Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta-analysis of six cohort studies

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d6628712e370">Background</h5> <p id="P1">Concerns about teratogenicity and offspring complications limit use of lithium in pregnancy. We aimed to investigate the association between in-utero lithium exposure and risk of pregnancy complications, delivery outcomes, neonatal morbidity and congenital malformations. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d6628712e375">Methods</h5> <p id="P2">Meta-analysis of primary data analyzed using a shared protocol. Six study sites participated: Denmark, Canada, Netherlands, Sweden, UK, and US, totaling 727 lithium-exposed pregnancies compared to 21,397 reference pregnancies in mothers with a mood disorder, but unexposed to lithium. </p> <p id="P3">Main outcome measures included: (1) pregnancy complications, (2) delivery outcomes, (3) neonatal readmission to hospital within 28 days of birth, and (4) congenital malformations (major malformations and cardiac malformations). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were generated using logistic regression models. Site-specific prevalence rates and ORs were pooled using random-effects meta analytic models. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d6628712e382">Findings</h5> <p id="P4">Lithium exposure was not associated with any of the pre-defined pregnancy complications or delivery outcomes. There was an increased risk for neonatal readmission in lithium exposed (27·5%) versus reference group (14·3%) (Pooled aOR1·62; 95% CI: 1·12–2·33). Lithium exposure during first trimester was associated with increased risk of major malformations (7·4% versus 4·3%; pooled aOR 1·71, 95% CI: 1·07–2·72). Similarly, more lithium exposed children had major cardiac malformations, albeit not stasticially significant (2·1% versus 1·6%; pooled aOR 1·54, 95% CI: 0·64–3·70). Limitations in our study include: Serum lithium levels were not available, hence no analyses related to dose-response effects could be performed, and residual confounding from e.g. substance abuse cannot be ruled out. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d6628712e387">Interpretation</h5> <p id="P5">Treatment decisions must weigh the potential for increased risks, considering both effct sizes and the precision of the estimates, in particular associated with first-trimester lithium use against its effectiveness at reducing relapse. </p> </div>