Psychiatric Annals

CME Article 

Psychotropic Medications for Bipolar Disorder in Pregnancy

Andrea Favini, MD; Sarah Homitsky, MD

Abstract

Women with bipolar disorder are at high risk for relapse throughout pregnancy and in the postpartum period, especially when mood stabilizer medication is discontinued. Postpartum disruption of circadian rhythms, immune dysregulation, and abrupt fluctuation of reproductive hormones can precipitate postpartum psychosis, a psychiatric emergency with an increased risk of suicide and a 4% risk of infanticide. Fortunately, effective treatments exist for managing bipolar disorder in pregnancy, with the aim of preventing episode recurrence and maintaining function. Risks associated with psychotropic medication in pregnancy must be balanced against risks of untreated bipolar illness. In this review, we present risk profiles of existing treatments for bipolar disorder in pregnancy and breast-feeding, concluding with key evidence-based resources for clinicians and patients. [Psychiatr Ann. 2019;49(9):392–398.]

Abstract

Women with bipolar disorder are at high risk for relapse throughout pregnancy and in the postpartum period, especially when mood stabilizer medication is discontinued. Postpartum disruption of circadian rhythms, immune dysregulation, and abrupt fluctuation of reproductive hormones can precipitate postpartum psychosis, a psychiatric emergency with an increased risk of suicide and a 4% risk of infanticide. Fortunately, effective treatments exist for managing bipolar disorder in pregnancy, with the aim of preventing episode recurrence and maintaining function. Risks associated with psychotropic medication in pregnancy must be balanced against risks of untreated bipolar illness. In this review, we present risk profiles of existing treatments for bipolar disorder in pregnancy and breast-feeding, concluding with key evidence-based resources for clinicians and patients. [Psychiatr Ann. 2019;49(9):392–398.]

Women with bipolar disorder are at risk for illness recurrence in the peripartum period, and discontinuation of psychotropic medication in pregnancy significantly increases relapse risk. In a prospective cohort study of 89 women with bipolar disorder who were euthymic at the time of conception, 85.5% of women who stopped mood stabilizer medications experienced a new mood episode as compared to 37% who continued treatment.1 Women who discontinued medication spent 43.3% of time while pregnant in a bipolar mood episode versus 8.8% of women who continued medication.1

Women with bipolar disorder may be at increased risk for experiencing psychosis in the postpartum period, a severe manifestation of bipolar disorder. Physiologic changes after delivery, including disruption of circadian rhythms, immune dysregulation, and abrupt fluctuation of reproductive hormones, increase vulnerability for psychosis in women with bipolar disorder.2 Although relatively rare, affecting 1 or 2 in 1,000 women, postpartum psychosis is associated with an increased risk of suicide and a 4% rate of infanticide.3

Despite these risks, many women with bipolar disorder choose to discontinue medication in pregnancy, and providers often lack adequate information to guide an informed risk-benefit discussion. Risk associated with medication exposure must be weighed against risk of maternal and fetal exposure to illness. Untreated bipolar disorder in pregnancy has been associated with preterm birth, intrauterine growth restriction, low birth weight, and reduced infant head circumference.4

Background Risk of Congenital Malformations

Major congenital malformations are defined by the European Surveillance of Congenital Anomalies as structural abnormalities that impair viability or require surgical, medical, or cosmetic intervention.5 All pregnant women start with a 3% to 5% chance of having a baby with a birth defect, and congenital heart defects are the most common type of malformation.6 Because maternal obesity, alcohol use, and tobacco exposure independently increase risk for heart defects, clinicians should address these modifiable risk factors in a risk-benefit conversation about psychotropic medications in pregnancy.6

Lithium

Congenital Malformations

Lithium exposure in pregnancy has been associated with an increased risk of congenital heart defects in offspring, yet the strength and nature of this association has been debated. In the 1970s, reports from the International Register of Lithium Babies suggested that Ebstein anomaly, a rare cardiac malformation involving downward displacement of the tricuspid valve, was 400 times more common in infants exposed to lithium in-utero versus their unexposed counterparts.7 This figure has since been criticized due to the registry's retrospective enrollment of voluntarily submitted cases and lack of a control group, suggesting an overestimation of risk. Subsequent studies have consistently shown a lower magnitude of risk, with an estimated 1 to 2 per 1,000 (0.1%–0.2%) cases of Ebstein anomaly in infants exposed to lithium in the first-trimester.8

First-trimester lithium exposure has been associated with increased risk of overall cardiac malformations. If the absolute risk of cardiovascular malformations in unexposed infants is 1.15%, the risk rises to 1.9% in infants exposed to lithium.9 One study reported a dose-dependent effect, with lithium doses >900 mg/day conferring greater risk (corresponding maternal serum lithium levels were not available).9 Further research is needed regarding effects of maternal lithium dose and serum level on risk of fetal cardiac malformations. Importantly, in-utero lithium exposure has not been associated with increased risk of other congenital malformations.

