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Reviews and Overviews
Management of Bipolar Disorder
During Pregnancy and the Postpartum Period
Kimberly A. Yonkers, M.D.
Katherine L. Wisner, M.D.
Zachary Stowe, M.D.
Ellen Leibenluft, M.D.
Lee Cohen, M.D.
Laura Miller, M.D.
Rachel Manber, Ph.D.
Adele Viguera, M.D.
Trisha Suppes, M.D., Ph.D.
Lori Altshuler, M.D.
Objective: Bipolar disorder affects 0.5%– 1.5% of individuals in the United States. The typical age at onset is late adoles- cence or early adulthood, placing women at risk for episodes throughout their re- productive years. General guidelines for the treatment of bipolar disorder are available from the American Psychiatric Association, but additional issues arise when these guidelines are applied in the treatment of peripartum women. The au- thors summarize knowledge regarding the management of bipolar disorder dur- ing pregnancy and the postpartum pe- riod, with a focus on managing mania, hypomania, and the psychotic compo- nents of the illness. Method: An expert panel reviewed arti- cles that address the management of bi- polar disorder and the consequences of the use of mood stabilizers during preg- nancy, and a consensus document was generated. Results: The treatment of bipolar disor- der in pregnant women involves signifi-
cant challenges. Some mood stabilizers, e.g., sodium valproate and carbamaze- pine, are human teratogens. On the other hand, the teratogenicity associated with lithium may have been overestimated in the past. Conclusions: Since treatment can be managed most effectively if pregnancy is planned, clinicians should discuss the is- sue of pregnancy and its management with every bipolar disorder patient who has childbearing potential, regardless of future reproductive plans. Additional re- search should address the risks of dis- turbed sleep to pregnant and postpartum women with bipolar disorder, as well as structural and behavioral consequences to offspring when mood stabilizers are used during pregnancy. Longitudinal and cohort studies can promote these efforts. Given the rate of bipolar disorder in the general population, research efforts will need to be broad based and include mul- tiple collaborating centers.
(Am J Psychiatry 2004; 161:608–620)
B ipolar disorder is a serious psychiatric condition that
affects 0.5%–1.5% of individuals in the United States. The prevalence is similar in men and women, although female patients are more likely to have the rapid-cycling form of the illness and more likely to display depressive character- istics (1). Women with bipolar disorder are typically in their teens and early 20s at onset of the illness, placing them at risk for episodes throughout their reproductive years. The issue of whether bipolar illness improves dur- ing pregnancy is controversial (2–6), but, in any case, preg- nancy is not protective for all women with bipolar disorder (6), and management of the illness in pregnancy is most difficult when the pregnancy is unanticipated. Since many pregnancies are unplanned and women with bipolar dis- order do not all experience symptom improvement during pregnancy, it important for clinicians to be knowledgeable about approaches to and risks associated with medication treatment during pregnancy.
Women with bipolar disorder are at high risk for symp- tom exacerbation during the immediate postpartum pe- riod (3, 5, 7), as indicated by a nearly sevenfold higher risk of admission for a first episode and a nearly twofold higher
risk for a recurrent episode in puerperal women, com- pared with nonpostpartum and nonpregnant women (5). Among women with bipolar disorder who elect to discon- tinue lithium therapy in the puerperium, the estimated risk of relapse is threefold higher than for nonpregnant, nonpuerperal women (7). Symptom emergence is often rapid and may commence a few weeks before (2) or within the first few days to weeks after parturition (3, 5). General guidelines for the treatment of bipolar disorder are available from the American Psychiatric Association (APA) (8), but additional issues arise when these guide- lines are applied in the treatment of pregnant and post- partum women. This report summarizes knowledge re- garding the management of bipolar disorder during pregnancy and the immediate postpartum period, with a focus on managing mania, hypomania, and psychotic components of the illness. We review 1) the risks to off- spring of mothers treated with mood stabilizers or adjunc- tive medication during pregnancy and 2) clinical issues in the use of mood-stabilizing agents to treat pregnant women with bipolar disorder. We then present informa- tion on the risks of breast-feeding associated with treat-
YONKERS, WISNER, STOWE, ET AL.
ments for bipolar disorder. This report was assembled by a group of psychiatrists who specialize in the treatment of pregnant women with bipolar disorder. The group was convened under the aegis of APA. Because the use of anti- depressants during pregnancy has been addressed re- cently by APA guidelines (9), this topic is not addressed here.
