Bipolar disorder in pregnant women: Treatment of mania and hypomania

Author
Victoria Hendrick, MD
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Oct 2014. | This topic last updated: Jul 24,
2014.
INTRODUCTION Medications are commonly used to treat pregnant patients,
including those with manic and hypomanic episodes [1]. At least one prescription
drug is taken by more than 60 percent of pregnant patients [2], and psychotropic
drugs are taken by 21 to 33 percent [3,4].
This topic discusses pharmacotherapy for pregnant patients with mania or
hypomania. Treatment of bipolar major depression during pregnancy, prenatal
maintenance pharmacotherapy for bipolar disorder, the teratogenic and postnatal
risks of medications used for bipolar disorder, and the general treatment of mania
and hypomania is discussed separately.
DEFINITION OF BIPOLAR DISORDER Bipolar disorder is characterized by
episodes of mania (table 1), hypomania (table 2), and major depression (table 3)
[5]. The subtypes of bipolar disorder include bipolar I and bipolar II. Patients with
bipolar I disorder experience manic episodes, and nearly always experience major
depressive and hypomanic episodes. Bipolar II disorder is marked by at least one
hypomanic episode, at least one major depressive episode, and the absence of
manic episodes. Additional information about the clinical features and diagnosis of
bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Clinical
features" and "Bipolar disorder in adults: Assessment and diagnosis".)
INDICATIONS Pharmacotherapy is indicated for pregnant patients with manic
and hypomanic episodes that are characterized by [6]:
Suicidal or homicidal ideation or behavior
Aggressive behavior
Psychotic features (delusions or hallucinations)
Poor judgement that places the patient or others at imminent risk of being harmed
Moderate to severe impairment of social or occupational functioning
Involvement in pleasurable activities that have a high potential for painful
consequences (eg, unrestrained buying sprees or sexual indiscretions)
Medications may not be indicated for some episodes of hypomania. However, it is
not clear which untreated hypomanic episodes will progress to mania that requires
pharmacotherapy.
MANAGEMENT
General principles Bipolar mood episodes during pregnancy are usually
treated by perinatal or general psychiatrists in collaboration with obstetricians and

primary care clinicians [4,7-10].

For manic and hypomanic pregnant patients, treatment is based upon randomized
trials that excluded pregnant patients [11], as well as observational studies, birth
registries, and clinical experience [12].
For pregnant bipolar patients treated with pharmacotherapy, clinicians should
attempt to use [1,4,13,14]:
-Drugs with fewer known teratogenic effects
-Monotherapy
-Doses at the low end of the therapeutic range
The risks of teratogenic effects from medications commonly used to treat bipolar
disorder are discussed separately. (See "Teratogenic and postnatal risks of
antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy".)
For pregnant patients with bipolar mood episodes that occur during maintenance
pharmacotherapy, we favor increasing the dose within the therapeutic dose range
rather than starting a second medication [4,15,16]. This includes ensuring serum
concentrations are in the therapeutic range for medications such as lithium, as well
as increasing the dose to achieve a higher serum level within the therapeutic
range, provided that side effects do not intervene. However, many patients require
medication combinations [9,17-19].
Following recovery from prenatal bipolar mood episodes with pharmacotherapy, we
suggest that patients receive maintenance treatment. For patients who decline
maintenance pharmacotherapy, abrupt discontinuation of medications should be
avoided. Rather, clinicians should attempt to taper and discontinue drugs over the
course of at least 15 days to minimize the risk of relapse, based upon
observational studies [20]. Prenatal maintenance pharmacotherapy and the risk of
abruptly discontinuing pharmacotherapy are discussed separately. (See "Bipolar
disorder in women: Preconception and prenatal maintenance pharmacotherapy"
and "Bipolar disorder in women: Contraception and preconception assessment and
counseling", section on 'Relapse after discontinuing pharmacotherapy'.)
Setting The setting for prenatal treatment of bipolar mood episodes depends
upon the type and severity of symptoms, level of psychosocial functioning, and
available support [15,21,22]:
Inpatient hospitalization is often required for safety and stabilization of patients
with severe symptoms (eg, suicidal ideation with a specific plan or intent)
Partial hospital (day) treatment may be feasible for managing moderate
symptoms (eg, suicidality that does not pose an imminent risk, such as fleeting
thoughts of killing oneself with vague or nonexistent plans and no intent)

