Striking the Balance: Bipolar Disorder in the Perinatal Period
Abstract
The authors reviewed the literature, published between 2018 and 2023, on treating bipolar disorder in the perinatal period in order to summarize current treatment perspectives. Mood episodes occur during pregnancy and there are high rates of both initial onset and recurrence in the postpartum period. Bipolar disorder itself is associated with higher risks of adverse pregnancy outcomes, including gestational hypertension, hemorrhage, cesarean delivery, and small for gestational age infants. A general principle of perinatal treatment includes maintaining psychiatric stability of the pregnant person while reducing medication exposure risk to the fetus. A variety of factors can compromise psychiatric stability, including rapid discontinuation of stabilizing medications, decreased efficacy due to physiologic changes of pregnancy, and exacerbation of underlying psychiatric illness. Psychosocial interventions include optimizing sleep, increasing support, and reducing stress. The American College of Obstetricians and Gynecologists recommends against discontinuing or withholding medications solely due to pregnancy or lactation status. Individualized treatment involves a discussion of the risks of undertreated bipolar disorder weighed against the risks of individual medication choice based on available evidence regarding congenital malformations, adverse neonatal and obstetrical events, and neurodevelopmental outcomes. Valproate is not a first-line treatment due to higher risks. Data are lacking on safety for many newer medications. The authors review current safety data regarding lithium, lamotrigine, and antipsychotics, which are the most commonly used treatments for managing bipolar disorder in the perinatal period. Due to physiologic changes during pregnancy, frequent therapeutic drug monitoring and dose adjustments are required.
Bipolar disorder is characterized by episodes of mania, hypomania, and depression that significantly affect functioning. The “Bipolar and Related Disorders” chapter of DSM-5 categorizes bipolar disorder into subtypes: bipolar I, bipolar II, cyclothymia, bipolar disorders that are substance induced or due to a general medical condition, and other specified bipolar and related disorders. Bipolar I requires an episode of mania, whereas bipolar II requires an episode of hypomania as well as an episode of major depression. The peripartum onset specifier can be applied to the most recent mood episode if onset began during pregnancy or within 4 weeks of parturition (1), although some advocacy groups argue for an extension up to 1 year based on psychosocial factors.
Epidemiology and Natural History
The prevalence of bipolar spectrum disorders is approximately 2.4% among adults. More than half of individuals diagnosed as having bipolar disorder have three or more comorbid mental health conditions (2).
In adolescents, bipolar disorder is associated with a 20 times higher risk of early pregnancy and 25 times higher risk of repeated early pregnancy, even after adjusting for confounding factors. However, long-term use of mood stabilizers and second-generation antipsychotics can help reduce this risk (3).
The impact of pregnancy on the course of bipolar disorder is not well understood due to limitations in study design and use of medication. Discontinuation of medication during pregnancy leads to a twofold increased risk of relapse, shorter time to recurrence, and more symptomatic weeks; however, this risk is not greater than in periods outside of pregnancy, and thus it is not clear whether higher rates of relapse are due to the pregnancy state itself (4). Recent research indicates risk of bipolar disorder recurrence during pregnancy, with rates ranging from 4% to 73% (5, 6). A systematic review found that pregnant individuals with bipolar disorder are more likely to experience depressive or mixed episodes rather than hypomanic or manic episodes (7).
There is consistent evidence of high rates of both initial onset and recurrence of bipolar disorder in the postpartum period (8). In a meta-analysis of over 3,000 patients diagnosed as having bipolar disorder, the postpartum recurrence rate was 35% (6). Another study reported that 30% of pregnant individuals diagnosed as having bipolar disorder experienced an episode postpartum (9). A history of bipolar disorder is linked to a greater risk of psychiatric hospitalization in the postpartum period (10). Additionally, individuals diagnosed as having bipolar disorder during the perinatal period faced an increased risk of experiencing postpartum suicidality (11).
The immediate postpartum period is a critical time of heightened risk for both mania and psychosis, with most episodes occurring within 4–6 weeks of the birth (9, 11). Pregnant individuals diagnosed as having bipolar I disorder are more likely to experience postpartum mania or psychosis compared with bipolar II disorder, with rates as high as 23% reported for this group (12).
A subsequent diagnosis of bipolar disorder is more common when the initial presentation involves postpartum psychotic symptoms. Up to 69% of pregnant individuals who experience postpartum psychosis as their initial psychiatric episode are likely to develop bipolar disorder, with a minority experiencing isolated postpartum psychosis (13). Prophylactic treatment during pregnancy has proven benefits, as individuals who used such medications experienced a significantly lower rate of relapse compared with those who did not take any medication (6).
There is growing evidence that affective episodes have unique characteristics within the perinatal period, because childbirth may act as a “pathoplastic trigger” that modifies the presentation of bipolar disorder. A small within-subjects retrospective study demonstrated differences in manic episodes during the postpartum period compared with others outside of this period where mania presented with mixed features, characterized by more depressive symptoms, guilt and confusion, and fewer “classic” manic symptoms such as pressured speech and increased sociability (14). With respect to depressive episodes, postpartum bipolar depression has been associated with atypical depressive symptoms, mixed features, and psychotic features (10). Another study reported that an initial bipolar disorder depressive episode occurring in the postpartum period had a more favorable course of illness, characterized by fewer suicide attempts and depressive episodes (15).
