Michele Fornaro1, Elena Maritan1, Roberta Ferranti1, Leonardo Zaninotto1, Alessandro Miola1, Annalisa Anastasia1, Andrea Murru1, Eva Solé1, Brendon Stubbs1, André F Carvalho1, Alessandro Serretti1, Eduard Vieta1, Paolo Fusar-Poli1, Philip McGuire1, Allan H Young1, Paola Dazzan1, Simone N Vigod1, Christoph U Correll1, Marco Solmi1. 1. Departments of Neuroscience, Reproductive Science, and Dental Science and Section of Psychiatry, University School of Medicine "Federico II," Naples (Fornaro); Department of Neurosciences, University of Padua, Padua, Italy (Maritan, Miola, Solmi); Department of Mental Health, Local Health Unit 6 "Euganea," Padua (Ferranti, Zaninotto); National Social Security Institute, Latina, Italy (Anastasia); Department of Psychiatry and Psychology, Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain (Murru, Solé, Vieta); Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London (Stubbs); Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, and South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, U.K. (Stubbs, Young); Centre for Addiction and Mental Health, Toronto (Carvalho); Department of Psychiatry, University of Bologna, Bologna, Italy (Serretti); Early Psychosis: Interventions and Clinical Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Fusar-Poli, McGuire, Dazzan, Solmi); OASIS service, South London and Maudsley NHS Foundation Trust, London (Fusar-Poli); Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy (Fusar-Poli); Women's College Research Institute and Department of Psychiatry, Women's College Hospital, Toronto, and Department of Psychiatry, Faculty of Medicine and Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto (Vigod); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y. (Correll); Department of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, N.Y. (Correll); Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll); Padova Neuroscience Center, University of Padua, Padua (Solmi).
Abstract
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.
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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