Highlight
- Lithium exposure during pregnancy is associated with a two-fold increased risk of spontaneous preterm birth.
- Use of lithium is linked to a higher incidence of congenital cardiac malformations and large-for-gestational-age (LGA) infants.
- No significant association was found between lithium and overall major congenital malformations.
- Findings persist even when analysis is limited to women diagnosed with bipolar disorder or schizophrenia, highlighting clinical complexity.
Study Background
Lithium remains a cornerstone in the management of bipolar disorder and other mood disorders, known for its efficacy in mood stabilization and prevention of relapse. However, its use during pregnancy presents a clinical dilemma due to concerns about fetal safety and adverse perinatal outcomes. Preterm birth—particularly spontaneous preterm delivery—is a critical contributor to neonatal morbidity and mortality globally. Additionally, concerns about teratogenicity, including congenital malformations and abnormal fetal growth parameters, necessitate an evidence-based evaluation of lithium exposure impacts during pregnancy. In this context, robust population-based data are essential to guide clinical decision-making and counseling.
Study Design
This investigation was a statewide retrospective cohort study conducted in Victoria, Australia, including all recorded births from 2009 to 2020. The cohort encompassed 867,454 births, of which 234 (0.03%) had documented maternal lithium exposure during pregnancy. The study applied inverse probability weighted regression adjustment to control for confounding factors, assessing associations between lithium exposure and adverse perinatal outcomes.
Key outcomes measured were spontaneous preterm birth (defined as birth before 37 weeks’ gestation without medical induction), large for gestational age infants (birthweight above the 90th percentile), macrosomia (birthweight > 4000 g), major congenital malformations overall, and specifically congenital cardiac malformations.
Key Findings
The primary finding was a statistically significant two-fold increased risk of spontaneous preterm birth among lithium-exposed pregnancies compared with unexposed pregnancies (8.1% vs. 2.4%; adjusted relative risk [aRR] 2.18, 95% confidence interval [CI] 1.45–3.30). This substantial elevation underscores a clinically important association that may influence perinatal outcomes.
Regarding fetal growth, lithium exposure was associated with an increased risk of delivering an LGA infant (13.7% vs. 6.4%; aRR 1.94, 95% CI 1.36–2.76), suggesting that lithium may influence in utero growth trajectories. Macrosomia was reported but not highlighted as significantly altered.
As for congenital anomalies, lithium was associated with a higher risk of congenital cardiac malformations (3.0% vs. 0.8%; aRR 2.64, 95% CI 1.26–5.53), echoing previous concerns about lithium’s teratogenic potential in cardiac development. However, when considering major congenital malformations overall, the association did not reach statistical significance (aRR 1.51, 95% CI 0.92–2.50), indicating the risk may be specific to cardiac anomalies rather than a broad teratogenic effect.
Importantly, sensitivity analyses restricting the population to women diagnosed with bipolar disorder or schizophrenia maintained the associations with spontaneous preterm birth (aRR 1.88, 95% CI 1.06–3.32) and LGA infants (aRR 1.68, 95% CI 1.07–2.65), suggesting that the findings are not solely attributable to underlying psychiatric diagnoses or their confounders.
Expert Commentary
The study by Mitchell et al. contributes significant real-world evidence to the complex risk-benefit framework surrounding lithium use in pregnancy. The robust sample size and use of statistical methods to address confounding enhance the validity of findings. These data reinforce existing caution about lithium-associated teratogenic cardiac risks while highlighting an emergent concern about spontaneous preterm birth risk, an outcome with profound neonatal implications.
While the increased risk of LGA infants might reflect lithium’s pharmacologic effects on fetal growth or placental function, the mechanisms remain to be elucidated. Clinicians should weigh these risks against the severe maternal relapse risk when lithium is discontinued, which itself can jeopardize maternal and fetal health.
Limitations of retrospective cohort designs apply, such as potential misclassification or residual confounding by unmeasured factors including lithium dosage, timing of exposure, adherence, and concomitant medications. Furthermore, generalizability to other populations should be approached cautiously given regional differences in obstetric care and psychiatric management.
Conclusion
This population-based study highlights that lithium use during pregnancy is associated with a doubling of spontaneous preterm birth risk and increased risk of cardiac malformations and excessive fetal growth. These findings underscore the importance of comprehensive preconception counseling and shared decision-making involving psychiatric and obstetric specialists. Consideration of alternative mood stabilizers, close fetal monitoring, and tailored obstetric management may be warranted. Future prospective studies focusing on timing, dosage, and mechanisms underlying these associations are needed to further optimize maternal and neonatal outcomes.
Funding and ClinicalTrials.gov
The study was conducted using statewide data from Victoria, Australia. No specific funding information or clinical trial registration was provided in the original publication.
References
- Mitchell AR, Lindquist A, Hiscock RJ, et al. Lithium Use in Pregnancy and the Risk of Spontaneous Preterm Birth: An Australian Statewide Retrospective Cohort Study. BJOG. 2026 Jul 7. PMID: 42415243.
- Munk-Olsen T, Laursen TM, Pedersen CB, Olsen J, Mortensen PB, Vestergaard M. Risks and benefits of lithium treatment in pregnancy: a review. Acta Psychiatr Scand. 2012;126(1):2–13.
- Huybrechts KF, Leonard SA, Stein CR, et al. Lithium Use in Pregnancy and the Risk of Cardiac Malformations. N Engl J Med. 2016;375(23):2245–2254.
- Yonkers KA, Wisner KL, Stewart DE, et al. The management of bipolar disorder in pregnancy and childbirth: a review. JAMA Psychiatry. 2011;68(11):1091–1100.