Outpatient treatment may be suitable for patients with less acute symptoms (eg,
thoughts that family members would be better off if the patient was dead, with no
plan or intent to commit suicide)
Monitoring the patient The psychiatric status of pregnant bipolar patients
should be regularly monitored, with particular attention to suicidal ideation and
psychosis [7,23]. Patients taking medications are also assessed for therapeutic
and adverse effects. In addition, serum concentrations of medications with
established therapeutic levels (eg, lithium) should be checked. Monitoring pregnant
patients who take lithium is discussed separately. (See "Bipolar disorder in women:
Preconception and prenatal maintenance pharmacotherapy", section on
'Refractory patients'.)
The frequency of assessing pregnant bipolar patients generally ranges from daily
to monthly, depending upon the type and severity of symptoms. Hospitalized
patients are monitored daily, and patients with active suicidal ideation, a specific
plan, and intent to kill themselves typically require constant observation.
Outpatients who have not achieved substantial improvement in the number,
intensity, and frequency of symptoms are generally seen weekly; patients who
have improved substantially may be seen every two to four weeks until they remit.
Duration of individual drug trial We suggest treating pregnant patients with
mania and hypomania for three weeks before determining whether a specific drug
is beneficial, based upon the duration of most randomized trials (which excluded
pregnant patients) [11]. Response is defined as stabilizing the patients safety and
substantial improvement in the number, intensity, and frequency of symptoms.
SPECIFIC TREATMENTS Despite clinical differences between mania and
hypomania (eg, hypomania is less severe than mania), for the purpose of
treatment these mood elevated syndromes are considered to be similar and thus
treated with the same medications [15,21,22].
First line medications For manic and hypomanic pregnant patients, we
suggest first-generation antipsychotics, which have been widely used during
pregnancy [4,24]. We prefer haloperidol, based upon its demonstrated efficacy in
randomized trials (which excluded pregnant patients) [11], and other studies that
suggest haloperidol is not associated with an increased risk of congenital
anomalies [3,25]. Using haloperidol is consistent with practice guidelines from the
United Kingdom National Institute for Health and Clinical Excellence [23,26], and
haloperidol is preferred by many authorities [1,18,27]. Other first-generation
antipsychotics that are reasonable alternatives to haloperidol include
chlorpromazine, fluphenazine, perphenazine, thiothixene, and trifluoperazine [28].
Clinicians can expect that response to a first-generation antipsychotic will occur in
approximately 50 percent of patients, based upon trials in nonpregnant patients
[29].

The efficacy of haloperidol for treating mood elevated syndromes appears to be

comparable to risperidone and olanzapine, and superior to quetiapine and lithium
[11]. In addition, there is more experience using haloperidol during pregnancy
compared with second-generation antipsychotics, and the reproductive safety
profile of haloperidol is generally regarded as superior to lithium. The efficacy of
haloperidol, risperidone, olanzapine, quetiapine, and lithium (in randomized trials
that excluded pregnant patients) is discussed separately, as is the reproductive
safety profile of these drugs, and the dose, side effect profile (table 4), and
pharmacology of haloperidol. (See "Bipolar disorder in adults: Pharmacotherapy for
acute mania and hypomania" and "Teratogenic and postnatal risks of
antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy" and "Firstgeneration antipsychotic medications: Pharmacology, administration, and
comparative side effects".)
For pregnant bipolar patients who cannot tolerate the usual minimal therapeutic
dose of haloperidol (5 to 10 mg per day) because of extrapyramidal symptoms
(EPS), we suggest cautiously reducing the dose (eg, by 1 to 2 mg per day), while
closely monitoring the patient for exacerbation of mood elevated symptoms. If
decreasing the dose is unfeasible or inadequate, we suggest tapering and
discontinuing haloperidol over one to two weeks and at the same time starting and
titrating up a low-potency agent (eg, chlorpromazine) [30]. Haloperidol is tapered
by the same amount for each dose decrease. As an example, haloperidol 8 mg per
day is decreased by 2 mg per day every one to three days. The dose and side
effects of chlorpromazine are discussed separately. (See "First-generation
antipsychotic medications: Pharmacology, administration, and comparative side
effects", section on 'Chlorpromazine'.)
For pregnant patients receiving haloperidol who develop Parkinsonism or dystonia,
a reasonable alternative to switching drugs is to add diphenhydramine. Reviews
suggest that the risk of teratogenicity with antihistamines such as diphenhydramine
appears to be low [31], and that fetal organ malformation appears to be less likely
with diphenhydramine than amantadine, benztropine, and trihexyphenidyl [30,32].
Additional information about the treatment of extrapyramidal symptoms and the
teratogenic risks of antiparkinsonian drugs is discussed separately. (See
"Pharmacotherapy for schizophrenia: Side effect management", section on
'Extrapyramidal symptoms' and "Teratogenic and postnatal risks of antipsychotics,
benzodiazepines, lithium, and electroconvulsive therapy", section on
'Antiparkinsonian drugs used for treating extrapyramidal symptoms'.)
Resistant patients In our clinical experience, pregnant patients with manic and
hypomanic episodes often do not respond to or tolerate haloperidol. (Response is
defined as stabilizing the patients safety and substantial improvement in the
number, intensity, and frequency of symptoms.) For these resistant patients, we
suggest in order of preference risperidone, quetiapine, or olanzapine, based upon
their efficacy and side effects in randomized trials (that excluded pregnant patients)
[11], as well as study findings that suggest these drugs are not associated with an
increased risk of major malformations [19,33,34]. Using second-generation

antipsychotics during pregnancy is consistent with the practice of many perinatal

