Published: 7 March 2019

Publications

Lithium and pregnancy

Prescriber Update 40(1): 4–6
March 2019

Background

Lithium is a mood stabiliser used in the treatment of bipolar disorder¹. The use of lithium in pregnancy was recently reviewed by the Medicines Adverse Reactions Committee (MARC) following the publication of new information².

Inconsistent results from clinical studies and a lack of studies with sufficient power to confidently describe the level of risk have led to uncertainty about whether women with bipolar disorder should take lithium during pregnancy.

The New Zealand data sheets for lithium strongly recommend that use of lithium be discontinued before a planned pregnancy due to the risk of teratogenicity, particularly during the first trimester^3–5.

Women with bipolar disorder have a significant risk of relapse during pregnancy and post-partum⁶. The risks of lithium during pregnancy therefore need to be weighed against its effectiveness at reducing relapse.

Recent studies

Two recently published studies investigated the risk of congenital cardiac malformations^6,7. Fetal exposure to lithium during the first trimester of pregnancy had previously been considered a significant risk for congenital cardiac malformations. Both studies aimed to clarify this risk further. The risk of cardiac malformations was lower than previously believed, based on birth registry data from the 1970s⁷. The risk was estimated at around 2–2.5 percent in both studies. The background rate of congenital cardiac malformations is around 1 percent⁸ (but can vary depending on the data source). The risk of congenital malformations associated with lithium in these studies was still greater than has been reported for antipsychotic medicines⁹.

International guidelines

In April 2018, the National Institute for Health and Care Excellence (NICE) published updated guidelines on the clinical management and service requirements for antenatal and postnatal mental health in the UK¹⁰. The guidelines included recommendations concerning the use of lithium during the reproductive years and during pregnancy. The MARC considered that these guidelines are also relevant and useful for New Zealand. The NICE recommendations for using lithium are summarised in Table 1.

Table 1. Treatment decisions, advice and monitoring regarding the use of lithium in women who are planning a pregnancy, pregnant or in the postnatal period – recommendations from NICE

Lithium Do not offer lithium to women who are planning a pregnancy or pregnant, unless antipsychotic medication has not been effective. If antipsychotic medication has not been effective and lithium is offered to a woman who is planning a pregnancy or pregnant, ensure: the woman knows that there is a risk of fetal heart malformations when lithium is taken in the first trimester, but the size of the risk is uncertain the woman knows that lithium levels may be high in breast milk with a risk of toxicity for the baby lithium levels are monitored more frequently throughout pregnancy and the postnatal period. If a woman taking lithium becomes pregnant, consider stopping the medicine gradually over 4 weeks if she is well. Explain to her that: stopping medication may not remove the risk of fetal heart malformations there is a risk of relapse, particularly in the postnatal period, if she has bipolar disorder. If a woman taking lithium becomes pregnant and is not well or is at high risk of relapse, consider: switching gradually to an antipsychotic or stopping lithium and restarting it in the second trimester (if the woman is not planning to breastfeed and her symptoms have responded better to lithium than to other drugs in the past) or continuing with lithium if she is at high risk of relapse and an antipsychotic is unlikely to be effective. If a woman continues taking lithium during pregnancy: check plasma lithium levels every 4 weeks, then weekly from the 36th week adjust the dose to keep plasma lithium levels in the woman's therapeutic range ensure the woman maintains an adequate fluid balance ensure the woman gives birth in hospital ensure monitoring by the obstetric team when labour starts, including checking plasma lithium levels and fluid balance because of the risk of dehydration and lithium toxicity stop lithium during labour and check plasma lithium levels 12 hours after her last dose.

Source: NICE guideline. 2014. Antenatal and postnatal mental health: clinical management and service guidance April 2018. URL: www.nice.org.uk/guidance/cg192/chapter/1-recommendations (accessed 14 November 2018).

New Zealand cases

Up to 1 November 2018, four cases of congenital malformations associated with the use of lithium in pregnancy had been reported to the Centre for Adverse Reactions Monitoring (CARM). Three of these cases described cardiac defects (case numbers: 026387, 069446 and 116642).

Data sheet update

It is important for prescribers to discuss the benefits and risks of continuing lithium during pregnancy with women who have bipolar disorder and who are planning to or have become pregnant. Medsafe is working with the New Zealand sponsors of lithium-containing medicines to provide up-to-date information on the risk of fetal abnormalities with lithium use in pregnancy.

References

1. Oruch R, Elderbi MA, Khattab HA et al. 2014. Lithium: a review of pharmacology, clinical uses, and toxicity. European Journal of Pharmacology 740: 464–73. DOI: 10.1016/j.ejphar.2014.06.042 (accessed 10 October 2018).
2. Medsafe. 2019. Minutes of the 176^th Medicines Adverse Reactions Committee Meeting 6 December 2018. URL: https://medsafe.govt.nz/profs/adverse/Minutes176.htm (accessed 1 February 2019).
3. Mylan New Zealand Ltd. 2017. Lithicarb FC 250 mg, 400 mg film-coated tablets New Zealand Data Sheet 30 August 2017. URL: www.medsafe.govt.nz/profs/Datasheet/l/LithicarbFCtab.pdf (accessed 1 February 2019).
4. Douglas Pharmaceuticals Ltd. 2017. Lithium Carbonate 250 mg capsule New Zealand Data Sheet 18 April 2017. URL: www.medsafe.govt.nz/profs/Datasheet/l/Lithiumcarbonatecap.pdf (accessed 1 February 2019).
5. WM Bamford & Co Ltd. 2017. Priadel 400 mg modified release tablets New Zealand Data Sheet 10 July 2017. URL: www.medsafe.govt.nz/profs/Datasheet/p/priadeltab.pdf (accessed 1 February 2019).
6. Munk-Olsen T, Liu X, Viktorin A et al. 2018. Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta-analysis of six cohort studies. The Lancet Psychiatry 5(8): 644–52. DOI: https://doi.org/10.1016/S2215-0366(18)30180-9 (accessed 20 October 2018).
7. Patorno E, Huybrechts KF, Hernandez-Diaz S. 2017. Lithium use in pregnancy and the risk of cardiac malformations. The New England Journal of Medicine 376(23): 2245–54. URL: www.nejm.org/doi/pdf/10.1056/NEJMoa1612222 (accessed 20 October 2018).
8. Centers for Disease Control and Prevention. 2018. Data and statistics on congenital heart defects 2 November 2018. URL: www.cdc.gov/ncbddd/heartdefects/data.html (accessed 4 February 2019).
9. Hendrick V. 2017. Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy 22 June 2017. In: UpToDate. URL: www.uptodate.com/contents/teratogenicity-pregnancy-complications-and-postnatal-risks-of-antipsychotics-benzodiazepines-lithium-and-electroconvulsive-therapy (accessed 5 February 2019).
10. NICE guideline. 2014. Antenatal and postnatal mental health: clinical management and service guidance April 2018. URL: www.nice.org.uk/guidance/cg192/chapter/1-recommendations (accessed 14 November 2018).