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

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

Lithium Use during Pregnancy and the Risk of Miscarriage.

Recent studies have provided new data on the teratogenicity of lithium. Less is known about the risk of miscarriage after lithium use during pregnancy. The aim of this study was to investigate the association between lithium use during pregnancy and miscarriage. Participants were women with bipolar I disorder and one or more pregnancies, of which information on medication use and pregnancy outcome was available (n = 443). The unadjusted odds ratios for miscarriage after lithium use during pregnancy was calculated. Multilevel logistic regression was used to calculate the odds ratio, adjusted for the age at conception and the clustering of pregnancies per woman. Miscarriages occurred in 20.8% of the lithium-exposed pregnancies (16/77), compared with 10.9% of the unexposed pregnancies (40/366) (OR = 2.14; 95% CI: 1.13-4.06). The adjusted odds ratio of miscarriage after lithium use during pregnancy was 2.94 (95% CI: 1.39-6.22). Lithium use during pregnancy may increase the risk of miscarriage

Neurodevelopment in school-aged children after intrauterine exposure to antipsychotics

Objective: Antipsychotics are increasingly prescribed in pregnancy, yet little is known about potential long-term developmental effects on children. In this study, we investigated the effect of prenatal antipsychotic exposure on neurodevelopmental functioning in school-aged children. Methods: We performed a cross-sectional neurodevelopmental assessment of 91 children aged 6–14 years whose mothers had severe mental illness and were either exposed or unexposed to antipsychotic medication during pregnancy. Neurodevelopmental outcomes were assessed using validated neurodevelopmental assessment instruments to examine the child's IQ and global cognitive functioning, and the presence of any psychiatric disorders and/or learning problems in the child was assessed by parental report. Results: No statistically significant associations were found between antipsychotic exposure during pregnancy and either adverse neurodevelopmental outcomes (IQ, neuropsychological function), likelihood of psychiatric diagnosis, or learning problems based on parental report. Analyses were likely limited in power to detect subtler differences in neurodevelopmental functioning because of small sample size and heterogeneity of the sample. Conclusions: In this exploratory cohort study, intrauterine exposure to antipsychotics was not associated with any adverse effect on IQ or neurodevelopmental functioning in a cohort of school-aged children (6–14 years)

Brain development after intrauterine exposure to lithium: A magnetic resonance imaging study in school-age children

Objective: Lithium is often continued during pregnancy to reduce the risk of perinatal mood episodes for women with bipolar disorder. However, little is known about the effect of intrauterine lithium exposure on brain development. The aim of this study was to investigate brain structure in children after intrauterine exposure to lithium. Methods: Participants were offspring, aged 8?14 years, of women with a diagnosis of bipolar spectrum disorder. In total, 63 children participated in the study: 30 with and 33 without intrauterine exposure to lithium. Global brain volume outcomes and white matter integrity were assessed using structural MRI and diffusion tensor imaging, respectively. Primary outcomes were total brain, cortical and subcortical gray matter, cortical white matter, lateral ventricles, cerebellum, hippocampus and amygdala volumes, cortical thickness, cortical surface area and global fractional anisotropy, and mean diffusivity. To assess how our data compared to the general population, global brain volumes were compared to data from the Generation R study (N?=?3243). Results: In our primary analyses, we found no statistically significant associations between intrauterine exposure to lithium and structural brain measures. There was a non-significant trend toward reduced subcortical gray matter volume. Compared to the general population, lithium-exposed children showed reduced subcortical gray and cortical white matter volumes. Conclusion: We found no differences in brain structure between lithium-exposed and non-lithium-exposed children aged 8?14 years following correction for multiple testing. While a rare population to study, future and likely multi-site studies with larger datasets are required to validate and extend these initial findings

The effect of prenatal lithium exposure on the neuropsychological development of the child

Objectives: Lithium is an effective treatment for bipolar disorder, also during pregnancy to prevent the recurrence of episodes in the perinatal period. Little is known about the neuropsychological development of lithium-exposed offspring. The current study was designed to investigate neuropsychological functioning in lithium-exposed children with the aim to provide further knowledge on the long-term effects of lithium use during pregnancy. Methods: Participants were offspring of women with a diagnosis of bipolar spectrum disorder, aged 6–14 years. In total, 99 children participated in the study, 56 were exposed to lithium in utero and 43 were not exposed to lithium. Neuropsychological tests were administered, including the Snijders-Oomen Nonverbal Intelligence Test and the NEPSY-II-NL assessment. Linear and negative binomial regression models were used to investigate the association between prenatal lithium exposure and neuropsychological functioning. In secondary analyses, the association between lithium blood level during pregnancy and neuropsychological functioning was assessed. Additionally, norm scores and percentiles for task outcomes were calculated. Results: Lithium use during pregnancy was associated with the total number of mistakes made on the Auditory Attention task, but not statistically significant after full adjustment for potential confounding factors. No association between prenatal lithium exposure and IQ was found. Also, no relationship between lithium blood level during pregnancy and neuropsychological functioning was found after adjustment for potential confounders. Task outcomes in both groups were comparable to the general population. Conclusion: In this study, we found no evidence for significantly altered neuropsychological functioning of lithium-exposed children at the age of 6–14 years, when compared to non-lithium-exposed controls

Chronic hypoxia leads to an increase in Fulton index.

<p>(a) Experimental groups. (b) Study design. (c) Representative images of whole hearts (upper panels), haematoxylin & eosin (H&E) stained 4-chamber paraffin sections (second panels), high magnification H&E stained free right ventricular wall histological sections (third panels), high magnification sirius red stained free right ventricular wall sections (lower panels. The following groups are compared: normoxia on normal chow diet (N/Cu+), normoxia on copper depleted diet (N/Cu-), hypoxia on normal chow diet (H/Cu+) and hypoxia on copper depleted diet (H/Cu-). (d) Heartweight corrected for bodyweight in grams per gram. (n = 9) *P<0.05. (e) Fulton index calculated as ratio of RV free wall weight over septum plus LV free wall weight. (f) Liverweight in grams. (g) Lungweight in grams. (h) Bodyweight in grams. (i) Representative images of wheat germ agglutinin (WGA) stained sections. (j) Quantification of average cell surface area using WGA stained sections. (n≥610) *P<0.05 (mean ± s.e.m.).</p

Chronic hypoxia induces a decrease in right ventricular ejection fraction.

<p>Right ventricular ejection fraction (EF) measured by MRI at 4 and 8 weeks. The following groups are compared: normoxia on normal chow diet (N/Cu+), normoxia on copper depleted diet (N/Cu), hypoxia on normal chow diet (H/Cu+) and hypoxia on copper depleted diet (H/Cu-). (b) Right ventricular end systolic volumes in cm³ and (c) right ventricular end diastolic volumes in cm³. (n = 6) (d) Griffonia simplicifolia 1 (GS-1)-stain on representative right ventricular free wall paraffin sections. (e) Quantification of GS-1 stain, expressed as relative vessel number. (f) Real-time PCR analysis of transcript abundance for cardiac stress marker genes in right ventricles at 8 weeks. (n = 3) *P<0.05 (mean ± s.e.m.).</p