Lithium in Pregnancy Worth Reconsidering?

Batya Swift Yasgur, MA, LSW

June 08, 2017

Use of lithium during the first trimester of pregnancy is associated with an increased risk for cardiac malformations in infants. However, new research shows the risk is much smaller than previously thought.

Researchers at the Brigham and Women's Hospital, Boston, Massachusetts, found a twofold increased risk for cardiac malformations in infants exposed to lithium compared to unexposed infants. The risk was also higher than in infants exposed to lamotrigine (Lamictal, GlaxoSmithKline). However, the risk was lower than expected and was dose dependent.

"In the context of limited and conflicting evidence regarding the safety of lithium for the developing fetus, this paper provides further information on the fetal safety of lithium," lead investigator Elisabetta Patorno, MD, DrPH, told Medscape Medical News.

"In light of this new information, clinicians and patients may decide to reconsider the balance between the relatively small increase in the risk of cardiac malformations and the comparative benefits of lithium vs other mood-stabilizing strategies in deciding whether or not to prescribe and use lithium in women of reproductive age or pregnant women," she said.

The study was published online June 7 in the New England Journal of Medicine.

Overestimation of Risk

Results from the International Register of Lithium Babies, published in the early 1970s, suggested a highly increased risk for cardiac defects —particularly Ebstein's abnormality, a right ventricular outflow tract (RVOT) obstruction defect — in infants exposed to lithium during early pregnancy. Subsequent research has consisted of case reports and small studies with "inconclusive results," the authors write.

Despite these concerns, lithium has remained a first-line treatment for women of reproductive age who have bipolar disorder, and its "persistent use" has been justified by evidence showing reductions in risk for mood episodes during pregnancy and the postpartum period.

"Some women discontinue lithium therapy or terminate their pregnancy to avoid the potential teratogenicity of the drug," the authors note, necessitating more extensive, rigorous studies to explore the actual risks of lithium to a developing fetus.

To investigate this question, the researchers collected data from a Medicaid database for the years 2000 through 2010, including data relating to all pregnancies in women aged 22 to 55 years that resulted in live births.

Exposure to lithium was defined as a patient's filling at least one prescription for lithium during the first trimester of pregnancy. The primary reference group consisted of women who had not been dispensed lithium or lamotrigine during the 3 months prior to the onset of pregnancy or during the first trimester.

The secondary reference group consisted of women who had filled at least one prescription for lamotrigine during the first trimester. Patients exposed to both lithium and lamotrigine were excluded.

The researchers explain that their rationale for choosing lamotrigine as a comparator was its effectiveness in the treatment of bipolar disorder and its lack of association with increased risk for congenital malformations.

Of the total study cohort (n = 1,325,563 pregnancies) that met the inclusion criteria, 0.05% (n = 663) were in women exposed to lithium, and 0.15% (n = 1945) were in women exposed to lamotrigine during the first trimester.

The prevalence of cardiac malformations was higher in infants exposed to lithium than in unexposed infants or in infants exposed to lamotrigine (2.41 vs 1.15 and 1.39 per 100 live births, respectively).

Dose-Dependent Effect

The adjusted risk ratio (RR) for cardiac malformations among lithium-exposed infants, as compared to unexposed infants, was 1.65 (95% confidence interval [CI], 1.02 - 2.68); it was 2.25 (95% CI, 1.17 - 4.34) as compared with lamotrigine-exposed infants. The adjusted RR for cardiac malformations among infants exposed to lamotrigine, as compared with unexposed infants, was 0.89 (95% CI, 0.61 - 1.30).

The researchers reported an adjusted RR of 1.22 (95% CI, 0.81 - 1.84) for noncardiac defects among infants exposed to lithium, as compared with unexposed infants.

The prevalence of RVOT obstruction defects was 0.60 per 100 live births among infants exposed to lithium, vs 0.18 per 100 among unexposed infants. The adjusted RR for specific cardiac malformations associated with lithium was 2.66 (95% CI, 1.00 - 7.06) for RVOT obstruction defects and 1.46 (95% CI, 0.84 - 2.57) for other cardiac defects. Most were consistent with cardiac defects that frequently co-occur with Ebstein's anomaly.

The researchers conducted dose-response analyses, based on the first lithium prescription in pregnancy. After propensity-score adjustment, the RR was 1.11 (95% CI, 0.46 - 2.64) for a daily dose of ≤600 mg, 1.60 (95% CI, 0.67 - 3.80) for 601 to 900 mg, and 3.22 (95% CI, 1.47 - 7.02) for >900 mg.

All RVOT defects identified in lithium-exposed infants occurred with a daily dose >600 mg. By contrast, there was no evidence of a dose-response relationship for lamotrigine, the researchers report.

"Our results support previous findings of an association between lithium use in pregnant women and cardiac defects in infants. Therefore, they were expected," Dr Patorno said. "The apparent dose effect was something we had hypothesized, although it had only been observed in animals before."

She acknowledged being "surprised by the relatively low magnitude of the increased risk of cardiac malformations, compared to that originally proposed by the International Register of Lithium Babies."

Immediate Clinical Implications

Commenting on the study for Medscape Medical News, Kimberly Yonkers, MD, director, Center for Wellbeing of Women and Mothers, Yale School of Public Health, New Haven, Connecticut, called the study "important because of its large sample size and the fact that it is population based."

Additionally, the study includes "an attempt at using an active comparison group, lamotrigine, although it is a treatment for bipolar depression and not really bipolar mania," said Dr Yonkers, who was not involved with the study.

Although Dr Yonkers described the study design as "strong," she noted that, "as with many registry studies, the limitations include lack of ability to control for use of illicit substances, which occurs at a higher rate among individuals with vs without bipolar disorder."

The study is also "slanted socioeconomically to those who are on Medicaid, while higher socioeconomic status can mitigate some birth risk factors."

The findings did not surprise her, she said. "We all know that the lithium register overestimated the risk of lithium. What was surprising, though, was the lack of risk for noncardiac malformations that have been reported by other workers."

The study has an immediate take-home message for psychiatrists and ob/gyns, Dr Yonkers added. "It puts use of lithium in pregnancy in context. There is some risk of first trimester use, but it is not as high as estimated from the lithium register, and the risk increases as the dose increases."

The study "provides an immediately clinically applicable message that can guide treatment decisions for women with bipolar disorder in reproductive age and pregnancy," said Dr Patorno.

"Women of childbearing age with bipolar disorder who are planning to become pregnant should speak with their doctor to discuss what the best option is for them and their baby," she said.

The study was supported by a grant from the National Institute of Mental Health.One coauthor received grant support from the National Institute of Mental Health and from Eli Lilly, Baxalta, Pfizer, Pacira, and the National Institute of Child Health and Human Development, as well as personal fees from Optum outside the submitted work.

N Engl J Med. Published online June 7, 2017. Abstract

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