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FEATURES
Collaborative Management of Women with BipolarDisorder During Pregnancy and Postpartum:Pharmacologic ConsiderationsSheila Ward, CNM, MSN, and Katherine L. Wisner, MD, MS
Bipolar disorder is a chronic condition characterized by periods of mania, depression, or mixed states(co-occurring mania and depression). The postpartum period is associated with a high risk for symptomrelapse or intensification, which can be reduced with the use of medications. Abrupt discontinuation of thesemedications increases the probability of relapse, which is associated with high-risk behaviors, significantfamily dysfunction, and suicide. Drugs used to treat patients with bipolar disorder vary in teratogenicpotential. Although first trimester lithium use is associated with Ebstein’s anomaly, the risk wasoverestimated in the past. Valproate and its derivatives and carbamazepine are human teratogens.Lamotrigine does not negatively impact major reproductive outcomes, but the data are limited. Typicalantipsychotic medications are relatively well studied and the data do not identify major morphologicteratogenicity. There are fewer studies of newer atypical antipsychotic medications, and registries have beendeveloped to collect prospective data. Clinical management of bipolar disorder during pregnancy,postpartum, and lactation requires a careful balancing of maternal and fetal risks and benefits. Communi-cation and careful comanagement between the obstetric and psychiatric team is essential when treatingwomen with bipolar disorder during the reproductive years. J Midwifery Womens Health 2007;52:3–13© 2007 by the American College of Nurse-Midwives.keywords: antimanic drugs, antipsychotics, bipolar disorder, contraception, depression, lactation, lithium,
mood stabilizers, postpartum, pregnancybhbpindavftstewg
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NTRODUCTION
ipolar disorder, formerly known as manic depression, isserious, recurrent psychiatric illness with an estimated
ifetime prevalence of up to 4%.1 Bipolar disorder isypically treated with antimanic agents, such as lithium,ntipsychotic medications,2 and anticonvulsants, all ofhich have potential risks for the fetus and significant
ide effects for the mother. Because of its relatively highrevalence during the reproductive years, managing bi-olar disorder is a challenge for the woman and herbstetric health care professional who is collaborativelyanaging the treatment of the pregnant or postpartumoman with a mental health specialist. This paper will
eview important information for midwives who areomanaging the care of women with bipolar disorder; aiscussion of primary management of pharmacologicherapy is beyond the scope of this paper.
Bipolar disorder is a spectrum disorder, with 4 majoriagnostic subcategories. Diagnostic criteria are shownn Table 1. Bipolar I disorder has a similar prevalence in
ale and female populations,2 although bipolar II disor-er and some subtypes (such as rapid-cycling) are moreommon in women.3 Bipolar I disorder is characterized
ddress correspondence to Sheila Ward, CNM, MSN, PMHNP, Depart-
dent of Obstetrics, Gynecology & Women’s Health, University of Louisvillechool of Medicine, Louisville, KY 40292. E-mail: [email protected]
ournal of Midwifery & Women’s Health • www.jmwh.org
2007 by the American College of Nurse-Midwivesssued by Elsevier Inc.
y at least one episode of mania, with or without aistory of depression. A manic episode is characterizedy at least 1 week of elevated or irritable mood accom-anied by at least 3 additional symptoms from a list thatncludes inflated self-esteem or grandiosity, decreasedeed for sleep, pressure of speech, flight of ideas,istractibility, increased involvement in goal-directedctivities or psychomotor agitation, and excessive in-olvement in pleasurable activities with a high potentialor painful consequences.3 If the mood is irritable (ratherhan inflated or expansive), at least 4 of the aboveymptoms must be present. Marked impairment in func-ion or hospitalization must be associated with thepisode. Mania may be associated with psychosis inhich the patient experiences delusions (which are oftenrandiose), and visual and/or auditory hallucinations.3
Hypomania is a symptomatically mild form of manian which a woman may enjoy a sense of well-being andxperience optimal functioning and enhanced productiv-ty. The same symptoms as mania are present and arebservable by others, but the episode is not enough toisrupt normal functioning. Some women experiencenusual irritability during periods of hypomania. Withoutroper treatment, hypomania can lead to mania or heraldperiod of ongoing mood instability.4 Persons who havead only episodes of hypomania that alternate with
epression have bipolar II disorder.33
1526-9523/07/$32.00 • doi:10.1016/j.jmwh.2006.09.002
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Compared to episodes of depression in patients withnipolar disorder, depressive episodes in patients withipolar disorder are more commonly characterized bysychomotor retardation, extreme lethargy, hypersomnia,nd more suicidal ideation.5 Women with bipolar depres-ion often describe themselves as unable to get out ofed. Women with bipolar depression are more likely toxhibit weight gain, instead of weight loss, as is ofteneen in unipolar depression. Psychosis is more commonn bipolar depression than in unipolar depression.3
Mixed episodes occur when manic and depressiveymptoms exist together.3 A woman may feel sad,opeless, and suicidal while at the same time energizednd irritable. Mixed episodes are more common amongomen,3 and are often severe and impair daily function-
ng and relationships. A mixed episode can last from 1eek to several months and is generally followed by aepressive episode.3
CREENING AND DIAGNOSIS
atients who present with depression are inadequatelycreened for bipolarity, which contributes to the signifi-ant delay in diagnosis (about 11 years) from illnessnset to the confirmation of bipolar disorder.6 In addi-ion, antidepressant medication without an antimanicgent increases the risk for cycle acceleration, mania, ormixed state.7 The mood criterion symptoms for hypo-ania (high mood and/or irritability) can be used as a
imple screen: “Have you ever had 4 continuous days inhich you felt so good, high, excited, or ‘hyper’ that
heila Ward, CNM, MSN, PMHNP, is currently affiliated with theniversity of Louisville School of Medicine, Department of Obstetrics,ynecology and Women’s Health and the Department of Psychiatry.