Bipolar disorder is associated with higher risks of adverse pregnancy outcomes, including preterm birth, cesarean section, small for gestational age, gestational hypertension, and hemorrhage. Pregnant individuals diagnosed as having bipolar disorder who undergo cesarean section are more likely to experience pregnancy complications and comorbid hypothyroidism (10, 15–17). A study of 174 mother-infant pairs revealed that pregnant individuals diagnosed as having bipolar disorder who did not receive medication during pregnancy had infants with smaller head circumferences compared with both treated pregnant individuals and healthy individuals. This finding remained significant even after considering potential confounding factors (18).
In summary, mood episodes occur during pregnancy, have a high rate of recurrence in the postpartum period, and are associated with adverse pregnancy outcomes. Adequate treatment may reduce these risks.
Biopsychosocial Underpinnings
The underlying etiology of bipolar disorder in the general population is still being elucidated, but it is highly heritable and thought to involve complex interactions between genetic background, environmental exposures, and epigenetic changes (19, 20). Several risk factors during pregnancy have been identified as potential triggers for the development of bipolar disorder in offspring, including peripartum asphyxia, maternal stress, obstetric complications, and low birth weight (21).
Regarding bipolar disorder in the perinatal period, family history is a strong risk factor for postpartum mood changes, although the utility of genetic risk scores remains inconclusive (22). For individuals with a previous diagnosis of major depressive disorder, a family history of bipolar disorder was the strongest risk factor for a diagnostic change peripartum from major depressive disorder to bipolar II disorder, with switch rates up to 11-fold higher than outside the peripartum period (23). A history of perinatal affective psychosis or depression is a significant risk factor for recurrence during subsequent pregnancies with similar clinical presentation and timing (9, 11). Primiparity is also a risk factor for development of manic or psychotic depression, with 35% risk after a first pregnancy, 20% after a second, and 14% after a third (24). Sleep loss, hormonal shifts, and immunological changes are believed to contribute to the altered course of bipolar disorder and increased susceptibility to episode recurrence in the postpartum period (25).
Assessment and Differential Diagnosis
Accurate diagnosis of bipolar disorder in the peripartum period requires a thorough assessment of lifetime history of manic, hypomanic, and depressive episodes. In addition to a comprehensive diagnostic interview, initial screening with tools like the Edinburgh Postnatal Depression Scale and Mood Disorder Questionnaire can be useful (26). Assessment involves examining symptom patterns in previous pregnancies, family history of bipolar disorder, peripartum mood disorders, and symptoms of postpartum psychosis. In addition to the typical differential diagnosis for bipolar disorder, one must also consider unique perinatal psychiatric and medical conditions (13, 27–30) (see Box 1).
BOX 1. Differential diagnosis for bipolar disorder in the postpartum period (13, 27–30)
Baby blues (self-limited mood symptom that resolves within 2 weeks without functional impact)
Postpartum depression
Postpartum obsessive-compulsive disorder
Postpartum anxiety
Postpartum psychosis
Trauma- and stress-related disorder or posttraumatic stress disorder
Postpartum autoimmune exacerbation
Limbic encephalitis
Postpartum thyroid dysfunction
Postpartum hypopituitarism caused by necrosis of the pituitary gland
Medication-induced mood episode
Substance misuse or substance use disorder
Similar to diagnosing bipolar disorder across the lifespan, it can be challenging to differentiate between acute episodes of bipolar depression and unipolar depression on the basis of clinical presentation alone. However, a pregnant person who is experiencing a first episode of depression during the postpartum period is more likely to have a family history of bipolar disorder. Detecting a postpartum depressive episode should prompt closer evaluation for potential bipolar spectrum illness (12). Additionally, special consideration should also be given to postpartum psychosis, which is a severe mood disorder that develops suddenly after childbirth. Postpartum psychosis is often characterized by mania or a mixed mood episode and may herald the onset of bipolar spectrum illness (25).
Treatment and Outcomes
General Approach
Preconception.
We recommend discussing pregnancy intentions with all patients who are capable of becoming pregnant. For patients not currently considering pregnancy, discussions of contraception should include reviewing interactions of contraceptives with current medications and the impact of contraceptive choice on mood (31, 32).
For patients who intend to become pregnant, preconception counseling involves a thorough review of psychiatric and medication history, followed by a careful risk-risk discussion (33). An optimal plan preconception would be individualized on the basis of the patient’s prior history but would, when possible, avoid medications, such as valproic acid, that have a high risk of teratogenicity (34).
