Background
Lithium during pregnancy
Efficacy
Dosing and monitoring of blood levels during pregnancy and around delivery
Obstetric complications
Study | Design | Sample size | Findings |
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Petersen et al. (2016) | Registry-based study | Exposed = 35 Disease matched non-exposed = 84 Controls = 320.853 | No difference in the rate of caesarean sections |
Frayne et al. (2017) | Cohort study | Exposed = 33 | No difference in the rate of obstetric complications between the women that continued (n = 19) or discontinued (n = 14) lithium |
Munk-Olsen et al. (2018) | Meta-analysis (six study sites) | Exposed = 727 Disease matched controls = 21,397 | No association between lithium exposure in utero and preeclampsia (OR 0.97, 95% CI 0.52–1.80), gestational diabetes (OR 1.20, 95% CI 0.81–1.78), fetal distress (OR 1.00, 95% CI 0.76–1.32), postpartum hemorrhage (OR 1.28, 95% CI 0.64–2.57) and caesarean section (OR 0.94, 95% CI 0.66–1.33) |
Consequences for the developing child
Congenital malformations
Study | Design | Sample size | Findings |
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Schou et al. (1973) | Cohort study | Exposed = 118 | Nine children with congenital malformations, of which six with cardiovascular malformations |
Nora et al. (1974) | Retrospective cohort study | Teratogenic history obtained in 733 women | Two lithium exposed pregnancies and both children were born with Ebstein anomaly |
Weinstein and Goldfield (1975) | Cohort study | Exposed = 143 | Cardiovascular abnormalities found in 9.1% of cases of exposure to lithium in 1st trimester |
Kallen and Tandberg (1983) | Registry-based study | Exposed = 59 Other drugs = 38 Disease matched non-exposed = 80 Controls = 110 | Four children with heart defects after lithium exposure. No cases of Ebstein anomaly |
Jacobson et al. (1992) | Prospective cohort study | Exposed = 138 Controls = 148 | No difference in the rate of major malformations |
Reis and Kallen (2008) | Registry-based study | Exposed = 79 | Eight children with congenital malformations, of which four with cardiac malformations |
Diav-citrin et al. (2014) | Prospective cohort study | Exposed = 183 Disease matched non-exposed = 72 Controls = 748 | Single center comparison: no difference in major malformations, increased risk of cardiovascular malformations (RR 7.23, 95% CI 1.97–26.53), not after excluding cases that spontaneously resolved (RR 5.78, 95% CI 0.82–40.65) |
Patorno et al. (2017) | Registry-based study | Exposed = 663 Lamotrigine = 1945 Controls = 1,322,955 | Increased risk of cardiac malformations after first trimester lithium exposure compared to controls (RR 1.65, 95% CI 1.02–2.68) and lamotrigine-exposed (RR 2.25, 95% CI 1.17–4.34) |
Munk-Olsen et al. (2018) | Meta-analysis (six study sites) | Exposed = 727 Disease matched controls = 21,397 | First trimester lithium exposure was statistically significant associated with congenital malformations (OR 1.62, 95% CI 1.12–2.33) but not with cardiac malformations in specific (OR 1.54, 95% CI 0.64–3.70) |
Neonatal outcomes
Study | Design | Sample size | Findings |
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Jacobson et al. (1992) | Prospective cohort study | Exposed = 138 Controls = 148 | No difference in the rate of preterm birth Higher birthweight in lithium exposed neonates |
Troyer et al. (1993) | Cohort study | Exposed = 60 Disease matched non-exposed = 290 | Cohort of manic-depressive women: risk ratio for prematurity of 2.54 No difference in birthweight |
Cohort study | Exposed = 24 | Lower Apgar scores, longer hospital stays and higher rates of CNS and neuromuscular complications in infants with high lithium levels No statistically significant association with preterm birth or low birth weight | |
Diav-citrin et al. (2014) | Prospective cohort study | Exposed = 183 Disease matched non-exposed = 72 Controls = 748 | 2.3 times higher rate of preterm delivery in exposed group (13.7% versus 6.0%) No differences in birth weight |
Frayne et al. 2017 | Cohort study | Exposed = 19 | Eight neonates admitted to a special care unit |
Munk-Olsen et al. (2018) | Meta-analysis (six study sites) | Exposed = 727 Disease matched controls = 21,397 | No association between lithium exposure in utero and preterm birth (OR 1.24, 95% CI 0.83–1.84), low birth weight (OR 0.98, 95% CI 0.72–1.35) or small for gestational age (OR 0.90, 95% CI 0.67–1.21) A significant higher rate of neonatal admission (OR 1.62, 95% CI 1.12–2.33) |
Long term developmental outcome
Study | Design | Sample size | Follow-up | Findings |
