Long-term neurodevelopmental consequences of intrauterine exposure to lithium and antipsychotics: a systematic review and meta-analysis

Abstract

Lithium and antipsychotics are often prescribed to treat bipolar disorder or psychotic disorders in women of childbearing age. Little is known about the consequences of these medications during pregnancy for the developing child. The objective of this article is to systematically review findings from preclinical and clinical studies that have examined the neurodevelopmental consequences of intrauterine exposure to lithium and antipsychotics. A systematic search was performed in Embase, Medline, Web of Science, PsychINFO, Cochrane, and Google Scholar. Clinical and experimental studies were selected if they investigated neurodevelopment of offspring exposed to lithium or antipsychotics during gestation. Quality of clinical and preclinical studies was assessed by the Newcastle-Ottawa Scale and the SYRCLE's risk of Bias tool, respectively. In total, 73 studies were selected for qualitative synthesis and three studies were selected for quantitative synthesis. Of preclinical studies, 93% found one or more adverse effects of prenatal exposure to antipsychotics or lithium on neurodevelopment or behaviour. Only three clinical cohort studies have investigated the consequences of lithium exposure, all of which reported normal development. In 66% of clinical studies regarding antipsychotic exposure, a transient delay in neurodevelopment was observed. The relative risk for neuromotor deficits after in utero exposure to antipsychotics was estimated to be 1.63 (95% CI 1.22-2.19; I² = 0%). Preclinical studies suggest long-term adverse neurodevelopmental consequences of intrauterine exposure to either lithium or antipsychotics. However, there is a lack of high-quality clinical studies. Interpretation is difficult, since most studies have compared exposed children with their peers from the unaffected population, which did not allow correction for potential influences regarding genetic predisposition or parental psychiatric illness.

Keywords: Antipsychotics; Intrauterine exposure; Lithium; Neurodevelopment; Pregnancy.

Fig. 1

Flowchart of the study selection process in this systematic review and meta-analysis. ^aOutcome of the excluded studies: cell development (n = 4), teratogenicity (n = 5), neonatal outcome only (n = 14), obstetric outcome and teratogenicity (n = 9), fetal development (n = 2), endocrine and cardiologic follow-up (n = 1), weight gain and mortality (n = 1), treatment choice (n = 1), sexual development (n = 1)

Fig. 2

Relative risk estimates including the 95% confidence interval limits of neuromotor deficits for antipsychotic exposure for all reported follow-up assessments

Fig. 3

Relative risk estimates including the 95% confidence interval of neuromotor deficits for antipsychotic exposure at 6 months of follow-up. The pooled relative risk was estimated using a fixed-effects estimation