Continuing medication during pregnancy reduces the risk of recurrence of bipolar disorder (35). In one study, the most common reasons for stopping or switching medications after a consultation were fear of teratogenicity, followed by antipsychotic-induced hyperprolactinemia. One-year outcomes revealed that adjustments to lower risk medications did not result in significant illness decompensation (36). Table 1 shares resources that may be helpful for patients, physicians, and other health care professionals in making these decisions.
| Medical professional–specific resources | Resources for both patients and medical professionals |
|---|---|
| National Library of Medicine Drugs and Lactation Database (LactMed): https://www.ncbi.nlm.nih.gov/books/NBK501922 | National Maternal Mental Health Hotline: 1-833-943-5746 |
| Postpartum Support International: Free consult line available to medical professionals who have mental health care questions regarding pregnant or postpartum patients and preconception planning: https://www.postpartum.net/professionals/perinatal-psychiatric-consult-line | Postpartum Support International Helpline: 1-800-944-4773, www.postpartum.net |
| Hale’s Medications & Mother’s Milk textbook or app for purchase: http://www.infantrisk.com | MGH Center for Women’s Mental Health: Blog and topic reviews on reproductive mental health topics: https://www.womensmentalhealth.org |
| Reprotox—subscription service summarizes literature on medications in pregnancy: https://reprotox.org | Mother to Baby Program, Organization of Teratology Information Specialists (OTIS)—Patient-focused fact sheets on specific medications: http://mothertobaby.org |
| National Curriculum in Reproductive Psychiatry: Interactive curriculum designed to teach reproductive psychiatry to mental health professionals: https://ncrptraining.org | Lifeline for Moms: Toolkits and other resources: https://umassmed.edu/lifeline4moms |
| Royal College of General Practitioners Perinatal Mental Health Toolkit: Focus for U.K. physicians | Best Use of Medication in Pregnancy: Patient tracking and leaflets from U.K. teratology: https://www.medicinesinpregnancy.org |
Pregnancy.
A key principle in treating bipolar disorder during pregnancy is maintaining psychiatric stability of the pregnant person while minimizing medication exposure to the fetus. Psychiatric stability can be compromised by a variety of factors, including abrupt discontinuation of medication, decreased efficacy due to physiologic changes of pregnancy, and exacerbation of underlying psychiatric illness. When assessing medication risks, consider timing of medication exposure, evidence regarding outcomes (e.g., congenital malformations, adverse obstetrical and neonatal events, and neurodevelopmental outcomes), and the compounded risk from multiple medication exposures. The American College of Obstetricians and Gynecologists recommends against discontinuing or withholding medications solely due to pregnancy or lactation status (37). If a patient lacks decision-making capacity, it is critical to seek multidisciplinary and ethics consultation and to identify a surrogate decision maker if the patient cannot be restored to capacity in a timely manner (38).
Discussion about the risk of congenital malformations primarily focuses on medication exposures during the first trimester of pregnancy, as formation of major organ systems in the fetus is completed within this period. When assessing individual risk of a medication, consider the risk of malformations relative to the baseline incidence of major malformations of newborns (2%–4% in the United States) (39, 40). Adverse neonatal events encompass a diverse range of physical and behavioral symptoms observed in newborns that are related to drug exposure near the time of delivery. Lastly, it is important to carefully assess the available evidence regarding the potential for adverse neurodevelopmental outcomes in the infant including cognitive deficits and development of behavioral disorders associated with medication exposure (40, 41). Research in this field is constantly evolving, and further studies are required to better understand the relationship between medication exposure during pregnancy and its impact on exposed infants. These risks must be weighed relative to the risk of psychiatric instability for each pregnant individual. Table 2 describes a framework for the risk-risk discussion.
| Risks of untreated or undertreated bipolar disorder in pregnancy and (or) lactation | Considerations regarding medication choice |
|---|---|
| Risk of recurrence of mood episodes | Timing of medication exposure in pregnancy and lactation |
| | Treatment response to prior medication trials |
| Risk of adverse obstetrical outcomes related to untreated psychiatric illness | Compounded risk from multiple medication exposures |
| Risks of severe psychiatric outcomes including hospitalizations, suicide attempts and self-injury, risk of harm to the infant, legal system involvement, functional impairment | Considerations re: individuals’ medication exposure during pregnancy: risk of congenital malformations, risk of adverse neonatal events, risk of adverse obstetrical outcomes, risk of adverse neurodevelopmental outcomes |
| Risk for child protection concerns and parent-child relationship disruption due to psychiatric illness | Considerations re: medication exposure during lactation: health status of the infant, frequency of breast feeding, drug dosage, metabolism, and frequency of ingestion, pharmacokinetic properties of the medication, relative infant dose (RID), severity of adverse drug reaction |
Lactation.
The decision to breastfeed is complex for individuals who have a diagnosis of bipolar disorder. The potential impact of sleep deprivation that results from breastfeeding on psychiatric stability must be weighed in the context of the availability of parental support, benefits of breastfeeding for the infant-parent dyad, personal preferences regarding breastfeeding, health status of the infant and parent, and exposure risk to the infant of medications excreted in breast milk.
