the agent is
studied, the greater the number of adverse
e(ects reported Case re
ports, whether anecdotal or through
registries, prescrip
tion records, or -I> referrals, can suggest the
possibilit# of ris5, but cannot '
u
antif# that ris5 Case"controlled and cohort
studies are more valid, but the numbers
involved are relativel# small If adverse
events are un
covered, case"controlled studies ma# become
almost im
possible due to ethical concerns It ta5es
#ears and large n
u
mbers of e$posures in children before a
complication is recogni=ed &or e$ample,
nearl# 8,777 e$posed infants would be
re'uired to detect a teratogen that increases
the ris5 of a speci.c birth defect from 71K to
1K )188* Bnderstanding the nature of the

cause"and"e(ect rela
tionship with the medication ta5es man#
more #ears
Attempts have been made to shorten this
process with animal studies Bnfortunatel#,
rodent studies produce limited, even
misleading, results +erhaps the limited use
of primates could be considered for those
drugs that raise the greatest clinical concerns
%drugs that ma# be more widel# used
because of a promising safet# pro.le
!owever, we do not need primates to tell us
that certain medications, including ;+A, must
be used with great caution
0athering and disseminating information in
this area is an ongoing challenge -o date,
the Bnited >tates has no compulsor#
reporting s#stem for medication use during
pregnanc# or the e(ects on o(spring As a
result, clinicians and their patients must rel#
heavil# on data reported voluntaril# and
collected b# pharmaceutical companies, -I>s,
or individual organi=ations such as the A?1
2egistr# 9ne issue for the 81st centur# will
certainl# be more e(ective gathering and
disseminating of information on outcomes of
drug e$posure during pregnanc#%perhaps a
centrali=ed pregnanc# registr# or some form
of mandator# but con.dential reporting%with
the goal of protecting the ne$t generation
-he goal of this chapter has been to help
clinicians as5 themselves the right 'uestions
and begin their navigation toward the best
available answers in their time -here are
few, if an#, permanent answers here In fact,
there are new developments even as this
chapter is being published
!C0#."E*,(E#$S
The authors than! "hahanara Ali and Peter #eidy $or
their research assistance and support%
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