psychiatrists [18]. Up to 50 to 60 percent of patients may respond, based upon
trials in nonpregnant patients [29].
The efficacy of risperidone and olanzapine appears to be superior to quetiapine
and lithium; quetiapine appears to be better tolerated than olanzapine; and
although the efficacy of quetiapine and lithium appear comparable, quetiapine may
be better tolerated [11]. In addition, study findings suggest that second-generation
antipsychotics are not associated with an increased risk of major malformations
[18,19,33,34], whereas lithium is generally regarded as teratogenic [35-37]. The
preference for treating pregnant bipolar patients with risperidone, quetiapine, or
olanzapine rather than lithium is consistent with practice guidelines from the United
Kingdom National Institute for Health and Clinical Excellence [23,26].
However, second-generation antipsychotics, particularly olanzapine, may cause
metabolic complications (eg, hyperglycemia and obesity) that are associated with
risks to the mother and fetus [38,39]. These risks are discussed separately, as is
monitoring of metabolic parameters in pregnant patients taking second-generation
antipsychotics. (See "Bipolar disorder in women: Preconception and prenatal
maintenance pharmacotherapy", section on 'Metabolic complications'.)
To switch drugs, haloperidol is tapered and discontinued over one to two weeks
while at the same time risperidone is started and titrated up. We generally taper
haloperidol by the same amount for each dose decrease. As an example,
haloperidol 8 mg per day is decreased by 2 mg per day, every one to three days.
For resistant pregnant bipolar patients who do not respond to or tolerate treatment
with one second line medication, we suggest tapering and discontinuing the failed
medication over one to two weeks at the same time that another second-line
medication is started and titrated up. The failed medication is generally tapered by
the same amount for each dose decrease. As an example, risperidone 6 mg per
day is decreased by 1 to 2 mg per day, every one to three days.
The efficacy of risperidone, quetiapine, and olanzapine for treating mood elevated
syndromes (in randomized trials that excluded pregnant patients) is discussed
separately, as are the doses, side effects (table 4), pharmacology, and reproductive
safety profiles. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania
and
hypomania"
and
"Second-generation
antipsychotic
medications:
Pharmacology, administration, and comparative side effects", section on 'Individual
medications' and "Teratogenic and postnatal risks of antipsychotics,
benzodiazepines, lithium, and electroconvulsive therapy", section on 'Secondgeneration'.)
Refractory patients Based upon clinical experience, prenatal manic and
hypomanic episodes generally respond to sequential trials of haloperidol,
risperidone, quetiapine, and olanzapine. (Response is defined as stabilizing the
safety of the patient, as well as substantial improvement in the number, intensity,
and frequency of symptoms.) However, for refractory patients who do not respond
to antipsychotics, we suggest in order of preference lithium and electroconvulsive

therapy (ECT) [40]. For patients unresponsive to sequential trials of lithium and
ECT, other options include lithium plus an antipsychotic, carbamazepine, and
valproate.
Lithium For pregnant patients with manic episodes that do not respond to
multiple antipsychotics, we suggest lithium, based upon its efficacy and side effects
in randomized trials (which excluded pregnant patients) [11]. Although lithium is
generally regarded as teratogenic due to increased risks of cardiac defects (eg,
Ebsteins anomaly) [35-37], many authorities consider the absolute risk small
[1,4,17,32,41]. Clinicians can expect that up to approximately 50 percent of
patients will respond, based upon trials in nonpregnant patients [29].
The dose schedule for lithium, use of serum concentrations to establish the proper
dose, and lithium toxicity are discussed separately, as are using lithium during
pregnancy and lithiums reproductive safety profile. (See "Bipolar disorder in adults
and lithium: Pharmacology, administration, and side effects" and "Bipolar disorder
in women: Preconception and prenatal maintenance pharmacotherapy", section on
'Refractory patients' and "Teratogenic and postnatal risks of antipsychotics,
benzodiazepines, lithium, and electroconvulsive therapy", section on 'Lithium'.)
Electroconvulsive therapy For pregnant patients with moderate to severe
manic episodes that do not respond to sequential trials of antipsychotics and
lithium, we suggest electroconvulsive therapy (ECT), which is generally regarded
as efficacious and safe [42,43]. The use of ECT for pregnant bipolar patients is
consistent with recommendations in multiple practice guidelines [7,26,44-46].
Evidence for the efficacy of ECT includes studies that found ECT is effective for
mania in patients who are not pregnant. (See "Bipolar disorder in adults:
Indications for and efficacy of electroconvulsive therapy (ECT)", section on
'Mania'.)
In addition, a review of observational studies of pregnant patients treated for mood
or psychotic disorders with ECT found that among 68 cases with outcome data, at
least partial remission occurred in 78 percent [47]. Among the seven patients with
bipolar disorder, remission occurred in five and partial remission in one.
ECT during pregnancy is generally regarded as safe for the mother and fetus
[43,48,49]. Many authorities think that ECT poses fewer risks than untreated
bipolar mood episodes and medications that are potentially teratogenic (eg,
valproate and carbamazepine, and to a lesser extent lithium) [1,43,47,50,51]. The
reproductive safety profile of ECT is discussed separately. (See "Teratogenic and
postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive
therapy", section on 'Electroconvulsive therapy'.)
ECT is typically well tolerated and there are no absolute contraindications to ECT,
even among patients whose general medical status is compromised [43]. However,
safety concerns regarding ECT necessitate preprocedure obstetric consultation
(consistent with guideline recommendation), with emphasis upon assessing risk
factors for spontaneous abortion, preterm labor, abruption, and uteroplacental

