Expert: Ivan Goldberg, M.D. - 8/7/2009

Question
I have been diagnosed with a mild bipolar.  In order to relieve my symptoms I take 900mg of Lithium per day which I have been told based on my blood work is just above therapeutic.  My husband and I are ready to conceive but we are still getting mixed answered from doctors we have contacted regarding the safest course of action for myself and my child.  Can I remain on the Lithium during pregnancy at these levels.  Do you have other suggestions?  Thank you very much!

Answer
Hi Christie . . .

The use of lithium during pregnancy is very controversial. I suggest you read as much about it as you can. below are a few abstracts on the topic.

Best regards . . .

Ivan
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1: CNS Drugs. 2009;23(5):397-418. doi: 10.2165/00023210-200923050-00004.Related Articles, Links
Lithium: updated human knowledge using an evidence-based approach: part III: clinical safety.

Grandjean EM, Aubry JM.

Phidalsa Institute for Clinical Investigation, Geneva, Switzerland.

Lithium use in mental diseases has changed over the years but remains a cornerstone of treatment in bipolar disorders. In two companion papers, we have reviewed existing (and especially recent) data on lithium efficacy and updated basic knowledge regarding the practical fundamentals of lithium therapy. The present paper reviews safety data on lithium available to date. Gastrointestinal pain or discomfort, diarrhoea, tremor, polyuria, nocturnal urination, weight gain, oedema, flattening of affect and exacerbation of psoriasis are typical complaints of patients receiving long-term lithium therapy. Renal involvement results in a reduced urinary concentrating capacity, expressed as obligate polyuria, with secondary thirst. With long-term therapy, this may result in nephrogenic diabetes insipidus. In addition, glomerular filtration rate falls slightly in about 20% of patients. The view that only a few patients receiving long-term lithium are at increased risk of glomerular impairment and progressive renal insufficiency should be regarded with caution. The risk is increased in case of concomitant diseases or medications. Lithium treatment may inhibit thyroid hormone release and induce goitre. Consequently, the prevalence of both overt and subclinical hypothyroidism is increased, with circulating thyroid auto-antibodies frequently being found. Much less commonly, thyrotoxicosis may also develop in association with lithium therapy. Long-term lithium treatment may also be associated with persistent hyperparathyroidism and hypercalcaemia, as well as with hypermagnesaemia. Overweight of up to 4-10 kg is found in approximately 30% of lithium-treated patients. Most neurological manifestations are benign, for example, the fine postural and/or action tremor present in 4-20% of patients. This is increased by high caffeine consumption and concomitant use of other psychotropic agents. A number of rare, potentially serious neurological adverse effects have been reported, including extrapyramidal symptoms, 'pseudotumour cerebri' or occasionally cerebellar symptoms. Severe neurological sequelae are exceptional. Cognitive disturbances are often mentioned as a lithium-related adverse effect. The few controlled studies do show a statistically significant negative effect of lithium on memory, vigilance, reaction time and tracking. There are frequent reports of mild effects of lithium on cognition at therapeutic serum concentrations. A number of deaths associated with lithium treatment have been reported. The most serious issue is that of non-accidental overdose, i.e. either long-term overdosage or acute overdose on long-term treatment. Progressive renal insufficiency, an exceptional complication of long-term lithium therapy, may also have a fatal outcome. In relation to pregnancy, lithium salts are rated as category D (positive evidence of risk). Therefore, prescription of lithium should be avoided during the first trimester of pregnancy unless the benefit to the mother exceeds the risk to the fetus. Although lithium transfer into breast milk is well established, the long-term fate of babies breast-fed by mothers receiving lithium therapy is unknown. Whether lithium therapy is safe in breast-feeding women is controversial. Although there is no absolute contraindication, it is known that the kidney is particularly sensitive to lithium just after birth. Intoxication in patients on long-term treatment with lithium in the absence of history of acute ingestion is not rare. Contributing factors include change in daily dose, long-term high dosage, kidney disease or drug interaction. In suspected cases, serum concentrations should be obtained early and repeatedly. In addition to supportive measures, haemodialysis is the treatment of choice for severe cases. Thorough knowledge of the limitations and drawbacks of lithium therapy is mandatory for its optimal use, especially at a time when its risk/benefit profile needs to be compared accurately with that of antiepileptic drugs and other mood stabilizing medications.