Risks Associated With Mood-Stabilizing
Agents During Pregnancy
The risk of fetal malformations associated with mater- nal drug use depends on the properties of the drug and the time period of the fetus’s exposure. Exposure up to 32 days after conception can affect neural tube development and closure; exposure 21–56 days after conception may affect heart formation; and exposure during days 42–63 may in- fluence development of the lip and palate. Craniofacial anomalies can also occur after the first trimester. In addi- tion, neurobehavioral teratogenicity can result from expo- sure after the first trimester. The following review is orga- nized by domain of reproductive toxicity, including structural malformations, growth retardation, perinatal toxicity, and adverse neurobehavioral sequelae. The cur- rent U.S. Food and Drug Administration (FDA) classifica- tion of teratogenicity is being revised to better address and inform clinicians about the risks of fetal exposure (10). Therefore, the FDA classification is not used in this review.
Lithium
Although lithium is effective for only a subgroup of patients with bipolar disorder (11), it remains one of the mainstays for acute and maintenance treatment.
Organ dysgenesis. Shortly after lithium came into com- mon use, concerns arose about an association between prenatal lithium exposure and congenital malformations. The Register of Lithium Babies (12), a voluntary physician- reporting database, noted a 400-fold higher rate of cardio- vascular malformations, most notably Ebstein’s anomaly, in offspring exposed in utero, compared with the general population. This congenital anomaly, characterized by downward displacement of the tricuspid valve into the right ventricle and variable levels of right ventricular hy- poplasia, occurs at a rate of 1:20,000 in the general popula- tion (13). Subsequent investigations identified a risk of Eb- stein’s anomaly among offspring of lithium users of 1: 1,000 (0.1%) to 2:1,000 (0.05%), or 20 to 40 times higher than the rate in the general population (14–16). Thus, the relative risk for Ebstein’s anomaly with prenatal lithium exposure is somewhat higher than in the general popula- tion, although the absolute risk remains small.
Intrauterine growth effects. Lithium-exposed infants were found to weigh significantly more than comparison subjects by a mean of 92 g (3475 g, compared with 3383 g) (15), even though lithium-treated women were more likely to smoke cigarettes, which typically decreases birth
weight. The maternal lithium dose did not correlate with birth weight. Neurobehavioral teratogenicity. In a follow-up study of children included in the Register of Lithium Babies, 60 children exposed to lithium either during the first trimes- ter or throughout pregnancy did not differ behaviorally from their nonexposed siblings (17). In another study (15), the attainment of major developmental milestones for 22 lithium-exposed subjects was similar to that for nonex- posed comparison subjects. Neonatal toxicity. The most common toxicity effect in offspring exposed to lithium during labor is the “floppy baby” syndrome, characterized by cyanosis and hypoto- nicity (18, 19). Cases of neonatal hypothyroidism and nephrogenic diabetes insipidus have also been described (20, 21). Close monitoring of lithium levels in the mother during labor is now routine. Use during pregnancy. Lithium has a relatively short half-life (8–10 hours) and produces substantial peak and trough serum levels. More frequent dosing (three to four times a day) allows patients to maintain therapeutic se- rum levels and avoid peaks, although it is unclear whether this technique benefits the fetus (22). Lithium serum lev- els, which may be affected by vomiting, sodium intake, and febrile illnesses, should be monitored closely (22). As pregnancy progresses, renal lithium excretion increases, generally necessitating an increase in dose (23). Lithium levels in umbilical cord blood have been found to be equivalent to maternal blood levels (23), and the concen- tration of the cation may be higher in amniotic fluid than in blood (24). The significance of this finding is unknown. Some experts advise decreasing the dose of lithium at the onset of labor to avoid toxicity associated with the rapid reduction of vascular volume at delivery (25). Vigilant monitoring of symptom and lithium serum levels is re- quired to avoid relapse or toxicity during delivery and the immediate postpartum period (7, 16). Adequate hydration should be maintained, and use of intravenous fluids should be considered for patients in prolonged labor. In the case of first-trimester exposure, anomalies can be identified with prenatal screening with a high-resolution ultrasound examination and fetal echocardiography at 16–18 weeks gestation (16, 26). This procedure aids par- ents in decisions regarding pregnancy termination and perinatal interventions after delivery.
