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Lithium 

From: Exposure to Psychotropic Medications and Other Substances during Pregnancy and Lactation: A Handbook for Health Care Providers

Examples

Carbolith, Duralith, Lithane, Lithizine

Lithium is an anti-manic medication used to treat bipolar disorder,* which affects more than 444,000 (2.6%) Canadians between 25 and 64 years of age.1

Bipolar disorder usually begins in late adolescence and often first appears as depression during the teenage years, though it can also begin in early childhood or later in life. An equal number of men and women develop the illness, which is found among all ages, races, ethnic groups and social classes. A significant number of women of childbearing age suffer from bipolar disorder and may therefore require treatment with lithium.

Early information about the teratogenic risk associated with lithium exposure during pregnancy came from biased retrospective reports.2 More recent epidemiological data indicates that the risk is much lower than previously suggested.3

*Lithium can also be used as adjunct therapy for several other treatment-refractory disorders.

Summary and Recommendations

  • A level II ultrasound and fetal echocardiogram can be performed at 16 to 18 weeks gestation to rule out cardiac anomalies.
  • Toxic effects can be minimized by monitoring serum lithium levels and keeping minimally effective plasma levels throughout gestation, particularly during the last month of pregnancy. In addition, briefly suspending lithium therapy prior to delivery can reduce perinatal complications. Specialized pediatric personnel should be available at the time of delivery, especially for women on high doses.
  • Suspending therapy in the first trimester of pregnancy may be an option for some women with mild to moderate illness, or for women with a long history of euthymia during pre-pregnancy treatment. However, treatment should be reintroduced either in later pregnancy or immediately postpartum.
  • The newborn should be monitored carefully for possible lithium toxicity, which can include cyanosis, hypotonia, bradycardia, thyroid depression with goitre, atrial flutter, cardiomegaly, hepatomegaly and diabetes insipidus. These toxic effects are usually self-limiting and resolve upon renal excretion of the drug within one to two weeks.
  • Women who are committed to breastfeeding need to be informed that therapeutic drug monitoring of lithium in their breast milk and/or in their infant’s blood (e.g., regular blood tests), coupled with close monitoring of adverse effects, will be necessary as long as they continue to breastfeed.

Fetal effects

Lithium has been associated with an increase in birth weight.4

Major malformations

By 1983, the International Registry of Lithium-Exposed Babies reported a total of 225 cases of children whose mothers who took lithium while pregnant.2 Evaluation of the registry at that time revealed that the number of cases of Ebstein’s anomaly far exceeded the spontaneous occurrence in the general population. However, there were no population-based, prospective, controlled studies to compare the occurrence rate of Ebstein’s or to ascertain the actual incidence.

In 1992, one study recruited and followed 148 women who took lithium during their first trimester. Pregnancy outcome was compared with that of controls, who were matched for maternal age. Rates of major congenital malformations did not differ between the lithium (2.8 per cent) and control (2.4 per cent) groups. One woman in the lithium group chose to terminate her pregnancy after a prenatal echocardiogram detected Ebstein’s anomaly.3

In another cohort of 59 children who had been exposed to lithium in utero, four (i.e., 6.8 per cent) had congenital heart disease but none had Ebstein’s anomaly.5 In a case-control study of children with cardiac defects, including 25 cases of Ebstein’s anomaly, none of the mothers had been exposed to lithium.6

These results appear to indicate that lithium is not a major human teratogen, and that the risk for Ebstein’s anomaly is 0.05 per cent (i.e., one in 2,000) for babies whose mothers take lithium during pregnancy. A further review—upon analysis of the results of various cohort, prospective and retrospective studies and a small number of case reports—indicates that lithium is a “weak” human teratogen. The malformations mainly attributable to lithium are cardiac defects. There is a possibility that lithium may be associated with Ebstein’s anomaly, but present evidence cannot definitely confirm or rule out this connection.4,7

Spontaneous abortion

No studies have examined whether lithium use results in an increased risk for spontaneous abortion.

