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Comparative Study
. 2017 Jun 8;376(23):2245-2254.
doi: 10.1056/NEJMoa1612222.

Lithium Use in Pregnancy and the Risk of Cardiac Malformations

Free PMC article
Comparative Study

Lithium Use in Pregnancy and the Risk of Cardiac Malformations

Elisabetta Patorno et al. N Engl J Med. .
Free PMC article


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.).


Figure 1
Figure 1. Study Cohort
Women included in the study population could have had more than one pregnancy.
Figure 2
Figure 2. Absolute and Relative Risk of Cardiac Malformations among Lithium-Exposed and Lamotrigine-Exposed Infants as Compared with Unexposed Infants, Stratified According to the Mother’s Dose of the Drug
Stratification was according to thirds of the first prescribed daily dose that was filled during the first trimester. A separate exposure propensity score was estimated in each dose stratum as the predicted probability of receiving the treatment-dose range of interest versus no treatment, conditional on the covariates reported in Tables S6 through S9 in the Supplementary Appendix. For each estimated propensity score, the population in the nonoverlapping areas of the propensity-score distributions was trimmed, and 50 strata were created on the basis of the distribution of the treated women. Weights for the reference group were calculated according to the distribution of the exposed women among propensity-score strata and were used to estimate adjusted risk ratios and 95% confidence intervals.

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