August 23, 2018 from ObGynNews

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

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