Neurodevelopmental outcome of perinatal intracranial haemorrhage in patients born at term: A prospective study

Abstract

Aim: To assess the neurological and neurodevelopmental outcome of infants born at term with perinatal intracranial haemorrhage (pICH) and examine the clinical and neuroimaging associations.

Method: A prospective, consecutive, single-center observational study of longitudinally followed children with pICH identified in the fetal or neonatal period (≤28 days of life) between January 2014 and November 2022. Neurodevelopmental outcome was rated using the Pediatric Stroke Outcome Measure (PSOM) and the modified Rankin Scale (mRS).

Results: Sixty-eight infants were included (67.6% diagnosed postnatally and 32.4% diagnosed antenatally). Intraventricular haemorrhage was the most common bleeding type (n = 43, 63.2%) and was more common in infants diagnosed prenatally (p = 0.004). Twenty-nine (42.6%) infants were diagnosed with cerebral palsy and 19.1% with remote epilepsy. PSOM was performed at a median age of 3 years 8 months (range = 1 year-9 years 5 months). According to the PSOM, outcome was normal in 29 (42.6%) infants. Twelve (17.6%) patients had mild impairment, 11 (16.2%) had moderate impairment, and 16 (23.5%) had severe impairment. There was no difference in neurological outcomes between patients diagnosed antenatally or postnatally. Remote epilepsy (p = 0.002), multi-compartment ICH (p = 0.048), vermian hemorrhage (p = 0.048), posthaemorrhagic ventricular dilatation (p = 0.037), thalamic volume loss (p = 0.037), white matter loss (p = 0.048), Wallerian degeneration (p = 0.026), and abnormal myelination in the posterior limb of the internal capsule (p = 0.005), were associated with less favourable PSOM scores. Anterior horn width correlated with PSOM total scores (r = 0.6).

Interpretation: pICH carries a significant risk of long-term adverse neurological outcomes with no difference in neurological outcome between those diagnosed antenatally or postnatally. Epilepsy and neuroradiological markers are associated with unfavourable neurodevelopmental outcomes.

FIGURE 1

Factors associated with unfavourable outcome according to the Pediatric Stroke Outcome Measure (PSOM). The star signifies p < 0.05 (the p‐value was corrected for false discovery rate). Genetic testing was performed in 34 patients, 14 with unfavourable neurological outcomes. Abbreviations: ICH, intracranial haemorrhage; IUGR, intrauterine growth restriction; IVH, intraventricular haemorrhage; PLIC, posterior limb of internal capsule; PHVD, posthaemorrhagic ventricular dilatation; PVHI; periventricular haemorrhagic infarction.

FIGURE 2

Correlation heatmap map illustrating the variables associated with the PSOM total scores and subscales. A p < 0.05 was deemed statistically significant (bold font). The heatmap corresponds to the Spearman correlation coefficient r, with values between −1 and 1, with r < 0 indicating a negative correlation (red) and r > 0 indicating a positive correlation (green). Abbreviations: GMFCS, Gross Motor Function Classification System; HC, head circumference; mRS, modified Rankin Scale; PSOM, Pediatric Stroke Outcome Measure.