atherine L. Wisner, MS, MD, is Professor of Psychiatry, Obstetrics andynecology and Reproductive Sciences, Epidemiology, and Women’s
Table 1. Summary of DSM-IV-TR* Classification of Bipolar Disorders
Disorder Characteristics
ipolar I One or more manic or mixed episodes,usually accompanied by majordepressive episodes
ipolar II One or more major depressive episodesaccompanied by at least onehypomanic episode
yclothymia At least 2 years of numerous periodsof hypomanic and depressivesymptoms
ot otherwise specified (NOS) Bipolar features that do not meetcriteria for any specific bipolardisorders or not enough informationavailable to classify
Source: American Psychiatric Association, 2000.3
tudies, and Director of Women’s Behavioral HealthCARE, at the Westernsychiatric Institute and Clinic, University Pittsburgh School of Medicine. S
ther people thought you were not your usual self or youot into trouble? Have you ever had 4 continuous dayshen you were so irritable you found yourself shouting
t people, or starting fights or arguments?”6 Other im-ortant historical information that may be helpful indentifying a patient with bipolar disorder are presentedn Table 2.8 If the patient is symptomatic, inquiry abouter safety risk is warranted: “Along with your moodymptoms, have you had thoughts of dying, wishing youere dead, or taking your own life?” Women who screenositively should be referred to a psychiatric professionalor an evaluation and treatment recommendations. Diag-osed bipolar disorder requires collaborative manage-ent with a psychiatric professional.
ANAGEMENT OF BIPOLAR DISORDER
harmacologic Treatment
he risk–benefit decision making model (as described byisner et al.9 and Yonkers et al.10) is used here to
tructure and present the available data on medicationssed to treat bipolar disorder in pregnant women. Thisodel directs the psychiatric professional to structure the
reatment decision based on the risk of no treatmentersus reproductive toxicity in 5 domains: intrauterineetal death, physical malformations, growth impairment,ehavioral teratogenicity, and neonatal toxicity. Al-hough treatment decisions are made by the psychiatricrofessional, the information presented will be useful toealth care professionals in the obstetric setting who areomanaging women with bipolar disorder.
o Treatment
atients who discontinue mood-stabilizing medicationfter conception increase their risk of relapse into depres-ion or mania,11 either of which could lead to complica-ions and untoward effects on the fetus. Depressionuring pregnancy has been linked to low birth weight andreterm delivery.12 These effects may be mediated by thellness itself or by other factors that indirectly affect birthutcomes. For example, depression during pregnancy is
Table 2. Characteristics Suggesting Bipolar Disorder in Patientswith Recurrent Depression
Onset of psychiatric symptoms during adolescenceFrequent mood swingsPeriods of increased energy, activity, or reduced need for sleepSusceptibility to impulsivity, attention problems, or difficultymaintaining relationshipsSudden or frequent employment changeLegal problemsSubstance abuseLong list of antidepressant therapy with lack of benefit or adverseeffects
ource: Swann et al.8
Volume 52, No. 1, January/February 2007
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ssociated with decreased appetite, substance use andbuse, and lower utilization of prenatal care.12 Untreatedania may also be associated with perinatal risks, as a
regnant patient in a manic state may engage in impul-ive, high-risk behaviors that endanger her and theetus.13
ntimanic (Mood Stabilizing) Agents
ntimanic drugs include lithium, many anticonvulsants,nd antipsychotics, all of which are used to treat andrevent manic symptoms, as well as for maintenancereatment. Because so few patients have a completeesponse to single drug treatment, polypharmacy isommon. Because patients vary in their response tontimanic agents, there is no single preferred medicationor bipolar disorder, regardless of reproductive status.he preferred medication is what has been effective fornd has been tolerated by the individual patient. A reviewf these medications is presented in Table 3.
ithium
ithium is a first line drug for acute and maintenancereatment of bipolar disorder.