During pregnancy, drug concentration in fetal serum is similar to the therapeutic concentration in maternal serum. In contrast, the amount of drug exposure to the infant through breast milk is typically significantly reduced compared with the drug exposure to the infant during pregnancy (42).
All psychotropic medications are secreted into breast milk to a certain extent and most are hepatically metabolized; however, the concentrations of individual medications can vary significantly. Several factors—including dosage, frequency of medication ingestion and breastfeeding, parental drug metabolism, pharmacokinetic properties of the medication, and timing of medication exposure in the life of the infant—can influence medication exposure risk. Newborns and premature infants are more susceptible to medication effects due to their lower capacity for hepatic drug metabolism (40, 42).
The relative infant dose (RID) is a measure that is used to calculate the percentage of a weight-adjusted dose of a drug that an infant receives through breast milk. A reference range of 5%–10% is commonly used to determine the acceptable level of drug exposure to the infant through breast milk and assess likely risk of adverse drug reactions. Additionally, available data for an individual medication exposure during breastfeeding and severity of specific potential adverse drug reactions (e.g., respiratory depression vs. gastrointestinal distress) should also be considered when evaluating overall risk (42, 43). Decision making regarding lactation involves a nuanced discussion regarding the impact of breastfeeding on psychiatric stability, health benefits for parent and infant, and infant exposure to medication.
Psychosocial Treatments
Preserving a euthymic state is a primary treatment goal, with a focus on preserving sleep, providing psychoeducation, increasing social support, and reducing parental stress. Addressing discomfort and modifying sleep positions can improve sleep during pregnancy. Postpartum, enlisting support for infant care to prioritize longer stretches of uninterrupted sleep (ideally up to 4 hours) is critical. For breastfeeding parents, this may include pumping breast milk so that a support person can provide feeds to the infant while the lactating parent rests (42). A lactation consultant may be able to assist with developing sleep schedules to promote both sleep preservation and breastfeeding goals. Psychosocial interventions such as cognitive-behavioral therapy, interpersonal psychotherapy, and mindfulness-based cognitive therapy have some evidence in reducing symptoms and improving outcomes in perinatal people diagnosed as having major depressive disorder and those diagnosed as having bipolar disorder outside of the perinatal period (44–46). Interpersonal and social rhythm therapy is particularly notable as an adjunctive treatment for bipolar disorder, focusing on resolving interpersonal problems and stabilizing daily and nightly routines, including sleep patterns (47). Although potentially costly, options such as doulas and newborn night nurses provide valuable respite as well as emotional, physical, and educational support to families during the peripartum period.
Pharmacotherapy
Lithium, anticonvulsants, and second-generation antipsychotics (SGAs) have U.S. Food and Drug Administration (FDA) indications for the treatment of bipolar disorder. Here we review medication treatment exposure risks based on teratogenicity, obstetrical outcomes, neonatal outcomes, long-term effects, and outcomes through breast milk exposure for a broad range of medications used to treat bipolar disorder. Valproic acid and carbamazepine are not included because they are not first-line agents and carry high risks in pregnancy (48). Electroconvulsive therapy, transcranial magnetic stimulation, and light therapy are all treatment options that have no significant risks perinatally and may be underutilized (49–54). We focus our discussion on lithium, lamotrigine, and the SGAs.
Lithium
Lithium demonstrates efficacy for both acute and maintenance treatment of mania and depression, and for its antisuicidal properties (55). There is a growing body of evidence that supports its role in preventing postpartum psychosis in high-risk perinatal patients (56, 57). Lithium’s therapeutic efficacy in maintaining mood stability during pregnancy and postpartum for individuals diagnosed as having bipolar disorder has been extensively supported by meta-analytic data and a recent large-scale cohort study, which demonstrates a significant decrease in perinatal episodes compared with non-use (26.4% vs. 46.7%) (6, 9).
Teratogenicity.
Lithium crosses the placenta, resulting in fetal exposure (56). Initial reports suggested a 400-fold higher occurrence of congenital heart defects, particularly Ebstein’s anomaly. However, subsequent studies have challenged these findings, and highlight methodological limitations, including the underlying illness as a confounding factor (58, 59). Contemporary large-scale studies, including a cohort of over 1.3 million pregnancies, have shown a slightly increased risk ratio of 1.65 for cardiac malformations with first-trimester lithium exposure, equivalent to one to two additional cases per 100 exposures, which is much lower than previously reported. The study also found that daily doses over 900 mg are associated with a 3.22-fold escalation in risk compared with a 1.11-fold increase with doses under 600 mg (60). Although subsequent meta-analyses did not find a significant difference in the rate of cardiac malformations, a low overall increase in malformation risk was observed (55, 59). A recent, smaller Swedish study, after adjusting for psychiatric illness, also found an association with cardiac malformation, but relied on dispensed prescriptions without verifying actual consumption (61). Further research is needed to inform individualized risk-benefit assessments for lithium use in the first trimester, including evaluating dose-reduction strategies while considering the risk of recurrence.
Obstetrical outcomes.
