The Management of Bipolar Disorder During Pregnancy

Zachary N. Stowe, MD; D. Jeffrey Newport, MD, MS, MDiv
Medscape Psychiatry & Mental Health. 2007; ©2007 Medscape

Posted 12/14/2007

Introduction

The management of mental illness during pregnancy and the postpartum period, specifically the use of psychiatric medications during pregnancy and lactation, remains the center of vigorous debate. Despite the burgeoning attention, there has been limited focus on the management of bipolar disorder (BPD) over the course of pregnancy.

BPD is a significant and often chronic psychiatric condition that affects 0.5% to 1.5% of individuals in the United States. The emerging literature regarding "bipolar spectrum disorders" suggests that the incidence may be much higher than early estimates. In contrast to major depression, the prevalence of BPD is similar in men and women. Women with BPD typically are more likely to have rapid-cycling (more than 4 episodes per year) and depressive episodes with illness onset in their teens or early twenties.^[1] The age of onset usually precedes family planning and necessitates developing management guidelines that address the myths associated with BPD during pregnancy.

General guidelines for the treatment of BPD are available from the American Psychiatric Association (APA),^[2] and treatment algorithms from the Canadian Health Network^[3] and Texas Algorithm project^[4] have outlined incremental levels of intervention for BPD. A recent review of management of women with BPD during pregnancy and the postpartum period provided an overview of the extant data on course of illness and treatment options.^[5] The treatment of women with BPD during pregnancy, specifically the use of medications, has also been incorporated into a Practice Bulletin for the American College of Obstetrics and Gynecology (ACOG) published in November 2007.^[6]

Navigation of the complexity of the clinical decisions in the management of women with BPD during pregnancy requires a working knowledge of:

Course of illness; Impact of maternal illness; Available treatment options; Reproductive safety data on treatment options; Pharmacologic strategies to reduce risks; and Incorporation of this information into a general approach to minimize risks.

Course of Bipolar Disorder During Pregnancy and the Postpartum Period

The natural course of illness for women with BPD over the course of pregnancy is obscure. Kraepelin observed that attacks of mania and melancholia were more common after childbirth than during pregnancy.^[7] Similarly, several early case reports suggested that some women with BPD maintain euthymia during pregnancy even after discontinuation of medication.^[8-11] Lier and colleagues^[10] found that pregnancy was not associated with significantly altered risk for BPD recurrence. Furthermore, a retrospective study by Grof and colleagues^[11] suggested an apparent protective effect of pregnancy on the course of lithium-responsive type I BPD.

In contrast, 3 retrospective studies and some case reports suggest that pregnancy is not protective and may instead represent a time of substantial risk for relapse.^[12-14] In one large, well-characterized clinical sample, Blehar^[12] found that 45% of women with BPD experienced an exacerbation of their illness during pregnancy. More recently, Freeman and colleagues^[13] found that at least 50% of a sample of women with BPD became symptomatic during pregnancy. A retrospective study of women with BPD who discontinued lithium proximate to conception found nearly identical high rates of recurrence within 40 weeks in 42 pregnant (52%) and 59 nonpregnant (58%) women.^[14] Recurrence rates were similar for BPD I and II subtypes, higher in those with more than 4 prior episodes or who discontinued lithium therapy, especially rapidly or abruptly. Prospective investigations supported by the National Institute of Health (NIH) have demonstrated significant risk for relapse (greater than 70%) in women discontinuing mood-stabilizing medications compared with those who continued medications (approximately 25% relapsed).^[15,16]

The postpartum period is a particularly high-risk period for women with BPD. Recurrence rates in women with BPD during the first 3-6 months postpartum are at least 20% to 50%, and recent observations suggest that the postpartum relapse risk without mood-stabilizer therapy may be as high as 70%.^[17-28] Symptom emergence is often rapid and may occur in late pregnancy or within the first few days to weeks after delivery. Women with BPD are at very high risk for postpartum psychosis (10% to 20%), at least 200-fold higher than the background rate of 0.05%.^[25-27]

In summary, women with BPD have a variable course during pregnancy that is significantly influenced by decisions regarding pharmacotherapy. In contrast, the postpartum period is a time of increased risk, and the prophylactic benefit of continued pharmacotherapy warrants further investigation.

Impact of Maternal Bipolar Disorder on Outcome

The data regarding the potential effects of maternal BPD on obstetrical and infant outcome are limited. Given that the majority of BPD relapses during pregnancy are "depressive,"^[14,16] it is feasible that symptomatic women with BPD may have the same risks as those with major depression. Studies have found an association between maternal depressive symptoms and poor neonatal outcome.^[29,30] The burgeoning clinical and preclinical data indicate that even modest maternal depression/stress can adversely affect infant well-being.^[31] These data underscore the value of maternal emotional well-being in optimizing outcome.