PMID: 19453201 [PubMed - in process]

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2: Isr J Psychiatry Relat Sci. 2008;45(2):95-106.Related Articles, Links
Comment in:
Isr J Psychiatry Relat Sci. 2008;45(4):300-1; author reply 301.

Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review.

Yacobi S, Ornoy A.

Department of Anatomy and Cell Biology, The Hebrew University Hadassah Medical School, Jerusalem, Israel.

BACKGROUND: Lithium is a drug used mainly for the treatment of Bipolar Disorder (BD). Case reports and several retrospective studies have demonstrated possible teratogenicity, but the data in the different studies was inconclusive. METHODS: We summarized all published studies in English, including case reports. RESULTS: We found 24 case reports, of which six infants had congenital anomalies, five having cardiac anomalies, one of them being Ebstein's anomaly. In the retrospective studies there were, in the Lithium Baby Registry, 225 registered cases with 25 anomalies, 18 of them being cardiac, of which six had Ebstein's anomaly. An additional retrospective study on 59 cases found seven anomalies, four of them being cardiac. On the other hand, none of the prospective studies (296 liveborn infants) demonstrated any increase in the rate of congenital anomalies, although two had Ebstein's anomaly. All case control studies regarding Ebstein's anomaly were negative, and among 222 infants with Ebstein's anomaly and 44 with tricuspid atresia none of the mothers had taken lithium during pregnancy. CONCLUSIONS: Considering the serious limitations of the retrospective and case control studies that are also retrospective, lithium does not seem to be a significant teratogen, and hence should be given, if indicated, in pregnancy. It is, however, advisable to perform a fetal echocardiography to exclude the possibility of cardiac anomalies. Lamotrigine seems to be a possible alternative.

Publication Types:
Review

PMID: 18982835 [PubMed - indexed for MEDLINE]

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3: Curr Drug Saf. 2006 Jan;1(1):25-33.Related Articles, Links
The safety of medications for the treatment of bipolar disorder during pregnancy and the puerperium.

Dodd S, Berk M.

Department of Clinical and Biomedical Sciences - Barwon Health, University of Melbourne, Geelong, Australia. seetald@barwonhealth.org.au

Risks associated with pharmacological treatment of bipolar disorder are heightened during reproductive events. Treatments need to be planned with the mutual agreement of both the treating physician and the patient and tailored to the needs of the individual so as to minimise risk while providing adequate treatment. Conventional treatments have all been associated with teratogeny in first trimester exposure, lithium with cardiac malformation and valproate and carbamazepine with neural tube malformations. There have been an insufficient number of first trimester exposures to the newer anticonvulsant mood stabilisers, lamotrigine and oxcarbazepine, to determine whether there is a safety advantage in switching to these agents. Increasingly, atypical antipsychotics are being suggested as useful agents for the treatment of bipolar disorder. While not known to be teratogenic, there are other reproductive safety concerns associated with these agents. Bipolar disorder patients may be prescribed antidepressants, and many of these agents are associated with a low safety risk during reproductive events, however data regarding use of these agents are currently equivocal. Adverse outcomes from inadequate pharmacological prophylaxis have been documented for both the mother and the baby. Risks and benefits need to be carefully balanced based on an accurate review of the evidence.

Publication Types:
Review

PMID: 18690912 [PubMed - indexed for MEDLINE]

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4: Am J Psychiatry. 2005 Nov;162(11):2162-70.Related Articles, Links
Lithium placental passage and obstetrical outcome: implications for clinical management during late pregnancy.