insufficiency due to the association of ECT with transient increases or decreases in

blood pressure and uterine contractions. The patients general medical status is
also evaluated; medical consultation prior to ECT is discussed separately, as is the
use of ECT for patients with general medical conditions. (See "Medical consultation
for electroconvulsive therapy" and "Overview of electroconvulsive therapy (ECT)
for adults", section on 'Patients with comorbid general medical illness'.)
A review of observational studies found that the most frequent maternal
complication from ECT during pregnancy is induction of premature labor [47].
Among 339 pregnant patients treated with ECT, there were 20 maternal
complications, of which 18 were thought to be related to ECT:
Status epilepticus one case
Placental abruption one case (possibly related to acute hypertension)
Vaginal bleeding two cases
Uterine contractions and/or preterm labor 12 cases
Hematuria one case
Abdominal pain one case
The general adverse effects of ECT include cardiopulmonary events, aspiration
pneumonia, fractures, dental and tongue injuries, headache, nausea, and cognitive
impairment [43]. (See "Overview of electroconvulsive therapy (ECT) for adults",
section on 'Adverse effects'.)
Common general adverse effects after each ECT treatment are usually treated as
follows [43]:
Headache and/or myalgia Acetaminophen (nonsteroidal anti-inflammatory
drugs may alter maternal and fetal hemostasis, and lead to early constriction or
closure of the fetal ductus arteriosus)
Nausea Meclizine, metoclopramide, or prochlorperazine
A review found that the most frequent fetal complication from prenatal ECT is
bradyarrhythmia [47]. Among 339 pregnant patients treated with ECT, there were
25 fetal or neonatal adverse events, of which 11 were thought to be related to ECT:
Fetal death due to maternal status epilepticus one case
Miscarriage 24 hours post-ECT one case
Multiple brain infarctions after multiple ECT courses during pregnancy one case
Transient fetal arrhythmias (typically bradycardia, thought to be the result of
hypoxia) eight cases
ECT is generally given three times per week on alternate days. Most patients
regardless of indication remit with 6 to 12 treatments, but some patients require 20

or more. A review of prenatal ECT found that the mean number of treatments per
ECT course was 11 [47]. The number and frequency of treatments in the general
use of ECT is discussed separately, as are the adjustments in ECT technique for
pregnant patients. (See "Overview of electroconvulsive therapy (ECT) for adults",
section on 'Treatment course' and "Technique for performing electroconvulsive
therapy (ECT) in adults", section on 'Pregnancy'.)
Following a course of ECT, clinicians usually prescribe maintenance
pharmacotherapy. (See "Bipolar disorder in women: Preconception and prenatal
maintenance pharmacotherapy", section on 'Specific drugs'.)
Other options For pregnant bipolar patients with moderate to severe manic
episodes that do not respond to sequential trials of antipsychotics, lithium, and
ECT, we suggest in order of preference:
Lithium plus an antipsychotic For patients who do not respond to lithium
monotherapy and decline or do not have access to ECT, we suggest adding either
a first or second-generation antipsychotic to lithium, based upon randomized trials
that excluded pregnant patients. (Response is defined as stabilizing the safety of
the patient, as well as substantial improvement in the number, intensity, and
frequency of symptoms.) For patients who do not respond to antipsychotics,
lithium, and ECT, we concurrently start lithium plus an antipsychotic. No head-tohead trials have compared medication combinations consisting of lithium plus an
antipsychotic; we typically use lithium plus haloperidol, risperidone, quetiapine, or
olanzapine. The choice of an antipsychotic is based upon factors including past
response to medications, side effect profiles, comorbid general medical conditions,
potential for drug-drug interactions, patient preference, and cost. As an example, if
the patient previously showed a modest response to haloperidol and no response
to risperidone, quetiapine, or olanzapine, we would choose lithium plus haloperidol.
The efficacy of lithium plus an antipsychotic in randomized trials (that excluded
pregnant patients) is discussed separately, as are the doses, side effects,
pharmacology, and reproductive safety profiles. (See "Bipolar disorder in adults:
Pharmacotherapy for acute mania and hypomania" and "Second-generation
antipsychotic medications: Pharmacology, administration, and comparative side
effects", section on 'Individual medications' and "Teratogenic and postnatal risks of
antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy".)Specific
medication interactions that can occur may be determined using the drug
interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be
accessed from the UpToDate online search page or through the individual drug
information topics in the section on Drug interactions.Refractory patients who do
not respond to or tolerate one lithium/antipsychotic combination should be treated
with a second combination. We usually taper and discontinue the failed
antipsychotic at the same time that a different antipsychotic is started and titrated
up. The failed antipsychotic is generally tapered over one to two weeks by the
same amount for each dose decrease (eg, haloperidol 8 mg per day is decreased
by 2 mg per day, every one to three days).

