Talking psychiatry...Psychiatric disorders in pregnancy

INDEX

 INTRODUCTION

 PSYCHIATRY DISORDERS IN
PREGNANCY

 MANAGEMENT OF PSYCHIATRY
DISORDERS IN PREGNANCY

INTRODUCTION

The course and treatment of illnesses during pregnancy can generate considerable clinical anxiety as the clinician
assesses the risks and benefits of intervention against a backdrop of limited information and myriad review
articles that provide less than definitive direction. This clinical decision is complicated further by the mandate of
do no harm and the desire of many women to protect the child at all costs. There is widespread acceptance that
some conditions warrant treatment secondary to the potential adverse impact of the illness (eg, hyperemesis,
hypertension, infection, and epilepsy). In contrast, the treatments for some illnesses are continued in absence of
evidence that such conditions pose a significant risk to the pregnancy (eg, allergies and insomnia). The location of
psychiatric illnesses along this continuum of medical severity or risk is unclear, complicated further by the lack
of objective tests and the subjective nature of many of the symptoms, thereby leading to reliance on clinical
judgment with respect to the need for intervention. Given the high rate of psychiatric morbidity in women of
reproductive years, it is important to clarify the course, potential impact, and treatment options for psychiatric
illnesses during pregnancy.

The importance of extending this information to all subspecialties is evident: the birth rate in the United States

has topped the 4 million mark annually; approximately 50% of these pregnancies represent inadvertent
conception; women have higher rates of several anxiety disorders (eg, panic disorder [PD], post-traumatic stress
disorder [PTSD], and generalized anxiety disorder), major depression, and eating disorders (EDs) compared
with men; the reproductive years represent the greatest window of risk for psychiatric morbidity; psychiatric
comorbidity with other medical conditions is common and often complicates treatment planning; and the
treatment of psychiatric illness increasingly has fallen under the auspices of various clinical subspecialists,
including nurse practitioners and physician's assistants. Conservatively, more than 500,000 pregnancies each
year involve women who have psychiatric illnesses that either predate or emerge during the pregnancy, and half
of these are unplanned. This estimate underscores the need to treat women of reproductive capacity clinically,
like they are pregnant from the very first visit, and to be familiar with the extant literature on the course of
illness in pregnancy and the impact of illness or treatment on obstetric outcome.

The literature on the impact of psychiatric illness or treatment on obstetric outcome is highly confounded.
Clinical and basic science investigators routinely use measures of anxiety, stress, and depression almost
interchangeably and in the absence of validation of such measures in pregnancy. The overlap and relationship
between anxiety, stress, and depression may be intuitive but formally remain obscure. Similarly, treatment
outcome investigations rely on retrospective reporting, poison control centers, and case series. To date, no
obstetric outcome study of in utero psychotropic medication exposure has controlled prospectively for tobacco,
alcohol, or drug use; concomitant medications; or psychiatric symptoms during pregnancy.

Given the limitations of the current literature, this review addresses salient questions to aid the clinician in a
better understanding of where psychiatric illness and its treatments lie in the continuum of risk to the patient,
pregnancy, and child. Broadly, these questions are: (1) Do women experience psychiatric illness in pregnancy?
(2) Does psychiatric illness improve during pregnancy? (3) Does psychiatric illness pose a risk to pregnancy
outcome? and (4) Which psychiatric treatment options are the best choices for pregnancy?

PSYCHIATRY DISORDERS IN PREGNANCY

Historically, pregnancy has been perceived as a time of emotional well-being. There is limited data, however, to
support such a contention. There are few investigations of the incidence or prevalence of psychiatric illnesses
during pregnancy. There are even fewer studies that have looked at the course of pre-existing psychiatric illness
across pregnancy. Although depression has received the most investigative attention, it is not the most common
psychiatric illness in women.

 Anxiety disorders

Anxiety disorders include PD, obsessive-compulsive disorder (OCD), generalized anxiety disorder, PTSD, social
anxiety disorder, and phobias. They are the most commonly occurring psychiatric disorders, with approximately
13.3% of Americans aged 18 to 54 years meeting diagnostic criteria. Women are two times as likely to be
diagnosed than men, and almost one third of women experience a variant of an anxiety disorder during their
lifetime [1–3]. Unfortunately, general practitioners, who usually see patients more often than those in other
medical disciplines, miss a large proportion of diagnosable psychiatric disorders, with anxiety disorders missed
most often 4.

PD is characterized by recurrent panic attacks, which come out of the blue and include an intense discomfort or
fear. Symptoms include palpitations, sweating, trembling, shortness of breath, choking feelings, chest pain,
nausea, dizziness, a detached dream-like state of derealization, fear of dying, and fear of losing control 5. The
incidence of PD during pregnancy is unknown. Retrospective studies suggest that pregnancy is protective against
panic attacks [6–8], with one group theorizing that alterations in the Pco2 during the course of pregnancy reduce
the physiologic trigger of anxiety 8. In contrast, a recent prospective study fails to corroborate these findings and
finds that the severity of the disorder before pregnancy predicts the course of the disorder during pregnancy 9.
The literature includes a total of 260 pregnancies in women who have had PD, and indicates that 30% of women
experience symptom improvement, whereas 19% worsen [10,11].

