Lithium Exposure During Pregnancy and the Postpartum Period: A Systematic Review and Meta-Analysis of Safety and Efficacy Outcomes

Michele Fornaro, Elena Maritan, Roberta Ferranti, Leonardo Zaninotto, Alessandro Miola, Annalisa Anastasia, Andrea Murru, Eva Solé, Brendon Stubbs, André F Carvalho, Alessandro Serretti, Eduard Vieta, Paolo Fusar-Poli, Philip McGuire, Allan H Young, Paola Dazzan, Simone N Vigod, Christoph U Correll, Marco Solmi
American Journal of Psychiatry 2020 January 1, 177 (1): 76-92

OBJECTIVE: Uncertainty surrounds the risks of lithium use during pregnancy in women with bipolar disorder. The authors sought to provide a critical appraisal of the evidence related to the efficacy and safety of lithium treatment during the peripartum period, focusing on women with bipolar disorder and their offspring.

METHODS: The authors conducted a systematic review and random-effects meta-analysis assessing case-control, cohort, and interventional studies reporting on the safety (primary outcome, any congenital anomaly) or efficacy (primary outcome, mood relapse prevention) of lithium treatment during pregnancy and the postpartum period. The Newcastle-Ottawa Scale and the Cochrane risk of bias tools were used to assess the quality of available PubMed and Scopus records through October 2018.

RESULTS: Twenty-nine studies were included in the analyses (20 studies were of good quality, and six were of poor quality; one study had an unclear risk of bias, and two had a high risk of bias). Thirteen of the 29 studies could be included in the quantitative analysis. Lithium prescribed during pregnancy was associated with higher odds of any congenital anomaly (N=23,300, k=11; prevalence=4.1%, k=11; odds ratio=1.81, 95% CI=1.35-2.41; number needed to harm (NNH)=33, 95% CI=22-77) and of cardiac anomalies (N=1,348,475, k=12; prevalence=1.2%, k=9; odds ratio=1.86, 95% CI=1.16-2.96; NNH=71, 95% CI=48-167). Lithium exposure during the first trimester was associated with higher odds of spontaneous abortion (N=1,289, k=3, prevalence=8.1%; odds ratio=3.77, 95% CI=1.15-12.39; NNH=15, 95% CI=8-111). Comparing lithium-exposed with unexposed pregnancies, significance remained for any malformation (exposure during any pregnancy period or the first trimester) and cardiac malformations (exposure during the first trimester), but not for spontaneous abortion (exposure during the first trimester) and cardiac malformations (exposure during any pregnancy period). Lithium was more effective than no lithium in preventing postpartum relapse (N=48, k=2; odds ratio=0.16, 95% CI=0.03-0.89; number needed to treat=3, 95% CI=1-12). The qualitative synthesis showed that mothers with serum lithium levels <0.64 mEq/L and dosages <600 mg/day had more reactive newborns without an increased risk of cardiac malformations.

CONCLUSIONS: The risk associated with lithium exposure at any time during pregnancy is low, and the risk is higher for first-trimester or higher-dosage exposure. Ideally, pregnancy should be planned during remission from bipolar disorder and lithium prescribed within the lowest therapeutic range throughout pregnancy, particularly during the first trimester and the days immediately preceding delivery, balancing the safety and efficacy profile for the individual patient.

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