A case-control study on the association between first trimester exposure to lithium and Ebstein's anomaly

Eli Zalzstein, Gideon Koren, Tom Einarson, Robert M. Freedom

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


Lithium carbonate is considered to be a first-line drug in the management of manic depressive psychosis. According to Food and Drug Administration figures 0.1% of pregnant women are using this medication.1 During the last 2 decades accumulated data have suggested that lithium carbonate may be teratogenic in humans.2 The Danish registry has accumulated over 200 cases, among which there was a 10% occurrence rate of cardiac malformations.3 This rate appears high when compared to the 0.1% risk for such malformations in the general population.2 In particular, the Danish registry reported 8 cases of the rare Ebstein's anomaly which occurs spontaneously in only 1 of every 20,000 births, suggesting a relative risk of 500-fold above that in the general population. However, the information in this registry has been collected by a voluntary reporting system and does not represent systematically collected data. It has been argued that families and physicians caring for malformed babies are more likely to report adverse fetal outcomes to the registry than normal outcomes,4 as was the case with retinoic acid.5 This reporting bias may create a false impression of a teratogen when, in fact, the drug may not be teratogenic. The implication of wrongful incrimination of a drug like lithium may be immense; women may not be optimally treated during conception and pregnancy or, if treated before pregnancy was recognized, they may wish to terminate pregnancy to avoid an increased teratogenic risk. Since our team provides counselling for women in greater Toronto on the safety of drugs and chemicals, we are continuously witnessing both these options being taken by women. To the best of our knowledge no controlled studies have tried to define the teratogenic risk of lithium in humans. In dealing with a rare malformation such as the Ebstein's anomaly, a sample size > 400 women exposed to lithium and a similar group of nonexposed women would have to be collected prospectively in order to detect a 10-fold increased risk with an alpha of 0.05 and power of 0.8. A more realistic approach to try to address this question would therefore be the case-control study where one focuses on the rare event, namely the Ebstein's anomaly, and compares maternal drug exposure in pregnancy of children having this malformation with those of a control group. Because our cardiology division is the tertiary referral center for a population of about 6 million, we have had the rare opportunity to ascertain a large number of cases of Ebstein's anomaly and thus to test the association between first trimester exposure to lithium and this malformation.

Original languageEnglish
Pages (from-to)817-818
Number of pages2
JournalAmerican Journal of Cardiology
Issue number11
StatePublished - 15 Mar 1990
Externally publishedYes


Dive into the research topics of 'A case-control study on the association between first trimester exposure to lithium and Ebstein's anomaly'. Together they form a unique fingerprint.

Cite this