PTSD occurs after the experience of a traumatic event, which evokes intense fear or helplessness. Recurrent,
intrusive, distressing recollections or dreams or a reliving of the experience follows the event. There often is

persistent avoidance of stimuli associated with the trauma 5. In women, the event often includes sexual or
physical abuse either of themselves or their children [12,13]. The incidence and course of PTSD in pregnancy are
unknown. In some cases, pregnancy and childbirth may exacerbate symptoms of PTSD, particularly if the
pregnancy is a result of rape or if the pregnancy experience triggers memories of sexual trauma [14,15]. Several
investigators suggest that the experience of childbirth itself may precipitate PTSD [16–18], with a resultant fear
of pregnancy, referred to as tocophobia. A phenomenon only recently begun to be studied is the idea of
pretraumatic stress, an intense fear of the upcoming birth 19. Some women report a fear of vaginal birth in
general, resulting in a rise in the number of cesarean sections requested. This fear is associated with personality
traits that predispose women to anxiety and their and their partner's dissatisfaction with their relationship and
the life they are living 20. Although nearly 20% of women report being afraid of childbirth 20, 2.3% meet full
diagnostic criteria for PTSD. Predictors of this pretraumatic stress include previous psychiatric problems or
previous psychiatric counseling for childbirth, high trait anxiety scores, and depressive symptomatology. Risk
factors include a previous traumatic birth experience or previous traumatic experiences in general, poor stress
coping skills, and low perceived social support 19. A single investigation suggests that PTSD might be associated
with a higher risk for obstetric complications, such as ectopic pregnancy, spontaneous abortion, hyperemesis,
preterm contractions, and excessive fetal growth 21.

OCD is characterized by the occurrence either of obsessions or compulsions. Obsessions are recurrent,
persistent, intrusive and inappropriate thoughts, impulses, or images that cause marked anxiety or distress.
Compulsions are repetitive behaviors or mental acts that an individual is driven to perform in response to an
obsession, which are aimed at preventing or reducing distress 3. The incidence of OCD in pregnancy is unknown.
Despite limited formal investigation, most clinicians and researchers agree that pregnancy seems to be a potential
trigger of OCD symptom onset with more than 30% of the women in a specialized OCD clinic experiencing
symptom onset during pregnancy 22. Given the potential similarities between OCD and maternal behaviors (eg,
baby proofing), such data is not surprising. It generally is accepted that OCD worsens in the postpartum period
and that obsessions are a common component of postpartum depression [23,24]. One group proposes that
hormonal alterations are a risk factor for exacerbation of OCD symptoms 25. The impact of OCD on obstetric
outcome is limited to a single study. An investigation of eight women who had OCD found that two had pre-
eclampsia, three delivered preterm, and five had cesarean section 26.

Elevated levels of prenatal maternal anxiety and stress are shown to be one of many factors that cause poor
pregnancy outcomes 27, such as forcep deliveries, prolonged labor, precipitate labor, clinical fetal distress 28,
preterm delivery [29,30], and spontaneous abortion 31; a direct causal relationship, however, is not established.
Increased levels of maternal cortisol, often seen in response to stress, late in pregnancy are associated with lower
developmental scores in early infancy 32; increased levels of adrenocorticotropic hormone at 24 weeks' gestation
are associated with inadaptability early in infancy 32; and maternal anxiety in late pregnancy independently
predicts slowed mental development in 2-year-old children 33. Pre-eclampsia, a severe complication in
pregnancy, although not associated with raised salivary cortisol and pregnancy-associated maternal stress 34,
may be associated with the presence of maternal depression and anxiety 35. Research in this area is emerging,
but some investigators believe stress hormones may increase levels of oxidative stress circulating in the mother's
system and impair uteroplacental blood flow, creating a higher vascular resistance index in blood flow through
the placenta 34.

Despite the high incidence of anxiety disorders in women, there is limited information about the incidence and
clinical course of these disorders during pregnancy and, for some disorders, such as generalized anxiety disorder,
there is no data. These investigations fail to demonstrate any clear palliative effects of pregnancy on anxiety
disorders, and the obstetric complications from maternal anxiety and stress can be significant. In comparison,
there is considerably more information on mood disorders in pregnancy.

 Mood disorders

The most common mood disorder is major depression and it is characterized by a depressed or irritable mood,
diminished interest or pleasure in activities, weight loss or gain, appetite and sleep changes, and loss of energy,
among other symptoms 5. Women are two times more likely as men to experience a major depressive episode at
some point in their lives 36, and despite the Diagnostic and Statistical Manual, Fourth Edition's 5 assertion that
women are most likely to experience their first depressive episode during their childbearing years, research

involving depression during pregnancy is limited. Recent investigations show that depression occurs at the same
frequency in gravid women as it does in nongravid women; approximately 10% to 16% fulfill diagnostic criteria
for a major depressive episode during pregnancy, whereas approximately 70% of pregnant women report
experiencing depressive symptoms [36–39]. Many symptoms of depression, including weight gain, changes in
appetite, sleep disturbance, loss of libido, and fatigue, also are associated with pregnancy and often are dismissed
by professionals and laypersons [36,40]. Additionally, many pregnant women never are assessed for other
medical disorders that potentially can contribute to depressive symptoms, such as anemia, gestational diabetes,
and thyroid dysfunction 41. These factors make an accurate diagnosis of a depressive disorder in a pregnant
woman challenging. The course of depression during pregnancy has received limited attention. In the authors'
initial study of women taking antidepressants at conception, more than 60% experienced depressive symptoms
during pregnancy 42. A recently completed collaborative prospective study of 207 pregnant women who had a
history of depression and were taking antidepressants proximate to conception demonstrates that 68% of women
who discontinued medications experienced a depressive episode in pregnancy 43. More than 25% of the women
in this study who continued antidepressant medication experienced relapse.

Maternal depression is associated with problems not only for the mother but also for the developing fetus. There
is a greater incidence of premature birth, very low birth weight, and postnatal complications in mothers
suffering from depression 44 and increased life stress; decreased social support; poor weight gain; or tobacco,
alcohol, and drug use 45, all of which demonstrate an adverse effect on obstetric outcome. The relationship
between poor pregnancy outcomes and depression becomes much stronger when the mother is depressed during
the late second to early third trimester 46, and the relative risk for poor pregnancy outcomes rises 5% to 7% for
each point increase in the mother's score on the Beck Depression Inventory 47. In addition to the problems noted
previously, maternal depression also is associated with decreased fetal growth 46, raised newborn cortisol and
catecholamine levels 48, and newborns who cry more and are more difficult to console 49. Later in life, children
of depressed mothers are more prone to suicidal behavior, conduct problems, and emotional instability and
require psychiatric care more often [50,51].

