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Neurocognitive sequelae of antenatal corticosteroids in a late preterm rabbit model. BACKGROUND: Late-preterm birth (PTB) is associated with short-term respiratory and adaptive problems. Although antenatal corticosteroid (ACS) seems to reduce the respiratory burden, this may come at the cost of adverse neuropsychological outcomes later in life. This impact has not been investigated. Herein, we investigate what the short- and long-term neurodevelopmental effects are of a single course of betamethasone in simulated late PTB. METHODS: Time-mated pregnant does received 0.1mg/kg betamethasone (n=8) or 1mL saline IM (n=6) at postconceptional age (PCA) 28 and 29 days. ACS dose and scheme were based upon previous studies and comparable to routine clinical use. Caesarean delivery on PCA 30 days (term = 31 days) was done and new-born rabbits were foster cared for 28 days and thereafter cared for in group housing. Neonatal lung function testing and short-term neurobehavioral testing was done. Open field (OFT), spontaneous alteration (TMT) and novel object recognition (NORT) tests were subsequently performed at 4 and 8 weeks of age. On postnatal day 1 and at 8 weeks a subgroup group was euthanized and transcardially perfuse fixated and ex-vivo high-resolution Magnetic Resonance Imaging was used to calculate Diffusion Tensor Imaging (DTI) derived fractional anisotropy (FA) and mean diffusivity (MD). Fixated brains underwent processing and were serial sectioned and a set of 3 coronal sections underwent anti-NeuN, Ki67 and TUNEL staining. RESULTS: ACS exposure was associated with improved neonatal lung function yet resulted in a long-term growth deficit that coincided with a persistent neurobehavioral deficit. We demonstrated lower neonatal motor scores; a persistent anxious behavior in the OFT with more displacements, running and self-grooming episodes; persistent lower alternations scores in the TMT; and lower discriminatory indexes in the NORT. Upon neuropathological assessment ACS exposure resulted in a persistent lower neuron density and fewer Ki67+ cells in particularly the hippocampus and corpus callosum. This coincided with lower DTI-derived FA scores in the same key regions. CONCLUSIONS: Clinical equivalent ACS exposure in this late preterm rabbit model resulted in improved neonatal lung function however compromised neonatal and long-term neurocognition.