For many women with bipolar disorder, lamotrigine (Lamictal) is an effective mood stabilizer. Given its favorable reproductive safety profile, lamotrigine is a reasonable option for women who require treatment with a mood stabilizer during pregnancy.
When advising women regarding the use of medications during pregnancy, we typically recommend that women remain on the dose of medication that has kept them well prior to pregnancy. Reducing the dosage of medication may result in sub-therapeutic levels, which may increase the risk of relapse during pregnancy despite maintenance of the medication.
Maintenance of adequate dosage during pregnancy is especially important; there are data to indicate that levels of many medications may decrease during pregnancy due to changes in fluid volume and increases in hepatic metabolism. Lamotrigine levels can decline significantly during pregnancy. Estrogen increases the clearance of lamotrigine by inducing the liver enzymes involved in its metabolism. Thus, more rapid metabolism can result in lower, and possibly sub-therapeutic, levels of lamotrigine.
As estrogen levels gradually rise over the course of pregnancy, lamotrigine levels may drop by as much as 50%. As there is substantial variability in lamotrigine clearance between individuals, some women may experience a large drop in lamotrigine blood levels during pregnancy while others may experience a more modest decline. In the setting of falling levels, some women may experience clinical destabilization.
A recent study indicates that increases in lamotrigine clearance can begin as early as 5 weeks gestational age, often before women are aware that they are pregnant, and clearance continues to increase through gestational week 13.
Recommendations for Dose Adjustment
Most of our data on this topic comes from women taking lamotrigine for the management of seizure disorders during pregnancy. A recent article proposed the following guidelines for adjusting lamotrigine (LTG) dose during pregnancy and the postpartum period.
- Prior to pregnancy, obtain a reference LTG plasma concentration (RC).
- After conception, plasma concentrations of LTG should be measured every 4 weeks.
- If the LTG plasma concentration falls below the RC, the dose of LTG should be increased by 20-25%.
- After delivery, the plasma concentration of LTG should be measured within the first or second week.
- If the LTG plasma concentration is higher than the RC, the LTG dose should be reduced by 20-25% and the procedure repeated until RC is re-established.
While there is no reason to believe that women with bipolar disorder metabolize lamotrigine differently than women with epilepsy, many psychiatrists do not routinely adjust lamotrigine doses during pregnancy. Because there is no established therapeutic blood level for lamotrigine, information gleaned by blood level monitoring may be difficult to interpret.
For women taking lamotrigine prior to pregnancy, a pre-pregnancy blood level of lamotrigine may be established as a baseline and subsequently used as a guideline for dosing during pregnancy. However, careful monitoring of clinical symptoms may be equally as effective in managing dose adjustments as measuring blood levels during pregnancy and the postpartum period.
Lamotrigine serum levels return to prepregnancy values within 3 to 4 weeks after delivery. If the dose of lamotrigine was increased substantially during pregnancy, the patient should be monitored for any signs of toxicity (e.g. nausea, dizziness, vision changes, altered mental status) during the first few weeks after delivery, and the dose should gradually be decreased to pre-pregnancy levels.
Lingering Controversies
Where our group typically does not increase the dose of lamotrigine prophylactically in women with bipolar disorder, Clark and colleagues use an approach modelled after the management of seizure disorders and recommend adjusting lamotrigine dosing during pregnancy according to blood levels. However, in a response to this article, Sharma and colleagues questioned this approach, as there was no evidence in this small case series to indicate that lower blood levels of lamotrigine were associated with relapse. They also noted that if recurrent symptoms do emerge during pregnancy, other medications, such as the atypical antipsychotics, may prove to be more effective than lamotrigine for managing sleep disruption, hypomania or mania and may also act more quickly.
In patients with seizure disorders, blood levels of lamotrigine in a given individual are strongly correlated with seizure control. However, in patients with bipolar disorder, there is more likely a broader range of therapeutic blood levels for lamotrigine. Thus, women may be able to tolerate fluctuations in LTG levels during pregnancy without significant risk for relapse. In patients who present prior to pregnancy, it may be helpful to measure a baseline serum LTG level to guide dosing decisions later on during pregnancy; however, we do not have clear evidence at this point to indicate that tight control of lamotrigine levels during pregnancy is required or if this approach decreases the risk of relapse. Following the patient’s symptoms closely and making medication adjustments as needed allows us to use lower doses of medication; however, in patients who are very sensitive to changes in LTG dosage, closer monitoring of LTG blood levels may be preferable.
Ruta Nonacs, MD PhD
Clark CT, Klein AM, Perel JM, Helsel J, Wisner KL. Lamotrigine dosing for pregnant patients with bipolar disorder. Am J Psychiatry. 2013 Nov 1;170(11):1240-7.
Fotopoulou C, Kretz R, Bauer S, Schefold JC, Schmitz B, Dudenhausen JW, Henrich W. Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res. 2009 Jul;85(1):60-4.
Karanam A, Pennell PB, French JA, Harden CL, Allien S, Lau C, Barnard S, Callisto SP, Birnbaum AK. Lamotrigine clearance increases by 5 weeks gestational age: Relationship to estradiol concentrations and gestational age. Ann Neurol. 2018 Oct;84(4):556-563.
Sabers A. Algorithm for lamotrigine dose adjustment before, during, and after pregnancy. Acta Neurol Scand. 2012 Jul;126(1):e1-4.
Sharma V, Sommerdyk C. Management issues during pregnancy in women with bipolar disorder. Am J Psychiatry. 2014 Mar;171(3):370-1.
The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.
Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.
Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.
Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extract databasefound an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics (2016;73[9]:938-46).
Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population (2018 Aug 16. doi: 10.1176/appi.ajp.2018.18010098).
The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).
The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.
Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.
Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (2017;376:2245-54). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry (2018 Aug;5[8]:644-52), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).
Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.
Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email him at .