Carbamazepine or valproate (divalproex) For pregnant patients with manic

episodes, we typically avoid carbamazepine and valproate because of the risks of
teratogenic and postnatal developmental effects [1]. However, for patients who do
not respond to sequential treatment with antipsychotics, lithium, ECT, and lithium
plus antipsychotics, and have previously responded to carbamazepine or valproate
for preconception mood episodes, it is reasonable to use either of these
antiepileptics [23,26], both of which have demonstrated efficacy in randomized
trials that did not include pregnant patients [11]. The evidence of efficacy, dose,
side effects, and pharmacology of carbamazepine and valproate are discussed
separately, as is the management of pregnant patients receiving these drugs, and
the risks of teratogenic and postnatal effects; much of this information is based
upon treatment of epilepsy. (See "Bipolar disorder in adults: Pharmacotherapy for
acute mania and hypomania" and "Pharmacology of antiepileptic drugs" and
"Management of epilepsy and pregnancy", section on 'Management during
pregnancy and delivery' and "Risks associated with epilepsy and pregnancy",
section on 'Effect of antiepileptic drugs on the fetus'.)Patients treated with valproate
or carbamazepine during pregnancy should also receive folic acid 4 mg per day,
which may prevent neural tube defects [52]. In addition, the obstetrician should be
informed to screen for teratogenic effects [23]. (See "Management of epilepsy and
pregnancy", section on 'Management during pregnancy and delivery' and "Folic
acid supplementation in pregnancy", section on 'Anticonvulsant therapy' and
"Prenatal screening and diagnosis of neural tube defects".)Valnoctamide (not
available in the United States) is an analogue of valproate that appears to be less
teratogenic in mice than valproate, and may possibly benefit acutely manic,
pregnant patients [53]. A randomized trial compared adjunctive valnoctamide (400
mg three times daily) with placebo in 32 nonpregnant, manic patients treated with
risperidone (1 to 4 mg per day); manic symptoms improved significantly more with
adjunctive valnoctamide [54].
SUMMARY AND RECOMMENDATIONS
Bipolar disorder is characterized by episodes of mania (table 1), hypomania (table
2), and major depression (table 3). (See 'Definition of bipolar disorder' above and
"Bipolar disorder in adults: Clinical features", section on 'Clinical presentation' and
"Bipolar disorder in adults: Assessment and diagnosis", section on 'Diagnosis'.)
Pharmacotherapy is indicated for pregnant patients with manic or hypomanic
episodes that are characterized by (see 'Indications' above):
Suicidal or homicidal ideation or behavior
Aggressive behavior
Psychotic features (delusions or hallucinations)
Poor judgement that places the patient or others at imminent risk of being harmed
Moderate to severe impairment of social or occupational functioning
Involvement in pleasurable activities that have a high potential for painful
consequences (eg, unrestrained buying sprees or sexual indiscretions)

Clinicians treating pregnant patients with manic or hypomanic episodes should

attempt to use drugs with fewer known teratogenic effects, monotherapy, and
doses at the low end of the therapeutic range. An individual drug trial typically lasts
three weeks before determining the medication is beneficial. (See 'General
principles' above.)
For manic and hypomanic pregnant patients, we suggest first-generation
antipsychotics rather than other medications (Grade 2B). We prefer haloperidol,
but reasonable alternatives include chlorpromazine, fluphenazine, perphenazine,
thiothixene, and trifluoperazine. (See 'First line medications' above)
For pregnant patients with manic or hypomanic episodes who do not respond to
or tolerate first-generation antipsychotics, we suggest in order of preference
risperidone, quetiapine, and olanzapine, rather than other drugs (Grade 2C). (See
'Resistant patients' above.)
Pregnant patients with refractory manic or hypomanic episodes that do not
respond to antipsychotics are often treated with lithium, electroconvulsive therapy
(ECT), or lithium plus an antipsychotic. (See 'Refractory patients' above.)

