Table 1.

Summary of animal experimental models of FGR and their neuropathology

General description	Brain structure and microstructure in FGR offspring	References
Guinea pig; unilateral uterine artery ligation; onset 0.45 gestation (30 of 67 days gestation)
FGR classified as <2 SDs below controls Fetal body weight reduced by 22–50% Brain sparing present Reduced crown‐rump length Reduced forebrain and cerebellar weight	Ventriculomegaly and reduced basal ganglia volume Reduced hippocampal volume and number of CA1 pyramidal neurons Reduced cerebellar volume (molecular layer, internal granular layer, and white matter) with delayed development Reduced number of cerebellar Purkinje neurons Altered dendritic morphology of hippocampal neurons with reduced dendritic length, outgrowth and branch number Altered myelination profile with reduced total myelin, more unmyelinated axons and thinner myelin sheaths Reduced white matter volume at 60 days’ gestation, normalised by young adulthood Transient delay in oligodendrocyte maturation and myelination, restored postnatally Astrocyte proliferation around blood vessels Sensorimotor deficits	Nitsos & Rees, 1990; Dieni & Rees, 2003; Rehn et al. 2004; Mallard et al. 2000; Tolcos et al. (2011)
Rabbit; ligation of 40–50% of uteroplacental vessels; onset 0.8 gestation (25 of 31 days gestation)
Birth weight reduced by 26–40%	Reduced total brain volume Immature white matter organisation (less organised) that persists into early adulthood Diffusion MRI demonstrates decreased FA in hippocampus and subventricular white matter Reduced fibre tract connectivity, with altered connectivity correlated to neurobehavioural and cognitive deficits	Eixarch et al. 2012; Illa et al. 2013
Rats; uterine artery ligation; onset 0.86 gestation (19 of 22 days gestation)
Body weight reduced at birth (10–20%), and persists until postnatal day 21 Gradient in the degree of FGR, depending on site of the fetus in utero Brain sparing present	Neuronal degeneration, apoptosis and sparse structure of the cerebral cortex, observed antenatally persistent to adulthood Reduced organisation of stratified cortical layer structure, reduced number of synapses Reduced hippocampal neuron number at birth Altered hippocampal astrocyte and immature oligodendrocyte number that was region and sex‐specific Lesions observed in the cingular white matter and internal capsule, with neuroinflammation and astrogliosis Reduced number of mature oligodendrocytes, but not oligodendrocyte precursor cells, at postnatal day 14 Apoptosis of pre‐oligodendrocytes, oligodendrocyte loss and reduced density of myelinated fibres persistent to day 21	Tashima et al. 2001; Reid et al. 2003; Olivier et al. 2005, 2007; Liu et al. 2011; Delcour et al. 2012; Fung et al. 2012; Reid et al. 2012; Basilious et al. 2015
	Deficits in white matter utrastructure, with disorganised fibre tracts, swollen axons and hypomyelination Astrogliosis present at postnatal day 14, but not observed in adulthood Transient hypervascularisation within the white matter, present at birth and normalised by postnatal day 14 Locomotor deficits in mature male FGR rats, but not females Locomotor hyperactivity and deficits in short‐ and long‐term object memory in adult rats, correlated with birth weight Strength and coordination deficits present at postnatal day 14 and persisting into adulthood to a lesser degree
Rats; chronic hypoxia; 10% O2 from day 5 to 19 of gestation
Body weight reduced by 15% at postnatal day 3	Increased neuroinflammation (number of activated microglia) in periventricular white matter Increased cell death in periventricular white matter Astrogliosis in cingulate white matter Reduced density of myelinated fibres in cingulate and lateral white matter	Pham et al. 2015
Sheep; placental embolisation with microspheres; onset 0.8 gestation (120 of 145 days gestation)
Chronic intermittent hypoxaemia (O2↓30–50%) Body weight reduced 20% near‐term Brain sparing present	Reduced density of myelinated fibres with thinner myelin sheaths in cortical white matter Reduced cerebellar volume (molecular layer and external granular layer) Reduced number of cerebellar Purkinje neurons Astrogliosis in the cerebral cortex and cortical white matter Blood vessels appeared dilated	Mallard et al. 1998
Sheep; single umbilical artery ligation (SUAL); onset 0.7 gestation (105 of 145 days gestation)
Chronic fetal hypoxaemia (O2↓20–25%) Birth weight reduced by 25% Brain sparing present	Disorganisation of white matter tracts with reduced density of myelinated fibres Neuronal degeneration in hippocampal CA3 cells No change in the number of immature/ mature oligodendrocytes in most white matter regions Axonal injury and evidence of lipid peroxidation (oxidative stress) in white matter tracts	Miller et al. 2014
Sheep; carunclectomy; prior to mating
Birth weight reduced by 30% Chronic fetal hypoxaemia (O2↓30–45%) Brain sparing present	Reduced growth of cortical neuropil, and reduced synapse density Reduced number of cerebellar Purkinje cell dendritic spines and area of arborisation	Bisignano & Rees 1988; Rees et al. 1998