While the use of lithium has been in decline over the last 20 years, lithium continues to be a useful and highly effective mood stabilizer for women with bipolar disorder.  We have long been aware of its teratogenic effects, with some, but not all, studies documenting an increased risk of cardiovascular malformations.  A new study published in the American Journal of Psychiatry conducts a systematic review and meta-analysis to look at outcomes in children with prenatal exposure to lithium.  Most previous articles have focused on risk of major malformations; this review includes ….

Researchers identified a total of 24 articles covering 29 studies which reported qualitative information on the safety of lithium during pregnancy or the postpartum period for the exposed women and/or the fetus or newborn; these were suitable for the narrative synthesis.  Of those, 13 studies (covered by eight articles) were suitable for the meta-analysis.

In the meta-analysis, they analyzed eight studies reporting on 13 comparisons between lithium-exposed and unexposed control subjects (N=1,349,563 pregnancies) .  This allowed for the pooling of data on the effects of prenatal exposure to lithium on risk for several different outcomes:

Spontaneous abortion:  While two studies indicated that lithium exposure during the first trimester of pregnancy was associated with a increased risk of spontaneous abortion, this difference was not statistically significant when compared with unexposed women with affective disorders.

Preterm birth and low birth weight: Lithium exposure during pregnancy was not associated with an increased risk of preterm birth when compared to any unexposed control group.  Nor was lithium exposure associated with low birth weight.

Congenital malformations:  Lithium exposure during pregnancy was associated with a significantly increased risk of any congenital anomaly when compared with any unexposed group (four studies, N=23,300; odds ratio=1.81, 95% CI=1.35–2.41).

Cardiac malformations:  Lithium exposure during pregnancy was associated with a significantly increased risk of cardiac malformations (four studies N=1,348,475; odds ratio=1.86, 95% CI=1.16–2.96) when compared with any unexposed group and with the general population.  However, when compared to unexposed women with affective disorders, the difference was not statistically significant (four studies, N=24,699; odds ratio=1.59, 95% CI=0.91–2.77).

Risk of relapse: Lithium was significantly more effective than no prophylaxis in preventing postpartum mood episodes (any polarity; follow-up range, 4 weeks to 2 years) in women with mood disorders (two studies, N=48; odds ratio=0.16, 95% CI=0.03–0.89).

Impact of lithium dosage: According to a single study, the risk of cardiac malformations seemed to triple with dosages >900 mg/day compared to dosages ?600 mg/day.  The risk of neonatal complications was higher in women with a median lithium serum level >0.64 mEq/L.

Lithium Continues to Be a Viable Option

This meta-analysis does not give us any surprises and basically confirms what earlier studies have revealed.  While some studies have shown an increased risk of spontaneous abortion, preterm birth and low birth weight among women taking lithium, this analysis concludes that this risk may be driven by the illness itself.  When compared to non-users with an affective illness, women taking lithium do not experience any higher risk of these adverse outcomes.  

Consistent with previous studies, lithium exposure is associated with a small but statistically significant increased risk of cardiovascular malformations.    While this report suggests that there may be an increase in the risk of major malformations in children prenatally exposed to lithium, we must point out that this study does not necessarily mean that women should discontinue or avoid treatment with lithium during pregnancy.  

For women with bipolar disorder, lithium is one or the most effective prophylactic treatments.  While some women may desire to discontinue lithium during pregnancy, decisions regarding the use of lithium during pregnancy must take into consideration the high risk of relapse during pregnancy and the postpartum period.  Some women may be able to switch to lamotrigine or to atypical antipsychotics, taking into consideration the risks associated with exposure to these medications and the risk for relapse in the setting of a medication change.  However, for some women with bipolar disorder, lithium may be the best option.  

 

Ruta Nonacs, MD PhD

Fornaro M, Maritan E, Ferranti R, Zaninotto L, et al.  Lithium Exposure During Pregnancy and the Postpartum Period: A Systematic Review and Meta-Analysis of Safety and Efficacy Outcomes.  Am J Psychiatry. 2019 Oct 18.