Anticonvulsants
A number of anticonvulsants, most notably sodium val- proate and carbamazepine, have been used in the acute treatment of bipolar disorder. Some of these anticonvul- sant agents represent more potent teratogenic risks than lithium. Exposure is associated with a twofold increase in the rate of malformations (27), which include neural tube defects (spina bifida, anencephaly), craniofacial anoma- lies, growth retardation, microcephaly, and heart defects
YONKERS, WISNER, STOWE, ET AL.
for the main compound and the epoxide metabolite, al- though not all reports concur (10). If possible, it is best to monitor unbound levels of the compound.
Women who are started on the drug after conception in- cur more risk of serious side effects (agranulocytosis, he- patic failure, and Stevens-Johnson syndrome) than indi- viduals who are undergoing carbamazepine treatment at conception, since the risks are higher within the first 8 weeks after treatment is initiated (52).
Carbamazepine can cause fetal vitamin K deficiency. Since adequate levels of vitamin K are necessary for nor- mal mid-facial growth and for the functioning of clotting factors, carbamazepine exposure in utero could increase the risk of neonatal bleeding and mid-facial abnormali- ties. Most experts recommend administering 20 mg/day of oral vitamin K in the last month of pregnancy in women taking carbamazepine (30, 41). Pediatricians should also administer 1 mg i.m. of vitamin K to neonates after in utero carbamazepine exposure.
Lamotrigine
Organ dysgenesis. Lamotrigine was recently approved as a maintenance therapy for bipolar disorder. Two studies have demonstrated an increased time to subsequent mood episodes in patients treated with lamotrigine (53, 54). The obstetrical outcome data contained in the Lamo- trigine Pregnancy Registry maintained by GlaxoSmith- Kline (54) includes data from international registries and postmarketing surveillance. As of September 30, 2003, a total of 1,081 cases have been registered and 693 birth out- comes have been obtained. Nine major defects were iden- tified in offspring of women treated with monotherapy (N=415), yielding an estimate of 2%, while the rate was 3.4% in the 278 women undergoing treatment with several anticonvulsants. These rates are similar to the general population rate for major malformations. These defects included one instance of anencephaly and two instances of ventral septal defects. Polytherapy that included val- proic acid was associated with a higher rate of malforma- tions—10.4% (7/67).
Intrauterine growth effects. The impact of lamotrigine on intrauterine growth has not been detailed.
Neurobehavioral teratogenicity. A single follow-up of 23 infants demonstrated no alterations in development at 12 months of age (55).
Neonatal toxicity. Clinicians should be aware of reports of hepatotoxicity in adults taking lamotrigine and con- cerns about the development of lamotrigine-related skin rash in a fetus or neonate whose antigen characteristics are different from those of the mother. An additional con- cern is that lamotrigine is metabolized exclusively by means of glucuronidation, a metabolic process that is very immature in the fetus and neonate. Measurement of the clearance of lamotrigine in neonates over the first 72
hours of life demonstrated only a 25% decrease relative to umbilical cord blood concentrations (56). Use during pregnancy. The clearance of lamotrigine during pregnancy has generated attention secondary to its increased use and the characteristics of its metabolic pathway. Two studies have found a significant increase in the clearance rate during pregnancy (i.e., a decrease in se- rum concentration) (57, 58). It is noteworthy that the rate of clearance returned to preconception levels rapidly after delivery, indicating the need for careful dose management in the early postpartum period.