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Schou (1976) | Prospective cohort study | Exposed = 60 Controls = 57 | Mean = 7 years | No difference in development based on questionnaire filled out by the mother |
Jacobson et al. (1992) | Prospective cohort study | Exposed = 22 Controls = n.r. | 1–9 years, mean = 61 weeks | No difference in attainment of milestones |
van der Lugt et al. (2012) | Cohort study | Exposed = 15 | 3–15 years | Normal developmental milestones (n = 15), minor neurological dysfunction (n = 1), low verbal + total IQ, normal performance IQ (n = 1), subclinical anxiety problems (n = 2), subclinical oppositional problems (n = 1) |
Forsberg et al. (2017) | Cohort study | Exposed = 20 Disease matched non-exposed = 8 Controls = 11 | 4–5 years | No differences in total, performance and verbal IQ |
Lithium use during pregnancy
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Maintenance of lithium during pregnancy is effective in the prevention of relapse during pregnancy and the postpartum period.
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The first and second trimester are characterized by a significant decrease in blood levels for lithium.
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Fetal anomaly ultrasound including detailed fetal cardiac scanning, should be offered at 20 weeks gestational age.
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In the third trimester, weekly monitoring of lithium blood levels is recommended. Preferably, lithium blood levels should be measured before and 24 h after delivery.
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Lithium blood level, TSH and free T4 should be evaluated in umbilical cord blood sample.
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Lithium use during pregnancy has not been associated with obstetric complications. However, the association with preterm birth and birthweight remains uncertain.
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Lithium exposure during the first trimester is associated with congenital malformations in several studies, recent studies estimate the risk lower than previously reported. Tapering of lithium during the first trimester should be considered but weighed against the risks of relapse.
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Lithium exposure is associated with increased risk of neonatal complications. Lithium-exposed neonates should be observed directly post-delivery.
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Little is known about the developmental consequences of intrauterine exposure to lithium.
Lithium use postpartum
Efficacy
Dosing and monitoring of blood level
Breastfeeding
Study | Design | Sample size | Findings |
---|---|---|---|
Schou et al. (1973) | Case series | 8 mother–infant pairs | Infant/maternal serum lithium concentration of 1/2 in first week and 1/3 during the following weeks |
Sykes et al. (1976) | Case report | 1 mother–infant pair | Breast milk lithium level of 1/4 of maternal serum level, infant had good excretion of lithium into urine |
Moretti et al. (2003) | Case series | 11 mother–infant pairs | Infant lithium dose of 0–30% of the maternal dose/kg Infant serum level of 17–50% of maternal serum level |
Case series | 10 mother–infant pairs | Mean infant serum level of 0.16 meq/L (range 0.09–0.25) In four infants: transient elevations of TSH, blood urea nitrogen and creatinine | |
Bogen et al. (2012) | Case series | 3 mothers with 4 infants | Infant lithium levels ranged from 10 to 17% of maternal levels at 1 month postpartum |
Frew (2015) | Case report | 1 mother–infant pair | Infant/maternal serum lithium concentration ratio of 0.58. No adverse events |
Lithium use postpartum
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When lithium is discontinued during pregnancy, lithium should be restarted immediately after delivery and is an effective strategy for relapse prevention in the immediate postpartum.
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For women with an isolated episode of postpartum psychosis or mania in history lithium prophylaxis immediately after delivery is effective for relapse prevention, there is no need to use lithium during pregnancy.
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Consider a high target therapeutic lithium level immediately after delivery and during the first month postpartum to optimize relapse prevention (e.g., 0.8–1.0 mmol/L).
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Obtain lithium blood levels twice weekly during the first 2 weeks postpartum.
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Breastfeeding while taking lithium is not recommended.