Bipolar disorder (BPD), historically called manic-depressive disorder, is a serious psychiatric disorder affecting
1.5% of Americans. BPD is characterized by distinct periods of abnormally and persistently elevated, expansive,
or irritable mood, during which the following can occur: inflated self-esteem or grandiosity, decreased need for
sleep, pressured speech, flight of ideas or racing thoughts, distractibility, increase in goal-directed activity or
psychomotor agitation, and excessive involvement in pleasurable activities that have a high potential for painful
consequences (unrestrained buying sprees, sexual indiscretions, or foolish business investments) 5. It typically is
recurrent, usually begins in adolescence or early adulthood, and tends to cause a significant amount of distress
and dysfunction. BPD often is accompanied by substance abuse disorders and has high mortality rates because of
high suicidality [52,53]. The incidence of BPD in pregnancy is unknown. The course of illness typically has been
investigated as a risk for relapse with medication discontinuation. A single study indicates that lithium-
responsive pregnant women have a recurrence rate during pregnancy lower than predicted 54. In contrast, a
larger body of research suggests that pregnancy is a time of substantial risk of relapse, particularly after
discontinuation of pharmacologic treatment [55–58], the majority of these relapses being depressive episodes 55.
An expert panel recently completed an extensive review of BPD and its treatment during pregnancy 59.

The data on mood disorders clearly indicates there is minimal evidence of improvement and that the clinical
course through pregnancy in the context of medication discontinuation is laden with relapse. The obstetric
complications of maternal depression can be acute and have a long-lasting adverse impact on infant
development, temperament, and behavior. Although the obstetric impact of BPD is unknown, it can be assumed
to have an adverse impact as the majority of episodes in pregnancy are depressive.

 Schizophrenia and psychosis

Schizophrenia is a severe and persistent mental illness characterized by psychotic symptoms, such as delusions
and hallucinations; residual negative symptoms, such as flat affect; and significant occupational and social
dysfunction 5. Gender differences in the clinical expression of schizophrenia have been reported for some time.
Research shows that men have greater negative symptoms, worse level of functioning, and an earlier age of onset
compared with women 60, whereas women report a higher occurrence of auditory hallucinations 61 and higher
levels of paranoia, depressed mood, obsessional thinking and behavior, and impulsivity, which generally

manifests itself as sexually inappropriate behavior and indiscretion 62. Although schizophrenia occurs in
approximately only 1% to 2% of women, the most common age of initial onset is during a woman's childbearing
years 63, giving physicians cause for concern. The incidence in pregnancy is unknown and there is sparse
information about the course of illness that is confounded by alterations in pharmacotherapy and unreported
pregnancies. With regard to the high risk of decompensation during pregnancy and post partum, continuous
antipsychotic medication often is warranted 64. Data indicates that women who have psychoses neither improve
during pregnancy nor require smaller doses of maintenance medication while pregnant.

Women who have schizophrenia experience more obstetric complications than women who do not have mental
illness 65. One study finds that they also have high rates of poverty and substance abuse and are less likely to
receive consistent prenatal care 66. In contrast, a recent investigation does not confirm this data 67. Maternal
schizophrenia also is associated with a higher rate of perinatal death 68. Mothers who have schizophrenia are
significantly more likely to deliver a low birth weight (LBW) newborn [69,70], are at increased risk for preterm
delivery 71, and are more likely to require interventions during delivery 67 than mothers who do not have a
diagnosis of schizophrenia. Women admitted to the hospital for acute psychotic episodes during pregnancy seem
to be at the greatest risk for adverse pregnancy outcomes, including stillbirth and infant death 72. Untreated
schizophrenia during the postpartum period can have disastrous consequences for mother and child. There are
cases of maternal self-mutilation [73,74], infanticide 75, and denial of pregnancy, resulting in the patient's refusal
of prenatal care 76.

 Eating disorders

EDs seldom are screened for in nonpsychiatric clinics. EDs, including anorexia nervosa and bulimia, affect more
than 5% of Americans, and 90% of these are women of childbearing age [5,77]. In addition, almost half of the
women who have anorexia exhibit bulimic behaviors, and 30% to 80% of women who have bulimia have a
history of anorexia 78. Anorexia is defined as the failure to maintain body weight at 85% of the norm for one's
height. Weight loss is accompanied by extreme fear of gaining weight and distortions of body image. Dieting, self-
induced vomiting, extreme exercising, laxatives, diuretics, and thyroid hormone can be used to cause weight loss.
Bulimia is defined as recurrent episodes of binge eating, characterized by lack of control of eating and recurrent
inappropriate, compensatory behavior to prevent weight gain, such as self-induced vomiting; misuse of laxatives,
diuretics or enemas; fasting; and excessive exercise 5. Although fertility is reduced markedly in women who
suffer from anorexia nervosa, women do conceive despite maintaining suboptimal weight and not menstruating
79. There may be a protective value of pregnancy against EDs. One study reports that pregnant women who have
EDs were less concerned with weight than nonpregnant women, had lower dietary restraint, and attempted to
lose weight less frequently 80. Although many women show substantial improvement in bulimic symptoms
during pregnancy, possibly because of societal approval of weight gain during pregnancy and cultural pressures
to care for the fetus [81,82], there are cases reported in which the symptoms worsen 83. Furthermore, patients
who have bulimia seem to have a higher risk of affective disorders after delivery, including postpartum
depression [81–83].

