Women who take lithium during early pregnancy have a slightly increased risk of giving birth to a child with a cardiac malformation, a large retrospective cohort study from the USA has found.

Demographic, healthcare and prescription data were obtained from the Medicaid Analytic eXtract (MAX). The cohort comprised a total of 1,325,563 pregnancies resulting in a live birth between 2000 and 2010.

Lithium and lamotrigine use was defined as the redemption of at least one prescription during the first trimester. Lamotrigine was chosen as a comparator because it is also used in the treatment of bipolar disorder but has not been associated with a raised risk of congenital malformations. Women who were exposed to both drugs were excluded.

Stratified propensity score analysis was used to adjust for a wide range of potential confounders such as age, ethnicity, smoking and comorbidity.

Cardiac malformations occurred in:

• 16 out of 663 infants exposed to lithium (2.41%)

• 15,251 out of 1,322,955 unexposed infants (1.15%)

• 27 out of 1,945 infants exposed to lamotrigine (1.39%)

Compared with unexposed infants, infants exposed to lithium were significantly more likely to have a cardiac malformation; adjusted risk ratio (RR) 1.65 (95% CI: 1.02-2.68).

The results suggest a dose-risk relationship, with the RR increasing from 1.11 (95% CI: 0.46-2.64) for a daily dose ≤ 600 mg to 3.22 (95% CI: 1.47-7.02) for a daily dose > 900 mg.

Compared with unexposed infants, those exposed to lithium were more likely to have a right ventricular outflow tract obstruction defect RR 2.66 (95% CI: 1.00-7.06).

Similar results were obtained when lamotrigine-exposed infants were used as the reference group.

Pregnant women enrolled in Medicaid are young, racially diverse and on low incomes,1 but there is no good reason why these results should not apply to more affluent populations.

Propensity score analysis does not eliminate the possibility of confounding by indication, but the similar results obtained when lithium was compared with lamotrigine suggest this was not a significant problem. The wide confidence intervals despite the large sample size reflect the difficulty of studying an uncommon side effect of an uncommonly prescribed drug.

NICE recommends that lithium should not be offered to women who are planning a pregnancy or pregnant, unless antipsychotic medication has not been effective. Where lithium is offered it is essential to discuss the risk of cardiac malformations ‘but the size of the risk is uncertain.’²

This study now provides clarification: there is a risk but this is smaller than was previously thought: approximately one additional case per 100 exposed infants.

GPs should review their lithium registers and ensure that any women of childbearing age are aware of the risk and of the importance of seeking specialist preconception advice.

When a woman presents with an unplanned pregnancy, NICE recommends that we consider stopping the lithium gradually over a four-week period if she is well.

This is a difficult decision that should only be made under specialist guidance. There is a need to balance the small risk of harm against the substantially increased risk of relapse, particularly during the postpartum period, if lithium is stopped.

A recent meta-analysis found that in women with bipolar disorder, continuation of prophylactic treatment during pregnancy (lithium in most studies) was ‘critically important for maintaining mood stability after delivery.’³

When discussing whether or not to stop lithium, it is essential to discuss absolute, not relative risks. The evidence suggests that, out of 100 women with bipolar disorder who choose to stop their lithium for the duration of their pregnancy, one will thereby prevent their child from being born with a cardiac defect but 43 will suffer a postpartum relapse that they could otherwise have prevented.³

For those who are unwell or at high risk of relapse, NICE recommends either switching gradually to an antipsychotic, stopping lithium and restarting it in the second trimester, or continuing lithium if an antipsychotic is unlikely to be effective.²

However, the authors of the meta-analysis recommend that all women with bipolar disorder should continue their prophylactic medication.³

Dr Phillip Bland