Psychiatric Annals

CME Article 

Bipolar Disorder Through Pregnancy and Postpartum

Wendy Marsh, MD, MS; Adele Viguera, MD, MPH

Abstract

CME Educational Objectives

  1. Describe, as you would to a patient, relative mood relapse risk during pregnancy of: a) no mood stabilizing medication; b) abrupt discontinuation of mood stabilizer; and c) continuation of mood stabilizer. Include information about mood episode risk postpartum and your recommendation on whether to treat postpartum.

  2. Rank relative known fetal outcome (good to poor) of in utero exposure to: lithium; atypical antipsychotics; typical antipsychotics; carbamazepine; lamotrigine; and valproic acid.

  3. List one key fetal outcome for each medication option listed in question 2 that you would address with a patient considering that medication.

The postpartum period is a time of increased risk of severe mood episodes in bipolar disorder, and pregnancy is not protective against bipolar mood episodes. Care of women with bipolar disorder during these perinatal reproductive periods is complicated by fetal exposure to psychotropic medications. This article reviews critical information in making treatment decisions during the perinatal period with an emphasis on risks of fetal exposure to mood stabilizing psychotropic medication.

This article reviews the literature on pregnancy and postpartum care of women with bipolar disorder, with a focus on mood stabilizer teratogenicity, perinatal complications and neurodevelopmental outcomes, and exposure during lactation. This review highlights findings published since 2004.

Discussion of treatment of bipolar disorder in pregnancy and postpartum with reproductive-age women is critical and needs to highlight: a) fetal exposure risk; b) risk of mood episode recurrence if untreated; and c) risk of mood episode recurrence with mood stabilizer discontinuation. The goal of medication treatment is to use minimum effective dose as all psychotropic medications pass through the placenta as well as into breast milk. Given the significantly increased risk of mood episodes in the postpartum period, prophylactic mood stabilization is recommended. If a woman plans to breast-feed, it is recommended she remain on the medication used during pregnancy to avoid multiple exposures to her infant. However, there is considerable uncertainty regarding the relative safety of particular psychotropic drugs during lactation, and about the degree to which nursing infants are exposed to these medications.

Evidence-based guidelines are lacking in the treatment of bipolar disorder during the perinatal period. Fetal exposure occurs for all bipolar mood stabilizers and yet the risks of untreated illness often necessitate treatment during pregnancy and especially postpartum. Detailed discussion with the patient is critical in deciding treatment choice.

Abstract

CME Educational Objectives

  1. Describe, as you would to a patient, relative mood relapse risk during pregnancy of: a) no mood stabilizing medication; b) abrupt discontinuation of mood stabilizer; and c) continuation of mood stabilizer. Include information about mood episode risk postpartum and your recommendation on whether to treat postpartum.

  2. Rank relative known fetal outcome (good to poor) of in utero exposure to: lithium; atypical antipsychotics; typical antipsychotics; carbamazepine; lamotrigine; and valproic acid.

  3. List one key fetal outcome for each medication option listed in question 2 that you would address with a patient considering that medication.

The postpartum period is a time of increased risk of severe mood episodes in bipolar disorder, and pregnancy is not protective against bipolar mood episodes. Care of women with bipolar disorder during these perinatal reproductive periods is complicated by fetal exposure to psychotropic medications. This article reviews critical information in making treatment decisions during the perinatal period with an emphasis on risks of fetal exposure to mood stabilizing psychotropic medication.

This article reviews the literature on pregnancy and postpartum care of women with bipolar disorder, with a focus on mood stabilizer teratogenicity, perinatal complications and neurodevelopmental outcomes, and exposure during lactation. This review highlights findings published since 2004.