Other Anticonvulsants
The utility of gabapentin for treatment of mania has not been established (59, 60) and is not discussed in this re- port. Selected newer anticonvulsants, including zonisa- mide and levetiracetam, are under investigation for use in the treatment of mania and depression.
First-Generation Antipsychotic Agents
One of the largest databases available is for the older, first-generation antipsychotic agents, although even this information is limited. Phenothiazines and butyrophe- nones have historically been used to treat hyperemesis gravidarum, nausea, and, less commonly, psychotic disor- ders in pregnant women. First-generation antipsychotic agents are often prescribed with anticholinergic agents such as benztropine mesylate. Risks associated with this adjunctive agent are covered in the section on ECT. Organ dysgenesis. The best-studied phenothiazine is chlorpromazine, which was prescribed for hyperemesis gravidarum during the 1950s, usually in low doses (61, 62). In a case-control study of 315 exposed and 11,099 nonex- posed women, investigators found a slightly higher rate of malformations (3.5% versus 1.6%) among exposed off- spring (61). However, in a survey of more than 50, mother-child pairs that identified 142 first-trimester expo- sures and 284 total exposures to chlorpromazine, there was no elevation in the rate of physical malformations with chlorpromazine (62). The latter study also suggests that re- lated compounds, including trifluoperazine, perphena- zine, and prochlorperazine, are similarly not associated with higher-than-expected rates of malformations (62). In one of the few studies to assess antipsychotic use in pregnant psychotic women, 52 women who took chlor- promazine throughout pregnancy were compared with 110 pregnant women with psychosis who were not ex- posed to chlorpromazine (63). The rates of malformations among offspring in the two groups were similar but ap- proximately twice the rate in the general population. This finding suggests that the higher rate of anomalies may be influenced by the underlying illness. Genetic factors or behaviors such as smoking, substance abuse, and poor prenatal care may account for the higher rate of malfor- mations.
BIPOLAR DISORDER DURING PREGNANCY
A few case reports have suggested an association be- tween haloperidol and limb reductions, but large case se- ries have not supported this finding (64). A meta-analytic study of first-trimester exposure to low-potency neurolep- tics found an increase of one case of malformation for ev- ery 250 pregnancies in which exposure occurred (26).
Neonatal toxicity. A withdrawal-emergent syndrome (irritability, tongue thrusting with feeding difficulty, ab- normal hand posturing, and tremor of all extremities) last- ing 6 months was described in an infant exposed to halo- peridol during pregnancy (65). Extrapyramidal symptoms, including hypertonicity, tremors, motor restlessness, spasticity, and difficulty with feeding, have been found in infants exposed to chlorpromazine (66). Such symptoms have been reported to last up to 10 months, but most re- solve within days. On the other hand, hypotonicity can oc- cur in the neonate if the mother’s dose of chlorpromazine is high (67). Some of these complications may have been related to use of concomitant anticholinergic and anti- histaminergic agents.
Behavioral teratogenicity. Investigations did not find diminished intelligence among 4-year-old progeny ex- posed to phenothiazines or butyrophenones (62). Chil- dren with and without histories of neuroleptic exposure showed no differences in behavioral functioning or IQ when followed up to 5 years of age (68).
Use during pregnancy. First-generation antipsychotic agents continue to have a role in the acute treatment of mania during pregnancy (69). Some experts consider the risk associated with first-generation antipsychotic agents, which have been available for decades, to be less than the risk associated with selected mood stabilizers (26). Clini- cians may elect to switch a patient’s medication from lithium or an anticonvulsant to a first-generation anti- psychotic either for the entire pregnancy or for the first tri- mester. This strategy is particularly useful for patients who have benefited from mood stabilization with antipsy- chotic medications in the past. First-generation antipsy- chotic medications may also be a choice for women with bipolar disorder who elect to discontinue medication dur- ing pregnancy but begin to experience a recurrence of symptoms while pregnant.