Newport DJ, Viguera AC, Beach AJ, Ritchie JC, Cohen LS, Stowe ZN.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA. jeff.newport@emory.edu

OBJECTIVE: Lithium has been used during pregnancy for more than four decades, but quantification of fetal lithium exposure and clinical correlations of such exposure are limited. The study objectives were to 1) quantify the rate of lithium placental passage, 2) assess any association between plasma concentration of lithium at delivery and adverse perinatal events, and 3) determine whether lithium concentrations can be reduced by briefly suspending therapy proximate to delivery. METHOD: Maternal blood and umbilical cord blood were obtained at delivery for assay of lithium concentrations, and obstetrical outcome data were collected prospectively for 10 participants. These data were combined with results from MEDLINE and PsycINFO searches that identified 32 cases in which maternal lithium was administered throughout delivery. Statistical analysis of the pooled data was conducted. RESULTS: The ratio of lithium concentrations in umbilical cord blood to maternal blood (mean=1.05, SD=0.13) was uniform across a wide range of maternal concentrations (0.2-2.6 meq/liter). Significantly lower Apgar scores, longer hospital stays, and higher rates of CNS and neuromuscular complications were observed in infants with higher lithium concentrations (>0.64 meq/liter) at delivery. Withholding lithium therapy for 24-48 hours before delivery resulted in a 0.28 meq/liter reduction in maternal lithium concentration. CONCLUSIONS: Lithium completely equilibrates across the placenta. Higher lithium concentrations at delivery are associated with more perinatal complications, and lithium concentrations can be reduced by brief suspension of therapy proximate to delivery. Treatment guidelines are proposed to improve neonatal well-being when lithium use is indicated in late pregnancy.

Publication Types:
Research Support, N.I.H., Extramural

PMID: 16263858 [PubMed - indexed for MEDLINE]

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5: Am J Obstet Gynecol. 2002 Jul;187(1):245-9.Related Articles, Links
Case report and review of the perinatal implications of maternal lithium use.

Pinelli JM, Symington AJ, Cunningham KA, Paes BA.

School of Nursing and the Department of Pediatrics, McMaster University, Faculty of Health Sciences, Hamilton, Ontario Canada.

The purpose of this study was to review the use of lithium in pregnancy and its effects on the neonate. This was a case study and review of the published literature.Lithium is commonly used in the treatment of psychiatric disorders, specifically bipolar depression. Bipolar disorders that require treatment with lithium demand special consideration when the woman becomes pregnant. Reported neonatal problems with maternal lithium therapy include Ebstein's anomaly, poor respiratory effort and cyanosis, rhythm disturbances, nephrogenic diabetes insipidus, thyroid dysfunction, hypoglycemia, hypotonia and lethargy, hyperbilirubinemia, and large-for-gestational-age infants.Lithium can have adverse effects on the fetus and newborn infant, but data suggest normal behavioral patterns in childhood.

Publication Types:
Case Reports
Review

PMID: 12114921 [PubMed - indexed for MEDLINE]

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6: J Affect Disord. 2000 Dec;61(1-2):31-9.Related Articles, Links
Comment in:
J Affect Disord. 2002 Oct;72(1):107-8; author reply 103-5.

Protective effect of pregnancy in women with lithium-responsive bipolar disorder.

Grof P, Robbins W, Alda M, Berghoefer A, Vojtechovsky M, Nilsson A, Robertson C.

Department of Psychiatry, University of Ottawa, Ottawa, Canada. pgrof@rohcg.on.ca

BACKGROUND: Recent psychiatric literature, while indicating a high incidence of postpartum depression, contains a few clinical reports which support our observations that women with episodic bipolar disorder often remain well without treatment during pregnancy. Our retrospective study statistically examines the clinical course of 28 women with RDC typical bipolar disorder, type I, who became pregnant prior to receiving successful lithium prophylaxis. METHODS: We derived all data from the International Group for the Study of Lithium-treated Patients (IGSLI) database of excellent lithium responders. Data were compared both intraindividually, using data from three 9-month periods - immediately prior to pregnancy, pregnancy and postpartum - and interindividually, using never-pregnant women as controls. RESULTS: Intraindividual data show that women with typical bipolar disorder, type I, experience significantly fewer and shorter recurrences during pregnancy than either before or after. Interindividual comparisons indicate that the recurrence risk during pregnancy is markedly lower than the clinical course would predict. Moreover, the few recurrences observed during pregnancy all took place in the last 5 weeks. Limitations: Limiting cases to lithium responsive patients could have reduced heterogeneity and perhaps generalizability. CONCLUSIONS: The findings, nonetheless, indicate a marked improvement of the clinical course of typical bipolar disorder, type I, lithium-responsive, during pregnancy. Exploring the underlying protective mechanisms may lead to new understanding of the pathophysiology of mood disorders and to new approaches to treatment and prevention.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 11099738 [PubMed - indexed for MEDLINE]