FIGURE 3

Illustrative magnetic resonance imaging (MRI) cases. (a1–4) A nine‐month‐old male infant with presumed perinatal left grade 2 IVH and PVHI. Axial susceptibility‐weighted imaging (SWI) showing haemosiderin deposits in the deep medullary veins (a1). Axial T2 shows mild gliosis in the centrum semiovale and posterior periventricular white matter with white matter volume loss (a2, a3) and mild ipsilateral Wallerian degeneration (arrow) (a4). At age 4 years, the child has unilateral CP, GMFCS level I, with normal cognition. PSOM score = 1. (b1–4) Fetal MRI at 32 GA showing right germinal matrix‐IVH on coronal T2 (b1), with progressive enlargement of the right ventricle at 36 GA (b2). MRI at 2 days of life shows PHVD of the right ventricle with periventricular white matter oedema suggestive of hydrocephalus (coronal T2, b3). Ventriculoperitoneal shunt insertion was performed. MRI at 9 months, shows white matter loss and porencephaly (coronal T1, b4). At age 8 years, the child has unilateral CP, GMFCS level II, and has combined language disorder, ADHD, and learning disabilities. PSOM score = 3. (c1–4) A five‐day‐old male presented with seizures and vomiting. Sagittal T1 (c1), axial T2 (c2), and SWI (c3) show haemorrhagic venous infarction of the left thalamus and bilateral acute‐subacute IVH due to vein of Galen thrombosis (c1, arrow). MRI at age 2 years shows periventricular white matter hyperintensity and left thalamic cystic encephalomalacia (c4). At 6 years of age, he has mild GDD, and electrical status epilepticus in sleep without developmental regression. PSOM score = 2.5. (d1–4) A 1‐day‐old male with bilateral grade 3 acute IVH, secondary to cerebral venous thrombosis showed on axial SWI (d1), coronal (d2) and sagittal (d3) T2. At age 6 years 3 months left PHVD with residual volume loss of the ipsilateral thalami (Axial T2, d4). At age 5 years and 8 months, he has GDD and refractory epilepsy. PSOM score = 3.5. (e1–4) A 1‐day‐old male infant with right temporal subpial haemorrhage (single asterisk) with venous infarct in the temporal lobe. Coronal T2 (e1), sagittal T2 (e2), axial T2 (e3), and axial ADC (e4). At age 8 years, total PSOM score = 1. (f1–3) An 8‐day‐old male infant with pontine haemorrhage and associated oedema on axial SWI (f1) and sagittal T2 (f2). MRI at age 29 months demonstrates thinning of the brainstem and loss of the normal pons budge secondary to encephalomalacia (sagittal T2, f3). At age 4 years 7 months, he has CP, GMFCS level IV; abnormal neurological findings include cranial nerve palsies, hemiparesis and ataxia, vision and hearing impairment, and low‐functioning ASD. PSOM score = 10. (g1–4) Neonatal subdural haemorrhage caused by factor X deficiency. Sagittal T1 at 7 (f1), 17 (f2), and 34 (f3) days shows supratentorial and infratentorial subdural haemorrhage with complete resolution at age 4.5 months (f4). At 14 months, the infant is developing typically. PSOM score = 0. (h1–4) Cerebellar haemorrhage diagnosed in the first day of life, extending to the fourth ventricle, related to CSVT (not shown). MRI at 26 months shows posterior fossa residual haemorrhage involving the vermis, small supratentorial subdural haemorrhages are also noted on axial SWI (h1). On sagittal T1, vermian atrophy (h2) with progression at age 7 years 10 months (h3) is noted. At age 8 years, the child has ataxic CP, GMFCS level IV, and borderline IQ. PSOM score = 8. (i1–4) A 2‐day‐old male infant with mild IUGR, born via vacuum delivery. Axial SWI (i1) on day 2 shows multi‐compartment haemorrhage, including IVH and multiple parenchymal haemorrhages in the periventricular white matter and in the basal ganglia. Sagittal T2 (i2) shows thinning of the corpus callosum. MRI at 7 months shows on axial T2 (i3) abnormal bilateral T2 hyperintensity in the globus pallidum and thalami and the periventricular white matter gliosis with volume loss, irregular ventricular borders, and secondary grey matter loss. Abnormal, asymmetric configuration of the lenses is suggestive of bilateral cataracts (i4). WES identified a de novo COL4A1 missense mutation. At age 4 years, the child has severe GDD, microcephaly, severe vision impairment due to bilateral cataracts, bilateral CP, GMFCS level V, and refractory epilepsy. PSOM score = 10. Abbreviations: ADHD, attention‐deficit/hyperactivity disorder; ASD, autism spectrum disorder; GDD, global developmental delay; CSVT, cerebral sinovenous thrombosis; ICH, intracranial haemorrhage; IUGR, intrauterine growth restriction; IVH, intraventricular haemorrhage; PLIC, posterior limb of internal capsule; PSOM, Pediatric Stroke Outcome Measure; PHVD, posthaemorrhagic ventricular dilatation; PVHI; periventricular haemorrhagic infarction; WES, whole‐exome sequencing.