ntrauterine Fetal Death
here is no evidence for an increased risk of miscarriager intrauterine fetal death in women treated with lithium.acobsen et al.14 matched 138 women taking lithiumuring pregnancy with 148 nonexposed controls. Theontrol women had exposures to other medications thatere not known or suspected to be teratogenic. These
ubjects were matched for age, but not for bipolarisorder. The investigators observed one stillbirth in thexposed group, none the matched controls; this was notignificantly different.
hysical Malformations
he International Registry of Lithium Babies15 reportedncreased rates of cardiovascular malformations, such asbstein’s anomaly, in children whose mothers took
ithium during pregnancy. Ebstein’s anomaly is theownward displacement of the tricuspid valve withentricular hypoplasia. Functional sequelae vary with theeverity of the congenital lesion. The risk for thisalformation with first-trimester lithium exposure was
nitially proposed to be 400 times higher than theackground baseline rate of about 1/20,000 live births.owever, registry data has significant limitations: the reg-
stry is a voluntary, retrospective database, and the numberf cases not reported is unknown, nor is the number ofnreported normal outcomes of lithium exposure. De-pite the fact that the reliability of this initial estimate
as highly suspect, based on selective reporting of sournal of Midwifery & Women’s Health • www.jmwh.org
dverse outcomes, this report continues to influencelinical practice.
More recent controlled epidemiologic studies suggest aeal, but much more modest, teratogenic risk of Ebstein’snomaly following first-trimester lithium exposure.ased on a pooled analysis of the data, Cohen et al.16
stimated the risk of Ebstein’s anomaly to between/1000 (0.1%) to 2/1000 (0.2%), which is 10 to 20 timesigher than rates in the general population. Thus, whilehe relative risk for Ebstein’s anomaly is increased, thebsolute risk remains small. Pregnant women takingithium should be evaluated with a high-resolution ultra-ound and fetal echocardiography at 16 to 18 weeksestation to screen for cardiac anomalies.16
ntrauterine Growth Effects
here is no evidence of an association between intrauter-ne growth retardation and lithium use. Lithium-exposednfants were found to weigh significantly more thanontrols by a mean of 92 grams (3475 g vs. 3383 g)15
espite the fact that lithium-treated women were moreikely to smoke cigarettes.
eurobehavioral Teratogenicity
ixty children exposed to lithium either during the firstrimester or throughout pregnancy did not differ behav-orally from their nonexposed siblings.16 Attainment ofajor developmental milestones for 22 lithium-exposed
ubjects was comparable to controls.17,18
eonatal Toxicity
ases of lithium toxicity in the fetus and newborn haveeen reported and include: cyanosis, hypotonia, brady-ardia, thyroid abnormalities and goiter, atrial flutter,epatomegaly, electrocardiogram abnormalities, rhythmisturbances (such as supraventricular tachycardia), car-iomegaly, gastrointestinal bleeding, diabetes insipidus,olyhydramnios, seizures, and shock.17 However, therere no prospective studies to establish the incidence andisk factors for occurrence of these problems.
onitoring During Pregnancy
ithium dosages are determined by checking serumevels, with a target range of 0.5 to 1.2 mEq/L.2 Asregnancy progresses, renal lithium excretion increases,hich usually necessitates an increase in dose.19 Lithium
erum levels can be affected by vomiting, sodium intake,nd febrile illness.10 Newport et al.20 reviewed the 7ocumented cases of prenatal lithium toxicity and foundhe etiology identified in only 3 of the cases. In 2 cases,oxicity arose iatrogenically after the institution ofiuretic therapy and a sodium-restricted diet to managedema. Toxicity occurred in another case when a
odium-restricted diet was initiated to manage pre-5
Table 3. Medications Used to Treat Bipolar Disorders
Metabolism /Monitoring Morphologic Teratogenicity Neonatal Toxicity*/Behavioral Teratogenicity
Lithium● Clearance 1 30% to 50% 2nd half● Therapeutic serum level 0.8 to 1.2 meq/L● Half-life: 24 hours● Check levels q mo 1st half, q wk 2nd half● Maintain hydration in mother● Restrict in labor. Restart as soon as the patient is medically
stable postpartum, using preconception dose
● Pregnancy Category D†
● Risk of cardiac anomaly: High resolution ultrasound and fetalechocardiography for 1st trimester exposure advised by 18 weeks
● Tapered vs abrupt discontinuation preferred to reduce risk ofrelapse
● Neonatal: Poor sucking, abnormal respiratory pattern,cyanosis, hypotonia, arrhythmia, hypoglycemia,prematurity, large for gestational age.