Ferreting out the impact of pharmacologic agents from the impact of active maternal illness remains a central focus of investigations of:

Maternal depression; Anxiety; BPD; and Epilepsy.

Treatment Options for Women With Bipolar Disorder During Pregnancy

The literature is replete with review articles on the treatment of women with mental illness during pregnancy and lactation. The pharmacologic armamentarium approved by the US Food and Drug Administration (FDA) for the treatment of BPD has expanded:

Lithium; Antiepileptic medications including carbamazepine, lamotrigine, and valproic acid; and Atypical antipsychotic medications: aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone.

In addition, there are a variety of medications and adjunctive therapies that have not undergone the scrutiny of FDA approval.

Formal prospective investigation of the efficacy of individual medications in maternal BPD over the course of pregnancy is limited to continuation of lithium^[14,32] and lamotrigine.^[15]

Risks Associated With Mood-Stabilizing Agents During Pregnancy

The potential risks of medications during pregnancy include:

Malformations; Obstetrical and neonatal complications; and Long-term neurobehavioral effects.

Neurobehavioral teratogenicity can result from medication exposure after the first trimester of pregnancy. Unfortunately, there is a dearth of long-term studies of children of women with BPD exposed to medications during pregnancy. Maximizing safety requires familiarity with the impact of individual medications across these domains and interventional strategies to reduce risks.

Malformations associated with maternal drug use depend on the properties of the drug and the point of exposure:

Up to 32 days post-conception can affect neural tube development and closure; Days 21-56 after conception may affect normal heart formation; and During days 42-63 may influence development of the lip and palate.

Craniofacial anomalies can also occur after the first trimester. Given that more than 50% of pregnancies are unplanned, by the time women and their clinicians are aware of pregnancy, the period of susceptibility to these risks will have already occurred. As such, clinicians should provide maintenance treatments in anticipation of potential pregnancy and be aware of which medications pose the fewest risks.

Lithium. Lithium remains one of the mainstays of acute and maintenance treatment of BPD. The International Registry of Lithium Babies, a voluntary physician-reporting database,^[33-37] noted a 400-fold increased rate for cardiovascular malformations, most notably Ebstein's anomaly, associated with lithium exposure in utero. Subsequent investigations identified a risk for Ebstein's anomaly among lithium users at between 1 per 1000 (0.1%) to 2 per 1000 (0.2%), or 20-40 times higher than rates in the general population.^[34-37] Thus, the relative risk for Ebstein's anomaly is somewhat increased, though the absolute risk remains small.

Lithium use is associated with higher-weight babies, and there are numerous reports of neonatal complications in association with lithium treatment in late pregnancy, including:

Cardiac dysfunction; Diabetes insipidus; Hypothyroidism; Low muscle tone; Lethargy; Hepatic abnormalities; and Respiratory difficulties.

Recognizing lithium's low therapeutic index, it seems plausible that such complications are directly related to the level of lithium exposure proximate to delivery. In a small prospective sample, Newport and colleagues^[38] demonstrated that discontinuation of lithium proximate to delivery and reinstitution immediately after delivery significantly reduced neonatal complications while maintaining maternal euthymia.

Long-term follow-up data are sparse. Sixty children older than 60 months, identified from the International Registry as being exposed to lithium during either the first trimester or throughout pregnancy, did not differ behaviorally from their nonexposed siblings.^[39] A second investigation found that attainment of major developmental milestones for 22 lithium-exposed subjects was comparable to that of controls.

Carbamazepine. Carbamazepine is a known human teratogen.^[40-44] The rate for neural tube defects in that report and others ranges between 0.5% and 1%.^[40,43,44] The teratogenic potential of carbamazepine is enhanced when it is given with other agents, valproate in particular, perhaps because the toxic epoxide metabolites are increased.^[43] In theory, oxcarbazepine, which does not produce the epoxide metabolite, may be less teratogenic. However, studies have not been performed to confirm this speculation.

Carbamazepine has been associated with lower birth weight and mean head circumference (standardized for gestational age and sex). Carbamazepine can cause fetal vitamin K deficiency. Because adequate levels of vitamin K are necessary for normal mid-facial growth and for the functioning of clotting factors, carbamazepine exposure in utero could increase the risk for neonatal bleeding and mid-facial abnormalities.:

Most experts recommend administering vitamin K 20 mg by mouth daily throughout pregnancy. Pediatricians should also administer vitamin K 1 mg intramuscularly to neonates after in utero carbamazepine exposure. Case reports of transient symptoms, such as hepatic toxicity hyperbilirubinemia, in neonates exposed during pregnancy underscore the need for observation.