There is conflicting obstetric outcome data in women who have EDs. The majority of women in one study had
reasonably good outcome with a 6.1% rate of birth defects, but more than one third experienced postpartum
depression 84. In contrast, other studies find higher rates of pregnancy complications in women who have EDs,
including prematurity, LBW, and higher rate of miscarriage and cesarean section [85–87]. Stewart et al
discovered that women whose ED was in remission at conception gained more weight during pregnancy and had
babies with higher birth weights and 5-minute Apgar scores 88. Furthermore, babies of women who have EDs
post partum are at increased risk for food deprivation and inadequate weight gain and growth 89. There is
evidence that children born to mothers who have EDs also are at risk for EDs. This may begin as feeding
problems in infancy and continue through adolescence and adulthood as a result of mothers who have EDs
restricting food 90, not eating in front of their children 91, and demonstrating other behaviors associated with
the disorder. One study shows 50% of the children of mothers who had EDs also had other psychiatric disorders,
including OCD, antisocial and oppositional defiant disorder, and eneuresis.

EDs or a history of EDs seldom is assessed in the nonpsychiatric clinical setting. Although there is evidence that
EDs may have a more benign course in pregnancy compared with other psychiatric illnesses, the comorbidity
with depression and anxiety warrants concerns for obstetric outcome. Similarly, the impact of EDs in the

postpartum period seems to be potentially more problematic.

The data on the incidence, course, and impact of the psychiatric illnesses discussed previously are summarized in
Table 1 and include the most common Food and Drug Administration (FDA)–approved treatment options. These
data focus on pregnancy, and there is general consensus that the postpartum period represents considerable risk
for the majority of psychiatric illnesses.

Table 1. Summary of incidence, course, and impact of psychiatric illnesses in pregnancy

Adverse
Incidence in Impact on
Incidence in Course in impact of
Diagnosis general obstetric Treatment options
pregnancy pregnancy illness on
population outcome
children
Anxiety 13.3% overall Unknown Limited LBW, SGA, Yes CBT, IPT
disorders rate of any evidence of premature Antidepressants
anxiety improvement for delivery, Benzodiazepines
disorder PD OCD decreased fetal
probably growth
worsens
Major 12% in 10% No LBW, SGA, Yes CBT, IPT
depression women, 6.6% –16% improvement premature Antidepressants ECT
in men 70% delivery, Light therapy
experience decreased fetal
depressive growth
symptoms
High rate of
relapse with
medication
discontinuation
Bipolar 1.2% Unknown No Unknown Unknown Mood stabilizers ECT
disorder improvement Antipsychotics
High rate of
relapse with
medication
discontinuation
Schizophrenia 1.1% Unknown No LBW, SGA, Unclear, Antipsychotics
improvement reduced head confounded
circumference, by
premature birth, medication
higher rates of exposures
stillbirth and
infant death
Eating 0.5% Unknown Seem to LBW, inadequate Yes Psychotherapy
disorders –3.7% improve during or excessive Behavioral
of women pregnancy and weight gain, programsAntidepressants
suffer from potentially miscarriage,
anorexia, 1.1% worsen post hyperemesis
– 4.2% partum gravidarum,
suffer from premature
bulimia delivery, cesarean
delivery, and low
Apgar scores

Abbreviation: SGA, small for gestational age.

MANAGEMENT OF PSYCHIATRY DISORDERS IN PREGNANCY

The overlap in the potential treatment options for various psychiatric illnesses during pregnancy and lactation
warrant their discussion by category rather than by illness. There are limited studies of the efficacy of any
specific treatment during pregnancy, as the literature focuses on the reproductive safety of such treatments.
There is no data to suggest that a treatment is less effective in pregnancy than in nongravid conditions.

 Psychotherapy

Use of nonpharmacologic treatment alternatives, such as cognitive-behavioral therapy (CBT) 92 and
interpersonal psychotherapy (IPT) [93,94], for the treatment of psychiatric illnesses during pregnancy is
underinvestigated dramatically. Myriad studies show such structured psychotherapies to be effective in the
treatment of anxiety disorders and depression. IPT is associated with greater improvement in mood than a
parent education program during the prenatal period in one study 95. An elegant study of manual development
demonstrates the efficacy of IPT for depression in the postpartum period 94. There are case reports of the
efficacy of CBT in the treatment of PD in pregnancy. In one study, women in a postpartum prevention group,
who received one session of CBT during hospitalization in the days immediately after the birth, had significantly
more reductions in the frequency of depression than the control group 96.

 Light therapy

The use of light therapy in the treatment of depression, in particular seasonal affective disorder, demonstrates
efficacy. A single open-label trial of light therapy found it beneficial in reducing depressive symptoms during
pregnancy 97. Additional study is warranted and caution should be exercised in the use of such therapies if there
is diagnostic uncertainty.

 Electroconvulsive therapy

Electroconvulsive therapy (ECT) is an effective treatment of major depression and BPD that has few side effects
and may pose fewer risks than untreated mood episodes or pharmacotherapy with a teratogenic agent. There are
reports of congenital malformations in offspring exposed to ECT in utero 98, although confirmation of a causal
relationship is lacking. Overall, the reported complications of ECT during pregnancy are uncommon and
transient 99. The risk of fetal cardiac arrhythmias can be minimized by avoiding atropine, ensuring adequate
oxygenation, avoiding excessive hyperventilation, and elevating the right hip. Fetal cardiac monitoring during
ECT allows detection of arrhythmias and correction of any contributory problems. There are limited reports of
uterine contractions after ECT 100 but no risk of premature labor 99.

Although nonpharmacologic treatments seem promising, there is limited availability and funding to cover such
interventions, leaving many clinicians with the potential use of medications during pregnancy. The use of
psychotropic medications in pregnancy and lactation has been reviewed extensively 101.