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Bipolar disorder in pregnant women: Treatment of major depression

Author

Victoria Hendrick, MD
Literature review current through: Oct 2014. | This topic last updated: Apr 16,
2014.
INTRODUCTION Medications are commonly used to treat pregnant patients,
including those with bipolar major depression [1]. At least one prescription drug is
taken by more than 60 percent of pregnant patients [2], and psychotropic drugs are
taken by 21 to 33 percent [3,4].
This topic discusses treatment of pregnant patients with bipolar major depression.
Treatment of manic and hypomanic episodes during pregnancy, prenatal
maintenance pharmacotherapy for bipolar disorder, the teratogenic and postnatal
risks of pharmacotherapy for bipolar disorder, and the general treatment of bipolar
major depression are discussed separately.
DEFINITION OF BIPOLAR DISORDER Bipolar disorder is characterized by
episodes of mania (table 1), hypomania (table 2), and major depression (table 3)
[5]. The subtypes of bipolar disorder include bipolar I and bipolar II. Patients with
bipolar I disorder experience manic episodes, and nearly always experience major
depressive and hypomanic episodes. Bipolar II disorder is marked by at least one
hypomanic episode, at least one major depressive episode, and the absence of
manic episodes. Additional information about the clinical features and diagnosis of
bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Clinical
features" and "Bipolar disorder in adults: Assessment and diagnosis", section on
'Diagnosis'.)
INDICATIONS Pharmacotherapy is indicated for pregnant patients with bipolar
major depression that is characterized by [6]:
Suicidal or homicidal ideation or behavior
Aggressive behavior
Psychotic features (delusions or hallucinations)
Poor judgement that places the patient or others at imminent risk of being harmed
Moderate to severe impairment of social or occupational functioning
GENERAL PRINCIPLES AND MANAGEMENT Bipolar mood episodes during
pregnancy are usually treated by perinatal or general psychiatrists in collaboration
with obstetricians and primary care clinicians [4,7-10].
For pregnant patients with bipolar major depression, treatment is based upon
randomized trials that excluded pregnant patients [11-14], as well as observational
studies, birth registries, and clinical experience [15].
Additional information about the general principles and management of treating
bipolar mood episodes during pregnancy are discussed separately, as is the
general treatment of bipolar major depression. (See "Bipolar disorder in pregnant
women: Treatment of mania and hypomania", section on 'Management' and
"Bipolar disorder in adults: Pharmacotherapy for acute depression".)

Duration of individual drug trial We suggest treating pregnant patients with

bipolar major depression for six to eight weeks before determining whether a
specific drug is beneficial, based upon the duration of most randomized trials
(which excluded pregnant patients) [11-13,16]. Response is defined as stabilizing
the patients safety and substantial improvement in the number, intensity, and
frequency of symptoms.
SELECTING TREATMENT Bipolar major depression during pregnancy is
typically treated with pharmacotherapy because it is easier to administer, more
widely available, and more acceptable to patients than electroconvulsive therapy
(ECT). However, refractory patients may benefit from ECT.
First line treatment For pregnant patients with bipolar major depression, we
suggest lamotrigine as first line treatment, based upon efficacy in a meta-analysis
of randomized trials that excluded pregnant patients [14]. Up to 40 to 50 percent of
patients may respond (defined as stabilizing the patients safety and substantial
improvement in the number, intensity, and frequency of symptoms). In addition, the
reproductive safety profile of lamotrigine is generally regarded as favorable
[4,17,18]. The efficacy of lamotrigine and quetiapine appear to be comparable, but
there is more experience using lamotrigine during pregnancy than quetiapine. In
addition, there is more evidence supporting the efficacy of lamotrigine compared
with fluoxetine plus olanzapine or lamotrigine plus lithium, and prenatal treatment
with monotherapy is preferable to treatment with drug combinations due to
concerns about teratogenic effects.
The efficacy of lamotrigine, quetiapine, fluoxetine plus olanzapine, and lamotrigine
plus lithium; reproductive safety profile of these drugs; and the dose schedule, side
effects (table 4 and table 5) (including life-threatening skin rash), and
pharmacology of lamotrigine are discussed separately. (See "Bipolar disorder in
adults: Pharmacotherapy for acute depression" and "Teratogenic and postnatal
risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy"
and "Pharmacology of antiepileptic drugs", section on 'Lamotrigine' and "Bipolar
disorder in adults: Maintenance treatment".)
Treatment resistance For pregnant patients with bipolar major depression who
do not respond to lamotrigine or cannot tolerate it, we suggest quetiapine [19],
based upon randomized trials that excluded pregnant patients [20-23]. Up to 50 to
60 percent of patients may respond (defined as stabilizing the patients safety and
substantial improvement in the number, intensity, and frequency of symptoms). In
addition, other studies suggest that quetiapine is not associated with teratogenic
effects [24], and use of quetiapine for bipolar major depression during pregnancy is
consistent with practice guidelines from the United Kingdom National Institute for
Health and Clinical Excellence [25,26]. There is more evidence supporting the
efficacy of lamotrigine compared with fluoxetine plus olanzapine or lamotrigine plus
lithium, and prenatal treatment with monotherapy is preferable to treatment with
drug combinations due to concerns about teratogenic effects.
We generally taper and discontinue lamotrigine at the same time that quetiapine is