● May be modified by restriction of lithium in labor.● No differences observed in development
Valproate (Depakote)● Clearance varies● Therapeutic serum levels: 50-100 mg/ml● Half-life: 9-16 hours
● Pregnancy Category D†
● Spina bifida risk 1-5% (15-30 day postfertilization)● Craniofacial defects, heart defects, polydactyly, hypospadias, low
birthweight: High resolution ultrasound 1st trimester exposureadvised by 18 weeks
● 4 mg folic acid recommended● 20 mg per day of Vitamin K supplementation recommended
● Neonatal: Acute liver failure, hyperbilirubinemia.● Behavioral: Normal psychomotor development
Carbamazepine (Tegretol)● Clearance varies, serum levels recommended● Give Vitamin K in last month of pregnancy● Monitor serum concentration of unbound main compound● Half-life: variable
● Pregnancy Category D†
● Spina bifida 0.5-1.0% risk 15-30 day postfertilization● Meningomyelocele, anal atresia, ambiguous genitalia, heart defects,
torticollis. High resolution ultrasound and fetal echocardiography for1st trimester exposure advised by 18 weeks
● 4 mg folic acid recommended● 20 mg per day of Vitamin K supplementation recommended
● Neonatal: Small head circumference, Transienthepatic dysfunction
● Behavioral: Normal psychomotor development
Lamotrigine (Lamictal)● No standards for serum levels.● Half-life:25 hours (variable with enzyme-inducing
anticonvulsants)● Increase in clearance rate during pregnancy resulting in
lower serum levels, returns to preconception levels rapidlyafter delivery.
● Pregnancy Category C‡
● Data limited -No increase in congenital anomalies among availableregistries.
● Neonatal: Inadequate data● Behavioral: No adequate human studies
Typical antipsychotics: Haloperidol (Haldol), Trifluoperazine, Perphenazine, Prochlorperazine● No standard serum levels● Monitor clinically for extrapyramidal symptoms e.g.
involuntary movements, tremors and rigidity, bodyrestlessness, muscle contractions
● Pregnancy Category C‡
● Not associated with fetal anomalies.● Neonatal: Third trimester exposure:
Hyperbilirubinemia, impaired temperature regulation,agitation, hypertonicity, tremor, primitive reflexes,poor sucking
● Behavioral: Not associated with intellectual orbehavioral impairments
Atypical antipsychotics: Risperidone (Risperdal), Quetiapine (Seroquel), Olanzapine (Zyprexa), Ariprazole (Abilify)● No standard serum levels● Monitor clinically for metabolic effects including increased
weight gain, changes in glucose metabolism, and effect onlipid profiles.
● Pregnancy Category C‡
● Limited data● Neonatal: Unknown● Behavioral: No data
*Case reports.†FDA Pregnancy Category D: Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available.Drugs should be given only if the potential benefit justifies the potential risk to the fetus.‡FDA Pregnancy Category C: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a seriousdisease for which safer drugs cannot be used or are ineffective).
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clampsia. Maternal lithium toxicity is most likely toccur during the intrapartum period. Patients are encour-ged to have their lithium level monitored every 2 toweeks throughout pregnancy, weekly in the last month,
nd every few days shortly before and after delivery.10
igns and symptoms of lithium toxicity typically begin atserum level of 1.5 mEq/L and include central nervous
ystem symptoms, such as dizziness, drowsiness, excite-ent, coarse hand tremor, and muscle weakness.21 Other
ymptoms of toxicity include vertigo, gastrointestinalymptoms, and cardiac arrhythmias.21 Severe toxicityith levels of over 2.5 mEq/L may result in coma,
eizures, renal failure, and death.21
Lithium crosses the placenta, and studies haveound the ratio of lithium in umbilical cord bloodelative to maternal blood at birth is 1.05. This implieslmost one-to-one equilibration.20 Adverse neonatalutcomes are more extensive in the setting of higherithium concentrations at delivery. Lithium deliveryoncentrations can be significantly reduced at deliveryithout compromising pharmacotherapeutic efficacyy withholding lithium therapy from the onset ofabor.20
While lithium is associated with significant risks inll stages of pregnancy, it arguably remains the safestedication for the pregnant woman with bipolar dis-
rder. It is the only mood stabilizer with documentededuction of suicide in individuals with bipolar disor-er.22
nticonvulsants
here are no epidemiologic exposure data reported spe-ifically for women with bipolar disorder who takenticonvulsants during pregnancy. Most data refer toomen who take anticonvulsants for epilepsy, and thatisease state may have its own effects on pregnancy thatannot be separated from existing outcome information.omen who are started on anticonvulsants after concep-
ion have a disadvantage (compared to women who haveeen treated prior to pregnancy) because the occurrencef serious side effects (agranulocytosis, hepatic toxicity,nd Stevens–Johnson syndrome) has not been deter-ined in that individual.
