Does lithium cause Ebstein's anomaly?

Lithium and Ebstein's Anomaly: The Association

Yes, lithium exposure during pregnancy is associated with an increased risk of Ebstein's anomaly, though the magnitude of this risk is lower than historically believed. The FDA drug label explicitly states that lithium may cause fetal harm when administered to pregnant women, with specific mention of Ebstein's anomaly 1.

Evidence for the Association

• Lithium is documented in clinical guidelines as a risk factor for Ebstein's anomaly, with the European Society of Cardiology (ESC) guidelines specifically stating that "Ebstein's anomaly occurs more commonly if the mother has received lithium or benzodiazepines during pregnancy" 2.

• The FDA drug label for lithium clearly warns that "Data from lithium birth registries suggest an increase in cardiac and other anomalies, especially Ebstein's anomaly" 1.

• The risk appears to be dose-dependent, with a 2017 study showing that higher doses of lithium (>900 mg daily) were associated with a greater risk (adjusted risk ratio 3.22) compared to lower doses (≤600 mg daily, adjusted risk ratio 1.11) 3.

Magnitude of Risk

• More recent research has demonstrated that the risk is lower than initially reported in earlier studies:

  • A 2017 study involving over 1.3 million pregnancies found that cardiac malformations were present in 2.41% of infants exposed to lithium versus 1.15% in unexposed infants (adjusted risk ratio 1.65) 3.

  • Specifically for right ventricular outflow tract obstruction defects (including Ebstein's anomaly), the prevalence was 0.60% among lithium-exposed infants versus 0.18% among unexposed infants (adjusted risk ratio 2.66) 3.

• Historical perspective shows that initial estimates were much higher:

  • In the 1970s, the relative risk for Ebstein's anomaly was estimated to be 400 based on registry data 4.

  • Subsequent controlled studies have consistently shown a much lower risk 4.

Confounding Factors

• A 2024 study suggests that epidemiological studies on lithium's effects in pregnancy may be confounded by other factors associated with bipolar disorder, such as:
  • High rates of cigarette smoking, poor diet, alcohol abuse
  • Illicit drug use (cocaine, opioids, marijuana)
  • Obesity and poverty 5

Clinical Implications

• For women with bipolar disorder who become pregnant while taking lithium:

  • The FDA label recommends that "If the patient becomes pregnant while taking lithium, she should be apprised of the potential risk to the fetus" 1.

  • If possible, lithium should be withdrawn for at least the first trimester unless this would seriously endanger the mother 1.

• For pregnant women with Ebstein's anomaly or at risk:

  • Fetal echocardiography is recommended to screen for cardiac anomalies 6, 7.

  • Regular follow-up in specialized centers is essential for monitoring 2.

Conclusion

While lithium does increase the risk of Ebstein's anomaly, this risk is substantially lower than initially reported. The decision to use lithium during pregnancy should carefully weigh the benefits of mood stabilization against the potential cardiac risks to the fetus, with consideration of alternative medications when appropriate.