Lithium during pregnancy linked to modest increase in cardiac malformations

1. There has been concern about the linkage between lithium use during pregnancy and a risk of cardiac malformations, specifically Ebstein’s anomaly, with varying levels of association found in prior studies.

2. Using Medicaid data from over 1 million pregnancies, exposure to lithium during the first trimester was associated with an additional 1 case of cardiac malformation per 100 live births compared to a lithium-free scenario.

Evidence Rating Level: 2 (Good)

Study Rundown: Since the publishing of results from the International Register of Lithium Babies in the 1970s, there has been widespread concern about the linkage between lithium use during pregnancy and a risk of infant cardiac defects. The results from follow-up case reports and smaller case-control and controlled cohort studies have been mixed. At the same time, lithium remains a first-line therapy for women with bipolar disorder of reproductive age in the United States. In this large retrospective cohort study involving Medicaid data, the authors investigated the risk of cardiac malformations in the offspring of women taking lithium during their first trimester, compared to control groups of unexposed infants and infants exposed to lamotrigine. The results indicate an increase in the adjusted risk of cardiac malformations among infants exposed to lithium in the first trimester, compared to unexposed and lamotrigine exposed infants. There was a dose-dependent increase in this relative risk. Lithium exposure during the first trimester was associated with an additional 1 cardiac malformation case per 100 live births relative to lithium-free pregnancies.

This study lends credence to the linkage between maternal lithium use during the first trimester and increased risk of congenital heart abnormalities, especially right ventricular outflow tract obstruction defects. The reported risk is statistically significant but much more modest than previous studies. The study draws strength from its large size and propensity matching, but given its nonrandomized and database approach is subject to residual confounding by unmeasured variables and the possibility of misclassification bias.

Click to read the study, published in NEJM

Relevant Reading: Valproic acid monotherapy in pregnancy and major congenital malformations

In-Depth [retrospective cohort]: This retrospective cohort study assessed Medicaid data for 1 325 563 pregnancies between 2000 and 2010. Exposure was defined as having at least one filled prescription for lithium during the first trimester; the primary reference group was women without lithium or lamotrigine fillings during the 3 months prior to pregnancy or the first trimester. The primary outcome was infant cardiac malformations, with secondary outcomes of major congenital malformations. Covariates accounting for medical and social factors were used to derive a propensity-matched cohort. In the primary analysis, the adjusted risk ratio for cardiac malformations among lithium-exposed infants was 1.65 (95%CI 1.02-2.68) compared to unexposed infants and 2.25 (95%CI 1.17-4.34) compared to lamotrigine-exposed infants. The adjusted risk-ratio for right ventricular outflow tract obstruction defects was 2.66 (95%CI 1.00-7.06) for lithium compared to unexposed infants. There was a dose-response relationship noted between lithium prescribed during the first trimester and increasing cardiac malformation risk. There was differential incomplete data for important confounding covariates, such as obesity, smoking, and alcohol use orders, with this data more often missing in the group receiving lithium therapy; this would probably bias the adjusted risk estimates upward.

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