Lithium use in pregnancy is not associated with an increased risk of pre-eclampsia, gestational diabetes, preterm birth, low birth weight, or postpartum hemorrhage when compared with disease-matched control subjects (55, 59, 62). However, smaller studies have suggested a potential higher risk of spontaneous abortion (63, 64) and an increased risk of spontaneous preterm birth and birthing a large for gestational age infant (61, 65). There are case reports of polyhydramnios (56).
Neonatal outcomes.
Risks to the neonate include reversible neonatal hypothyroidism, goiter, nephrogenic diabetes insipidus, and cardiac arrhythmias (66). Infants with high lithium concentrations at birth may experience respiratory difficulties, hypotonicity, poor suck and grasp, lethargy, and tremor, with symptoms typically resolving within 1–2 weeks without intervention (58). Infants showing signs of toxicity may require intensive monitoring. Lithium exposure during pregnancy has been linked to lower Apgar scores and higher rates of neonatal hospital admission (55, 62, 67). No association with neonatal lithium levels at delivery and neonatal outcomes were found when levels were maintained within the therapeutic window (68).
Long-term effects.
Current evidence on long-term effects of lithium exposure is reassuring. In utero lithium exposure was not found to adversely affect IQ scores (69), nor has it been found to significantly alter neuropsychological functioning in children or changes in brain structure when compared with matched controls (70, 71). A potential negative association between lithium exposure and subcortical brain volume was observed in the Poels et al. (72) MRI study, however, the authors note that it was likely underpowered.
Lactation.
Breastfeeding while on lithium therapy is a topic of consideration for clinically stable lactating patients diagnosed as having bipolar disorder. It has an RID of 0%–30% (73, 74). Small studies and a recent larger one by Heinonen et al. (75) of 30 breastfed infants found no severe adverse events, with infant serum concentrations below 0.2 mmol/L after 1 month of age (74–76). In situations in which the infant has dehydration, prematurity, or impaired renal function, adverse events have been reported (77). Monitoring of infants who are exposed to lithium through breast milk should include assessments of lithium levels, thyroid, and blood urea nitrogen, with varying recommendations on timing and frequency (75, 78). We recommend close clinical monitoring for lethargy, decreased muscle tone, inadequate weight gain, coordination with the infant’s pediatrician, and education on recognizing signs of dehydration (71, 77).
Management during pregnancy.
The preconception period is an important time to consider medication adjustments for patients who are taking lithium and are planning pregnancy. For those who are clinically stable for 4–6 months, have a low risk of relapse, and wish to have a medication-free pregnancy, a gradual tapering of their lithium prior to conception may be appropriate (79). National Institute for Health and Care Excellence (NICE) guidelines discourage lithium use in the first trimester, except when antipsychotic medications are ineffective and after thorough risk-benefit discussions (79). Some physicians may choose to lower the dose below 900 mg given higher risk for teratogenicity, whereas in other circumstances, lowering the dose may put the person at too great a risk for decompensation. Developing a personalized treatment plan, including baseline serum lithium levels and thyroid function, allows for managing treatment effectively during pregnancy (79).
During pregnancy, lithium clearance increases by 30%–50%, which can impact serum levels and increase the risk of relapse (62, 80). We recommend monitoring lithium levels every 3–4 weeks from early pregnancy and increasing the frequency to weekly starting at 34 weeks gestation (68, 77). Split dosing of lithium is favored over once-daily dosing to avoid toxic levels and minimize the potential for teratogenic effects (81, 82). Steady-state serum concentrations should be measured at 12 hours after dosing, while those on once-daily dosing should be evaluated at 24 hours to prevent overestimations (81).
The practice of withholding or reducing the dose of lithium 24–48 hours before a scheduled cesarean section or at the onset of labor to minimize the risk of neonatal toxicity is controversial; some experts discourage this approach in order to maintain therapeutic levels and prevent relapse. Close monitoring of lithium levels around the time of delivery and appropriate fluid management is recommended. Consider reducing the dose to pre-pregnancy levels immediately postpartum and obtaining lithium blood levels approximately 24–48 hours after delivery, followed by biweekly monitoring with dose adjustments as needed. Maintaining a target therapeutic lithium blood level of 0.8–1.0 mmol/L immediately after delivery and during the first month postpartum is important, as relapse risks are highest during this period. It is also crucial to avoid nonsteroidal anti-inflammatory and nephrotoxic medications while taking lithium (68, 77, 83, 84).
Lamotrigine
Lamotrigine is approved by the FDA for the treatment of bipolar depression and maintenance treatment of bipolar disorder and is considered to be a rising first-line option for bipolar disorder treatment during pregnancy, particularly for individuals who have a higher prevalence of depressive episodes (85, 86). Studies suggest that lamotrigine is effective in preventing symptom relapse during pregnancy and the postpartum period (82, 86).
Teratogenicity.