Neonatal Outcomes

Exposure to lithium in pregnancy has not been shown to affect childhood IQ scores.10 Uncommon infant complications after prenatal exposure to lithium have been described in case reports, with no identified incidence. These include transient neonatal hypothyroidism, goiter, and nephrogenic diabetes insipidus.11 Symptoms concerning for neonatal lithium toxicity have also been observed including respiratory issues, hypotonia, tremor, and cardiac arrhythmias.11 As many of these adverse effects are likely dose-related, careful monitoring of maternal serum lithium levels is warranted.

Management During Pregnancy

It is recommended that women taking lithium during the first trimester should undergo high-resolution ultrasound as well as fetal echocardiography at 16 to 18 weeks gestation to evaluate for cardiac malformations.8 Multiple daily dosing is recommended to minimize peak serum lithium levels and reduce teratogenic risk.12 Normal, dynamic changes in glomerular filtration rate throughout pregnancy warrant close monitoring of maternal serum lithium levels; in the first and second trimesters, lithium blood levels decrease by 24% and 36% respectively, with a gradual return to preconception levels in the third trimester and postpartum.12 Guidelines recommend monitoring serum lithium levels frequently (ie, every 3–4 weeks) for the first 34 weeks of pregnancy, then weekly until delivery. Experts recommend holding lithium doses when going into labor or 24 hours before planned delivery to reduce newborn lithium concentration and minimize neonatal complications.12

Folic acid supplementation is recommended to reduce risk of cardiovascular defects associated with lithium exposure; its protective effects involve suppression of the Wnt/beta-catenin signaling pathway that regulates embryonic cardiogenesis.6 There is no current consensus on folic acid supplementation dosing (recommendations range between 1 and 5 mg daily), formulation, or duration of treatment for women taking lithium, and the effects of high doses of folic acid in pregnancy remain unclear. Although some studies associate folic acid with reduced risk of autism spectrum disorder (ASD), others report detrimental effects on fetal neuronal development and increased risk of ASD with excess folic acid supplementation.13

Breast-Feeding

Breast-feeding is supported for women taking lithium. A breast-fed infant's serum lithium level is roughly one-quarter of the maternal level, and available data show that lithium exposure does not negatively affect infant growth or development.14 Because of concerns for toxicity if renal clearance is impaired, infants must be carefully monitored for signs of poor feeding, lethargy, and dehydration, especially within the first week of life. As all newborns are screened for congenital hypothyroidism at birth, pediatricians interpret these results and determine need for follow-up thyroid testing. Routine monitoring of infant lithium level, thyroid-stimulating hormone, creatinine, and blood urea nitrogen is not recommended in the absence of clinical concern for lethargy or dehydration.

Second-Generation Antipsychotics

Congenital Malformations

Since the first systematic review on second-generation antipsychotics (SGAs) in pregnancy was published in 2004, subsequent studies have yielded inconsistent results.15 In 2008, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was created to prospectively gather data on the reproductive safety of SGAs and better quantify risk of congenital malformations.16

In the largest study on antipsychotic exposure and congenital malformations to date, Huybrechts et al.16 analyzed a cohort of 1,341,715 women using Medicaid insurance, including 9,258 women who filled at least one prescription for an SGA in the first trimester (versus 1,331,910 unmedicated controls). After adjusting for psychiatric and neurologic conditions, use of concomitant psychotropic medications, chronic maternal illness, and substance use, first-trimester exposure to SGAs as a class was not associated with increased risk of overall malformations (relative risk [RR] = 1.05; 95% CI, 0.96–1.16) or cardiac malformations (RR = 1.06; 95% CI, 0.90–1.24).16 Quetiapine, aripiprazole, olanzapine, and ziprasidone showed no increased risk when analyzed individually; risperidone, however, was associated with an increased risk of overall malformations (RR = 1.26; 95% CI, 1.02–1.56) as well as cardiac malformations (RR = 1.26; 95% CI, 0.88–1.81).16

Quetiapine is often a favored SGA in pregnancy due to its relatively lower rate of placental passage, defined as ratio of umbilical cord to maternal plasma concentrations measured at delivery. Placental passage rate for quetiapine is 21.4% compared to 72.1% for olanzapine.17 To date, there are no human data published on other evidence-based bipolar disorder treatments such as lurasidone, paliperidone, and iloperidone.