Second-Generation Antipsychotic Agents
Several second-generation antipsychotics, including quetiapine and risperidone, are currently under review but have not been approved by the FDA for acute and maintenance treatment of bipolar disorder. Olanzapine recently received approval from the FDA for treatment of acute mania, but experience with this drug in pregnancy is limited.
Organ dysgenesis. Olanzapine was not associated with malformations in several case reports and series (70, 71).
Neonatal toxicity. No data exist on neonatal toxicity.
Use in pregnancy. Data are limited, but olanzapine has been associated with weight gain, insulin resistance (72), gestational diabetes (73), and preeclampsia (73). Weight gain, blood sugar levels, and blood pressure should be monitored carefully in patients who are taking olanzapine.
Calcium Channel Blockers
The effects of calcium channel blockers, such as ver- apamil, in the treatment of bipolar disorder have been studied (74–76), although their efficacy remains unproven (77). Because verapamil is used to treat maternal hyper- tension and fetal arrhythmias, the effects on the fetus of exposure during the first trimester have been evaluated. In a controlled study, two of 66 subjects exposed to nifedi- pine or verapamil developed malformations, compared to none of a group of nonexposed comparison subjects, but the difference was not significant (p=0.27), and the study had sufficient power to rule out only a very large (fivefold) difference in risk (78). A higher rate of preterm delivery (28% versus 9% in the control group) (p=0.0003) was as- cribed to maternal disease for which the drugs were pre- scribed. In two therapeutic trials of verapamil among hy- pertensive pregnant women, no adverse drug-related effects were observed among infants (79).
Benzodiazepines and Other Sedative
Hypnotic Agents
Benzodiazepines are used commonly as adjunctive medications for mood stabilization or for anxiety, agita- tion, and sleep problems. The most commonly prescribed benzodiazepines for individuals with bipolar disorder are lorazepam and clonazepam. Organ dysgenesis. There are no reports of malforma- tions associated with lorazepam or clonazepam. The re- productive safety of the prototype drug in this class, diazepam, is controversial. Early reports described an in- creased risk of oral clefts after first-trimester exposure to drugs such as diazepam (80), but later studies have not supported this association (81, 82). A recent meta-analysis found an association between oral cleft and benzodiaz- epine use only among case-control studies (odds ratio= 1.79, 95% confidence interval=1.13–2.82) but not in cohort studies (83). The difference in findings among studies is probably due to the greater sensitivity of case-control studies in analyzing events that are rare. Results from case-control studies of the relationship between benzodi- azepine exposure and cleft lip or palate have suggested a risk rate of about 11:10,000 births, an increase of about 80% over the base risk rate of 6:10,000 births in the general population, but still a rate that yields rare events (83). Use during pregnancy. Although the risk of physical anomalies with benzodiazepines is not greatly elevated, it may be even less for the high-potency agents in this class. The high-potency compounds may also be preferable, since they have shorter half-lives, have less accumulation, and are less likely to cause sedation.
BIPOLAR DISORDER DURING PREGNANCY
logical interventions on mania, and no controlled clinical trials have evaluated these strategies during pregnancy. Structured daily activities, which help minimize sleep deprivation and reduce mood lability, are particularly im- portant during pregnancy.
Treatment Planning for the Pregnant
Patient With Bipolar Disorder
Preconception
Optimal treatment planning for women with bipolar disorder emphasizes overall care to promote preconcep- tion and prenatal health. Clinicians should not focus on psychotropic medication while ignoring other risk factors for poor perinatal outcome, such as obesity, smoking, and the use of alcohol or other substances of abuse. Healthy behavior, including adherence to a prenatal vitamin regi- men and to a schedule of prenatal care visits, maintenance of a healthy diet, and attendance at childbirth preparation classes, must be supported.
Treatment planning is critical for minimizing the risk to the mother and fetus while limiting the morbidity from ac- tive psychiatric illness. Ideally, discussions about treat- ment planning should occur before the patient becomes pregnant and while the patient is euthymic. These early discussions reduce the risk for abrupt changes in thera- peutic approach in the midst of an unplanned pregnancy. Informed choices coupled with close psychiatric follow- up and coordinated care with the obstetrician are the ele- ments of an optimal model for the management of psychi- atric disorders during pregnancy (9).
