Table 1.

Summary of post-mortem studies of preterm-born infants, including analysis of the GM, highlighting the case characteristics, regions of interest, and the GM and WM injuries described.

Reference    / Study location    / Years of sample collection	Number of cases (n)    / Gestational age at birth    / Survival time	Pathologists description of injury    / Post-mortem delay	Nature of cases designated as controls	Regions of interest	Gray matter pathology (description of what was analyzed)	White matter pathology (description of what was analyzed)
Andiman et al. (119)    / Dept. of Pathology, Children's Hospital Boston, MA, USA    / 1993–2007	20 WMI, 15 controls    / WMI = 33.9 ± 4.3, Control = 33.1 ± 6.2    / WMI = 5.9 ± 14.0 weeks, Controls = 13.2 ± 23.6 (NS diff)	PVL or diffuse WMI as diagnosed by a histopathologist    / Post-mortem delay not reported	Prematurity with respiratory distress syndrome, n = 4; congenital heart disease, n = 2; primary pulmonary hypertension, n = 1; hydrops fetalis due to placental chorioangiomas, n = 1; hydrops fetalis, n = 1; sacral teratoma, n = 1; cystic lymphatic malformation of the neck, n = 1; Werdnig–Hoffmann disease, n = 1; foreign body aspiration, n = 1; Blackfan–Diamond syndrome, n = 1 and bronchiolitis, n = 1 No difference in mean Apgar scores at 5 min (6.8 for both groups) or in other disorders    / confounders	In the WMI cases, the cortex overlying WMI and compared it to similar cortical areas in control cases	No sig. difference in the presence of fractin-immunopositive neurons in any cortical layer No sig. difference in the incidence of the percent of MAP2-stained pyramidal cells in layer V or obvious cortical anomalies. Significant reduction (67%) in the density (MAP2) of layer V pyramidal neurons No sig. difference in the cortical or laminar thickness (MAP2, H&E)	Periventricular focal necrosis in the deep white matter with surrounding diffuse reactive gliosis and microglial activation (previous neuropathologic studies)
Haynes and van Leyen (120) 12    / 15-Lipoxygenase    / Dept. of Pathology, Children's Hospital Boston, MA, USA    / Collection epoch not reported	13 PVL, 17 controls    / PVL −29 to 43 PC weeks (median = 35.5) and 0–8 PN weeks (median = 1.5), Controls −20 to 43 PC weeks (median = 33.5) and 0–2.5 PN weeks (median = 1)    / Survival time not reported	PVL as diagnosed by a histopathologist    / PVL = 6–25 h, Control = 4–25 h	Control cases did not have PVL or other significant brain pathology upon standard histologic examination. Autopsy reports were reviewed for major clinical findings, systemic autopsy diagnoses, and neuropathologic findings	Subcortical white matter and the cortex overlying WMI and compared it to similar cortical areas in control cases	No increase in 12/15-LOX expression in neurons of the cerebral cortex in PVL. Cell death or total cell number not assessed in the gray matter	PVL had “focal” necrotic component in the periventricular region, and “diffuse” component characterized by reactive gliosis and activated microglia in the surrounding white matter Increased 12/15-LOX expression in large round CD68+ cells, lectin double positive and O4 double positive cells and scattered TUNEL- positive cells
Haynes et al. (121) Diffuse axonal / Dept. of Pathology, Children's Hospital Boston, MA    / Collection epoch not reported	13 PVL, 17 Control (spread across acute and later stages)    / Mean gestational age (wks) PVL =36 ± 3, Controls = 32 ± 7    / Mean postnatal age (wks)—PVL = 7.5 ± 17, Control = 10.5 ± 27	PVL as diagnosed by a histopathologist    / PVL = 6–44 h (median = 17), Controls = 1.5–132 h (median = 14)	Control cases did not have PVL or other significant brain pathology upon standard histologic examination. Causes of death included Noonan's syndrome 1, Fetal hydrops 1, Neonatal hepatic disease 1, Immune thrombocytopenia 1, Possible mitochondrial disorder 1, Sudden unexplained death in childhood, 1, Trisomy 21 1, Unexplained stillbirth	The area of study for axonal damage in PVL was distant from the infarct, i.e., in a separate section with no overlying cortical damage	Approximately 1/3rd PVL cases had thalamic gliosis, neuronal loss, and    / or microinfarcts as determined by conventional histopathologic examination. Visually appreciable neuronal loss was present in the overlying cerebral cortex in 15% of the PVL cases. None of the non-PVL, non-axonal controls examined showed evidence of thalamic and    / or cerebral cortical damage	PVL based on histopathologic criteria—periventricular focal necrosis in association with diffuse reactive gliosis and microglial activation Diffuse axonal injury, as determined by the apoptotic marker fraction, in the gliotic (non-necrotic) cerebral white matter in the acute and organizing stages of focal PVL
