Lithium Use in Pregnancy and the Risk of Spontaneous Preterm Birth: An Australian Statewide Retrospective Cohort Study

OBJECTIVE: To investigate whether lithium exposure in pregnancy is associated with spontaneous preterm birth, congenital malformations and abnormal fetal growth. DESIGN: Statewide retrospective cohort study. SETTING: Victoria, Australia. POPULATION: 867 454 births (2009-2020), including 234 (0.03%) exposed to lithium during pregnancy. METHODS: Inverse probability weighted regression adjustment to investigate the association between maternal lithium use and perinatal outcomes. MAIN OUTCOME MEASURES: Spontaneous preterm birth (< 37 weeks' gestation), large for gestational age (LGA) (birthweight > 90th percentile), macrosomia (birthweight > 4000 g), major congenital malformations, congenital cardiac malformations. RESULTS: Lithium use was associated a two-fold increased risk of spontaneous preterm birth compared with unexposed pregnancies (8.1% vs. 2.4%; adjusted relative risk [aRR] 2.18, 95% CI 1.45-3.30). Lithium was associated with an increased risk of an LGA infant (13.7% vs. 6.4%; aRR 1.94, 95% CI 1.36-2.76), and congenital cardiac malformations (3.0% vs. 0.8%; aRR 2.64, 95% CI 1.26-5.53). Lithium was not associated with an altered risk of major congenital malformations overall (aRR 1.51, 95% CI 0.92-2.50). Restricting the cohort to women with bipolar disorder or schizophrenia diagnoses, associations remained between lithium exposure and spontaneous preterm birth (aRR 1.88, 95% CI 1.06-3.32) and birth of an LGA infant (aRR 1.68, 95% CI 1.07-2.65). CONCLUSIONS: In our study, lithium exposure during pregnancy was associated with a two-fold increased risk of spontaneous preterm birth. Lithium use was also associated with an increased risk of cardiac malformations and having an LGA infant. These findings may be useful for shared decision-making around lithium use during pregnancy.