The most important clinical factors that influence treat- ment planning during pregnancy are illness history and the reproductive risks of medications. Historical factors that should be identified include the patient’s prior re- sponse to various medications, illness severity, duration of euthymia while taking medication and while not taking medication, time to relapse after medication discontinua- tion, and time to recover with reintroduction of pharma- cotherapy.
The clinician and patient need to decide if the patient requires medication during the period before conception and during the first trimester. Stable patients may be able to discontinue taking a mood stabilizer before attempting to conceive (2, 6). Discontinuation of a maintenance phar- macologic treatment is associated with high rates of re- lapse, especially if discontinuation occurs abruptly, and thus the medication should be tapered slowly (94). Given the difficulty of predicting the amount of time a woman will require to conceive, a woman who discontinues med- ication while trying to become pregnant may be free of prophylactic treatment for many months and may be in a precarious position with regard to her risk of manic re- lapse. A pregravid trial of a medication taper allows the cli- nician and patient to assess the patient’s response and
plan accordingly. Recurrence of symptoms may prompt the woman to consider the difficult choice to continue taking medication during pregnancy. Treatment of women with severe illness presents the greatest challenge. These women are likely to continue taking medication through conception. Some women may await early documentation of pregnancy before they dis- continue taking medication, and this course of action af- fords prophylaxis for the longest period of time up to and around the time of conception. Caution is required with some compounds, such as valproate (see earlier discus- sion), since teratogenic risk is greatest when exposure oc- curs early in pregnancy. When pregnancy is recognized, the mood stabilizer will have to be discontinued abruptly, and the abrupt discontinuation enhances the risk for ill- ness relapse. Adjunctive (antipsychotic) medication may be used to assist in mood stabilization while medications such as valproate are tapered, but the efficacy of this ap- proach has not been established. Women who elect to switch their medication to an older antipsychotic or to risperidone while they are trying to conceive face other issues. These medications increase prolactin levels, thereby decreasing menstrual cyclicity and adversely affecting fertility. Since it may take several months before a woman taking these medications con- ceives, an agent that has less effect on prolactin may be preferable.
Early Conception
Patients who discontinue medication before pregnancy or during the first trimester and who remain well may or may not decide to restart medication later in the preg- nancy. While the best option for some patients is to rein- troduce medication only with early signs of relapse, other patients may opt to reinstitute medication regardless of whether relapse seems imminent. If the patient’s history includes self-harm, protracted recovery time, impaired in- sight, or evidence that her support system cannot tolerate another episode, pharmacological treatment may reduce overall risk to both mother and fetus. For women who are required to or prefer to continue taking medication during the first trimester, it is impor- tant to emphasize that exposure to one psychotropic medication may be safer than exposure to multiple agents (95). The lowest effective dose of a medication must be used, and agents with the least teratogenic potential should be selected in preference to those that pose a higher risk. However, an agent known to be effective for a particular patient has already been proven useful in treating the disease, which may justify exposure to the drug for that patient. Older agents with case and cohort data are preferable, since drugs are not tested in preg- nant women and assessment of the reproductive toxic- ity of a newer agent is often delayed for years after its introduction.
YONKERS, WISNER, STOWE, ET AL.
Second and Third Trimester
The periods of highest risk for teratogenicity are during the first trimester. However, other perinatal risks are re- lated to later exposure. They include risks for minor mal- formations, behavioral effects, low birth weight, and pre- term delivery. Given how little is known about these risks and about whether mood-stabilizing agents affect these risks, it is difficult to make recommendations. However, for a woman who is doing well, changing medication for the purpose of avoiding theoretical risks to potential off- spring may place the woman’s current stability at risk and may not be the most prudent course.
