Long-term neuropathological and/or neurobehavioral effects of antenatal corticosteroid therapy in animal models: a systematic review

Background Antenatal corticosteroids (ACSs) are recommended to all women at risk for preterm delivery; currently, there is controversy about the subsequent long-term neurocognitive sequelae. This systematic review summarizes the long-term neurodevelopmental outcomes after ACS therapy in animal models. Methods An electronic search strategy incorporating MeSH and keywords was performed using all known literature databases and in accordance with PRISMA guidance (PROSPERO CRD42019119663). Results Of the 669 studies identified, eventually 64 were included. The majority of studies utilized dexamethasone at relative high dosages and primarily involved rodents. There was a high risk of bias, mostly due to lack of randomization, allocation concealment, and blinding. The main outcomes reported on was neuropathological, particularly glucocorticoid receptor expression and neuron densities, and neurobehavior. Overall there was an upregulation of glucocorticoid receptors with lower neuron densities and a dysregulation of the dopaminergic and serotonergic systems. This coincided with various adverse neurobehavioral outcomes. Conclusions In animal models, ACSs consistently lead to deleterious long-term neurocognitive effects. This may be due to the specific agents, i.e., dexamethasone, or the repetitive/higher total dosing used. ACS administration varied significantly between studies and there was a high risk of bias. Future research should be standardized in well-characterized models.