orphologic Malformations
tudies performed through the late 1990s suggest thathe risk of morphologic malformations in infantsxposed to valproate (Depakote; Abbott Laboratories,bbott Park, IL) and carbamazapine (Tegretol; Novar-
is, East Hanover, NJ) is about 2 to 3 times higher than inhe general population.23 The most common malforma-ions in exposed offspring are similar to those seen in theeneral population (e.g., heart defects, hypospadias, cluboot, and cleft lip or palate). No single malformation has
een associated with a specific antiepileptic drug, with dournal of Midwifery & Women’s Health • www.jmwh.org
he exception of spina bifida, which is more commonith exposure to valproic acid (1–5% of exposed infants)
nd carbamazepine (0.5–1%). Malformations are alsoore common after exposure to polytherapy than after
xposure to a single drug. Additional evidence for aigher teratogenic potential of valproate comes from theorth American registry, in which malformations were 4
imes more common among infants exposed to valproiccid than in those exposed to all other antiepilepticonotherapies combined.24
The manufacturer of lamotrigine (Lamictal; Glaxo-mithKline, Philadelphia, PA) lists 17 major birthefects among 595 infants (2.9%) with a first trimesteronotherapy exposure (GlaxoSmithKline, written
ommunication, 2005). These rates are similar to theeneral population rate for major malformations.here was an 11.7% rate of malformations when
amotrigine was used in combination with valproate inhe first trimester (GlaxoSmithKline, written commu-ication, 2005).
ntrauterine Growth Effects
ntrauterine growth retardation is included in descrip-ions of the fetal valproate syndrome,25 but the inci-ence has not been established. Carbamazepine isssociated with reductions in mean birth weight (about50 gms).26
eurobehavioral Teratogenicity
retrospective survey of British women between theges of 16 to 40 who were exposed to antiepileptic drugsuring pregnancy evaluated the subsequent need forpecial education for their exposed children.27 Thosexposed to valproate monotherapy had a higher likeli-ood of needing special education (OR, 3.4; 95%I 1.63–7.10). In contrast, carbamazepine had no statis-
ically significant effect (OR, 0.26; 95% CI 0.06–1.15).olytherapy including valproate had similarly high oddsatios for lower academic achievement (OR, 2.51; 95%I 1.04–6.07) compared with those exposed to polythe-
apy excluding valproate (OR, 1.51; 95% CI 0.56–4.07).lthough these findings should be treated with caution,
hey suggest that monotherapy or polytherapy with val-roate during pregnancy carries particular risks for theeurodevelopment of children exposed in utero. A pro-pective study of children’s intelligence quotients (IQs;ean age 7 years) compared IQs in children of epilepticothers to the IQs of children in a control group.28
gain, children exposed to valproate prenatally had aean IQ that was 11 points lower than those childrenho were not exposed. The same study found no asso-
iation between carbamazepine and cognitive dysfunc-ion.29 A single follow-up of 23 infants exposed toamotrigine demonstrated no alterations or delays in
evelopment at 12 months of age.30 Data are still7
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nadequate to determine the risks of developmentalffects of fetal exposure to lamotrigine. No evidence ofrowth problems, post-birth discovery of occult malfor-ations, neonatal seizures, or deviations in psychomotor
evelopment to 1 year of age were observed in 62 infantsxposed to lamotrigine in utero.27
eonatal Toxicity
anifestations of withdrawal, including irritability,itteriness, abnormal tone, feeding difficulties, andeizures have been described in infants whose mothersook valproic acid during pregnancy. The frequency ofithdrawal symptoms was significantly related to theose of valproate given to the mothers in the thirdrimester, and there was a tendency for both therequency of the minor abnormalities and the majoralformations to be related to the valproate dosage in
he first trimester.31
aternal Vitamin Supplementation
aternal folate supplementation reduces the risk ofeural tube defects. However, risk reduction has noteen confirmed in pregnant women treated with anti-onvulsants. Some experts recommend a daily dose ofto 5 mg of folic acid before and during pregnancy, or
t least through the first trimester, for all women whoake antiepileptic drugs.10 Pernicious anemia can beasked by folate supplementation; therefore, a B12
evel obtained before beginning folate treatment is arudent recommendation. Carbamazepine has beenssociated with vitamin K deficiency.32 Because ade-uate levels of vitamin K are necessary for clotting, intero carbamazepine exposure could increase the riskf neonatal bleeding. Most experts recommend womenn carbamazepine take an additional 20 mg of vitamin
supplement daily throughout pregnancy.10
onitoring of Lamotrigine During Pregnancy
lthough monitoring of serum levels of lamotrigine isot clinically indicated, significant decreases in mater-al serum levels of lamotrigine have been documenteduring pregnancy, whereas levels increase postpar-um.33 Accordingly, patients appear to require in-reased dosages of lamotrigine in pregnancy and doseeduction after delivery. Rapid fluctuations in serumevels or overdose with lamotrigine have been associ-ted with Stevens–Johnson syndrome, a potentiallyatal disorder that initially presents with a rash.34
areful dose management in pregnancy and the earlyostpartum period is critical in order to avoid relapsef psychiatric symptoms and prevent serious sideffects. There are currently no established guidelinesor clinical use of serum levels for lamotrigine. The
arget dose approved by the US Food and Drug mdministration (FDA) is 200 mg. Lamotrigine dosings based on clinical symptomatology and the judgmentf the primary psychiatric professional.