Unplanned Pregnancy
A planned conception represents the ideal for women with bipolar disorder, but only about 50% of pregnancies are planned (88). In many instances, recognition of preg- nancy will occur during or after the peak risk period for some agents. Discontinuation of the medication at that point may place the woman’s clinical well-being at risk and confer minimal benefit. The patient’s stability, week of pregnancy, psychotropic agent, and treatment prefer- ences should be considered in adjusting the treatment plan. In addition, a higher dose of folic acid (3 mg/day) should be prescribed for the woman. Principles of stream- lining medication and using the minimal effective dose can be useful treatment approaches in this scenario. Man- agement strategies are summarized in Table 1.
Treatment During the Puerperium
and While Breast-Feeding
Pregnant women with bipolar disorder should be in- formed about the risk for relapse as they enter the postpar- tum period. The well-documented high rate of recurrence in this period underscores the need to consider prophylac- tic intervention (7). Medication prophylaxis during the im- mediate postpartum period should be considered, al- though data to support this practice are available only for treatment with lithium. Lithium postpartum prophylaxis has been found to reduce the rate of relapse from near 50% to less than 10% (96, 97). Since many women prefer to breast-feed, information about the use of mood stabilizers during breast-feeding is also needed.
Lithium
Lithium is secreted into breast milk and levels achieved are nearly half of maternal serum levels (19). The dimin- ished renal clearance in neonates can elevate serum levels of lithium. In a study of breast-fed offspring of women who were taking lithium, Schou and Amdisen (19) re- ported that lithium concentrations were detectable in the sera of neonates in all cases and were equivalent to con- centrations in breast milk (ranging from 0.1 mmol/liter to 0.6 mmol/liter). One concern regarding appreciable lith- ium levels is the propensity for rapid dehydration in neo-
nates with febrile illnesses. Another consideration is that the longer-term effects on the infant of sustained lithium levels are not known. The American Academy of Pediatrics recommends that breast-feeding be undertaken with cau- tion by women undergoing lithium treatment (98). In a breast-fed infant exposed to lithium, lithium serum con- centrations and the CBC should be monitored.
Valproate
Serum concentrations of valproate found in breast-fed neonates whose mothers took valproate during pregnancy ranged from 4% to 40% of maternal levels but declined from the time of birth (99). Breast-fed infants whose mothers did not take valproate during pregnancy had sub- stantially lower serum concentrations (6% or less of ma- ternal serum levels) (9, 100). No adverse effects have been reported among infants whose mothers were treated with valproate solely during breast-feeding (100). The Ameri- can Academy of Neurology advocates breast-feeding for mothers maintained on antiepileptic agents (101).
Carbamazepine
Concentrations of carbamazepine in breast milk are detectable but low. Most data on serum concentrations of carbamazepine in breast-feeding infants have been based on measurements in offspring of mothers who took the drug during pregnancy. Serum concentrations in such in- fants ranged from 6% to 65% of maternal levels (102). The American Academy of Neurology supports breast-feeding while undergoing carbamazepine treatment in selected cases (101). The American Academy of Pediatrics com- mittee on medications in breast-feeding lists both valp- roic acid and carbamazepine as compatible with breast- feeding (98).
Lamotrigine
Lamotrigine is excreted into human breast milk with a milk/plasma ratio of 0.61. Serum concentrations in nurs- ing infants (N=10) were approximately 30% of maternal serum concentrations. No adverse effects were noted in this study, but the authors recommended that the baby be monitored for rash (103).
First-Generation Antipsychotic Agents
Women with bipolar disorder who relapse during the immediate postpartum period (or the third trimester) may require antipsychotic medications. Ten reports have ad- dressed a total of 28 infants’ exposure to antipsychotic agents through nursing (99). In the majority of cases, no adverse events were observed.
Benzodiazepines
Like other psychotropic medications, benzodiazepines are secreted into breast milk. Although complications as- sociated with lorazepam and clonazepam have not been described, one case report has associated diazepam with sedation in the neonate (104).
