A statewide retrospective cohort study from Victoria, Australia analyzed 867,454 births from 2009 to 2020, including 234 pregnancies with documented lithium exposure. The investigators examined several perinatal outcomes: spontaneous preterm birth (delivery before 37 weeks), large for gestational age (LGA) infants (birthweight >90th percentile), macrosomia (birthweight >4,000 g), and major congenital malformations, with a particular focus on congenital cardiac malformations.
Analyses adjusted for maternal age, parity, body mass index, smoking in pregnancy, and conception via assisted reproductive technology. To address confounding by indication, subgroup analyses were performed restricting the sample to women with a diagnosis of bipolar disorder and/or schizophrenia. An additional comparison contrasted women who continued lithium during pregnancy with those who had used lithium in the 12 months before pregnancy but discontinued prior to conception.
Compared with unexposed pregnancies, women exposed to lithium during pregnancy differed on multiple baseline characteristics: they were older, more likely to smoke during pregnancy, more likely to have conceived using reproductive technology, and more likely to have prescriptions for other psychotropic medications (antidepressants, antipsychotics, antiepileptics). They also had higher prevalences of pre-existing hypertension, pre-existing diabetes, or gestational diabetes.
Key reported associations included:
Spontaneous preterm birth: lithium exposure was associated with a two-fold increased risk (8.1% vs 2.4%; adjusted risk ratio [aRR] 2.18, 95% CI 1.45–3.30).
Large for gestational age (LGA): lithium exposure was associated with an increased risk of LGA infants (13.7% vs 6.4%; aRR 1.94, 95% CI 1.36–2.76).
Congenital cardiac malformations: lithium exposure was associated with an increased risk of cardiac malformations (3.0% vs 0.8%; aRR 2.64, 95% CI 1.26–5.53).
Major congenital malformations overall: the study did not find a statistically significant increase for major malformations as a whole (aRR 1.51, 95% CI 0.92–2.50), suggesting the excess risk may be concentrated in cardiac anomalies rather than reflecting broad teratogenicity.
When analyses were limited to women with bipolar disorder or schizophrenia, the increased risks for spontaneous preterm birth (aRR 1.88, 95% CI 1.06–3.32) and LGA (aRR 1.68, 95% CI 1.07–2.65) persisted, indicating these associations were not entirely explained by underlying psychiatric diagnosis. However, comparisons between women who continued lithium during pregnancy and those who had discontinued lithium in the year prior to conception did not show statistically significant associations, a finding that raises concern for residual confounding by illness severity or other unmeasured factors.
The Victorian cohort’s results parallel a prior Swedish population-based study from the same group, which similarly reported about a two-fold increased risk of spontaneous preterm birth and associations with LGA and congenital cardiac malformations. These newer findings reinforce a pattern observed in some large observational cohorts.
Conversely, a 2018 multinational meta-analysis pooling data from six cohorts across several countries did not find an increased risk of preterm birth when comparing lithium-exposed pregnancies with pregnancies in women with mood disorders who were not exposed to lithium. That discrepancy demonstrates heterogeneity in the literature and suggests that study design, sample size, covariate adjustment, and residual confounding may influence results.
Regarding congenital cardiac malformations, multiple prior studies and meta-analyses, including a large 2017 analysis, have reported an increased relative risk associated with first-trimester lithium exposure. These consistent findings indicate a cardiac-specific signal, although the absolute risk reported across studies remains low.
Lithium remains an important and effective mood stabilizer for some women with bipolar disorder, but its use in pregnancy requires individualized decision-making that balances maternal mental health needs against potential fetal risks. Key points to inform clinical discussions:
There is a reproducible signal across multiple studies of a small but statistically significant relative increase in the risk of congenital cardiac malformations with first-trimester lithium exposure; absolute risks are relatively low.
Some cohorts, including the recent Victorian study, report an increased risk of spontaneous preterm birth and of delivering an LGA infant with lithium exposure; other pooled analyses have not confirmed an increased preterm birth risk, so findings are heterogeneous.
Residual confounding by illness severity is difficult to eliminate in observational data. The lack of significant associations when comparing continuers with recent discontinuers suggests that differences between women who continue versus stop lithium may account for some observed risks.
Decisions about continuing or discontinuing lithium during pregnancy should weigh the risk of relapse and harms from untreated bipolar disorder against the measured fetal risks of exposure. For women who continue lithium, enhanced monitoring is advised, including fetal echocardiography and level 2 ultrasound to assess for cardiac malformations, and increased surveillance later in pregnancy for preterm labor or excessive fetal growth.
Roddy Mitchell A, Lindquist A, Hiscock RJ, Forsythe A, et al. Lithium Use in Pregnancy and the Risk of Spontaneous Preterm Birth: An Australian Statewide Retrospective Cohort Study. BJOG. 2026. (Reference cited in source)
Patorno E, Huybrechts KF, Bateman BT, et al. Lithium Use in Pregnancy and the Risk of Cardiac Malformations. N Engl J Med. 2017. (Reference cited in source)
Hastie R, Tong S, Hiscock R, et al. Maternal Lithium Use and the Risk of Adverse Pregnancy and Neonatal Outcomes. BMC Med. 2021. (Reference cited in source)
Munk-Olsen T, Liu X, Viktorin A, et al. Maternal and Infant Outcomes Associated With Lithium Use in Pregnancy: An International Collaborative Meta-Analysis. Lancet Psychiatry. 2018. (Reference cited in source)
Fornaro M, Maritan E, Ferranti R, et al. Lithium Exposure During Pregnancy and the Postpartum Period: A Systematic Review and Meta-Analysis. Am J Psychiatry. 2020. (Reference cited in source)