Recent data have provided reassurance regarding the potential teratogenic risks associated with lamotrigine use during pregnancy. Although early findings from the North American Antiepileptic Drug Registry suggested a slight increased risk of oral clefts in infants who are exposed to lamotrigine during the first trimester (87), subsequent population-based case-control research involving 10.1 million births found no significant association between lamotrigine use in pregnancy and overall malformation, including no elevated risk of cleft palate (88). These results are consistent with multiple international registries, which similarly reported no increased risk of malformations associated with first-trimester lamotrigine exposure (89–91).
Obstetrical outcomes.
Meta-analytic data indicate that there is no evidence of increased rates of spontaneous abortions, stillbirths, preterm deliveries, or infants classified as small for gestational age associated with lamotrigine exposure during pregnancy (92).
Neonatal outcomes.
No adverse neonatal effects have been linked to lamotrigine use during pregnancy (58).
Long-term effects.
Multiple studies have consistently shown that lamotrigine exposure during pregnancy is not associated with adverse neurodevelopmental outcomes or significant concerns regarding cognitive scores (58, 93, 94). The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study further supports these findings, indicating that lamotrigine does not result in worse neurodevelopmental outcomes in children at 2 years of age (95).
Lactation.
Infant plasma levels of breastfed infants of lactating parents who are taking lamotrigine range from 23% to 50% of maternal levels, with an estimated RID of 9.2% and a mean infant serum lamotrigine concentration of 1.6 mg/L (96–100). There are case reports of an infant with severe apnea linked to high maternal lamotrigine dosage and another infant with severe hypernatremic dehydration from a mother on multiple medications including lamotrigine (101, 102). With these exceptions, most case reports and larger case series indicate that infants breastfed by mothers who are taking lamotrigine generally do not experience serious adverse events and exhibit normal development, with no observed cases of rash or Stevens-Johnson syndrome (103). Further research is needed to fully understand the safety of lamotrigine in nursing infants, but current evidence suggests a low risk of adverse events, which provides reassurance to lactating patients who are taking lamotrigine.
Management during pregnancy.
Lamotrigine metabolism primarily occurs via glucuronic acid conjugation in the liver, with estradiol levels during pregnancy leading to increased clearance and decreased serum concentrations of lamotrigine (104). The metabolism of lamotrigine increases from early gestation to the third trimester, followed by a sharp decline in the first 2 weeks postpartum (83). Obtaining a preconception trough serum level can guide dosage adjustments during pregnancy. Monthly monitoring and dose increases of 20%–25% to maintain the baseline level or address clinical symptoms is recommended mirroring management for seizure control (104). In the absence of a preconception reference level, dosage adjustments or addition of other mood stabilizers may be based on clinical presentation (105). Postpartum, a reduction of 25% is suggested, with further decreases until reaching the pre-pregnancy dose while monitoring to prevent toxicity (83, 106). Symptoms of lamotrigine toxicity include dizziness, ataxia, and blurred vision, and preliminary evidence supports the use of split daily dosing during pregnancy (107).
Antipsychotics
Aripiprazole, olanzapine, and quetiapine are commonly prescribed SGAs in the perinatal period for maintenance and acute mania treatment of bipolar disorder, as well as psychotic illnesses. The first-generation antipsychotics (FGAs) generally prescribed in pregnancy are haloperidol, chlorpromazine, and perphenazine, and have among the best understood reproductive safety risks. In infants who have been exposed to haloperidol in utero, the major congenital malformation rates do not differ statistically (108) when compared with the general population. FGAs have among the best understood safety risks in pregnancy and will be the treatment of choice for some as a result. Given the change in prescribing patterns with more SGAs typically prescribed for bipolar disorder than FGAs, we will primarily focus on the older SGAs in this section. Newer SGAs, including lumateperone, cariprazine, lurasidone, and asenapine, have limited data regarding their safety in the peripartum period.
Teratogenicity.
SGAs are known to pass through the placenta (109). One large study indicated that first-trimester use of antipsychotics does not meaningfully increase the risk for congenital malformations, overall, or cardiac malformations, in particular (108). A small increase in the risk of cardiac malformations observed with risperidone requires additional study; however, it is important to note the absolute risk is low (110). A previous study showed that olanzapine use may be associated with an increased, statistically significant risk, but low absolute risk of major congenital malformations, specifically musculoskeletal. That study recommended that use during pregnancy should be restricted to situations in which no safer alternatives exist (111). One newer study showed that there were no specific patterns of malformations with lurasidone and quetiapine, and they did not appear to be teratogens; however, further research is needed (112). Additionally, newer data have shown olanzapine to be safer in pregnancy than previously thought, with no major malformations associated with olanzapine exposure in the first trimester (113).
Obstetric risks and maternal outcomes.
Individuals who are diagnosed as having psychiatric disorders have a higher risk of obesity than the general population, and some data show that patients who are exposed to SGAs begin pregnancy with higher body mass indexes (BMIs) than those who are unexposed (114). The continued use of olanzapine and quetiapine during pregnancy has shown to be associated with an increased risk of gestational diabetes (114). The use of SGAs, in general, may predispose pregnant individuals to hyperglycemia, and therefore risk for increased rates of maternal gestational diabetes (115).