eurodevelopment Effects of Antiepilepticrugs (NEAD) Study
he NEAD study35 is an ongoing prospective studycross 28 centers in the United Kingdom and Unitedtates which has enrolled pregnant women taking anti-pileptic drugs to examine the effects of commonly usedntiepileptic medications on long-term cognitive andehavioral neurodevelopment in their infants. A prelim-nary report of 322 mother/child pairs published in 2004n the journal Epilepsia detailed the incidence of seriousdverse outcomes, which were defined as congenitalbnormalities, gross developmental delay, or death. Theercentages of children with these adverse outcomes bygent were: carbamazepine, 14%; lamotrigine, 2%; andalproate, 25%.36
ther Anticonvulsants
ther anticonvulsants, such as oxcarbazepine (Trileptal;ovartis), tiagabine (Gabitril; Cephalon, Inc., Frazer,A), and topiramate (Topamax; Ortho-McNeil Neuro-
ogics, Inc., Titusville, NJ) are occasionally used inlinical practice as antimanic agents or to treat anxietyymptoms. Outcomes of 94 pregnancies in women ex-osed to oxcarbazepine found no anomalies related to itsse; however, these are too few to rule out adverseffects with confidence.37 The safety of tiagabine andopiramate for use in pregnancy has not been investi-ated.
ntipsychotic Agents
ntipsychotic drugs are often used as monotherapy ordjunctive medications for patients with bipolar disor-er.2 Antipsychotics are commonly used in the manage-ent of acute mania. The largest body of evidence
egarding safety for use in pregnancy exists for the older,rst-generation antipsychotics.The best-studied drug in this class is chlorpromazine
Thorazine; GlaxoSmithKline), used in the 1950s foryperemesis, and less commonly, for psychotic disordersn pregnant women. In a 1977 survey of more than0,000 mother-child pairs that identified 142 first tri-ester exposures and 284 total exposures to chlor-
romazine, there was no elevation in the rate ofhysical malformations.38 This survey also suggestshat related compounds, including perphenazine androchlorperazine (Compazine; GlaxoSmithKline), areimilarly not associated with higher-than-expected ratesf malformations.38 Several case reports have docu-ented transient extrapyramidal symptoms, including
otor restlessness, tremor, hypertonicity, dystonia, andVolume 52, No. 1, January/February 2007
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arkinsonism in neonates exposed to antipsychoticgents during pregnancy.39 These problems have typi-ally been of short duration and have been followed bypparently normal subsequent motor development.40
In a 2004 review of the management of bipolarisorder in pregnancy, Yonkers10 supports the role ofrst-generation antipsychotic agents both in the treat-ent of acute mania during pregnancy, and as an
lternative to selected mood stabilizers. Psychiatric cli-icians may elect to switch a patient’s medication fromithium or an anticonvulsant to a first-generation antipsy-hotic either for the entire pregnancy or for the firstrimester. This strategy is particularly recommended foratients who have benefited from mood stabilization withntipsychotic medications in the past. First-generationntipsychotic medications may also be a choice foromen with bipolar disorder who elect to discontinueedication during pregnancy but begin to experience a
ecurrence of symptoms while pregnant.10
typical Antipsychotic Agents
he atypical antipsychotics currently approved by theDA for the treatment of bipolar disorder in the Unitedtates include: risperidone (Risperdal; Janssen Pharma-eutica N.V., Beerse, Belgium), olanzapine (Zyprexa; Eliilly and Company, Indianapolis, IN), quetiapine (Sero-uel; AstraZeneca Pharmaceuticals, Wilmington, DE),iprazadone (Geodon; Pfizer Pharmaceutical Company,ew York, NY), and aripiprazole (Abilify; Bristol-yers Squibb, New York, NY).McKenna et al.41 examined 151 pregnancy outcomes
rom mothers enrolled in the Canadian Motherisk Pro-ram to determine whether atypical antipsychotics in-rease the rate of major malformations. These includedxposures to olanzapine (n � 60), risperidone (n � 49),uetiapine (n � 36), and clozapine (n � 6). The resultsuggest that atypical antipsychotics are not associatedith an increased risk for major malformations; however,
he limited numbers are inadequate to determine the riskf fetal exposure. In an industry-supported registry oflanzapine exposure, 1 major malformation out of 96nfants was reported (Eli Lilly and Company, writtenommunication, August 2004).