Neonatal effects

Lithium completely equilibrates across the placenta. Higher lithium levels at the time of delivery are associated with increased perinatal complications.8 Specifically, a review of the literature published from 1978 to 2004 identifies 30 babies (with adequate clinical description) who were exposed to lithium during gestation. A substantial number of these babies presented with neurodevelopmental deficits and depressed neurological status during the neonatal period, including hypotonia, respiratory distress syndrome, cyanosis, lethargy, and weak suck and Moro reflexes. The majority of these adverse effects resolved and most babies made a full recovery.4

Long-term effects on the child

There are no reports of long-term effects on children whose mothers took lithium during pregnancy.

Breastfeeding

In the past, lithium has typically been contraindicated for use in lactating women because of early reports suggesting high excretion into breast milk. A relatively recent study conducted to ascertain the excretion of lithium into human milk and to assess infant safety after breastfeeding found that lithium excretion in breast milk varies widely (from zero to 30 per cent of the maternal dose) from woman to woman.9

Withdrawal effects on the mother

Several reports have documented symptoms of abrupt discontinuation of lithium (e.g., rapid reoccurrence of mania). One review described 14 people who discontinued lithium abruptly, seven of whom subsequently became manic within 13 to 19 days. This review also identified depression and suicidal behaviour in the participants.10 Another study stated that three of 18 participants studied relapsed within four days of lithium being abruptly discontinued; several others exhibited hand tremors, polyuria, general muscular weakness, polydipsia and dry mouth.11

Effects of untreated illness

Pregnancy does not protect against mood fluctuations in untreated women. Maintenance of euthymia during pregnancy is critical because relapse during this period strongly predicts a difficult postpartum course.

One study comparing pregnant and non-pregnant women with bipolar disorder found similar rates of recurrence after discontinuation of lithium in the first 40 weeks, but the pregnant women had a high risk of recurrence during the postpartum period.12

References

  1. Wilkins, K. (2004). Bipolar I disorder, social support and work. Supplement to Health Reports, 15, 23–41. Ottawa: Statistics Canada. (Catalogue No. 82-003)
  2. Linden, S. & Rich, C.L. (1983). The use of lithium during pregnancy and lactation. Journal of Clinical Psychiatry, 44 (10), 358–361.
  3. Jacobson, S.J., Jones, K., Johnson, K., Ceolin, L., Kaur, P., Sahn, D. et al. (1992). Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester. Lancet, 339 (8792), 530–533.
  4. Giles, J.J. & Bannigan, J.G. (2006). Teratogenic and developmental effects of lithium [Review]. Current Pharmaceutical Design, 12 (12), 1531–1541.
  5. Warkany, J. (1988). Teratogen update: Lithium. Teratology, 38 (6), 593–597.
  6. Källén, B. & Tandberg, A., (1983). Lithium and pregnancy. A cohort study on manic-depressive women. Acta Psychiatrica Scandinavica, 68 (2), 134–139.
  7. Cohen, L.S., Friedman, J.M., Jefferson, J.W., Johnson, E.M. & Weiner, M.L. (1994). A re-evaluation of risk of in utero exposure to lithium. Journal of the American Medical Association, 271 (123), 1828–1829.
  8. Newport, D.J., Viguera, A.C., Beach, A.J., Ritchie, J.C., Cohen, L.S. & Stowe, Z.N. (2005). Lithium placental passage and obstetrical outcome: Implications for clinical management during late pregnancy. American Journal of Psychiatry, 162 (11), 2162–2170.
  9. Moretti, M.E., Koren, G., Verjee, Z. & Ito, S. (2003). Monitoring lithium in breast milk: An individualized approach for breast-feeding mothers. Therapeutic Drug Monitoring, 25 (3), 364–366.
  10. Mander, A.J. & Loudon, J.B. (1988). Rapid recurrence of mania following abrupt discontinuation of lithium. Lancet, 2 (8601), 15–17.
  11. Baldessarini, R.J., Suppes, T. & Tondo, L. (1996). Lithium withdrawal in bipolar disorder: Implications for clinical practice and experimental therapeutics research. American Journal of Therapeutics, 3 (7), 492–496.
  12. Viguera, A.C., Nonacs, R., Cohen, L.S., Tondo, L., Murray, A. & Baldessarini, R.J. (2000). Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. American Journal of Psychiatry, 157 (2), 179–184.

Exposure to Psychotropic Medications and Other Substances during Pregnancy and Lactation: A Handbook for Health Care Providers

General issues and background

Psychotropic medications and other substances: Properties, effects and recommendations

Resources

Index of drugs

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