Neonatal risks and infant outcomes.
There are limited data regarding the development of infants with prenatal exposure to antipsychotic medications. In a recent cohort study, findings suggested that prenatal FGA or SGA exposure did not increase the risk of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, preterm birth, or small for gestational age infants (116). One prospective study showed that infants who are exposed to SGAs in pregnancy showed no significant differences compared with unexposed infants at 2 months of age for cognitive, motor, and social-emotional functioning, or for language (117). Most recently, a birth cohort study of 3.4 million children found no meaningfully increased risk of neurodevelopmental disorders for prenatal antipsychotic exposure, with the possible exception of exposure to aripiprazole (118).
Lactation.
Historically, only quetiapine and olanzapine have been regarded as “acceptable” for use during breastfeeding (119). A comparative systematic review in 2016 that included breastfed infants exposed to SGAs showed the following: no olanzapine was detected in almost any of the samples, and quetiapine was not detected in any samples for patients who were taking 75 mg or less (120). Risperidone was excreted at relatively higher levels; however, no adverse events were reported (120). Aripiprazole has shown inconsistent RID values in the literature and may accumulate more easily than other SGAs in infants due to long half-life and infants' immature hepatic and function (120). Despite this, aripiprazole is not associated with higher rates of adverse effects than other SGAs. Infants exposed to antipsychotics through breast milk should be monitored for sedation. There has been one case report of agranulocytosis in an infant who was exposed to clozapine through breast milk, and therefore infants exposed to clozapine should be monitored for this possibility (121). Overall, current data indicate that SGAs are relatively safe in exposed infants for short-term usage, although additional studies, in particular for antipsychotics other than olanzapine, are needed to examine the short- and long-term effects of SGAs on the breastfed infant (42).
Management during pregnancy.
SGAs are metabolized by the cytochrome P450 system, including the CYP2D6 (risperidone) and CYP3A4 (lurasidone, aripiprazole, and quetiapine) enzymes. During pregnancy, the metabolism of SGAs is increased by these enzymes, and thus doses of these medications may need to be increased (106). Other strategies that may need to be employed include using a symptoms assessment at each office visit in order to determine the need for dosing adjustment, and decreasing doses postpartum back to the original preconception dose to prevent adverse side effects and toxicity (106). Patients who are most appropriate to receive long-acting injectables (LAIs) during pregnancy will be similar to the nonpregnancy population, including those who have a history of frequent and extended hospitalizations that are precipitated by medication nonadherence (122). Patients who have a history of psychiatric decompensation during previous pregnancies or in the immediate postpartum period are also good candidates for LAIs (122).
Benzodiazepines
Benzodiazepines, although not FDA-approved for bipolar disorder, are commonly used in the acute or manic phase as an adjunct. Benzodiazepines were previously thought to have increased risk for cleft lip and palate and other malformations in the first trimester, however, more recent data have shown that there is no associated risk for major malformations (123). Although there are data regarding obstetrical and neonatal risks such as preterm delivery, small for gestational age, increased risk of neonatal intensive care unit admissions, and neonatal withdrawal (124, 125), confounding variables such as having bipolar disorder, use of other psychiatric medications, and comorbid substance use cannot be ruled out as contributors to these findings. These data on long-term neurodevelopmental problems, such as impaired gross motor skills, lower academic achievements, and increased ADHD traits, have been contradictory (126). No associated risks have been found with the use of benzodiazepines in lactation (127). Lorazepam is preferred due to its shorter half-life and limited hepatic metabolism in consideration of infant hepatic immaturity. Generally, the philosophy of using the lowest effective dose necessary and using as-needed over scheduled dosing is recommended throughout pregnancy and lactation.
Table 3 (128–130) provides detail about management considerations during pregnancy for most commonly prescribed medications.
