While we use lithium less commonly now than we have in the past, lithium is still one of the very best mood stabilizers we have. And with regard to its reproductive safety, we have studies going back nearly 50 years.
In the 1970s, reports from the International Register of Lithium Babies suggested a very strong association between exposure to maternal lithium treatment during pregnancy and Ebstein’s anomaly, a right ventricular outflow tract obstruction defect of the heart. While it was initially estimated that Ebstein’s anomaly was about 400 times more common among children prenatally exposed to lithium than in unexposed children, these calculations were based on a registry of voluntarily submitted cases which most likely overestimated risk. More recent epidemiologic studies have consistently shown a much lower risk.
Most recently, Patoma and colleagues have estimated the risk of cardiac malformations in children exposed to lithium during the first trimester of pregnancy in a large retrospective cohort study of 1,325,563 pregnant women included in the U.S. Medicaid Analytic eXtract (MAX). In this study, exposure was defined as at least one filled prescription for lithium during the first trimester (first 90 days after the date of the last menstrual period). Two comparison groups were identified. The primary reference group included women with no lithium exposure. The researchers also compared outcomes to women with bipolar disorder who used lamotrigine as a mood stabilizer.
Overall Risk of Cardiovascular Malformations: The prevalence of cardiac malformations was 2.41 per 100 live births among lithium-exposed infants, 1.15 per 100 among unexposed infants, and 1.39 per 100 among lamotrigine-exposed infants exposed to lamotrigine. After controlling for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% confidence interval [CI], 1.02 to 2.68) when compared to nonexposed infants.
Risk of Specific Cardiovascular Malformations: The researchers then looked at risk for specific types of cardiac malformations. The prevalence of right ventricular outflow tract obstruction defects was 0.60 per 100 live births among infants exposed to lithium and 0.18 per 100 among unexposed infants. The adjusted risk ratio for specific cardiac malformations associated with lithium was 2.66 for right ventricular outflow tract obstruction defects (95% CI, 1.00 to 7.06) and 1.46 for other cardiac defects (95% CI, 0.84 to 2.57). None of the identified right ventricular outflow tract obstruction defects in the lithium-exposed infants were specifically coded as Ebstein’s anomaly; however, most of these cases were consistent with cardiac defects which frequently co-occur with Ebstein’s anomaly (e.g., pulmonary atresia and stenosis).
Dose-Response Relationship: The researchers also looked at the impact of lithium dosage on risk for malformations and observed that risk increased as the dose of lithium increased.
For a daily dose of 600 mg or less, the relative risk was 1.11 (95% CI, 0.46 to 2.64) and increased to 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.
Summary of the Findings and Clinical Implications
This study, which included 663 women who used lithium during the first trimester of pregnancy, is the largest study of prenatal lithium exposure to date. The findings of this study indicate a modest increase in the risk of cardiac malformations in infants with prenatal exposure to lithium. Compared to women with no known exposures, the relative risk of cardiac malformations calculated here was 1.65. The risk appears to be higher for right ventricular outflow tract obstruction defects – most likely Ebstein’s anomaly — than for other cardiac defects. Translating this into absolute risk, this means that if the risk of cardiovascular malformations is 1.15% in women with no exposure, the risk rises to about 1.9% in infants exposed to lithium. In this study, the risk of right ventricular outflow tract obstruction defects was 0.60 per 100 live births among infants exposed to lithium and 0.18 per 100 among unexposed infants.
While this is not a dramatic increase in absolute risk, this study confirms what we have known for many years, that lithium carries some teratogenic risk. As a rule, we try to avoid prescribing teratogens during pregnancy, but sometimes we simply cannot avoid this. Relapse rates in women with bipolar disorder are very high in women who discontinue mood stabilizers proximate to conception, and untreated bipolar illness in the mother carries risks, including risk of self-harm, alcohol and tobacco use, and poor compliance with prenatal care.
Some women may elect to stop treatment with lithium during pregnancy. With regard to alternatives, valproic acid (Depakote) is a significantly worse option, given its high teratogenic risk. Some women may be able to switch to lamotrigine (Lamictal), which has a good reproductive safety profile, although lamotrigine may not be as effective as lithium in protecting against manic symptoms. Atypical antipsychotic drugs are being used more commonly in this setting, although data on the reproductive safety of this class of medications is limited. But in many cases, lithium may remain the best option.
The finding of a dose-dependent association between lithium and cardiac malformations is interesting and may offer some possibilities for risk reduction. The risk is increased approximately threefold in doses above 900 mg per day. One might consider lowering the dose during the first trimester, although this approach may increase risk for relapse in some women. The other concern is that, since more than half of all pregnancies are unplanned, it may be difficult to adjust the dose of lithium after obtaining a positive pregnancy test and prior to the critical window of heart development (between 4 to 8 weeks after conception).
These findings are reassuring. While this report confirms previous studies showing that lithium carries some teratogenic risk, this study indicates only a modest increase in the risk of cardiac malformations in infants with prenatal exposure to lithium. Women taking lithium for the treatment of bipolar disorder should review their treatment options with their treaters prior to pregnancy. In addition, we recommend that women treated with lithium during the first trimester should undergo fetal echocardiography and level-2 ultrasound to identify cardiovascular malformations.
Ruta Nonacs, MD PhD
Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-Diaz S. N Engl J Med. 2017 Jun 8;376(23):2245-2254.