Lithium Use in Pregnancy and the Risk of Cardiac Malformations

N Engl J Med. 2017 Jun 8;376(23):2245-2254. doi: 10.1056/NEJMoa1612222.


Background: There has been concern that exposure to lithium early in pregnancy may be associated with a marked increase in the risk of Ebstein's anomaly (a right ventricular outflow tract obstruction defect) in infants and overall congenital cardiac defects, but data are conflicting and limited.

Methods: We conducted a cohort study involving 1,325,563 pregnancies in women who were enrolled in Medicaid and who delivered a live-born infant between 2000 and 2010. We examined the risk of cardiac malformations among infants exposed to lithium during the first trimester as compared with unexposed infants and, in secondary analyses, with infants exposed to another commonly used mood stabilizer, lamotrigine. Risk ratios and 95% confidence intervals were estimated with control for psychiatric and medical conditions, medications, and other potential confounders.

Results: Cardiac malformations were present in 16 of the 663 infants exposed to lithium (2.41%), 15,251 of the 1,322,955 nonexposed infants (1.15%), and 27 of the 1945 infants exposed to lamotrigine (1.39%). The adjusted risk ratio for cardiac malformations among infants exposed to lithium as compared with unexposed infants was 1.65 (95% confidence interval [CI], 1.02 to 2.68). The risk ratio was 1.11 (95% CI, 0.46 to 2.64) for a daily dose of 600 mg or less, 1.60 (95% CI, 0.67 to 3.80) for 601 to 900 mg, and 3.22 (95% CI, 1.47 to 7.02) for more than 900 mg. The prevalence of right ventricular outflow tract obstruction defects was 0.60% among lithium-exposed infants versus 0.18% among unexposed infants (adjusted risk ratio, 2.66; 95% CI, 1.00 to 7.06). Results were similar when lamotrigine-exposed infants were used as the reference group.

Conclusions: Maternal use of lithium during the first trimester was associated with an increased risk of cardiac malformations, including Ebstein's anomaly; the magnitude of this effect was smaller than had been previously postulated. (Funded by the National Institute of Mental Health.).

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Anticonvulsants / adverse effects
  • Anticonvulsants / therapeutic use
  • Antidepressive Agents / adverse effects*
  • Antidepressive Agents / therapeutic use
  • Antimanic Agents / adverse effects
  • Antimanic Agents / therapeutic use
  • Bipolar Disorder / drug therapy*
  • Cohort Studies
  • Female
  • Heart Defects, Congenital / chemically induced*
  • Heart Defects, Congenital / epidemiology
  • Humans
  • Infant
  • Infant, Newborn
  • Lamotrigine
  • Lithium Compounds / adverse effects*
  • Lithium Compounds / therapeutic use
  • Pregnancy
  • Pregnancy Complications / drug therapy*
  • Pregnancy Trimester, First
  • Prevalence
  • Triazines / adverse effects
  • Triazines / therapeutic use
  • Young Adult


  • Anticonvulsants
  • Antidepressive Agents
  • Antimanic Agents
  • Lithium Compounds
  • Triazines
  • Lamotrigine