Neonatal Outcomes

In 2011, the US Food and Drug Administration (FDA) updated the pregnancy label for all antipsychotic medications, highlighting risk for transient neonatal extrapyramidal symptoms or withdrawal after third-trimester exposure to antipsychotics.18 This warning was issued after 69 cases of adverse effects were reported to the FDA, with a range of symptoms including hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties.18 Due to lack of maternal and newborn blood samples at the time of delivery, it remains unclear as to whether these symptoms are caused by toxicity or withdrawal. Additionally, most of the 69 infants were exposed to concomitant medications such as antidepressants, benzodiazepines, and opiates, which are independently associated with neonatal withdrawal or poor adaptation.18

Neurodevelopment

Limited data are available on the effects of antipsychotics on neurodevelopment. Because antipsychotics are prescribed for a growing number of diverse indications, it remains difficult to separate effects of maternal illness from inherent effects of psychotropic medication. Johnson et al.19 found that infants with intrauterine antipsychotic exposure (9 exposed to first-generation antipsychotics, 12 exposed to one or more SGA, and only 32% of infants exposed to antipsychotics born to mothers diagnosed with bipolar disorder) scored significantly lower on standardized neuromotor scales at age 6 months compared to infants with intrauterine antidepressant exposure or no psychotropic exposure. More severe maternal psychiatric illness was also associated with suboptimal neuromotor performance.19 Peng et al.20 assessed development of 76 infants with in-utero exposure to SGAs as compared to controls who were not exposed. At age 2 months, infants with fetal SGA exposure scored lower on cognitive, motor, social-emotional, and adaptive behavior measures, yet at 12 months there were no significant differences between groups in any domain, suggesting that initial developmental delay may extinguish over time.20

Management in Pregnancy

Women maintained on SGA therapy in pregnancy are at increased risk of developing gestational diabetes.21 Close monitoring of weight gain and fetal growth as well as routine gestational diabetes screening is warranted.

Because of pregnancy-related changes in the cytochrome P450 system, dosing of SGAs may need to be increased as pregnancy progresses. Induction of CYP3A4 at all stages of pregnancy may result in lower concentrations of aripiprazole, quetiapine, and lurasidone.22 Dose adjustments in pregnancy are best guided by symptom assessment rather than by plasma levels, given the lack of an established therapeutic target for SGAs. Postpartum, the CYP450 system returns to baseline and women can resume pre-pregnancy dosing.

Breast-Feeding

Due to low levels produced in breast milk, quetiapine and olanzapine are preferred SGAs in breast-feeding. Table 1 compares safety of individual SGAs based on relative infant dose calculations.14 Relative infant dose <10% is generally considered safe in breastfeeding, as drug excretion is unlikely to cause adverse effects.14

Safety of Individual Second-Generation Antipsychotics Based on Relative Infant Dose Calculations

Table 1:

Safety of Individual Second-Generation Antipsychotics Based on Relative Infant Dose Calculations

Valproate

Congenital Malformations and Neurodevelopment

Valproate is not recommended in pregnancy given its high teratogenic potential. Valproate exposure in-utero is associated with increased risk of birth defects, with a prevalence of 10.3% for overall congenital malformations.5 First-trimester valproate exposure affects development of several organ systems, leading to neural tube, cardiac, orofacial/craniofacial, skeletal, and limb malformations.11 High-dose folic acid supplementation of 4 mg daily is recommended for reproductive age-women taking valproate to protect against neural tube defects, although this strategy does not completely mitigate risk.