started and titrated up. Lamotrigine is usually tapered by the same amount for each
dose decrease over a one to two week period. As an example, lamotrigine 200 mg
per day is decreased by 50 mg per day every three to four days.
Second-generation antipsychotics may cause metabolic complications (eg,
hyperglycemia and obesity) that are associated with risks to the mother and fetus
[27,28]. These risks are discussed separately, as are monitoring of metabolic
parameters in pregnant patients taking second-generation antipsychotics and the
efficacy, dose, reproductive safety, pharmacology, and side effects of quetiapine.
(See "Bipolar disorder in women: Preconception and prenatal maintenance
pharmacotherapy", section on 'Metabolic complications' and "Bipolar disorder in
adults: Pharmacotherapy for acute depression" and "Teratogenic and postnatal
risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy",
section on 'Second-generation' and "Second-generation antipsychotic medications:
Pharmacology, administration, and comparative side effects", section on
'Quetiapine'.)
Refractory patients Pregnant patients with bipolar major depression often do
not respond to sequential trials of lamotrigine and quetiapine. For these refractory
patients, we suggest tapering and discontinuing quetiapine over one to two weeks
at the same time that another medication regimen is started and titrated up.
(Response is defined as stabilizing the safety of the patient and others, as well as
substantial improvement in the number, intensity, and frequency of symptoms.)
Quetiapine is generally tapered by the same amount for each dose decrease. As
an example, quetiapine 600 mg per day is decreased by 50 to 100 mg per day,
every one to two days.
We suggest using the following treatments in sequence for pregnant patients with
refractory bipolar major depression, based upon their efficacy in randomized trials
(which excluded pregnant patients), reproductive safety profiles, and adverse
effects. Although the benefit of fluoxetine plus olanzapine and the combination of
lamotrigine and lithium appear to be comparable, neither fluoxetine nor olanzapine
appear to be associated with teratogenic effects. By contrast, lithium is generally
regarded as teratogenic [29-31]. The proportion of patients who respond to any of
the following treatment regimens may be as high as approximately 50 percent,
based upon trials in nonpregnant patients [11,12].
Fluoxetine plus olanzapine Fluoxetine plus olanzapine is efficacious for bipolar
major depression in nonpregnant patients [12,32]. However, second-generation
antipsychotics, especially olanzapine, may cause metabolic complications (eg,
hyperglycemia and obesity) that are associated with risks to the mother and fetus
[27,28]. These risks are discussed separately, as are monitoring of metabolic
parameters in pregnant patients taking second-generation antipsychotics and the
efficacy, dose, reproductive safety, pharmacology, and side effects of fluoxetine
and olanzapine. (See "Bipolar disorder in women: Preconception and prenatal
maintenance pharmacotherapy", section on 'Metabolic complications' and
"Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and
electroconvulsive therapy" and "Selective serotonin reuptake inhibitors:

Pharmacology, administration, and side effects" and "Second-generation

antipsychotic medications: Pharmacology, administration, and comparative side
effects" and "Bipolar disorder in adults: Pharmacotherapy for acute depression".)
Specific medication interactions that can occur may be determined using the drug
interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be
accessed from the online search page or through the individual drug information
topics in the section on Drug Interactions.
Lamotrigine plus lithium For pregnant patients with bipolar major depression
who do not respond to or tolerate fluoxetine plus olanzapine, we suggest
lamotrigine plus lithium [11]. Fluoxetine plus olanzapine are usually tapered and
discontinued concurrently over a period of one week, and subsequently lamotrigine
and lithium are started and titrated up. Fluoxetine is generally tapered by the same
amount for each dose decrease, as is olanzapine. As an example, fluoxetine 40 mg
per day is decreased by 10 mg per day every two days, and olanzapine 15 mg per
day is decreased by 5 mg per day every three days. Although lithium is generally
regarded as teratogenic due to increased risks of cardiac defects (eg, Ebsteins
anomaly) [29-31], many authorities consider the absolute risk small [1,4,18,33,34].
The reproductive safety profile of lamotrigine is generally regraded as favorable
[4,17,18], based primarily upon studies of patients with epilepsy. (See "Teratogenic
and postnatal risks of antipsychotics, benzodiazepines, lithium, and
electroconvulsive therapy", section on 'Lithium' and "Risks associated with epilepsy
and pregnancy", section on 'Lamotrigine'.)The dose schedule, side effects (table 4
and table 5) (including life-threatening skin rash), and pharmacology of lamotrigine
are discussed separately; as are the use of lithium during pregnancy, dose, use of
serum concentrations to establish the proper dose, side effects, and pharmacology
of lithium. (See "Pharmacology of antiepileptic drugs", section on 'Lamotrigine' and
"Bipolar disorder in women: Preconception and prenatal maintenance
pharmacotherapy", section on 'Refractory patients' and "Bipolar disorder in adults
and lithium: Pharmacology, administration, and side effects" and "Bipolar disorder
in adults: Maintenance treatment".)Specific medication interactions that can occur
may be determined using the drug interactions tool (Lexi-Interact Online) included
in UpToDate. This tool can be accessed from the online search page or through the
individual drug information topics in the section on Drug Interactions.
Electroconvulsive therapy (ECT) For refractory pregnant patients with bipolar
major depression that does not respond to sequential trials of lamotrigine,
quetiapine, fluoxetine plus olanzapine, and lamotrigine plus lithium, we suggest
electroconvulsive therapy (ECT). Lamotrigine and lithium are tapered and
discontinued over a period of one to two weeks prior to starting ECT. Lamotrigine is
generally tapered by the same amount for each dose decrease, as is lithium. As an
example, lamotrigine 200 mg per day is decreased by 50 mg per day every three to
four days, and lithium 1200 mg per day is tapered by 300 mg per day every three
to four days.Reviews have found that ECT is efficacious and safe for patients with
bipolar major depression who are not pregnant, as well as patients who are