Ligam et al. (122)    / Dept. of Pathology, Children's Hospital Boston, MA, USA    / Collection epoch not reported	22 PVL, 16 non-PVL    / Gestational age in PVL = 32.5 ± 4.8 gw, Controls = 36.7 ± 5.2 gw, Sig dif in gw.    / PVL = ~4 weeks, Controls = ~20 weeks (P = 0.07)	PVL as diagnosed by a histopathologist    / Post-mortem delay not described	Control cases did not demonstrate white matter features. Lower rates of NEC and sepsis in controls than in PVL	Thalamic sections were analyzed at one of the following levels: I (anterior), level of the mammillary bodies; II (mid), level of the red nucleus; and III (posterior), level of the lateral geniculate nucleus	Increased thalamic pathology via neuropathologist assessment (H&E) Trend to decreased neuronal density with H&E (p = 0.07)—criteria for neuronal discrimination not described Increased density of reactive astrocytes (GFAP) in the mediodorsal nucleus and the lateral posterior nucleus No significant increase in the density of CD68 + cells and numbers overall low No difference in the density of MDA-immunopositive neurons or percent of MDA-immunopositive neurons	Histopathology to confirm (or not) PVL, with “focal” necrotic component in the periventricular region, and “diffuse” component characterized by reactive gliosis and activated microglia in the surrounding white matter
Kinney et al. (123)    / Dept. of Pathology, Children's Hospital Boston, MA, USA    / 1998–2012	15 PVL, 10 controls    / The mean gestational age PVL = 32.8 ± 4.1 weeks in the, Control = 30.1 ± 5.9 weeks    / PVL = 34 ± 4.6 postconceptional weeks, Controls = 31.6 ± 6.6 postconceptional weeks	PVL as diagnosed by a histopathologist    / Causes of death in PVL: respiratory distress syndrome (n = 7); congenital heart disease (n = 3); primary skeletal disorders (n = 2); congenital diaphragmatic hernia (n = 1); inborn error of metabolism (n = 1) and VOGM (n = 1)    / PVL = median 14 h, Control = median 16.5 h	Controls did not demonstrate white matter abnormalities Causes of death in controls respiratory distress syndrome (n = 5); congenital heart disease (n = 1); hydrops fetalis due to placental chorioangiomas (n = 1); hydrops fetalis due to parvovirus (n = 1); primary pulmonary hypertension (n = 1); and bronchiolitis (n = 1)	Neurons in the ventricular/ subventricular region, periventricular white matter, central white matter, and subplate region in PVL cases and controls—including five subtypes of subcortical neurons: granular, unipolar, bipolar, inverted pyramidal, and multipolar	The neuronal density of the granular neurons in each of the four regions was 54–80% lower (p ≤ 0.01) in the PVL cases compared to controls adjusted for age and post-mortem interval The overall densities of unipolar, bipolar, multipolar, and inverted pyramidal neurons did not differ significantly between the PVL cases and controls	Analysis grouped neurons in the subplate and white matter collectively PVL was characterized by necrotic foci in the periventricular and/ or central white matter; and diffuse astrogliosis and microglial activation in the surrounding white matter
Pierson et al. (72)    / Dept. of Pathology, Children's Hospital Boston, MA, USA    / 1997–1999	17 PVL, 17 DWMI, 7 Negative (controls)    / PVL = 3.7 ± 4.1 (median = 2.3), DWMI = 3.4 ± 14.0 (median = 1.2), Negative = 0.8 ± 1.2 (n = number of samples)	PVL or diffuse white matter gliosis (DWMG) without necrosis    / Post-mortem delay not described	“Negative” white matter group with no diffuse gliosis or focal periventricular necrosis in the cerebral white matter	Seventeen gray matter regions, across the limbic system, cerebral cortex, deep gray nuclei, cerebellum and relay nuclei Seven white matter regions—frontal lobe, temporal lobe, parietal lobe, occipital lobe, corpus callosum, internal capsule and cerebellum	Sig increased neuronal injury in the cerebellar cortex and frontal cortex of PVL compared with DWMI or Negatives (H&E) No increase in astrogliosis (GFAP)	Focal periventricular necrosis; diffuse white matter gliosis