 Antidepressants

A Medline search conducted in February 2004 of antidepressants in pregnancy yielded 26 journal articles with a
total of 4556 participants. Information is derived from myriad sources, including birth registries, retrospective
surveys, case reports, case series, reports from poison control and teratology centers, and controlled
observational studies. Despite the capacious amount of reproductive safety information available on this class of
drugs, absolute numbers in each study are small, making definitive conclusions elusive. On the whole, findings
regarding pregnancy outcomes after the use of antidepressants in pregnancy are favorable. Antidepressants have
been in use for more than 4 decades with no confirmed reports of birth defects associated with in utero exposure.
A comprehensive meta-analysis in 1996 failed to identify any risk for in utero exposure to antidepressants 102,
and data on tricyclic antidepressants (TCAs) have not advanced significantly since that report.

The selective serotonin uptake inhibitors (SSRIs) have moved to the forefront of treating depression and anxiety.
To date, published retrospective and prospective reports of SSRI use during gestation consist of 1241 fluoxetine

exposures [103–110], 364 citalopram exposures 109, 309 paroxetine exposures [109–112], 225 sertraline
exposures [109,110,112], and 80 fluvoxamine exposures [106,112]. No published reports regarding prenatal
exposure to the new enantiomeric compounds, duloxetine and escitalopram, currently are available. Collectively,
these data provide no evidence that prenatal SSRI exposure is associated with an increased incidence of
congenital malformations.

Recent additions to the available regimen of antidepressants include a heterogeneous assortment of
antidepressants that work by distinct pharmacodynamic mechanisms. Antidepressants that do not fit into the
major categories include bupropion, mirtazapine, nefazodone, and venlafaxine. A recent report demonstrates no
adverse effects of fetal exposure to venlafaxine 113. Despite the paucity of data, physicians in the United States
increasingly are prescribing bupropion to treat depression during pregnancy, apparently as a consequence of its
inclusion by the FDA in the B risk category for pregnancy. The manufacturer of bupropion has maintained a
pregnancy registry for the compound since 1997; this registry, however, has not been submitted for publication
or peer review; as such, there are no published data regarding its safety or tolerability during gestation.
Likewise, there are no published reports regarding the use of mirtazapine or nefazodone during pregnancy.

Recent pharmacokinetic studies [110,114] demonstrate that antidepressants do cross the placenta, and rodent
investigations from the authors' group 115 indicate significant central nervous system exposure. Similarly,
additional studies indicate that during the course of pregnancy there are significant alterations in the clearance
of TCAs and SSRIs that may warrant dose adjustments [102,116,117].

In contrast, there are reports that attribute adverse obstetric outcome to antidepressant exposure. One study
finds that third-trimester exposure to fluoxetine is associated with higher rates of prematurity, admissions to
special care nurseries, poor neonatal adaptation, shorter birth length, and lower birth weight compared with
exposure during the first or second trimesters 105. Cohen et al 118 finds no significant differences in gestational
age at delivery, birth weight, Apgar scores, or timing of maternal-infant discharge between early and late
exposed infants; there were twofold and threefold increases, however, in neonatal complications and admissions
to special care nurseries between the two groups, respectively. One cohort study also finds higher rates of
spontaneous abortions in women exposed to TCAs (n=74) or fluoxetine (n=128) compared with matched control
subjects 103. Other groups have failed to come up with similar findings, reporting that no differences existed
between groups [108,112,119]. Because none of the studies that report associations between in utero
antidepressant exposure and poor pregnancy outcome controlled for maternal depression, concomitant
medication exposure, or alcohol and tobacco use, these results are provisional at best. Two landmark studies
conducted by Nulman et al [108,119] find that in utero exposure to TCA or fluoxetine did not affect children's
global IQ; temperament; or language, cognitive, and behavioral development; uncontrolled depression in the
latter study, however, was associated with lower cognitive and language achievements 119. Most commonly,
results are mixed, leaving the question of the safety of antidepressant medications during pregnancy unanswered.
Simon et al 120 conducted a study comparing pregnancy outcomes in patients exposed to TCAs and SSRIs with
those in control subjects. They found no significant differences between those exposed to TCAs and control
subjects in gestational age at birth, Apgar scores, birth weight, or head circumference; those exposed to SSRIs,
however, showed significantly lower Apgar scores, gestational age at birth, and birth weight 120. A similar
finding of lower birth weight associated with high doses of fluoxetine in later pregnancy raises questions
regarding the impact of these medications on birth weight 114.

Recently, much attention has been paid to selective serotonin discontinuation syndrome, a set of adverse effects
emerging after cessation of antidepressants (SSRIs and venlafaxine) [121–123]. Concern has emerged over
whether or not neonates suffer from discontinuation syndrome after delivery when exposure to SSRIs is stopped
abruptly at birth. Costei et al 124 find a high rate of neonatal complications, in particular respiratory distress, in
infants whose mothers took paroxetine (22%) throughout pregnancy compared with control infants (6%).
Earlier studies found that neonatal withdrawal symptoms occurred after third-trimester exposure to paroxetine
and were evident in the first days after birth for up to 1 month [125,126]. Symptom characteristics included
irritability, constant crying, shivering, increased tonus, eating and sleeping difficulties, convulsions, jitteriness,
poor gaze control, necrotising enterocolitis, vomiting, myclonus, and lethargy [125,126]. Although evidence for
perinatal serotonin discontinuation syndrome seems compelling, research in this area is confounded by the
presence of maternal smoking, polypharmacy, maternal health problems, and pregnancy and delivery
complications. Despite the limitations of these case reports, the FDA recently issued a warning concerning the use

of antidepressants proximate to delivery, although admitting they were unsure if this was a toxic or withdrawal
effect.