Fetal exposure to valproate is also strongly associated with cognitive deficits, including reduced IQ and impaired ability to process, encode, and learn both verbal and nonverbal material.23 The degree of cognitive impairment observed in children with fetal valproate exposure is great enough to affect educational and adaptive functioning.23 Teratogenic risk of valproate, both for structural defects and cognitive impairment, is observed to be dose-dependent.5,23

Breast-Feeding

Breast-feeding is not contraindicated with valproate monotherapy. Low levels of valproate are produced in breast milk, and exposure does not appear to impact growth and neurodevelopment.14 Given one reported case of thrombocytopenia24 (which resolved on cessation of breast-feeding) and theoretical risk for hepatotoxicity, breast-fed infants exposed to valproate should be monitored for signs of jaundice or bleeding.14

Lamotrigine

Neurodevelopment

Studies from epilepsy literature have consistently shown no adverse impact on IQ in children exposed to lamotrigine in-utero. In the large Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, children of women with epilepsy (exposed to lamotrigine, carbamazepine, phenytoin, or valproate monotherapy in-utero) were observed up to age 6 years, with periodic comprehensive neuropsychological assessments.25 A 2013 NEAD study publication reported no adverse effect on IQ, verbal or nonverbal abilities, memory, or executive function in children with in-utero exposure to lamotrigine, a finding that was replicated in a 2019 NEAD study publication.23,25 The significance of NEAD study findings associating lamotrigine with reduced verbal abilities compared to nonverbal abilities, as well as decreased verbal learning efficiency and lower Attention Concentration Index scores at age 6 years, remains unclear.23,25 Further studies including children of mothers with bipolar disorder are needed to control for effects of epilepsy on fetal neurodevelopment.

Congenital Malformations

In 2008, data published from the North American Antiepilpetic Drug Pregnancy Registry suggested a 10-fold increased rate of oral clefts in infants exposed to lamotrigine in-utero.26 No other study has replicated this finding, including subsequent publications from the same registry with larger sample sizes. It is widely agreed on that the rate of congenital malformations in infants exposed to lamotrigine in-utero (2.9%) is comparable to rates in the general population.5 Risk of congenital anomalies appears to be dose-dependent, as first trimester lamotrigine doses >325 mg/day are associated with higher prevalence of congenital malformations (4.3%) as compared to doses ≤325 mg/day (2.5%).5

Management in Pregnancy

Pregnancy increases clearance of lamotrigine due to estradiol-mediated upregulation of lamotrigine metabolism through uridine diphosphate-glucuronosyltransferase 1A4 (UGT1A4).27 Serum lamotrigine concentration begins to decrease early in the first trimester and reaches a nadir in the middle of the third trimester.27 Checking a serum trough lamotrigine level before conception (or in early pregnancy) can establish a therapeutic baseline and help guide perinatal dose adjustments. Experts recommend increasing lamotrigine dose by 20% to 25% in pregnancy to target worsening symptoms.27 If lamotrigine dose was increased in pregnancy, gradual dose reduction over a 2-week period is necessary to avoid postpartum lamotrigine toxicity.27

Breast-Feeding

Breast-feeding is recommended for mothers maintained on lamotrigine. Exposure to lamotrigine through breast milk does not appear to affect infant growth or development, and most infants have not experienced adverse effects. No case of Stevens–Johnson syndrome has been reported in infants exposed to lamotrigine in breast milk. There is one report of a 16-day-old infant who experienced two brief apneic episodes; this adverse event was likely caused by exposure to toxic levels of lamotrigine via breast milk, as the mother experienced signs of toxicity herself and was taking a lamotrigine dose of 850 mg daily.27 Given variability in levels of lamotrigine produced in breast milk and immature neonatal hepatic metabolism, monitoring of infant serum levels to rule out toxicity should be considered in case of lethargy or poor feeding.27

Carbamazepine and Oxcarbazepine

Congenital Malformations and Neurodevelopment

The prevalence of overall congenital malformations with carbamazepine therapy is 5.5%, with increased risk at doses >700 mg/day.5 Carbamazepine exposure is associated with orofacial cleft, craniofacial, neural tube, cardiac, and urinary tract malformations as well as fingernail hypoplasia.11 Several studies suggest an association between fetal carbamazepine exposure and cognitive impairment such as reduced verbal abilities and lower IQ, yet to a lesser degree than seen in children exposed to valproate in-utero.23

Data on oxcarbazepine are limited but reassuring, as rates of congenital malformations appear similar to the general population.5 Further studies are needed evaluating neurodevelopmental effects.