Lamotrigine. Lamotrigine is a potential maintenance therapy option for pregnant women with BPD owing to its^[45]:

Protective effects against BP depression; General tolerability; and Growing reproductive safety information relative to alternative mood stabilizers.

Briefly, the pooled risk for reported major fetal anomalies following exposure to lamotrigine during pregnancy is 2.6% (78 of 2974 first-trimester exposures, including a rate of 0.34% [8 of 2372 exposures] for midline cleft formations); these rates are within the range of births not involving drug exposures.^[46-53] A relatively high risk for midline facial clefts (0.89% of 564 exposures) was reported by 1 pregnancy registry,^[49] and another reported greater risk for birth defects at higher maternal daily doses (greater than 200 mg/day).^[51]

To date, there are no reports of obstetrical or neonatal complications associated with lamotrigine monotherapy exposure. There is very limited long-term follow-up information.

Valproate. Sodium valproate is a known human teratogen (neural tube, cardiovascular, craniofacial) with acute and long-term adverse effects on infant development.^[54-60] Exposure during the first trimester is associated with neural tube defect rates of approximately 5% to 9%.^{[54,55,59,60]} The effect of drug on neural tube development is related to the use of valproate 17-30 days post-conception and the risk is increased with higher maternal daily doses/serum concentrations.^[60,61] The neural tube defect found in exposed infants is more likely to be lumbosacral rather than anencephalic, which suggests a drug effect on neural crest closure.^[62]

Similar to carbamazepine, transient neonatal symptoms have also been reported, including:

Liver toxicity; Hypoglycemia; and Withdrawal symptoms of irritability, jitteriness, feeding difficulties, and abnormal muscle tone.

One of the greatest concerns is the burgeoning clinical and preclinical data showing that valproate is a profound neurobehavioral teratogen. Investigations in the mid 1980s utilized in utero exposure to valproate as an animal model for autism. Several human investigations have demonstrated^[63]:

Increased risk for mental retardation; Higher rate of special educational needs; and

Decrease in both overall and verbal intelligence quotient (IQ).

Atypical antipsychotic medications. The use of atypical antipsychotics has dramatically increased over the past decade in pediatric populations, patients with BPD, and as adjunctive medications for a variety of symptoms, such as depression, sleep, and agitation. Those more commonly used include:

Aripiprazole; Olanzapine; Quetiapine; Risperidone; and Ziprasidone.

A recent investigation demonstrated that atypical antipsychotics cross the placenta^[64]; however, the obstetrical outcome data on these medications are extremely limited. The largest single investigation failed to identify any pattern of defects, though sample sizes were limited.^[65]

The obstetrical complication data are limited to case reports on olanzapine of maternal^[66]:

Weight gain; Insulin resistance; Gestational diabetes; and Pre-eclampsia.

There are no published infant/child follow-up studies.

Typical antipsychotic agents. Typical antipsychotic agents continue to have a role in the acute treatment of mania during pregnancy. Some experts consider the risk associated with typical antipsychotic agents, which have been available for decades, to be less than the risk associated with mood stabilizers. One of the largest databases available is for the older, "typical" antipsychotic agents, although even this information is limited. Phenothiazines and butyrophenones historically have been used to treat hyperemesis gravidarum, nausea, and (less commonly) psychotic disorders in pregnant women; they are the drug classes with the largest amount of reproductive information within this broad group of medications.

Adjunctive/alternative medications. There are a variety of additional medications that may be used in the management of BPD, including:

Antidepressants; Benzodiazepines; and Sedative hypnotics.

These classes of medication are seldom efficacious as monotherapy for BPD, and their use during pregnancy has been the center of considerable debate.

Electroconvulsive therapy (ECT). When used in pregnant patients, ECT has relatively few side effects and may pose fewer risks than untreated mood episodes or pharmacotherapy with a teratogenic agent. Although there have been occasional reports of congenital malformations in offspring exposed to ECT in utero, neither the number nor the pattern of these implicates ECT as a causal factor. Overall, reported complications of ECT during pregnancy are uncommon and transient.^[67,68] Barbiturates and atropine can reduce beat-to-beat variability in the fetal heart rate, and atropine can cause fetal tachycardia. The risk for fetal cardiac arrhythmias can be minimized by:

Avoiding atropine; Ensuring adequate oxygenation; Avoiding excessive hyperventilation; and Elevating the right hip.

Fetal cardiac monitoring during ECT will allow for detection of arrhythmias and correction of any contributory problems.