Discussion of treatment of bipolar disorder in pregnancy and postpartum with reproductive-age women is critical and needs to highlight: a) fetal exposure risk; b) risk of mood episode recurrence if untreated; and c) risk of mood episode recurrence with mood stabilizer discontinuation. The goal of medication treatment is to use minimum effective dose as all psychotropic medications pass through the placenta as well as into breast milk. Given the significantly increased risk of mood episodes in the postpartum period, prophylactic mood stabilization is recommended. If a woman plans to breast-feed, it is recommended she remain on the medication used during pregnancy to avoid multiple exposures to her infant. However, there is considerable uncertainty regarding the relative safety of particular psychotropic drugs during lactation, and about the degree to which nursing infants are exposed to these medications.

Evidence-based guidelines are lacking in the treatment of bipolar disorder during the perinatal period. Fetal exposure occurs for all bipolar mood stabilizers and yet the risks of untreated illness often necessitate treatment during pregnancy and especially postpartum. Detailed discussion with the patient is critical in deciding treatment choice.

Introduction

Bipolar disorder is a serious mental illness that affects women at the same rate as men, but the clinical care of bipolar disorder in women is complicated by a woman’s reproductive phases. This article focuses on the complexity of care of bipolar disorder during the perinatal period of pregnancy and postpartum (see Sidebar).

Sidebar

  • Recognize that risk for relapse in pregnancy is high
  • Streamline regimen; offer minimum effective dose
  • Avoid stopping medications abruptly
  • Continuation of mood stabilizers reduces risk significantly by 2- to 3-fold and reduces maternal morbidity >4 fold
  • Consider differential teratogenic risk across mood stabilizers but also efficacy of mood stabilizer for the individual

Pregnancy is not protective against mood episodes in women with bipolar disorder.1–4 Epidemiologic studies report pregnancy is not associated with an increased risk of affective illness among women diagnosed with bipolar disorder;5–8 however, in better-designed prospective studies, recurrence rates run from 70% to 100%. For example, over 70% of 89 women with bipolar disorder prospectively followed through pregnancy had a mood episode (whether on a mood stabilizer or not), and in women who choose to stop their mood stabilizer the rate jumped to 85% to 100%.2 During the postpartum period, women with bipolar disorder who have affective symptoms during pregnancy are up to 10-fold more likely to experience new or continued mood or psychotic illnesses.

The early weeks following childbirth bring a markedly increased risk of onset or recurrence of mood disorders or psychosis.4–7 In 1987, Kendell and colleagues5 found an excess of psychiatric hospitalizations after childbirth compared with before childbirth, particularly sooner after delivery (6.8-fold within 30 days) than at later times (4.3-fold within 90 days). Relative risk for postpartum psychotic illnesses was even higher (24.6-fold within 30 days and 14.3-fold within 90 days of delivery).5 Recent epidemiologic studies have found high risks of onset or recurrence of bipolar disorder episodes soon after childbirth,4,6,7 and in 2008, Vesga-Lopez and colleagues8 found similar risks during pregnancy and postpartum. Less rigorous clinical studies also indicate that the early postpartum period carries increased recurrence rates of 30% to 70% for affective morbidity among women diagnosed with bipolar disorder.9

Given the ongoing risk of mood relapse in pregnancy and heightened risk postpartum, treatment of women with bipolar disorder can be challenging, especially when considering the risk of fetal medication exposure. This review addresses complexities of care during the perinatal period in women with bipolar disorder.

Approach to Treatment During Pregnancy

Women of childbearing age who have bipolar disorder should be counseled about family planning, especially in patients with severe or chronic illness and with major disability. Planning for pregnancy while the woman is relatively clinically stable provides opportunities for thoughtful treatment selection and avoids risk of precipitous changes in treatment in response to an unplanned pregnancy. Frequent clinical monitoring during pregnancy, ideally with close psychiatric and obstetric collaboration, is imperative for early detection of impending recurrence and for rapid, pre-planned intervention. Pregnant women with bipolar disorder should be considered as high-risk obstetric patients.

