For women taking lithium for the treatment of bipolar disorder, choosing whether to maintain or discontinue lithium during pregnancy is challenging. This is a process which requires careful and thoughtful consideration, weighing the risk of adverse outcomes associated with exposure to lithium against the risk of recurrent illness in the setting of medication discontinuation. While we have considerable information regarding the teratogenicity of lithium, we have much less data regarding other pregnancy and neonatal outcomes.  

Analyzing data from five linked Swedish national registers, Hastie and colleagues investigated the associations between lithium use during pregnancy and adverse pregnancy and neonatal outcomes.

Of the 854,017 women included in this analysis, 434 (0.05%) used lithium during pregnancy.  Compared to non-exposed controls, women using lithium during pregnancy had an increased risk of preterm birth (8.7% vs 3.0%; adjusted relative risk [aRR] 2.64; 95% CI 1.82-3.82) and large for gestational age infants (9.0% vs 3.5%; aRR 2.64, 95% CI 1.91-3.66). There was no association between lithium exposure and risk of preeclampsia or birth of a small for gestational age infant. 

These associations were significant after restricting the analysis to pregnant women with a diagnosed psychiatric illness (n=9552) and when comparing outcomes to a control group of women treated with lithium who elected to discontinue lithium prior to pregnancy.

Inconsistent Results Across Studies

In the current study including 434 lithium-exposed pregnancies, lithium use during pregnancy was associated with an increased risk of preterm birth and the birth of a large for gestational age infant. There was no association between lithium exposure and preeclampsia or the birth of a small for gestational age infant.

Previous studies have raised concerns regarding the impact of lithium on pregnancy outcomes; however, it is difficult to distinguish the effects of the medication from the effects of the underlying disorder. In a previous study analyzing data from the Medicaid Analytic eXtract and the outcomes of 874 lithium-exposed pregnancies, Cohen and colleagues were able to control for a wider range of potential confounders. After adjusting for these potential confounders, they found no association between lithium exposure and risk of several different negative pregnancy outcomes: preeclampsia, placental abruption, growth restriction and preterm birth.

In another study, Boden and colleagues analyzed pregnancy outcomes in women with bipolar disorder and concluded that bipolar disorder in women, whether treated with medication or not, was associated with worse pregnancy outcomes. The study suggests that while exposure to mood stabilizers during pregnancy may carry some risk, this exposure to medication is not the sole reason for adverse pregnancy outcomes in women with bipolar disorder, and it is important to note that the illness itself– or behaviors associated with having the illness– may also have a negative effect on pregnancy outcomes.

It’s Complicated

When counseling women with bipolar disorder who are pregnant or planning to conceive, we must focus on optimizing treatment during pregnancy, acknowledging that the avoidance of all medications is not necessarily the safest option. Women planning a pregnancy must be properly counseled regarding the risks of treatment versus the risks associated with the untreated psychiatric illness in the mother, and the woman’s health care provider plays an important role in weighing these individual risks and selecting the best options for treatment.

Lithium is not widely used; however, for a subset of women, it is a well-tolerated and efficacious treatment. For these women, there may not be effective alternatives. There is a well-documented increase in the risk of cardiac malformations associated with first trimester exposure to lithium. Based on the current available data, we must entertain the possibility that lithium is associated with certain adverse outcomes, including risk of preterm birth and large for gestational age; however, the findings are inconsistent. These potential risks must be balanced against the important benefit of treatment and should be used to guide shared decision-making.

Ruta Nonacs, MD, PhD

Hastie R, Tong S, Hiscock R, et al. Maternal lithium use and the risk of adverse pregnancy and neonatal outcomes: a Swedish population-based cohort study. BMC Med. 2021; 19(1):291.

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