Breast-Feeding

Relatively high levels of carbamazepine are produced in breast milk, and while most infants do not experience adverse effects, transient cases of cholestasis and hepatic dysfunction have been reported.14 Oxcarbazepine is not expected to cause adverse effects in breast-fed infants, but human data are limited to one case report.14

Benzodiazepines

Neonatal Outcomes

Studies examining risk of adverse obstetric and neonatal outcomes with in-utero benzodiazepine exposure present mixed results. Findings from a large prospective cohort study associated maternal benzodiazepine use in pregnancy with increased risk of cesarean delivery, low birth weight, and neonatal respiratory distress measured by need for newborn ventilator support.28 Although a subsequent study showed no risk of respiratory distress, infants with in-utero benzodiazepine exposure were more likely to have small head circumferences and require admission to a neonatal intensive care unit.29

In a case series of 38 women who took clonazepam during pregnancy, the majority of neonates did not experience toxicity or withdrawal symptoms.30 There were two separate complications (hypotonia and respiratory distress) reported in infants exposed to both clonazepam and imipramine.30 Further investigation is needed to stratify risks based on timing of exposure, as well as to disentangle effects of benzodiazepines from that of underlying psychiatric illness and concurrent psychotropic medications.

Congenital Malformations

Although early studies suggested an increased risk of cleft lip and palate with exposure to benzodiazepine in the first trimester, accumulated data show no clear increased risk of facial clefts or overall malformations.31

Breast-Feeding

Lorazepam is the preferred benzodiazepine in breast-feeding, given low levels produced in breast milk, short half-life, and lack of adverse effects in breast-fed infants with typical dosages.32 As clonazepam exposure can occasionally cause sedation in breastfed infants, avoiding exposure to concurrent sedating medications as well as monitoring infants for drowsiness is recommended.33

Conclusion

The risks associated with untreated bipolar illness in pregnancy may outweigh risks of medication. Table 2 includes additional resources to guide pharmacologic management of bipolar disorder in pregnancy. Nonpharmacologic treatments, such as adjunctive midday bright light therapy for bipolar depression and electroconvulsive therapy for treatment-resistant mood episodes, can also be considered as safe and effective options in pregnancy. Physicians can help guide patients through the decision-making process by sharing information related to risk of untreated bipolar illness in the perinatal period, by reviewing potential risks of medication exposure in pregnancy and lactation, and by considering a patient's own illness course, risk factors, and preferences to reach an informed and collaborative plan for treatment.

Perinatal Mental Health Resources for Clinicians and Patients

Table 2:

Perinatal Mental Health Resources for Clinicians and Patients

References

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Safety of Individual Second-Generation Antipsychotics Based on Relative Infant Dose Calculations

SGA Relative Infant Dosea
Quetiapine Low: 0.09% – 0.43%
Olanzapine Low: 0.3% – 4%
Risperidone Acceptable: 2.3% – 4.7%
Aripiprazole Data limited: RID not available
Ziprasidone Data limited: RID not available

Perinatal Mental Health Resources for Clinicians and Patients

Resource Description
MotherToBaby (a service of the Organization of Teratology Information Specialists) Information on exposures in pregnancy and breast-feeding Free fact sheets on risks of medications, herbal products, medical conditions, and substances of abuse <ext-link ext-link-type="uri" xlink:href="https://www.mothertobaby.org" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">https://www.mothertobaby.org</ext-link> (email and chat options available) Phone consultation with an expert: 866-626-6847
Reprotox (a database of summaries on reproductive effects of medicines, chemicals, and biologics) Comprehensive summaries on available scientific literature Information on membership at <ext-link ext-link-type="uri" xlink:href="https://www.reprotox.org" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">https://www.reprotox.org</ext-link>
LactMed (a free drug and lactation TOXNET database) <ext-link ext-link-type="uri" xlink:href="https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm</ext-link>
National Pregnancy Registry for Atypical Antipsychotics-Massachusetts General Hospital Enrolling pregnant women age 18–45 years taking atypical antipsychotics as well as controls <ext-link ext-link-type="uri" xlink:href="https://womensmentalhealth.org/research/pregnancyregistry/" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">https://womensmentalhealth.org/research/pregnancyregistry/</ext-link>
Authors

Andrea Favini, MD, is an Attending Psychiatrist. Sarah Homitsky, MD, is the Medical Director. Both authors are affiliated with Women's Behavioral Health, Allegheny Health Network.

Disclosure: The authors have no relevant financial relationships to disclose.

Address correspondence to Andrea Favini, MD, 4800 West Penn Hospital, Suite N1, Pittsburgh, PA 15224; email: andrea.favini@ahn.org.

10.3928/00485713-20190808-02

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