Decisions regarding whether or not to continue, change, or discontinue treatment during pregnancy must reflect an assessment of the following factors: 1) the highly variable but often poorly quantified risks of fetal exposure to maternal psychotropic drugs commonly used; 2) substantial risks to the patient, fetus, and family from untreated maternal bipolar illness; and 3) typically high risk of early and potentially severe relapse or exacerbation associated with discontinuation of maintenance treatment, particularly if it is abrupt.10 Clinicians who treat women with mood disorders must discuss risks associated with continuing or discontinuing treatments during pregnancy. Our own research and clinical experience suggests that patients given similar information, including women with comparable clinical illness histories, make very different decisions about medication use during pregnancy.11 Risks should be discussed frankly and repeatedly, before and after conception, and there should be collaborative and effective communication among the patient’s psychiatrist, obstetrician, and other clinicians, with comments of such discussions documented in the clinical record for clinical and legal purposes.

Evidence-based guidelines are lacking in the treatment of bipolar disorder during pregnancy. Given the severity and chronicity of bipolar disorder, maintenance treatment during pregnancy may be the safest option for the mother and fetus. In certain cases of refractory illness, one may decide to use a medication for which information regarding reproductive safety is sparse. Psychotropic dosing should be cautious and conservative throughout pregnancy, but kept at an effective minimum dose. Clinicians sometimes risk under-treating psychiatric illness in an attempt to minimize exposure in utero.

Risks of Pharmacotherapy in Pregnancy

All psychotropic drugs diffuse across the placenta as well as the blood–brain barrier, and no psychotropic drug has been approved by the US Food and Drug Administration (FDA) for use during pregnancy. For ethical reasons, it is virtually impossible to conduct randomized, placebo-controlled studies on medication safety in pregnant women. Accordingly, most information about the reproductive safety of drugs derives from reports and less well-designed studies.

The FDA classifies medications into five “risk categories” in pregnancy: A; B; C; D; and X based on data derived from human and animal studies. Category A medications are designated as safe for use during pregnancy (no psychotropics currently have this rating), whereas Category X drugs are contraindicated by having demonstrated fetal risks that outweigh any benefit to the patient. Drugs in Categories B, C, and D are considered to have intermediate risks that are believed to increase in severity from Category B to D. Most psychotropic drugs are classified as Category C, meaning they are agents for which adequate human studies are lacking, risk cannot be ruled out, and clinical judgment is required to balance potential risks and benefits. The FDA’s categories do not correlate well with information on teratogenicity from other sources and are not informative in clinical practice.12 Prescribers are left to rely on limited peer-reviewed studies and treatment consensus guidelines.13

The baseline incidence of major congenital malformations in newborns in the United States is 2% to 4%12 and represents a high background rate against which to compare suspected teratogenicity of psychotropic medications. Major organ formation is virtually complete within the first 12 weeks after conception, but pregnancy is often not diagnosed for 6 to 8 weeks after conception, during which time critical steps in organ development have already occurred.

Mood Stabilizers and Treatment in Pregnancy

Lithium

Teratogenically, lithium exposure is historically associated with Ebstein’s cardiac anomaly (displacement of the tricuspid valve into the right ventricle and right ventricular hyperplasia) in fetuses, but recent examination places the risk at approximately 0.01%, which, although greater than the population-wide risk (0.005%), remains a small absolute risk (see Table, page 187).14

Grouped Risk of Mood Stabilizers in Pregnancy for Poor Fetal Outcome

Table: Grouped Risk of Mood Stabilizers in Pregnancy for Poor Fetal Outcome

Perinatally, lithium-exposed fetuses are more often premature and large for gestational age (LGA) and can experience neonatal toxicity of hypothyroidism, nephrogenic diabetes insipidus, and “floppy baby” syndrome (ie, cyanosis and hypotonia).

Nonetheless, neurodevelopmentally, infants exposed to lithium in utero in a small study did not show adverse effects on growth, neurologic, cognitive, and behavioral development up to 15 years old.15

Lithium in Pregnancy

Due to concern for cardiac malformations associated with lithium exposure in the first trimester, a high-resolution ultrasound and fetal echocardiogram is recommended at 16 to 18 weeks of gestational age. Lithium levels should be monitored closely, as vomiting in early pregnancy and increased renal excretion in later pregnancy can affect levels.