Haldipur et al. (124)    / National Brain Research Centre, Manesar, India    / 2007–2010	40 cases    / Across the window of 28 weeks of gestation to 8 postnatal months    / 4 controls with 0 days survival and 32 cases of varying age at birth and survival	All cases are those in which the autopsy indicated minimum or no damage to the brain and cerebellum in particular    / Delay = <24 h	Still birth cases—with no obvious signs of injury as per cases with postnatal survival	Cerebellum	EGL cell density significantly increased by preterm birth EGL thickness reduced by preterm birth	None described
Marin-Padilla (3)    / Paediatric Autopsy Service, Dartmouth-Hitchcock Medical Center, Hannover, New Hampshire, USA (via ref 23)    / Collection epoch not reported	33 cases total    / 5 cases born preterm who all had short survival time    / 3 months through to 5 years survival	PVL as diagnosed by a histopathologist    / Post-mortem delay not described	No controls—description of changes over time after WM injury only	Gray matter overlying frank WM injury	No changes visible in the acute cases—which were the pre-term born infants In the cases surviving longer—late term and term born infants, no change in the upper cortical layer vascular and cellular distribution and morphology (H&E, Golgi) Axomatoised pyramidal neurons change from being long projecting to being local-circuit (Golgi). These cells have increased circuitry and altered neuronal morphology—populations of larger and smaller cells with altered distributions (Golgi, H&E, GFAP)	Cystic white matter lesions
Stolp et al. (42)    / Perinatal Pathology Department, Imperial Health Care Trust, London,	Non-WMI group, n = 7, WMI group, n = 6    / Non-WMI group = 23 + 2 to 28 + 1 gw, WMI group 26 + 5 to 29 + 3	Evidence of diffuse (non-cystic) white matter injury (WMI cases) including white matter gliosis and focal lesions    / 1–3 days—bodies stored at 4°C	Seven cases showed no significant brain pathology, non-neuropathologic controls (no WMI cases)	Interneurons of the frontal cortex and underlying white matter	No change in the total number of cortical neurons, identified by HuC/ HuD immunoreactivity, with 53,104 ± 11,009 immunopositive cells/ mm2 found in the control brains (n = 5)	No statistical differences in the number of SST or NPY subpopulations in the white matter between preterm infants with or without white matter injury. Significant decrease in the
UK    / Collection epoch not reported	gw    / Non-WMI group = 5 min to 43 h. WMI group 1 min to 5 weeks (comparison p = 0.002)				and 52,120 ± 6,327 cells/mm2 in the cortex of the white matter injury cases (n = 4) Significant decrease in the cortical calretinin+ cells Calbindin- and parvalbumin-positive cells were observed in low numbers in both cases, insufficient for determining statistically significant changes. Somatostatin and Neuropeptide Y only found in the white matter	arborization of Somatostatin and Neuropeptide Y interneurons in both of these interneuron classes As previously reported (125)
Panda et al. (4)    / New York Medical College and Albert Einstein College of Medicine, USA    / 2002–2016	Fetuses: 20–22 gw, n = 5, Infants: 23–28 gw, n = 5, Inafnat: 29–34 gw, n = 5    / 20–40 gestational weeks (gw): 26–27 gw infants surviving for 4–6 weeks were compared with 32–33 gw infants who lived for ~3 days. Therefore, both had PMA33 gw at their death	Excluded = moderate to severe intraventricular hemorrhage, major congenital anomalies, history of neurogenetic disorder, chromosomal defects, culture-proven sepsis, meningitis, or hypoxic–ischemic encephalopathy and infants receiving extracorporeal membrane oxygenation treatment    / post-mortem interval of ~18 h	None. Comparisons of effects of varying degrees of prematurity	Cortex (cortical plate), white matter (embryonic intermediate layer), and ganglionic eminences, which were cut at the level of the head of caudate nucleus	More prematurely born infants have fewer GAD67+ neurons in upper and not lower cortical layers More prematurely born infants have fewer Parvalbumin+ neurons in upper and not lower cortical layers More prematurely born infants have greater numbers of Somatostatin+ neurons in upper and not lower cortical layers Calretinin+ and neuropeptide Y+ interneurons not effected by preterm birth	No analysis undertaken.