As discussed previously, a major potential confound to these adverse reports is the overlap in reported adverse
outcomes related to antidepressant exposure (eg, LBW) and the data indicating that untreated maternal
depression and anxiety are associated with the same finding. Further research is needed to support existing
findings before definitive conclusions can be drawn.

 Benzodiazepines

Benzodiazepines have a wide spectrum of clinical indications, including the full array of anxiety disorders,
insomnia, alcohol detoxification, muscle relaxation, adjunctive use for seizure disorders, and conscious sedation
during invasive medical procedures. A retrospective survey of Medicaid prescription records from 1980 to 1983
for more than 100,000 pregnant women found that at least 2% were prescribed a benzodiazepine during
gestation 127. Initial studies of benzodiazepine-associated teratogenic effects report an increased risk of oral
clefts after in utero exposure to diazepam [128–130], but later studies fail to confirm this association [131–133].
Studies of first-trimester alprazolam exposure encompassing approximately 1300 pregnancies demonstrate no
excess of oral clefts or other congenital anomalies [134–136]. A subsequent meta-analysis by Altshuler et al 102,
pooling data from several studies, demonstrates that prenatal benzodiazepine exposure does confer an increased
risk of oral cleft, although the absolute risk increased by only 0.01%, from 6 in 10,000 to 7 in 10,000. This
conclusion is confirmed in a recent case control study of benzodiazepine exposure in more than 38,000 infants
compared with nearly 23,000 control children 137 that demonstrates no difference in the rate of congenital
anomalies.

Longitudinal follow-up studies describe a benzodiazepine exposure syndrome, including growth retardation,
dysmorphism, and mental and psychomotor retardation in infants exposed prenatally to benzodiazepines 138,
although other investigators dispute this finding [139–141]. Although the data regarding the teratogenic effects of
benzodiazepine exposure remain controversial, the occurrence of neonatal toxicity and withdrawal syndromes
are well documented. Many groups describe a floppy infant syndrome, characterized by hypothermia, lethargy,
poor respiratory effort, and feeding difficulties after maternal use of benzodiazepines shortly before delivery
[142–149]. Neonatal withdrawal syndromes, characterized by restlessness, hypertonia, hyperreflexia,
tremulousness, apnea, diarrhea, and vomiting, are described in infants whose mothers were taking alprazolam
134, chlordiazepoxide [150–152], or diazepam [153,154]. Symptoms of these neonatal syndromes are reported to
persist for as long as 3 months after delivery 155.

These data fail to confirm the excessive concern for direct teratogenic effects but underscore the need to be
mindful of neonatal symptoms when benzodiazepines are used proximate to delivery.

 Mood stabilizers

The management of BPD has received considerable attention and continues to be one of the most difficult
challenges of modern psychiatric practice 59. The current FDA-approved treatments of BPD include mood
stabilizers and atypical antipsychotic agents. Given the audience, an exhaustive review of the reproductive safety
data on anticonvulsants has been abbreviated. All mood stabilizers cross the placental barrier and demonstrate
complete placental passage 156.

 Lithium

Since the 1950s, lithium has emerged as the cornerstone of the available pharmacotherapies for BPD. Early
reports of congenital malformations after in utero lithium exposure led to the establishment in 1969 of the
Danish Registry of Lithium Babies. Additional registries were established in Canada and the United States,
culminating in the International Register of Lithium Babies, a physician-reporting registry. Early data suggested
that lithium exposure was associated with a 400-fold increase in the vulnerability for congenital heart disease, in
particular Epstein's anomaly [157,158], but a subsequent meta-analysis of the available data calculated the risk
ratio for cardiac malformations to be 1.2 to 7.7 and the risk ratio for overall congenital malformations to be 1.5
to 3.0 159. Altshuler et al 102 estimates that the risk for Epstein's anomaly after prenatal lithium exposure rises

from 1 in 20,000 to 1 in 1000. A series of more recent yet small studies also fails to confirm the early estimates
regarding the teratogenic potential of lithium [160–162].

Lithium's low therapeutic index also raises concerns regarding acute perinatal toxicities. Lithium exposure later
in gestation is associated with fetal and neonatal cardiac arrhythmias 163, hypoglycemia and nephrogenic
diabetes insipidus 164, reversible changes in thyroid function 165, polyhydramnios, premature delivery, and a
floppy baby syndrome similar to that witnessed with benzodiazepine exposure 166. Neonatal symptoms of
lithium toxicity, including flaccidity, lethargy, and poor suck reflexes, may persist for more than 7 days 167. A
recent study by the authors' group 156 demonstrates that stopping lithium within 48 hours of delivery
significantly reduces neonatal complications without compromising maternal emotional well-being.

The physiologic alterations of pregnancy are of particular importance in the management of lithium therapy
during the peripartum, warranting careful monitoring of lithium serum concentrations, although lithium is not
effective for all variants of BPD and the long-term sequelae of lithium exposure has given way to the increased
use of antiepileptic medications (AEDs). Arguably, the majority of the data for AEDs has been obtained from
women who have epilepsy and there is limited data on the outcomes of AEDs in women who have BPD, a fact
noted more than 2 decades ago 168. Conservative clinical management, however, warrants extension of these
data to women who have BPD pending additional investigations.

 Valproic acid (valproate)

Several anticonvulsants are used in the treatment of BPD. Foremost among these are valproate and
carbamazepine, which are superior to lithium for patients who experience mixed episodes or rapid cycling.
Anticonvulsants, however, with the possible exception of lamotrigine, have limited efficacy in the treatment of
bipolar depression. A major problem in psychiatric clinics with the use of AEDs is the limited appreciation of
risk for inadvertent conception and the need to treat women of reproductive capacity as though they are
pregnant from the first visit (eg, document birth control, educate about risk of medications, and provide
supplemental folic acid). Despite these potential problems, valproate and, to a lesser extent, carbamazepine
increasingly are preferred as first-line mood stabilizers by many clinicians.

