Do Sub-Ependymal Haemorrhages cause cerebral palsy?

The germinal matrix is a region in the immature brain where a large proportion of cortical neurones are formed before they migrate out to form the neo-cortex. It is intensely metabolically active as it is producing hundreds of thousands of neurones per minute. It has a very high blood flow as a result and large fragile vessels that bleed easily. Such germinal matrix/sub-ependymal haemorrhages are associated in most studies with no discernable effects on long term neurological, developmental or functional problems. This has always fascinated me, how can such a critical region of the developing brain be severely damaged in a way which is clearly visible on head ultrasound, without much effect on brain development? The plasticity of the newborn and especially the preterm brain is remarkable.

A new publication from the amazing group in Melbourne (Hollebrandse NL, et al. School-age outcomes following intraventricular haemorrhage in infants born extremely preterm. Arch Dis Child Fetal Neonatal Ed. 2020) suggests that such bleeds might indeed have impacts. Using data accumulated over many years they present the outcomes at years of age of 499 babies born at <28 weeks. The results are drawn from 3 cohorts that the group of studied from Victoria state in Australia, from 1991, 1997 and 2005.

The high-quality follow-up has been maintained over those time periods and includes IQ testing, academic achievement and executive function evaluation, motor function tests, and examination for cerebral palsy. The authors note that there was no appreciable difference in the results between the 3 time periods.

There were decreasing trends with worsening grade of IVH for multiple birth and antenatal corticosteroid treatment, and increasing trends for male sex, receiving surgery, postnatal corticosteroids, bronchopulmonary dysplasia and cystic PVL

In terms of IQ, academic achievement and executive function there was no apparent difference between babies with grade 1 or 2 IVH and control babies without IVH.

Babies with grade 3 or 4 IVH had a higher proportion of babies with IQ scores <-2SD, 22% and 42% respectively compared to 12% without IVH, and many more with at least one academic skill below the term norms. (There are only 23 babies with grade 3 and 12 with grade 4 IVH in these cohorts).

Executive function did not change with grade of IVH.

Although the methods mention the term-born controls on 2 or 3 occasions, they don’t present any comparisons between the term controls and the preterm babies. I think they mention the term controls (always one of the strengths of the publications from this programme) mostly as they are the source of the standardized scores for IQ and academic achievement.

The main finding of the study, to my mind, is the association between low grades of IVH and motor abnormalities, that is: any motor dysfunction, cerebral palsy, or a low MABC score. All are more frequent with grade 1 and in particular grade 2 IVH than among babies without a haemorrhage.

This is consistent with some other studies, but not all. As in all observational studies, we cannot be sure that this association is causative. The analysis was not adjusted for many complications of neonatal care that are known to be associated with poorer outcomes, such as postnatal steroids, BPD, late-onset sepsis, NEC, sex, or surgery. There was however a similar proportion of boys in the no IVH, grade 1 and grade 2 groups, so it would probably make no difference to adjust for sex. There was more BPD (44% controls, 56% grade 1 and 2 combined) and postnatal steroids (32% vs 46%), however, in those 2 groups, both of which are themselves associated with CP and could possibly account for these findings. One of the other studies that examined this issue (Payne AH, et al. Neurodevelopmental outcomes of extremely low-gestational-age neonates with low-grade periventricular-intraventricular hemorrhage. JAMA Pediatr. 2013;167(5):451-9) examined 1472 infants <27 weeks in the NICHD network. They did not show an impact of low-grade IVH on motor outcomes and had a much smaller difference in BPD between the grade 1 and 2 babies (53% with BPD) and the controls without IVH (47%), and no difference in postnatal steroid use (14% in each group). In other studies (EPIPAGE for example) grade 2 but not grade 1 haemorrhages were associated with CP in adjusted analyses.

My evaluation of all this is that it appears that low grade IVH may have an association with motor dysfunction in some cohorts, but it is not clear at all to me that it is causative. It could well be that babies who are somewhat more unstable in the first 3 days are more likely to have low-grade haemorrhage and more likely to develop BPD, more likely to have received postnatal steroids, and probably at somewhat greater risk of white matter injury. All of which may predispose them to develop motor problems. Low-grade IVH could be considered a potential marker for infants that require extra effort to ensure they get followed up and are evaluated repeatedly to see if they need intervention.

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
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