Treatment Planning for Women With Bipolar Disorder During Their Reproductive Years

Overall, the general approach to the treatment of women with BPD during pregnancy remains one of balancing the risk and benefits of illness vs treatment. Similarly, if pharmacologic treatment is deemed the best option, the clinician has several alternatives to reduce the risks. The following provides the clinician with a reasonable approach and rationale consistent with ACOG guidelines to minimize risks^[6]:

1. Treat all women of reproductive age: Document birth control method at every visit; Provide education about the risks of medications and potential pregnancy; Select maintenance medications with reduced teratogenic risk; Reduce other risk factors, including smoking, obesity, alcohol, and illicit drug use; and Supplement with folic acid: 1 mg for all, 3-5 mg for women treated with antiepileptic medications.

The rationale for instituting these measures throughout the reproductive years includes:

The high rate of inadvertent conception provides unanticipated exposure during organogenesis; and The primary potential benefits of folic acid occurs early in gestation often before knowledge of conception.

Although folic acid has not been definitively established in reducing the risks of antiepileptic drugs, the American Academy of Neurology has recommended 3-4 mg per day but states that the optimal dose has yet to be established.^[69]

2. Maintenance treatment that reduces risk in the context of inadvertent conception. All too often, clinicians are hesitant to consider optimal maintenance pharmacotherapy early in the treatment course for women with BPD. Of the available medication options, valproate is the most hazardous in pregnancy with respect to rates and severity of both malformations and adverse neurodevelopmental sequelae.

3. Monotherapy is preferable to multiple medications. There are very limited data about the impact of combined medications on pregnancy outcome. Extrapolation of the experience of our colleagues in neurology/epileptology clearly demonstrates an increased risk from multiple medications compared with monotherapy.

4. Develop an a priori treatment plan for pregnancy. BPD is a chronic medical illness and with onset typically prior to family planning. Therefore, it is likely that at some point over the course of treatment the clinician will encounter this situation.

5. Do not abruptly change or discontinue medications at knowledge of conception. Pregnancy is not a medical emergency. Abruptly changing or discontinuing medications in reaction to pregnancy simply increases the risks and seldom reduces fetal exposure. In fact:

Changing medications exposes the fetus to additional drugs, a situation with limited reproductive safety information; The change may increase the risk for maternal symptoms; Abruptly discontinuing medications appears to increase the risk for relapse; and The window of highest teratogenic risk for exposure may have already passed.

6. Over the course of pregnancy, maternal daily-dose adjustment may be required to maintain maternal well-being. Investigations of lithium, antiepileptic drugs, and antidepressants have all demonstrated decreased serum concentrations in later pregnancy. Failure to monitor and adjust the dose may result in exposure to both maternal symptoms and medications, hence the risk/benefit balance has failed.

7. Consider adjusting medications proximate to delivery. Preliminary studies with lithium suggest that reducing exposure proximate to delivery, ideally within 24 hours of a planned induction or planned cesarean section, reduces neonatal complications without compromising maternal well-being.

8. Postpartum treatment plan. There is good agreement that women with BPD are at risk for severe symptoms during the early postpartum period. A postpartum treatment plan and frequency of observation should be established prior to delivery.

9. Do not switch medications for breastfeeding. The central nervous system continues to have considerable growth and development during the postpartum years. Changing medications simply exposes the child to additional medications and, for a period of time, to multiple medications due to the delay of neonatal clearance of the original medication. Furthermore, abrupt medication switches in the immediate aftermath of delivery arguably increase the likelihood of maternal relapse.

In summary, the treatment of women with BPD during pregnancy remains a complex clinical situation that continues to generate angst for both the patient and clinician. Fortunately, the area of perinatal psychiatry has grown rapidly, and there are several academic programs that offer consultation and information in such situations.

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Zachary N. Stowe, MD, Women's Mental Health Program, Emory University School of Medicine, Atlanta, Georgia

D. Jeffrey Newport, MD, MS, MDiv, Women's Mental Health Program, Emory University School of Medicine, Atlanta, Georgia

Zachary N. Stowe, MD, has disclosed that he has received grants for clinical research from, grants for educational activities from, and has served as an advisor or consultant to GlaxoSmithKline, Wyeth, and Pfizer. Dr. Stowe has also disclosed that he has served as an advisor or consultant to Bristol-Myers Squibb and that he has served on the speaker's bureau for GlaxoSmithKline, Wyeth, Pfizer, and Eli Lilly.

D. Jeffrey Newport, MD, MS, MDiv, has disclosed that he has received grants for clinical research from Eli Lilly, GlaxoSmithKline, Janssen, and Wyeth. Dr. Newport has also disclosed that he has served on the speaker's bureau for AstraZeneca, Eli Lilly, GlaxoSmithKline, and Pfizer.