After delivery, assessment of cord blood lithium levels, neonatal thyroid function tests, and urea and electrolytes (kidney function) is recommended, particularly in infants with clinical symptoms of “floppy baby” syndrome.16

Antiepileptic Drugs

Among the commonly used anticonvulsants, emerging and compelling data from several pregnancy registries and studies suggest a differential teratogenic risk.12,17,18

Valproic Acid

The majority of evidence suggests that valproic acid is associated with the highest risk for all major malformations (including cardiac malformations, oral clefts, urologic defects, skeletal defects, and neural tube defects), with risk estimates in the range of 10% to 16%, representing a twoto threefold increased risk compared with lamotrigine and carbamazepine.17,18 Data also suggest that polytherapy combinations containing valproate carry a higher risk of major malformations than combinations not containing valproate.17,18 Risk for malformations appears to increase in a dose-dependent fashion, with higher rates of malformations at dosages greater than 1,000 mg/d.17–19

Perinatally, a significant association was found between sodium valproate and neonatal hypoglycaemia, with weaker findings for hepatic dysfunction, withdrawal symptoms, and reduced birth dimensions.20

Neurodevelopmentally, children exposed to valproic acid in utero are more likely to experience developmental delays, lower verbal IQ, and increased need for special education services compared with children exposed to other anticonvulsants.19–21

Valproic Acid in Pregnancy

Given these concerns regarding valproic acid use in pregnancy, the American Academy of Neurology (AAN) recommends avoidance of valproic acid during pregnancy,22 stating that it should be used only when clinical circumstances dictate no other treatment alternative. In these cases, preconceptional folic acid at 0.4 g/d or more may be effective in preventing major congenital malformations,22 and early assessment for neural tube defects is recommended.

Carbamazepine

Overall fetal malformation rate for carbamazepine has been reported at 2.9%,23 with a range of 2.2% to 8.2%.20 However, according to recent studies, the risk of cleft lip/palate is increased with carbamazepine.24 Perinatally, a recent review reports a significant and replicated association between carbamazepine and reduced head circumference, lower birth weight, and shorter length.20 Neurodevelopmentally, children exposed to carbamazepine in utero had IQs in the normal range,19,21 and, in review, carbamazepine was not associated with poor developmental outcomes.20

Carbamazepine in Pregnancy

Monitoring of carbamazepine levels in pregnancy is recommended.22 In 2009, the American Academy of Neurology reported insufficient evidence to recommend prenatal vitamin K supplementation for reducing hemorrhagic complications.22

Lamotrigine

Lamotrigine is considered a “safe” mood stabilizer in pregnancy, based mainly on major malformation rates similar to estimates from the general population, which is approximately 2% to 3% in multiple studies.17,20,25 Although a greater rate of oral-facial clefts has been reported,26 this finding was subsequently refuted.27 No significant effect of lamotrigine on perinatal outcomes has been reported at this time, although studies are few.20 Neurodevelopmental outcomes do not appear to be adversely affected by lamotrigine,20,28 including language and IQ scores in the expected normal range.21

Lamotrigine in Pregnancy

In the latter half of pregnancy, lamotrigine levels decline due to increased clearance. Thus, a lower threshold for increasing lamotrigine dose, potentially prophylactically and checking blood levels, is warranted during the second and third trimesters.29

Typical Antipsychotics

Reproductive safety of typical or first-generation neuroleptics, such as chlorpromazine, fluphenazine, haloperidol, perphenazine, thioridazine, and trifluoperazine, is supported by extensive data accumulated over the past 50 years, especially from experience in using such agents to treat hyperemesis gravidarum. No significant teratogenic effect has been documented with chlorpromazine, haloperidol, and perphenazine.13 The major malformation rate from the Swedish Medical Birth Register among 576 infants exposed to first-generation antipsychotics was 4.8%, suggesting a modest increase above the baseline malformation rate, but no statistically increased risk was found with any particular drug.30

Use in Pregnancy

In general, the higher- and mid-potency antipsychotics (eg, haloperidol, perphenazine) tend to be recommended clinically because they are less likely to have associated sedative or hypotensive effects.

