The hippocampus is a neuron-rich specialised brain structure that plays a central role in the regulation of emotions, learning and memory, cognition, spatial navigation, and motivational processes. In human fetal development, hippocampal neurogenesis is principally complete by mid-gestation, with subsequent maturation comprising dendritogenesis and synaptogenesis in the third trimester of pregnancy and infancy. Dendritogenesis and synaptogenesis underpin connectivity. Hippocampal development is exquisitely sensitive to perturbations during pregnancy and at birth. Clinical investigations demonstrate that preterm birth, fetal growth restriction (FGR), and acute hypoxic-ischaemic encephalopathy (HIE) are common perinatal complications that alter hippocampal development. In turn, deficits in hippocampal development and structure mediate a range of neurodevelopmental disorders, including cognitive and learning problems, autism, and Attention-Deficit/Hyperactivity Disorder (ADHD). In this review, we summarise the developmental profile of the hippocampus during fetal and neonatal life and examine the hippocampal deficits observed following common human pregnancy complications. Impact: The review provides a comprehensive summary of the developmental profile of the hippocampus in normal fetal and neonatal life. We address a significant knowledge gap in paediatric research by providing a comprehensive summary of the relationship between pregnancy complications and subsequent hippocampal damage, shedding new light on this critical aspect of early neurodevelopment.

The hippocampus is a vital brain structure deep in the medial temporal lobe that mediates a range of functions encompassing emotional regulation, learning, memory, and cognition. Hippocampal development is exquisitely sensitive to perturbations and adverse conditions during pregnancy and at birth, including preterm birth, fetal growth restriction (FGR), acute hypoxic–ischaemic encephalopathy (HIE), and intrauterine inflammation. Disruptions to hippocampal development due to these conditions can have long-lasting functional impacts. Here, we discuss a range of preclinical models of prematurity and FGR and conditions that induce hypoxia and inflammation, which have been critical in elucidating the underlying mechanisms and cellular and subcellular structures implicated in hippocampal dysfunction. Finally, we discuss potential therapeutic targets to reduce the burden of these perinatal insults on the developing hippocampus. Impact: The review explores the preclinical literature examining the association between pregnancy and birth complications, and hippocampal form and function. The developmental processes and cellular mechanisms that are disrupted within the hippocampus following perinatal compromise are described, and potential therapeutic targets are discussed.

Preterm brain injury involves persistent inflammation, making it a potential therapeutic target. Current large animal models focus on short-term outcomes, limiting understanding of long-term effects. We developed an ovine model of inflammation-induced preterm brain injury to assess long-term neuropathology at an age equivalent to early cerebral palsy diagnosis in human infants. Fetal sheep were instrumented at gestational day (d) 90-91 (term is 148d): one group received lipopolysaccharide (LPS 200 ng; n = 9) on 96d, 97d, and 98d (0.65 gestation, ∼25-26 weeks human brain development), and a control group received saline (n = 8). Birth was induced on 138d, and lambs were euthanised within 24 h of birth. Brains were evaluated for white matter injury, microglial/macrophage activation and astrogliosis in the subcortical (SCWM), periventricular (PVWM), and cortical (CWM) white matter, subventricular zone (SVZ), and corpus callosum (CC). Antenatal LPS administration was associated with significant persistent microglial/macrophage activation in the PVWM (P = 0.04), SCWM (P = 0.01), and CWM (P = 0.006). Furthermore, LPS exposure was associated with reduced oligodendrocyte cell number in the PVWM (P = 0.02), SCWM (P = 0.001), and CWM (P = 0.0001), and reduced myelination in CWM (CNPase, P < 0.0001 and MBP, P = 0.04) and SVZ (MBP, P = 0.05). No difference in astrogliosis or microhaemorrhages was observed. We demonstrated that in a large animal model of inflammation-induced intrauterine preterm brain injury, long-term persistent inflammation occurs, along with significant white matter injury, including loss of oligodendrocytes and reduced myelination in multiple white matter regions. This model paves the way for long-term evaluation of promising therapeutics and behavioral assessment in this clinically relevant model of persistent preterm brain injury.