Olanzapine is associated with serious metabolic sideffects that could potentially exacerbate maternal weightain and gestational diabetes, which is associated with anncreased risk for a large for gestational age newborn.2
ntidepressants
onotherapy with antidepressants—that is, use of anntidepressant without concomitant antimanic medica-ion—is not appropriate in the management of bipolarisorder. Use of antidepressants in a patient with bipolar
isorder may trigger a mood shift from depression to pournal of Midwifery & Women’s Health • www.jmwh.org
nduction of a manic, hypomanic, mixed episode, orapid cycling.2
REATMENT PLANNING
reatment planning is critical for minimizing the risko the mother and fetus from medications whilerotecting both from the potentially disastrous effectsf the disease. Treatment decisions for women withipolar disorder should always be made in collabora-ion with the treating psychiatric professional. Theost important clinical factors that influence treatment
lanning during pregnancy are illness history and theeproductive risks associated with medications. Theatient’s prior response to various medications, illnesseverity, duration of euthymia while taking medicationnd while not taking medication, time to relapse afteriscontinuing medication, and time to recovery withedication reintroduction are all critical consider-
tions in treatment planning.10
A prepregnancy trial of gradual discontinuation ofood stabilizers can be used to gauge the patient’s risk
f relapse during pregnancy. During any early indica-ion of an impending relapse, the mood stabilizer cane rapidly reintroduced. If the trial is successful, anttempt at a drug-free first trimester is a reasonableption. If the patient relapses during the trial, theeasibility of a pregnancy without an antimanic drughould be reconsidered.42 For women who tolerateiscontinuation of mood stabilizers, the decision re-arding resumption of therapy is based on clinicaludgment.42 Some patients and clinicians prefer toefer treatment until the symptoms reemerge; othersrefer to resume treatment immediately after theompletion of the first trimester.42
For women with severe bipolar disorder, with symp-oms such as rapid cycling, psychosis, and suicidalymptoms, maintenance treatment with an antimanicgent throughout pregnancy may be the most prudentption.2 For patients in whom lithium is effective, it isn agent of choice in pregnancy, and monotherapy isreferred when possible.42 For patients with severeepression, mania, mixed state, or psychosis, hospital-zation is often required, and electroconvulsive ther-py may be used because it presents less risk to theetus than some pharmacologic treatment options.42
For those women with bipolar disorder who presentor obstetric care past the first trimester, continuingreatment is probably the most prudent course.42 Preg-ancy is a time of substantial risk for relapse, particularlyollowing the discontinuation of mood stabilizing treat-ent.11 A suggested approach to treatment of the patientith bipolar disorder who wishes to conceive or is
regnant is presented in an algorithm in Figure 1.439
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ANAGEMENT OF BIPOLAR DISORDER IN THEOSTPARTUM PERIOD
here is widespread agreement that the early postpartumeriod presents an unusually high risk for recurrence ofipolar disorder and other psychiatric illnesses.2 A nearly-fold increase in psychiatric admissions in the postpar-um period has been reported.44 Pregnant women withipolar disorder should be informed of the unusuallyigh rate of relapse as they enter the postpartum period.rophylaxis with an appropriate agent should be stronglyecommended, especially for patients who have remainedntreated during pregnancy.42 Psychiatric consultationuring hospitalization at delivery is desirable. Follow-upor evaluation of psychiatric status should be scheduledithin the first 2 weeks postpartum. Because changes in
leep are common in the postpartum period, women with
Pregra
Discuss planned contraception Review risks associated with
conceiving on her medication Discuss risk for relapse off
medication Discuss alternatives to her current
medication, including psychotherapies, less-teratogenic psychotherapies and ECT
Wanting to conceive?
Continuemedication until closer to decision to conceive
Consider tapering off medication if prior illness was of mild-moderate severity and without multiple hospitalizations
If patient conceives, continue off medication until 2 nd trimester or throughout pregnancy if mood is stable
If relapse occurs before patient conceives or in 1st trimester, restart medication trial, choosing least teratogenic option
Continue medication through attempts at conception if prior course was characterized by multiple hospitalizations or marked morbidity
Yes
YesNo
igure 1. Suggested approach to the bipolar patient who wishes to concECT � Electroconvulsive therapy.Reprinted with permission from Altshuler et al.43
ipolar disorder and their families should be educated t
0
bout the need to prioritize the maintenance of a normalleep pattern to avoid precipitating manic episodes.2
reatment Considerations During Lactation
n clinical practice, the question of switching the moth-r’s medication to accommodate lactation often arises. Inost cases, infants of mothers diagnosed with bipolar
isorder will have already been exposed to at least onentimanic agent during the course of the pregnancy.ecause postpartum is the period of highest risk for
elapse of bipolar symptoms, changing from an effectiveedication to a new drug is not without risk. First, such
hanges may expose the developing infant to a secondrug (e.g., lithium in pregnancy and valproate duringactation) and there are no data on the risks of suchultiple exposures. Second, changing drugs may expose
Already pregnant?
First trimester?
uss specific ication and its for teratogenicitysider switching relatively safer rnative (e.g., valproate to
um) if no history eatment responsive to safer alternative ess current d and length of
lness, as well as rity of prior ssuss increased ntial for relapse abrupt ontinuation of a d stabilizer sider continuing ication in 1st
ester if prior rse was acterized by tiple admissions, aired judgment
Continue medications if she is taking them and mood is stable
Discuss risk for postpartum relapse
To decrease risk for postpartum relapse, discuss option to restart medications at end of 3rd trimester if mood is stable and patient is not on medications
Restart medications if mood is unstable and patient is not on medications
Discuss lactation and medication use
2nd and 3rd trimesters?