| Medication | Preconception | 1st trimester | 2nd/3rd trimester | Postpartum | Lactation relative infant dose |
|---|---|---|---|---|---|
| Lithium (Li) (68, 77, 100) | Baseline serum Li, thyroid and renal function studies; check these periodically throughout pregnancy | Monthly serum Li levels, monitor more closely with emesis | Monthly serum Li levels | Serum Li levels at 24–48 hours, then (bi-)weekly, adjusting doses to maintain high therapeutic levels (e.g., .8–1.0 mmol/L) for up to 1 month after delivery | .87%–7.29% |
| | Consider high-dose folic acid supplementation | Doses >900 mg/day associated with greater teratogenic risk | High level US at 16–20 wks gestation | Consider decreasing Li immediately to pre-pregnancy dose | Screen infant for dehydration, prematurity, and impaired renal function |
| | Split dose | | Consider dose adjustment due to increased clearance | Avoid NSAIDs or other nephrotoxic medications | Coordinate with infant’s pediatrician |
| | Counsel on risks | | Weekly levels beginning at 34 weeks | Periodically check infant serum Li, Cr, BUN, TSH | |
| | Consider taper if stable | | Consider holding Li 24–48 hrs prior to delivery | | |
| | | | Hospital delivery with high-level neonatology services | | |
| | | | Adequate hydration | | |
| Lamotrigine (LTG) (83, 100, 104) | Counsel on risks | Monthly LTG levels with dose increases of 20%–25% to maintain baseline level or address clinical symptoms | Monthly LTG levels with dose increases of 20%–25% to maintain baseline level or address clinical symptoms | Frequent monitoring to prevent toxicity | 6.62%–18.27% |
| | Baseline serum LTG | | | Reduction of dose by 25% immediately postpartum with further decreases every 3–4 days until reaching pre-pregnancy dose | |
| | Consider high-dose folic acid supplementation | | | | |
| | Split dosing | | | | |
| Carbamazepine (CBZ) (100, 128, 129) | Counsel on risks, including early exposure | Recommendation for low-dose CBZ therapy only with caution (up to 1000 mg daily) | Drug monitoring is optional and dosing adjustment is not necessary | Vitamin K 1 mg to newborn | 3.8%–5.9% |
| | Folic acid supplementation recommended (4 mg) | | Consider vitamin K in last month | Drug monitoring is optional and dosing adjustment is not necessary postpartum | Monitor infants for jaundice, drowsiness, adequate weight gain, and developmental milestones |
| Valproic acid (VPA) (34, 100, 128, 130) | VPA should not be prescribed to those of childbearing age | Lowest effective dose should be used | Drug monitoring and dosing adjustment is not necessary throughout pregnancy | Drug monitoring and dosing adjustment is not necessary postpartum | .99%–5.6% |
| | If prescribed, provide advice on effective contraception, pregnancy prevention, and risks associated with VPA use during pregnancy | | | | Monitor infants for jaundice or other signs of liver damage |
| | Folic acid supplementation recommended (4 mg) | | | | |
| Antipsychotics (APs) (100, 120–122) | Long acting injectables should be considered similarly in pregnant patients as nonpregnant patients | Decrease clozapine dose accordingly if patient reduces or stops smoking cigarettes during pregnancy | Consider dose adjustment due to increased clearance based on symptom assessments | Consider decrease back to the original preconception dose to prevent adverse side effects and toxicity | Aripiprazole: .7%–6.44%; haloperidol: .2%–12%; olanzapine: .28% - 2.24%; quetiapine: .02%–.1% |
| | | | | Monitor clozapine-exposed infants for up to 8 days | |
| | | | | Avoid co-sleeping on sedating APs | Infants exposed to APs through breast milk should be monitored for sedation |
| | | | | | Infants exposed to clozapine should be monitored for agranulocytosis |
| Benzodiazepines (includes Z-drugs) (BZD) (100, 125) | Counsel on risks | Lorazepam first-line, limit to lowest dose and as needed over scheduled dosing when possible | Lowest dose and as needed over scheduled dosing when possible to minimize neonatal withdrawal | Use may impact ability to stay alert for nocturnal signals of infant (54) | Lorazepam: 2.6%–2.9%; monitor infant for sedation. Clonazepam RID: 2.8%; monitor for infant sedation |
| | | | | Avoid co-sleeping | |
a
Cr=creatinine; BUN=blood urea nitrogen; NSAIDs=nonsteroidal anti-inflammatory drugs; TSH=thyroid-stimulating hormone; US=ultrasound.
Future Directions
Knowledge gaps remain regarding optimizing nonpharmacologic treatments. Larger randomized controlled trials of medications are needed to determine ideal dosing, efficacy, and safety. Emerging treatments such as glutamate receptor modulators, N-methyl-d-aspartate receptor antagonists, and psilocybin have promise, given rapid improvement and potential for lower time of exposure, but require additional study in bipolar disorder in the general population and have little data regarding safety or efficacy in pregnancy and lactation (131–133). Allopregnanolone agonists have a novel mechanism of action for the treatment of postpartum unipolar depression but require further study in bipolar depression (134).
Patients diagnosed as having bipolar disorder will have most favorable outcomes through active management, monitoring, and individualized discussion that balances the risks of specific medications with risks of undertreated bipolar disorder in the perinatal period.
Footnotes
The authors used OpenAI’s Chat Generative Pre-Trained Transformer (ChatGPT) to reduce word count and improve readability of the article, simplify language, and summarize certain sentences. The authors input the prompt “I am a psychiatrist writing an academic review article. Make the following more readable and reduce word count to XXX words.” The authors used some, but not all of the suggestions that were generated to modify word choice selection and sentence structure to improve clarity. The authors also used ChatGPT to reformat the references but did not use ChatGPT to select any of the references, all of which were searched by the authors using search engines such as PubMed.
The authors used ChatGPT for proofreading and word count reduction of the “Lithium,” “Lamotrigine,” and “Medication” sections of Table 3. Typical prompts involved using ChatGPT to condense the text while retaining essential data points and citations. All generated output was thoroughly reviewed to ensure accuracy and maintain the integrity of the information presented in the article.
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Published in print: Winter 2024
Published online: 16 January 2024
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The authors report no financial relationships with commercial interests.
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