YONKERS, WISNER, STOWE, ET AL.
ment and summarizes management strategies. Since treat- ment can be managed most effectively if pregnancy is planned, clinicians should discuss the issue of pregnancy and its management with every patient with bipolar disor- der who has childbearing potential, regardless of future reproductive plans.
Managing bipolar disorder during pregnancy can also be enhanced by additional research. Such an agenda might include studies that examine 1) the sleep of women with bipolar disorder during the childbearing years; 2) the maternal and fetal effects of agents used during preg- nancy, including detailed gestational timing and exposure
Patients Receiving ECT
Patients Receiving Lamotrigine
Patients Receiving As-Needed Medications Patients Receiving Other Medications First-Generation Antipsychotic Benzodiazepine
Calcium Channel Blockers Carbamazepine
Recommended for all patients
Recommended for all patients
Recommended for all patients
Recommended for all patients
Recommended for all patients
Recommended for all patients
Recommended for all patients
Recommended for all patients
Recommended for all patients
Recommended for all patients
Recommended for all patients
Recommended for all patients
Prenatal vitamins, folic acid
— a^ Prenatal vitamins, folic acid
Prenatal vitamins, folic acid
Prenatal vitamins, folic acid
Prenatal vitamins, folic acid, folate, vitamin K Position patient in left lateral decubitus position during treatment
— a^ Reduce dose of anticholinergic agent
— a^ — a^ — a
— a^ — a^ —a^ — a^ — a^ — a
— a^ — a^ —a^ — a^ — a^ Serum concentration of unbound main compound should be monitored
— a^ Previous reports suggest teratogenic risk
—a^ — a^ — a^ Previous reports suggest teratogenic risk — a^ — a^ —a^ — a^ — a^ — a
— a^ Previous reports suggest teratogenic risk
—a^ — a^ — a^ — a
— a^ — a^ —a^ Previous reports suggest teratogenic risk
— a^ — a
— a^ Previous reports suggest teratogenic risk
—a^ — a^ — a^ Previous reports suggest teratogenic risk
— a^ Assessment recommended
—a^ Assessment recommended
— a^ Assessment recommended — a^ — a^ —a^ — a^ — a^ — a
— a^ Monitor for declining serum concentration in mid-pregnancy
—a^ — a^ — a^ Monitor for declining serum concentration — a^ Monitor for rising serum concentration after delivery
—a^ — a^ — a^ — a
— a^ — a^ —a^ — a^ — a^ — a
BIPOLAR DISORDER DURING PREGNANCY
analyses; 3) novel therapies, including calcium channel blockers, omega-3 fatty acids, rapid transcranial magnetic stimulation, and light therapy, for women who cannot tol- erate or refuse agents with known efficacy; and 4) ways in which professional education can be enhanced to im- prove the likelihood that pregnant women with bipolar disorder will receive appropriate care. If such explorations are supported, it is likely that they will shed more light on the disorder and benefit all patients with bipolar illness.
Received March 31, 2003; revision received Aug. 5, 2003; accepted Aug. 9, 2003. From the Department of Psychiatry, Yale University School of Medicine; the Departments of Psychiatry, Obstetrics and Gy- necology, and Pediatrics, University of Pittsburgh, Pittsburgh; Western Psychiatric Institute and Clinic, University of Pittsburgh, Pittsburgh; the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta; the Pediatrics and Developmental Neu- ropsychiatry Branch, Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Md.; the Department of Psychia- try, Harvard Medical School and Massachusetts General Hospital, Bos- ton; the Department of Psychiatry, University of Illinois at Chicago, Chi- cago; the Department of Psychiatry and Behavioral Science, Stanford University, Stanford, Calif.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; and the Department of Psychiatry, David Geffen School of Medicine at the University of Califor- nia, Los Angeles. Address reprint requests to Dr. Yonkers, Department of Psychiatry, Yale University School of Medicine, 142 Temple St., Suite 301, New Haven, CT 06510; kimberly.yonkers@yale.edu (e-mail). The authors thank the Bipolar Disorder Subcommittee of the American Psychiatric Association Corresponding Committee on Re- search on Psychiatric Treatments for its support.
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