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7: J Clin Psychiatry. 1998;59 Suppl 6:57-64; discussion 65.Related Articles, Links
The use of lithium and management of women with bipolar disorder during pregnancy and lactation.

Llewellyn A, Stowe ZN, Strader JR Jr.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.

The introduction of lithium salts almost a century ago and the subsequent approval of lithium carbonate for the treatment of patients with bipolar disorder represent one of the cornerstones of modern psychopharmacology. The onset of bipolar disorder in women often occurs during the childbearing years, which complicates the treatment decisions secondary to the possibility of conception while taking medication. The establishment of the lithium registry for fetal teratogenesis in the late 1960s ushered in a heightened level of concern for the use of lithium during the reproductive years; although, in the years to come, it has become apparent that alternative pharmacologic treatments for bipolar disorder may exceed the teratogenic risk of lithium monotherapy. In this paper, the available data on the use of antimanic medications during pregnancy and lactation are reviewed with an emphasis on providing a realistic risk/benefit assessment for medication selection and management of these patients. Treatment strategies are discussed for (1) women who are contemplating pregnancy (2) women who inadvertently conceive while taking medications (3) women who choose to become pregnant while taking medication, and (4) women who intend to breastfeed while taking medications.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 9674938 [PubMed - indexed for MEDLINE]

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8: Pharmacopsychiatry. 1992 Jul;25(4):187-91.Related Articles, Links
Bipolar illness, lithium prophylaxis, and pregnancy.

van Gent EM, Verhoeven WM.

Willem Arntsz Huis, Utrecht, The Netherlands.

In advising bipolar patients wishing to become pregnant, Weinstein's guidelines were extended to seven stages: contraceptive measures; genetic counseling; discontinuing lithium in the first trimester or prescribing alternatives; ultrasound scanning for congenital anomalies, low lithium levels during pregnancy; discontinuing lithium at the end of pregnancy; starting immediately after birth, no breast feeding, observation of the neonate in the neonatal ward; and close observation of the patient in the follow-up year. Of the 15 bipolar patients, 11 gave birth to healthy children (five of them twice). Most patients knew nothing about the inheritance of bipolar illness. Four made no further attempt to become pregnant: two in view of a serious possibility of inheritance, the other two after a severe relapse. Three patients chose an alternative to lithium medication (carbamazepine and haloperidol). Postpartum, 27% of the patients who used medication relapsed and 60% of the patients who used none relapsed.

PMID: 1528958 [PubMed - indexed for MEDLINE]

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9: J Clin Psychiatry. 1990 Oct;51(10):410-3.Related Articles, Links
Lithium treatment during pregnancy, delivery, and lactation: an update.

Schou M.

Psychiatric Hospital, Risskov, Denmark.

Because prophylactic lithium treatment is often given to manic depressive women of fertile age, the answers to five questions are pressing: (1) Does lithium administration during pregnancy expose the unborn child to risk of malformations? (2) Does such exposure lead to later developmental anomalies? (3) Do changes in the pharmacokinetics of lithium during pregnancy and delivery require special precautions? (4) Does lithium treatment during pregnancy exert other effects? (5) Is it advisable that women in lithium treatment breastfeed their infants? The author discusses these questions in the light of present-day knowledge and proposes guidelines for lithium treatment during pregnancy, delivery, and lactation.

Publication Types:
Review

PMID: 2211538 [PubMed - indexed for MEDLINE]