For women with bipolar disorder, choosing whether to maintain or discontinue treatment with a mood stabilizer during pregnancy is challenging. This is a process which requires careful and thoughtful consideration, weighing the risk of adverse outcomes associated with exposure to a particular drug against the risk of recurrent illness in the setting of medication discontinuation.
Lithium is commonly used as a mood stabilizer in women with bipolar disorder. Most of the research on the use of lithium during pregnancy has focused on its teratogenicity, highlighting a small but statistically significant increase in the incidence of cardiac malformations in lithium-exposed infants. Far less research has addressed the long-term effects of lithium exposure on the developing fetus. A recent study from Poels and colleagues at the Leiden University Medical Center in the Netherlands looks at the impact of lithium exposure on IQ and neuropsychological functioning.
This study included children (aged 6 to 14 years) born to women with a diagnosis of bipolar disorder. From patients seen at the Leiden University Medical Center, a structured screening of the electronic medical record was performed in order to identify all women who consulted one of the perinatal psychiatry centers and gave birth to a living child between 2003 and 2011. Offspring with lithium exposure during pregnancy were selected, as well as a disease-matched lithium-unexposed group.
A total of 99 children participated in the study: 56 with exposure to lithium in utero and 43 with no exposure to lithium. Neuropsychological tests were administered, including the Snijders-Oomen Nonverbal Intelligence Test and the NEPSY-II-NL assessment.
The researchers first examined the association between prenatal lithium exposure and neuropsychological functioning. There was no association between prenatal lithium exposure and IQ. Multiple neuropsychological domains were investigated. In an unadjusted analysis, exposure to lithium during pregnancy was associated with an increased total number of mistakes made on the Auditory Attention task; however, this finding was no longer significant after fully adjusting for potential confounding factors.
The study also examined the association between lithium blood levels during pregnancy and neuropsychological functioning. They did not find a relationship between lithium blood levels during pregnancy and IQ or neuropsychological test outcomes. Because only 61% of the patients had data regarding lithium levels during pregnancy, this analysis was underpowered.
Interestingly, the researchers observed that, compared to unexposed children, those within the lithium-exposed group were more likely to have psychiatric disorders (19.6% vs. 11.6%) and learning disabilities (22.2% vs. 11.6%). Since this finding was outside the scope of this study, no statistical tests were performed to further analyze these differences. However, the authors did note that these differences may reflect differences in the severity of the illness in the mothers, specifically that mothers in the lithium-exposed group are more likely to have more severe illness.
These findings are consistent with previous studies using different standardized assessments:
Forsberg and colleagues (2018) found no differences in full scale IQ (FSIQ), verbal IQ (VIQ) and performance IQ (PIQ) between lithium-exposed and non-exposed children, using the Wechsler Preschool and Primary Scale of Intelligence 3rd edition. However, children exposed to major mood disorder during pregnancy, with or without lithium exposure, had significantly lower scores on the processing speed quotient (PSQ).
Van der Lugt and colleagues (2012) found no abnormalities in Verbal Intelligence Quotient, Performance Intelligence Quotient and Total Intelligence Quotient (Wechsler Preschool and Primary Scale of Intelligence or the Wechsler Intelligence Scale for Children), by comparing outcomes of lithium-exposed children with norm scores. For two children aged between 16 and 30 months, no abnormalities were found in the Bayley Scales of Infant Development. The authors note, however, that many children had (non-significant) lower scores on the performance tests, especially on the subtest block patterns. The block patterns subtest mainly measures spatial visualisation ability and also requires visuomotor coordination.
This is the largest study thus far to address the long-term neurodevelopmental effects of lithium exposure. Another strength of this study is its reliance on validated tests for the assessment of IQ and neuropsychological functioning in six different cognitive domains. While the findings are generally reassuring with regard to the long-term effects of lithium, further study is necessary so that women using lithium may make well-informed decisions regarding the use of lithium during pregnancy.
Ruta Nonacs, MD PhD
Forsberg L, Adler M, Romer Ek I, et al. Maternal mood disorders and lithium exposure in utero were not associated with poor cognitive development during childhood. Acta Paediatr. 2018; 107(8): 1379- 1388.
Poels EMP, Schrijver L, White TJH, Roza SJ, Zarchev MG, Bijma H, Honig A, van Kamp IL, Hoogendijk WJG, Kamperman AM, Bergink V. The effect of prenatal lithium exposure on the neuropsychological development of the child. Bipolar Disord. 2021 Sep 29.
Van der Lugt NM, van de Maat JS, van Kamp IL, Knoppert-van der Klein EA, Hovens JG, Walther FJ. Fetal, neonatal and developmental outcomes of lithium-exposed pregnancies. Early Hum Dev. 2012; 88(6): 375- 378.