pregnant [35,36]; ECT is thus recommended by several practice guidelines [7,3740]. The efficacy, adverse maternal and fetal effects, and reproductive safety of
ECT are discussed separately, as is the technique for performing ECT during
pregnancy. (See "Bipolar disorder in adults: Indications for and efficacy of
electroconvulsive therapy (ECT)", section on 'Bipolar major depression' and
"Bipolar disorder in pregnant women: Treatment of mania and hypomania", section
on 'Electroconvulsive therapy' and "Teratogenic and postnatal risks of
antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section
on 'Electroconvulsive therapy' and "Technique for performing electroconvulsive
therapy (ECT) in adults", section on 'Pregnancy'.)
ADJUNCTIVE TREATMENT
Psychotherapy For pregnant patients with bipolar major depression who are
treated with pharmacotherapy, we suggest adjunctive psychotherapy based upon
randomized trials in nonpregnant patients [2,6,41]. As an example, a one-year
randomized trial compared intensive psychotherapy plus pharmacotherapy with
brief psychoeducation plus pharmacotherapy in 293 nonpregnant patients with
bipolar major depression [42]. Intensive psychotherapy consisted of family therapy,
cognitive-behavioral therapy, or interpersonal and social rhythm therapy, with up to
30 sessions (50 minutes each) administered over nine months; brief
psychoeducation included three 50-minute sessions instructing patients about the
clinical features and treatment of bipolar disorder. Recovery occurred in more
patients who received adjunctive intensive psychotherapy compared with brief
psychoeducation (64 versus 52 percent), and outcome did not differ significantly
among the three intensive therapies. Using psychotherapy is also supported by
randomized trials in pregnant patients with unipolar major depression [43], and is
consistent with treatment guidelines [26].
Omega-3 fatty acids For pregnant patients with bipolar major depression,
dietary supplementation with omega-3 fatty acids (eg, eicosapentaenoic acid 1 to 2
grams per day) as adjunctive treatment is reasonable, based upon limited evidence
in meta-analyses of randomized trials (which excluded pregnant patients) [44,45]
and the apparent lack of serious side effects. In addition, prenatal intake of omega3 fatty acid supplements may have modest beneficial effects on fetal
neurodevelopment, and do not have known harmful effects. The efficacy of omega3 fatty acids and the risks and benefits during pregnancy are discussed separately.
(See "Bipolar disorder in adults: Pharmacotherapy for acute depression" and "Fish
consumption during pregnancy".)
RESIDUAL INSOMNIA Bipolar major depression in pregnant patients often
includes insomnia, which may persist despite resolution of the depressive
syndrome. For patients with residual insomnia, we suggest behavioral therapy,
including education about sleep hygiene (table 6) and stimulus control (table 7).
Patients unresponsive to behavior therapy typically receive additional treatment
with low dose doxepin. Treatment of insomnia is discussed separately. (See
"Treatment of insomnia".)

SUMMARY AND RECOMMENDATIONS

Bipolar disorder is characterized by episodes of mania (table 1), hypomania (table
2), and major depression (table 3). (See 'Definition of bipolar disorder' above and
"Bipolar disorder in adults: Assessment and diagnosis", section on 'Diagnosis'.)
Pharmacotherapy is indicated for pregnant patients with bipolar major depression
that is characterized by (see 'Indications' above):
Suicidal or homicidal ideation or behavior
Aggressive behavior
Psychotic features (delusions or hallucinations)
Poor judgement that places the patient or others at imminent risk of being harmed
Moderate to severe impairment of social or occupational functioning
An individual drug trial for pregnant patients with bipolar major depression
typically lasts six to eight weeks before determining whether treatment is beneficial.
(See 'General principles and management' above.)
For pregnant patients with bipolar major depression, we suggest lamotrigine as
first line treatment rather than other medications (Grade 2C). (See 'First line
treatment' above.)
For pregnant patients with bipolar major depression who do not respond to
lamotrigine or cannot tolerate it, we suggest quetiapine rather than other
medications (Grade 2C). (See 'Treatment resistance' above.)
Pregnant patients with refractory bipolar major depression that does not respond
to lamotrigine or quetiapine are often treated with fluoxetine plus olanzapine,
lamotrigine plus lithium, or electroconvulsive therapy. (See 'Refractory patients'
above.)
For pregnant patients with bipolar major depression who are treated with
pharmacotherapy, we suggest adjunctive psychotherapy (Grade 2B). (See
'Psychotherapy' above.)

55.
56.

57.

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