Atypical Antipsychotics

Although atypical antipsychotics have been available since the mid-1990s and are widely used by reproductiveage women, reliable data regarding the reproductive safety of these compounds remain limited. Thus far, evidence does not demonstrate a “signal” for an increased risk for major malformations or for any specific pattern of abnormalities among atypical antipsychotic–exposed infants, but studies are few.

In a prospective examination of 151 patients, investigators observed no increased risk of malformations or spontaneous abortions in fetuses exposed to atypical antipsychotics (olanzapine (n=60); risperidone (n=49); quetiapine (n=36); and clozapine (n=6)), compared to a non-exposed group.31 According to the Swedish Medical Birth Register, malformation rates among 147 infants exposed to atypical antipsychotics experienced a major malformation rate of 4.1% overall (clozapine, 5.6%; olanzapine, 3.8%; quetiapine, 0.0%; and risperidone, 3.9%].30

Perinatally, atypical antipsychotics may alter birth weight of newborns31 and may increase the risk for gestational diabetes and for cesarean delivery30 while reliable information on neurodevelopmental outcomes is lacking.

Use in Pregnancy

Based upon limited data, patients taking an atypical antipsychotic may choose to replace treatment with a better characterized typical antipsychotic. Those who use atypical antipsychotics should be watched closely for weight gain and gestational diabetes, and the growth rate of their fetus monitored. The National Pregnancy Registry for Atypical Antipsychotics was established in 2008 at Massachusetts General Hospital as the first hospital-based pregnancy registry in America to systematically and prospectively collect data on pregnancy outcomes following exposure to atypical antipsychotics.32

Psychotherapy

While the effectiveness of psychotherapy for mood stability in bipolar disorder during pregnancy has yet to be evaluated, in nonpregnant individuals, psychoeducation, cognitive-behavioral therapy and family interventions33 as well as interpersonal and social rhythm therapy34 are effective in bipolar disorder and offer potential benefit without fetal exposure. Psychotherapy, particularly interpersonal therapy, has been found beneficial in pregnancy for women experiencing unipolar depression.35

Antidepressants

Often used in bipolar disorder, guidelines recommend to only use antidepressants in combination with a mood stabilizer.36,37 Yet, pregnancy studies of polypharmacy are rare and find increased risk of poor outcome with mood stabilizers.17,18 A recent review of antidepressant use in pregnancy states that fetal outcomes associated with antidepressant use are also associated with untreated depression, with examples of fetal growth changes, shorter gestations, short-term neonatal irritability and neurobehavioral changes.38 However, it should be noted that late gestational use of selective serotonin reuptake inhibitor (SSRI) antidepressants is associated with transitory neonatal signs and a low risk for persistent pulmonary hypertension in the newborn.38

Postpartum

Overview

The postpartum is a time of significantly increased risk of severe and psychotic mood episodes in women with bipolar disorder. The postpartum is a critical time for treatment, if not prophylaxis, not just for the mother’s well-being, but for that of her newborn and family as well. Assessment of the mother’s intent to breast-feed is critical to the discussion of treatment postpartum.

Breast-feeding

Inherent benefits of breast-feeding for a mother with bipolar disorder and her infant are weighed against risks of neonatal exposure to psychotropics through breast milk. If a particular medication was effective during pregnancy, it is usually best to avoid switching to an alternative treatment for breast-feeding, if only to avoid exposing the infant to multiple medications.

All psychotropic medications are secreted in breast milk. Although medication exposure for the nursing infant is considerably less than in utero placental transfer39 there is considerable uncertainty regarding the relative safety of particular psychotropic drugs during lactation, and about the degree to which nursing infants are exposed to these medications.13,39 Data regarding drug excretion into human breast milk and infant exposures are rare, and usually limited to small studies of particular agents.

