The finding: Observational study findings showed that lithium exposure was associated with a relatively modest increase in the prevalence of cardiac malformations. Clinically speaking, lithium exposure was associated with an increase in prevalence of these defects in the range of up to two additional cases per 100 live births. The relative risk was higher for right ventricular outflow tract obstruction defects compared to other cardiac defects and there was no significant association between lithium and noncardiac defects. Previous studies have shown conflicting associations with many showing a higher magnitude of increased risk. This study suggests that the risk of cardiac malformations is indeed increased with lithium exposure, but not as high as previously suggested. Furthermore, there could potentially be a dose-response relationship between lithium exposure and cardiac malformations as indicated by the presence of right ventricular outflow tract obstructions in infants exposed to doses of 600mg or higher. The study further suggests that doses beyond 900mg daily increase the risk of cardiac malformations by a factor of three. This was not seen with infants exposed to lamotrigine.

Strengths:

• Very large sample size
• Large sample of women exposed to lithium
• Use of a control of non-exposed infants
• Inclusion criteria involved women with at least one bipolar diagnosis
• Use of lamotrigine exposure group to limit confounding by indication
• Relatively well-matched subjects between control and exposure groups
• Efforts to reduce misclassification:
  • Redefined exposure as two filled prescriptions
  • Required outcome to be based on ICD-9 diagnosis or procedure codes in infant records only
  • Use of very specific definitions for cardiac malformations and noncardiac malformations

Weaknesses:

• Limited to information available in Medicaid database; could miss other confounders
• Filled prescriptions do not guarantee medications were taken
• Lithium exposure may cause providers to preferentially investigate for cardiac malformations
• Restriction to live births

Relevance: Lithium is a very effective and often first-line treatment for bipolar disorder, particularly when compared to other medications. Clinical evidence suggests an association between lithium and reduced risk of mood-episode (depressive, manic, or mixed) recurrence during peripartum or postpartum period. Women with bipolar disorder who may benefit from lithium contend with conflicting evidence on the effects the medication may have on a developing fetus. This may adversely affect treatment adherence to the medication as well as influence a patient’s decision to continue a pregnancy. The study suggests that around 5-10% of elective abortions may be higher in lithium users than non-users. The results of this study may help providers better clarify the risks and the benefits of using lithium to manage bipolar disorder.