No
Yes
NoYes
Yes
is pregnant.
vid?
Discmedrisk
Conto aaltefromlithiof trnonthe
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eive or
he mother to relapse. In general, there are few reports of
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pecific adverse effects of antimanic medications inreastfed infants. Maintenance of optimal maternal men-al health is the primary goal in treating women whohoose to breastfeed.
ONTRACEPTIVE CHOICES
ome medications used for management of bipolar dis-rder induce cytochrome P-450 enzymes in the liver,hich can increase the metabolism of sex hormones and
ncrease the risk for contraceptive failure.45 These drugsnclude carbamazepine and oxcarbazepine at doses inxcess of 1200 mg/day, and topiramate at doses above00 mg/day. This enzyme-induced increased metabolismf hormonal contraceptive steroids impacts all formula-ions, including implantable and injectable forms.32 Con-raceptive failure has been reported (with no estimateegarding its prevalence) with subdermal levonorgestrelmplants in women taking carbamazepine.46 Medroxy-rogesterone acetate contraceptive injection (Depo-rovera; Pfizer) may provide a useful alternative because
he administered frequency of injection may be adjusted.ome authorities recommend that injections be givenvery 10 weeks instead of every 12 weeks if women areaking medications that induce hepatic enzymes.47
omen who receive these cytochrome P-450 enzyme-nducing drugs should use nonhormonal methods ofontraception, contraceptive injections, or should berescribed oral contraceptives containing 50 �g or moref the estrogenic component.2
Although lamotrigine does not appear to decrease theffectiveness of oral contraceptives, a recent industryeport described a significant reduction in serum drugoncentration when an oral contraceptive was added.48
osage adjustments for lamotrigine are recommendedor women taking oral contraceptives (GlaxoSmithKline,ritten communication, 2004). Considering the multiplerug interactions between hormonal contraception andntimanic agents, intrauterine contraception may be aavorable option for the patient with bipolar disorder.
SYCHOSOCIAL/EDUCATIONAL INTERVENTIONS
sychosocial interventions are important adjunctivereatments to medications for bipolar disorder. Psychos-cial therapies help the woman and her family to under-tand the disorder, adhere to medications, manage stress,nd prevent relapse. Interpersonal and social rhythmherapy is an individual psychotherapy designed specif-cally for the treatment of bipolar disorder.49 Adminis-ered in concert with medications, interpersonal andocial rhythm therapy combines the basic principles ofnterpersonal therapy with behavioral techniques to helpatients regularize their daily routines, diminish interper-onal problems, and adhere to medication regimens. Itodulates both biologic and psychologic factors to
itigate patients’ circadian and sleep–wake cycle vul- Aournal of Midwifery & Women’s Health • www.jmwh.org
erabilities, improve overall functioning, and better man-ge the potential chaos of bipolar disorder symptomol-gy.The importance of adequate sleep for the woman with
ipolar disorder cannot be overstated.50 This becomeshallenging during pregnancy, the postpartum period,nd especially when the woman is breastfeeding. Theell-established benefits of breastfeeding must beeighed against the potential risk for relapse secondary
o sleep deprivation. Women with bipolar disorder andheir families should be encouraged to use every avail-ble resource for assistance with childcare, housework,nd other responsibilities during the postpartum period.he timing of a woman’s return to employment shoulde determined by her psychiatric status. Information onccess to effective psychosocial interventions can bebtained from the Depressive and Bipolar Support Alli-nce (see Appendix).
ONCLUSIONS
ipolar disorder is a complicated illness that requiresareful management during the reproductive process.hile primary management of this disorder is assigned
o the psychiatric professional, the obstetric practitioneras the opportunity and obligation to monitor clinicalesponse and recognize the need for treatment adjust-ents. A positive outcome is maximized with collabo-
ative clinical management and decision-making thatnvolves the patient and her partner or other supporters.ome patients may tolerate a drug-free first trimester orntire pregnancy. Gradual medication reduction is pre-erred over abrupt withdrawal. Patients who are unstableequire treatment throughout pregnancy. There is littlealue in discontinuing effective medication after the firstrimester exposure. Patients with severe symptoms inregnancy may be treated with electroconvulsive ther-py. Postpartum is the most vulnerable time for decom-ensation. If a woman requires pharmacologic treatmenturing the postpartum period, the choice of medicationhould be based on the clinical status of the patient ander historical response to medication regardless ofreastfeeding status. Contraceptives for women withipolar disorder should be selected based on patientreference and their compatibility with her other medi-ations.
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Appendix. Resources
Resource Web Site
orth American Antiepileptic Drug Pregnancy Registry http://www.aedpregnancyregistry.org/ (888) 233-2334 (toll free)ART database: free drug search for pregnancy/postpartum about
any drug, pull up and click on DART databasewww.toxnet.nlm.nih.gov
DA guidance document http://www.fda.gov/cder/guidance/5917dft.htmepression and Bipolar Support Alliance http://www.dbsalliance.org
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