Grand Rounds

Lithium Exposure: What are the Risks During Pregnancy?

BACKGROUND AND PURPOSE:

Perinatal risks related to lithium exposure remains unclear
Fornaro et al. (American Journal of Psychiatry, 2019) sought to determine the efficacy and the safety of lithium use during pregnancy

Systematic review and random effects meta-analysis
Inclusion criteria
- Case-control, cohort, and interventional studies
- Studies that reported quantitative data on the safety or efficacy of lithium treatment during pregnancy and the postpartum period
- Review articles and series <10 subjects were excluded
Primary outcomes
- Safety: any congenital anomaly
- Efficacy: mood relapse prevention
Secondary outcomes
- Other safety outcomes during pregnancy and postpartum
- Major cardiac malformations: were defined VSD and Ebstein’s anomaly, but excluded ASD

13 studies | 1,349,563 pregnancies
Lithium prescribed during pregnancy was associated with higher odds of
- Any congenital anomaly
  - Prevalence: 4.1%
  - Odds ratio (OR): 1.81 (95% CI, 1.35 to 2.41)
  - Number needed to harm (NNH): 33 (95% CI, 22 to 77)
- Cardiac anomalies
  - Prevalence: 1.2%
  - OR: 1.86 (95% CI, 1.16 to 2.96)
  - NNH: 71 (95% CI, 48 to 167)
Lithium exposure during the first trimester was associated with higher odds of spontaneous abortion
- Prevalence: 8.1%
- OR: 3.77 (95% CI, 1.15 to 12.39)
- NNH: 15 (95% CI. 8 to 111)
Comparing lithium-exposed with unexposed patients with affective disorders
- There was still a significant increase in risk of
  - Any malformation (exposure during any pregnancy period or the first trimester)
  - Cardiac malformations (exposure during the first trimester)
- There was no increase in risk for
  - Spontaneous abortion (exposure during the first trimester)
  - Cardiac malformations (exposure during any pregnancy period)
- When cardiac anomalies were restricted to the first trimester, risk was significantly increased
  - OR: 1.75 (95% CI, 1.08 to 2.84)
Lithium was more effective than no lithium in preventing postpartum relapse
- OR: 0.16 (95% CI, 0.03 to 0.89)
- Number needed to treat: 3 (95% CI, 1 to 12)
Mothers with serum lithium levels <0.64 mEq/L and dosages <600 mg/day had more reactive newborns without an increased risk of cardiac malformations

Neonatal risks associated with lithium exposure in pregnancy are low
- Risk is higher for the first trimester or with higher-doses of lithium
- Risk needs to be balanced against benefit of medication and potential for other confounding factors including behavioral factors
The authors suggest that
- Preconception counseling would be of value
- Maintain lowest therapeutic range throughout pregnancy (especially during the first trimester)

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