Second-generation antipsychotic use during pregnancy and risk of congenital malformations

Abstract

Purpose To study if second-generation antipsychotic (S-GA) use during the first trimester of pregnancy is associated with an increased risk of major congenital malformations (MCM). Methods A population-based birth cohort study using national register data extracted from the Drugs and Pregnancy database in Finland, years 1996–2017. The sampling frame included 1,273,987 pregnant women. We included singleton pregnancies ending in live or stillbirth or termination of pregnancy due to severe malformation. Pregnancies with exposure to known teratogens were excluded. Women were categorized into three groups: exposed to S-GAs (n = 3478), exposed to first-generation antipsychotics (F-GAs) (n = 1030), and unexposed (no purchases of S-GAs or F-GAs during pregnancy, n = 22,540). We excluded genetic conditions and compared the prevalence of MCMs in S-GA users to the two comparison groups using multiple logistic regression models. Results Use of S-GAs during early pregnancy was not associated with an increased risk of overall MCMs compared to unexposed (adjusted odds ratio, OR 0.92; 95% CI 0.72–1.19) or to F-GA users (OR 0.82; 95% CI 0.56–1.20). Of individual S-GAs, olanzapine use was associated with an increased risk of overall MCMs (OR 2.12; 95% CI 1.19–3.76), and specifically, an increased risk of musculoskeletal malformations (OR 3.71; 95% CI 1.35–10.1) when compared to unexposed, while comparisons to F-GA users did not show significant results. Conclusions Olanzapine use is associated with an increased risk of major congenital malformations and specifically, musculoskeletal malformations. Use during pregnancy should be restricted to situations where no safer alternatives exist.

Association of In Utero Antipsychotic Medication Exposure With Risk of Congenital Malformations in Nordic Countries and the US

“…Teratogenicity is typically the principal concern in pregnancy for drug classes like antipsychotics that cross the placenta . The risk of congenital malformations following in utero exposure to antipsychotic medications has been evaluated in the context of spontaneous reporting systems, pregnancy exposure registries, case-control studies, and more recently cohort studies nested in health care utilization databases, and several systematic reviews and meta-analyses exist . While the results generally point toward antipsychotics not being major teratogens, findings have been conflicting and safety signals have emerged for outcomes such as cardiovascular malformations and oral clefts .…”

Place of the partial dopamine receptor agonist aripiprazole in the management of schizophrenia in adults: a Delphi consensus study

“…Given the limited amount of evidence, it is difficult to appreciate whether SGAs carry any teratogenic risk in humans, although, if it exists, this risk is likely to be low [ 50 , 65 – 69 ]. An increased risk of congenital malformations has been reported in women exposed to risperidone or olanzapine [ 70 , 71 ]. Whether exposure to antipsychotics in utero exposes the child to any neurodevelopmental toxicity is unknown [ 72 ], although there is no evidence for any deleterious psychiatric outcome [ 73 ].…”

Antidepressants and Antipsychotics in Human Pregnancy: Transfer Across the Placenta and Opportunities for Modeling Studies

“…[23][24][25][26][27] The non-specific musculoskeletal malformations reported in women prescribed olanzapine require further investigation. 28 An association also exists between using these medications in pregnancy and a higher occurrence of neonatal respiratory distress and other postnatal symptoms. 25 Given that antipsychotics efficiently penetrate the placenta, concerns over fetal toxicity cannot be completely ruled out at this stage, and medication use during pregnancy should optimally balance the risks and benefits.…”

“…Accumulating evidence from large‐scale cohort studies and related meta‐analysis indicates that exposure to antipsychotics during pregnancy does not confer an increased risk of major congenital malformations, although an increased risk of gestational diabetes was identified 23‐27 . The non‐specific musculoskeletal malformations reported in women prescribed olanzapine require further investigation 28 . An association also exists between using these medications in pregnancy and a higher occurrence of neonatal respiratory distress and other postnatal symptoms 25 .…”