Vontell et al. (125)    / Perinatal Pathology Department, Imperial Health Care Trust, London, UK    / Collection epoch not reported	7 WMI and 7 controls    / All <32 weeks' gestational age, vaginally delivered    / Survival time not reported	Cerebral white matter gliosis, lipid-laden macrophages, and focal lesions with evidence of WMI on pathologic examination (WMI cases)    / 1–3 days—bodies stored at 4°C	Also, extremely preterm, but with no significant brain pathology on gross and microscopic examination from post-mortem examination and had no visible brain abnormalities on post-mortem magnetic resonance imaging	Thalamus (medial dorsal (MD) nucleus, ventral lateral posterior (VLp) nucleus, ventral posterior lateral (VPL) nucleus) White matter [posterior limb of the internal capsule (PLIC) adjacent to the VLp (PLIC-VLp) and PLIC adjacent to the VPL (PLIC-VPL)]	No difference in the total average cell density in thalamic regions (H&E) Significant decrease in neurons in WMI cases in the MD, VLp, and VPL (HuC/ HuD) Significant increase in the ratio of astrocytes (GFAP+) to total cell count in thalamic regions in WMI cases, compared with MD (p < 0.01) and VLp (p < 0.01)—but not VPL Significant increase in IBA1+ cells in WMI cases in the MD, VLp, and VPL.	No difference in the average total cell density in white matter regions Significant increases in neurons in PLIC-VPL but not in PLIC-VLp Significant increase in IBA1+ cells in the PLIC-VPL (p < 0.05), but not in PLIC-VLp
Pogledic et al. (126)    / Hôpital Robert Debré, Paris, France    / Collection epoch not reported	Cystic (c)-WMI, n = 7, Controls, n = 18    / c-WMI = 24 + 4 to 27 gw, controls = 24 + 2 to 34 gw    / c-WMI = 0–4 weeks and 1 day, Control = 0–11 days	Cystic cases including focal lesions with macroscopic cysts associated or not with necrosis and    / or calcifications surrounded by diffuse pallor    / post-mortem interval <48 h	Non-cystic cases without tissue loss displayed pallor and gliosis (18/18 cases) associated with microscopic necrotic foci in a few cases (4/18 cases) and were considered to consist of diffuse lesions	Cortical regions located in the posterior part of the superior, middle and inferior frontal gyri and sulci, and the precentral gyrus and central sulcus corresponding to corresponding to the presumptive premotor and motor areas (areas 8-6-4) and contiguous prefrontal areas	Significantly increased cortical plate and subplate astrogliosis (GFAP) in c-WMI vs. control preterm WMI (no change in very preterm cystic and control cases) No increase in cortical plate and subplate microgliosis (IBA1) in c-WMI vs. control preterm WMI (for very preterm or just preterm cases)	White matter cysts were confined to the white matter without extending into superficial layers of the cerebral wall, such as the subplate and cortical plate

WM injury provided as context for overall injury severity.

Of the 12 studies identified, those highlighted in yellow (n = 6) report studies performed on tissues drawn from the same pool of post-mortem samples between the years of 1993–2007. It is unclear, and undeterminable from the case reports, how many times a single case appears across the six studies, and as such, how co-dependent the findings are. 12/15-LOX, 12/15-lipoxygenase; DWMI, diffuse white matter injury; EGL, external granule cell layer; h, hours; GAD67, glutamate decarboxylase 67; GFAP, glial fibrillary protein; gw, gestational weeks; H&E, hematoxylin and eosin; MAP2, microtubule associated protein 2; MD, Medial dorsal nucleus (thalamus); MDA, malondialdehyde; NEC, necrotising enterocolitis; PC, post-conceptional; PLIC, posterior limb of the internal capsule; PVL, periventricular leukomalacia; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; WMI, white matter injury; VLp, ventral lateral, posterior (thalamus); vPL, Ventral posterolateral nucleus (thalamus).