Lithium Use in Pregnancy

Doyle S 1, Green AJ1,2

1Department of Clinical Genetics, Our Lady’s Children’s Hospital, Crumlin
2School of Medicine and Medical Sciences, University College Dublin

Bipolar disorder (BPD) is a major affective disorder marked by severe mood swings, with manic and depressive episodes and a tendency towards remission and recurrence. Patients are at an increased risk of suicide. It has a worldwide prevalence of 1-5% and presents in early adulthood (15-24 years) with another peak in presentation in later life (45-54 years)1. It frequently affects women of childbearing age who have complex needs during and after pregnancy.

Management of the disorder with Lithium, which acts as a mood stabiliser, has been the standard pharmacological treatment for more than 60 years. It has greatly improved the quality of life of sufferers2.Treatment of BPD in pregnancy represents an even greater challenge for the patient and doctor dyad. Pregnancy does not protect all women from relapses of their illness and relapses are common during the pregnancy and postpartum period leading to increased risk to the mother and baby. Ongoing pharmacotherapy is often required. Lithium is used with caution in pregnancy3. Women who discontinue Lithium treatment in pregnancy are three times more likely to relapse than non-pregnant non-puerperal women who discontinue the drug4. Unfortunately, evidence from the 1970’s suggested that Lithium use in pregnancy resulted in an increased risk of Ebstein’s Anomaly (3%) (Right Ventricular Outflow Tract Obstruction) and Cardiac anomalies generally (8%). Regulatory bodies world- wide concluded that Lithium was teratogenic5 and the American Psychiatrists recommend that clinician’s balance the risks to the foetus with the benefits of treatment in caring for the mother6. Other pharmacological options also carry a teratogenic risk.

Little research, apart from case reports, has been published in recent decades analysing the teratogenic risk of Lithium. There is conflicting information regarding the risk to the foetus within these case reports. The decision around the use of this drug in pregnancy remains a challenge, with no studies clarifying the issue of teratogenicity. Clinicians balance this risk of teratogenicity with the benefits of adherence with long term treatment which include remaining symptom free, normal bonding in the new-born period and improved neonatal development as a result7.

A recent retrospective observational study published in the New England Journal of Medicine reviewed over 1.3 million pregnancies in the United States. Of the pregnancies reviewed, 663 women were exposed to Lithium during the first trimester. One thousand, nine hundred and forty-five women were exposed to Lamotrigine during the first trimester and 1,322,955 women were not exposed to either drug during the first trimester. The primary outcome of the study was the presence of cardiac malformations in the infants and the secondary outcome was major congenital malformations8.

Of the Lithium exposed pregnancies 16 out of 663 had cardiac malformations (a prevalence per 100 births of 2.41). The lamotrigine exposed pregnancies had 27 cardiac anomalies out of 1,945 exposed pregnancies (a prevalence of 1.39 per 100 live births), while the pregnancies not exposed to either (1,322,955) had 15,251 cardiac malformations (a prevalence of 1.15 per 100 births). This suggests that the risk of cardiac malformations on Lithium is higher than in lamotrigine or the reference sample (non-exposed). Given the previous link between Lithium exposure and Right Ventricular Outflow Tract Obstruction, the authors specifically quantified the incidence in this group and found that in the pregnancies exposed to Lithium (663) RVOTO was noted in <11 cases giving a prevalence of 0.6 per 100 livebirths. The original work from the 1970’s found a prevalence of three per 100 births. The incidence in the reference group was 0.18 per 100 births. The authors also detected an association between the dose of Lithium and incidence of cardiac defects. When the dose administered is above 900mg per day, in the first trimester, the risk of cardiac malformations is increased by a factor of three8.

In relation to the secondary outcomes, the study found that non-cardiac malformations occurred in 3.32 per 100 births in Lithium exposed pregnancies. This is higher than the reference group and the Lamotrigine exposed pregnancies which had a prevalence of 2.1 per 100 and 2.52 per 100, respectively. The authors highlighted that this was not a statistically significant increased risk but that some slightly increased risk could not be ruled out8. It is also worth noting that, the background risk of congenital malformations in a population is 2-4% meaning that there is no increased incidence in Lithium exposed pregnancies9.

This large study gives a new insight into the teratogenicity of Lithium. The authors have found that the prevalence of cardiac anomalies in babies of women taking Lithium in early pregnancy is not as high as previously believed. There is some increased risk and careful review of the dose of medication may reduce risk. The authors point towards the benefit of a lower dose of Lithium in pregnancy particularly in the first trimester. Psychiatrists must continue to counsel women of childbearing age of the importance of contraception as a significant number of pregnancies are unplanned. The rates of unplanned pregnancies in women suffering from depression is higher than those who are not, meaning this cohort is at increased risk10.Patients should be encouraged to consult their physician prior to pregnancy to discuss their treatment in pregnancy and the postpartum period and also to discuss the patients’ wishes regarding breastfeeding as Lithium is a relative contraindication to breastfeeding. Discussing the important decisions around treatment in pregnancy when the patient is euthymic allows for informed consent. The results of this large study should offer clinicians some guidance in counselling women.

Psychiatrists must endeavour to discuss the importance of preconception health with women as the use of medications like lithium are not the only risk to the developing foetus. The importance of folic acid supplementation, maintaining a normal Body Mass Index, avoiding smoking and drinking alcohol must be supported in conjunction with appropriate management of the patients’ Bipolar disorder.

Correspondence:
Samantha Doyle, Department of Clinical Genetics, Our Lady’s Children’s Hospital, Crumlin
Email:Samantha.doyle@ucd.ie

References:

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