Briefly, prenatal exposure to valproate is associated with many congenital malformations, including neural tube
defects [169–172], craniofacial anomalies 173, limb abnormalities 174, and cardiovascular anomalies [175–177].
A recent meta-analysis places the risk for neural tube defects at 3.8%, with particular vulnerability for the
infants of women whose daily dose exceeds 1000 mg 178. Additional studies support this dose-effect relationship
[179–182].

Fetal anticonvulsant syndromes are reported for several AEDs [182,183] and valproate is no exception. An initial
report 184, confirmed by other investigators [185–187], demonstrates a broad array of anomalies associated with
valproate exposure. Although there are some conflicting reports on exactly which features are part of this
syndrome, there is consensus that valproate exposure is responsible. Of concern also are retrospective reports
indicating various degrees of cognitive impairment in children who have fetal valproate syndrome [188–190]. A
recent review indicates that developmental delay is evident in 20% and mental retardation in 10% of children
exposed to valproate monotherapy prenatally 191.

Pharmacokinetic studies in women who have epilepsy indicate that maternal serum valproate concentrations
decline steadily across pregnancy, reaching levels up to 50% lower than preconception concentrations [192,193].
Consistent findings from other studies demonstrate that valproate is cleared more rapidly during gestation,
especially during the final month of pregnancy [194–196]. Recent data from the authors' group confirms this
effect in women who have epilepsy and BPD 197.

 Carbamazepine

Carbamazepine is another mood stabilizer, although the efficacy in BPD has limited its widespread acceptance as
a first-line pharmacotherapy. Carbamazepine is associated with many of the same risks as valproate during
gestation, although in many cases with less frequency or severity. For example, exposure to carbamazepine, like
valproate, during the first trimester is associated with a risk for neural tube defects, but the 0.5% to 1% risk for

neural tube defects in carbamazepine-exposed infants 198 is significantly less than the rate with valproate
exposure [171,198]. A recent epidemiologic study indicates that periconceptional folate supplementation is
associated with a lower rate of neural tube defects among the children of women taking carbamazepine during
pregnancy 199. A recent meta-analysis of five prospective studies encompassing 1255 prenatal exposures
indicates that carbamazepine exposure in utero is associated with an increased risk of neural tube defects, cleft
palate, cardiovascular abnormalities, and urinary tract anomalies 200.

As with valproate, a fetal carbamazepine syndrome is described 201 but has received considerably less attention
than fetal valproate syndrome. A subsequent study finds the phenotypic characteristic of fetal carbamazepine
syndrome evident in 6 of 47 children exposed to carbamazepine monotherapy during gestation 202. Other
investigations confirm this association with facial anomalies [190,203–205], but one of these studies demonstrates
similar facial abnormalities among children born to women who had epilepsy and were untreated during
pregnancy 204. There are conflicting reports regarding the relationship of the fetal carbamazepine syndrome to
developmental delays [188,190,201–203,205–207].

In contrast to other AEDs, the pharmacokinetic studies of carbamazepine clearance during gestation and
placental passage have produced mixed results. Some investigators report statistically significant increases in
carbamazepine clearance during the third trimester [208–210], but others find no changes in carbamazepine
clearance [195,211,212]. Placental passage investigations indicate that carbamazepine is lower than other
anticonvulsants [192,193,213], with fetal-maternal plasma ratios equaling 0.5 to 0.8 213.

The clinical import of the data on carbamazepine in light of the efficacy limitations in the treatment of BPD is
unclear, particularly regarding recent data on lamotrigine.

 Lamotrigine

Several investigations demonstrate that lamotrigine is efficacious in the treatment of BPD. Similarly, prescribing
trends indicate that lamotrigine is emerging rapidly as a first-line treatment of epilepsy and BPD during
pregnancy. One potentially unique facet of lamotrigine is demonstrated in clinical trials that indicate efficacy for
the depressed and manic phases of illness in BPD. Data from the Lamotrigine Pregnancy Registry maintained at
GlaxoSmithKline (Triangle Park, North Carolina) include United States and United Kingdom reports of
pregnancy exposure and have obstetric outcome for more than 500 cases. The results to date are reassuring, with
a risk of less than 2% for fetal malformation after first-trimester lamotrigine exposure. The registry has not
undergone the peer review process in its entirety 214 and clinicians are encouraged to request the information.
Although clinical data to date do not indicate a higher rate of neural tube defects among lamotrigine-exposed
infants, the Physicians' Desk Reference reports that premarketing laboratory animal data demonstrate that
lamotrigine is associated with decreased circulating folate concentrations 215. Consequently, routine folate
supplementation (4 to 5 mg/d) is recommended for all women of reproductive age, pregnant or not, who are
taking lamotrigine.

The pharmacokinetics of lamotrigine use during pregnancy have been scrutinized; the reliance on
glucyronidation, which changes dramatically during pregnancy, has generated considerable interest with respect
to how to use lamotrigine effectively during pregnancy. Several reports indicate collectively that lamotrigine
clearance steadily increases across gestation [216–220], necessitating periodic dose changes during pregnancy to
maintain seizure control in patients who have epilepsy. A series of small studies indicate that lamotrigine
concentrations in fetal circulation at delivery are equal to maternal concentrations [218,221–223]. Studies also
indicate that its rate of clearance declines abruptly after delivery [219,222]. Therefore, dose reductions typically
are necessary after delivery to avoid maternal symptoms of lamotrigine toxicity, such as dizziness, nausea and
vomiting, and diplopia 219.

Lamotrigine use during breastfeeding continues to generate concerns, although investigations are under way and
preliminary reports fail to demonstrate any adverse effects.