Mood Stabilizers in Lactation

Antiepileptic Drugs

An AAN review reports that carbamazepine and valproate may not penetrate into breast milk in potentially clinically important amounts. Lamotrigine transfers at a greater rate into the breast milk; however, none of the three showed consistent evidence of accumulation in the newborn. Nonetheless, the clinical consequences of ingesting antiepileptic drugs through breast milk on the new born remain unexamined.22

It is advised to check the infant’s LFTs, WBC, and anticonvulsant levels at age 6 weeks, particularly if concerned about the infant’s clinical status or behavior.

Lithium

While lithium passes through breast milk and is measurable at approximately one quarter of the concentration of that in the mother in breast-feeding newborns, a recent study showed no serious adverse events were observed and elevations of thyroid-stimulating hormone, blood urea nitrogen, and creatinine were few, minor, and transient.40 Nonetheless, following maternal and infant lithium levels, infant BUN/Cr and TSH at 6 weeks may be advised, particularly if the infant shows symptoms of lithium exposure.

Antipsychotics

While there are very few reports of infant exposure to first generation antipsychotics by breast milk, no adverse events occurred in most cases.16 In the second generation antipsychotics, olanzapine, in particular, was found in low serum concentrations in nursing infants and had adverse effects.41

Conclusions

Clinicians caring for women with bipolar disorder through the perinatal period should be aware of the clinical complexities they face. Pregnancy is unlikely to be protective against bipolar disorder and postpartum is a time of increased risk of severe mood episodes. Risk for morbidity associated with discontinuation of ongoing maintenance mood stabilizer treatment, particularly abruptly, are likely to be high for both the mother and her baby. Therefore, maintenance pharmacotherapy, in addition to appropriate psychosocial interventions, is recommended. Conceptualizing the care of pregnant and postpartum women with bipolar disorder as high-risk emphasizes the importance of close clinical monitoring and the need for coordinated care among a multidisciplinary team.

References

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Grouped Risk of Mood Stabilizers in Pregnancy for Poor Fetal Outcome

Relative Safety Mood Stabilizer Key Clinical Evidence
Safer Typical Antipsychotics (haloperidol, perphenazine)

Used clinically in pregnancy for over 50 years


Lamotrigine

No increase in teratogenicity

No delay in neurodevelopment

Caution Atypical Antipsychotics

While no major findings, data is limited


Lithium

Absolute risk of cardiac malformation rare

Watch for newborn ‘floppy baby’ syndrome


Carbamazepine

Potential increased risk of cleft lip/palate

Risk of reduced head circumference, lower birth weight and shorter length

Avoid as possible Valproic Acid

Increased risk of multiple malformations

Neurodevolopmentally lower IQ

Sidebar
  • Recognize that risk for relapse in pregnancy is high
  • Streamline regimen; offer minimum effective dose
  • Avoid stopping medications abruptly
  • Continuation of mood stabilizers reduces risk significantly by 2- to 3-fold and reduces maternal morbidity >4 fold
  • Consider differential teratogenic risk across mood stabilizers but also efficacy of mood stabilizer for the individual

Authors

Wendy Marsh, MD, MS, is Assistant Professor, Department of Psychiatry, University of Massachusetts, Worcester, MA. Adele Viguera, MD, MPH, is Associate Professor, Department of Psychiatry and Psychology, Cleveland Clinic Main Campus, Cleveland, OH.

Wendy Marsh, MD, MS, has disclosed no relevant financial relationships. Adele Viguera, MD, MPH, has received grants (payable to her institution) from Astra-Zeneca, Bristol-Myers Squibb, Ortho-McNeil Janssen, Sunovion, and Pfizer.

Address correspondence to: Wendy Marsh, MD, MS, Department of Psychiatry, University of Massachusetts, 361 Plantation Street, Worcester MA 01605; email: wmarsh@ummhc.org

10.3928/00485713-20120507-06

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