 Antipsychotic medications

The introduction of the atypical antipsychotic drugs has proved efficacious in the treatment of schizophrenia and

there are increasing reports of and FDA approval for such medications in the treatment of BPD. Many clinicians
have forgotten that the original clinical use of the phenothiazines was to treat first-trimester nausea and that
promethazine (Phenergan), a commonly prescribed antiemetic in pregnancy, is a phenothiazine.

Phenothiazines are useful as antipsychotic medications but also are used for their antiemetic, antinauseant, and
antihistamine effects 224. These medications are useful during labor and delivery because of their ability to
potentiate the effects of analgesics, sedatives, and general anesthetics 224. Of the typical antipsychotic
medications, chlorpromazine, haloperidol, and perphenazine have received the greatest scrutiny, as they produce
no significant increase in major congenital malformations [225–227]. In a study 228 of 100 women treated with
haloperidol (mean dose 1.2 mg/d) for hyperemesis gravidarum, no differences in gestational duration, fetal
viability, or birth weight were observed. In a large prospective study encompassing nearly 20,000 women treated
primarily with phenothiazines for emesis, Milkovich and Van den Berg 229 find no significant association with
neonatal survival rates or severe anomalies after controlling for maternal age, medication, and gestational age at
exposure. In contrast, one group 230 reports a significant association of major anomalies with prenatal exposure
to phenothiazines with aliphatic side chains but not with piperazine or piperidine class agents. Reanalysis of the
data obtained by Milkovich and Van den Berg 229 does find a significant risk of malformations associated with
phenothiazine exposure in weeks 4 through 10 of gestation 231. A meta-analysis 102 confirms an association
between phenothiazines with aliphatic side chains in lip and palate anomalies. One study examining 12 mothers
who received antipsychotic medication during the final trimester of pregnancy finds that at 3 and 14 days of age,
the infants of these women showed poor neonatal motor functioning on the Brazelton Neonatal Behavioral
Assessment Scale 232, indicating symptoms of withdrawal syndrome, including tremulousness, hypertonicity,
and poor motor maturity 233. A similar study followed 16 women and their infants throughout pregnancy and
up to 7 years post partum. All 16 of these women took phenothiazines throughout pregnancy; no apparent
adverse effects of the medication were found, however 234.

Although the atypical antipsychotic medications are emerging as the treatment of choice for psychosis, there also
is increasing use of such agents in refractory major depression. The data on these medications is limited. The
largest data set comes from several case reports (n=73) on clozapine 156 and there is no evidence of increased
birth defects. The second largest data set is derived from postmarketing surveillance at Eli Lilly (Indianapolis,
Indiana) for olanzapine (n=23). These women did not experience increased risk of spontaneous abortion,
stillbirth, or prematurity, and the newborns did not seem to be at greater risk for major malformations as a
result of the prenatal exposure to olanzapine 235. There is limited or no information on the remaining atypical
antipsychotic medications. A clinical concern for use in pregnancy is that several of these medications are
implicated in glucose metabolism alterations; therefore, the authors' group emipirically recommends conducting
the glucose tolerance test earlier in pregnancy for these women.

In summary, with respect to medication use during pregnancy, there is considerable variability in the potential
impact of medications on obstetric outcome and neonatal well-being. The clinician is forced to balance the risk of
such medications with the risk of the illness being targeted. Often, pharmaceutical companies and the FDA
render warnings and provide little support for the use of such treatments during pregnancy and lactation. A
quotation germane to the issues encountered, credited to Dr. Schou, one of the original authors of the lithium
registry, summarizes the usefulness of such warnings and cautions: “When manufacturers and official agencies
warn against drug treatment during pregnancy, their warnings serve to protect themselves and are of little use to
clinically responsible physicians” 236.

SUMMARY

This review, although not exhaustive, provides information on the potential impact of psychiatric illness on
obstetric outcome. There is clear evidence that psychiatric illness poses a risk to pregnancy outcome. The
reproductive safety data on many of the available treatments fail to demonstrate a clear risk from treatment. The
medications with clear teratogenic, neonatal, and developmental risks are, not surprisingly, those used to treat
some of the most severe and debilitating psychiatric illnesses. Even the amount of information available is
inadequate without some straightforward clinical guidelines. A model of risk for illness and treatments of
illnesses during pregnancy developed by the authors' group 237 reminds clinicians that nonexposure does not
exist. Rather, the decision is which type of exposure is in the best interest of the patient and family—exposure to
illness or exposure to treatment. Regardless of the choice, clinicians are encouraged to think in terms of reducing

the total number of exposures; that is, if choosing to treat, patients should be kept well by adjusting and
monitoring medications—partial treatment simply provides exposure to illness and treatment. Guidelines to
accomplish the goal of minimizing exposures include:

1. Treating women of reproductive capacity from the first visit as if they are pregnant: choosing treatments with
reproductive safety information (eg, new and improved=no data) and providing supplemental folic acid for all
women (800 µg), with higher doses for those treated with anticonvulsants (3 to 4 mg).

2. For women who conceive while taking a medication, and if it was efficacious for them, then the majority of
decisions for medication selection should be considered already made for pregnancy and lactation (eg, do not
switch medications once pregnant or for breastfeeding, as that simply exposes the baby to a second medication
and the data previously discussed do not apply).

3. Because the serum concentration of most medications decreases during pregnancy, establishing criteria a
priori for increasing the maternal daily dose; as a general rule, sleep patterns are good markers of psychiatric
illnesses.

4. Always preferring monotherapy to two medications.

5. Obtaining up-to-date information at (a website with links to many support groups, reproductive safety
registries) or other women's health websites.

These basic guidelines can help decrease the number of exposures and aid in conducting clinical care with at least
some reproductive safety data.

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