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We thank Drs Cowan, de Vries and Groenendaal for their interest in our study.(1) Their main concerns related to our findings that low-grade intraventricular haemorrhages (IVH) were associated with higher rates of cerebral palsy than experienced in their own centres and other published studies, and that other lesions apart from low-grade IVH may explain the higher rates of motor impairment and cerebral palsy noted in our cohorts.
Our cerebral palsy rates were determined at age 8 years, by experienced developmental paediatricians blinded to group and clinical history. Thus we are confident of the robustness of clinical ascertainment. We accept that our reported rates of cerebral palsy in low-grade IVH may be higher than those in some other studies, highlighting that our findings are likely specific to our population rather than others. However, our finding of increased cerebral palsy in low-grade IVH is not isolated, as we identified several studies describing 1.5-2 times the baseline rates in preterm cohorts born <33 weeks’ with low-grade IVH compared with no IVH.(2-4) We acknowledge that our data supports an association between low-grade IVH and cerebral palsy, and at no point did we imply a causal relationship.
We agree that cystic periventricular leukomalacia (cPVL) is a well-established cause of cerebral palsy. Co-existing cPVL in our low-grade IVH groups did not explain the associations with cerebral palsy. The independent relationships between low-gra...
We agree that cystic periventricular leukomalacia (cPVL) is a well-established cause of cerebral palsy. Co-existing cPVL in our low-grade IVH groups did not explain the associations with cerebral palsy. The independent relationships between low-grade IVH and cerebral palsy at 8 years remained after adjusting for cPVL [unadjusted OR 2.24 (95% confidence interval (CI) 1.21, 4.16); p=0.011; adjusted for cPVL OR 2.22 (95% CI 1.14, 4.29) p=0.018]. As brain magnetic resonance imaging was not widely available for the cohorts in this study, we are not able to confirm the possibility of other lesions explaining the rates of cerebral palsy observed in our low-grade IVH groups.
Our paper highlights the associations of all grades of IVH with adverse outcomes at school age. Regardless of whether the associations are explained by other brain lesions, the findings highlight the importance of long term follow up in all extremely preterm newborns in regard to risk of neurodevelopmental deficits, including those with low-grade IVH.
Jeanie Cheong, Alicia Spittle, Peter Anderson and Lex Doyle
1) Hollebrandse NL, Spittle AJ, Burnett AC, et al. School-age outcomes following intraventricular haemorrhage in infants born extremely preterm. Arch Dis Child Fetal Neonatal Ed 2020 Jul 30:fetalneonatal-2020-318989. doi: 10.1136/archdischild-2020-318989.
2) Klebermass-Schrehof K, Czaba C, Olischar M, et al. Impact of low-grade intraventricular hemorrhage on long-term neurodevelopmental outcome in preterm infants. Childs Nerv Syst 2012;28:2085–92.
3) Bolisetty S, Dhawan A, Abdel-Latif M, et al. Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics 2014;133:55–62.
4) Beaino G, Khoshnood B, Kaminski M, et al. Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study. Dev Med Child Neurol 2010;52:e119–25.
Hollebrandse et al are to be congratulated on achieving such a high follow-up rate at 8 years in a large cohort of preterm infants with intraventricular haemorrhage (IVH). Long-term outcomes related to specific cUS findings are increasingly important as many significant if more subtle neurodevelopmental problems are not detected at earlier follow-up.
It is reassuring that children with the milder grades of IVH had intellectual outcomes similar to the no-IVH group but of concern is the report of significant motor deficits and cerebral palsy (CP) following grades 1 and 2 IVH. However the outcomes given may not solely be related to IVH but to other pathologies notably cystic periventricular leukomalacia (cPVL) a well-known predictor of motor deficits and CP.[1,2] cPVL was found in 6% and 4% of the children with grades 1 and 2 IVH and 13% and 25% of those with grades 3 and 4 IVH. The authors neither adjust for this pathology, saying that “cPVL may lie along the causal pathway between IVH and adverse outcomes”, nor do they give evidence to support this statement. Indeed the contribution of cPVL to outcomes is not discussed or mentioned in the abstract. We are not aware of evidence that low grade IVH is in a causal pathway to cPVL, and suggested associations between cPVL and higher grades of IVH were based on studies using infrequent ultrasound protocols and without MRI scanning at term equivalent age. [3,4] We are aware of preterm infants who develop late-onset c-PVL no...
It is reassuring that children with the milder grades of IVH had intellectual outcomes similar to the no-IVH group but of concern is the report of significant motor deficits and cerebral palsy (CP) following grades 1 and 2 IVH. However the outcomes given may not solely be related to IVH but to other pathologies notably cystic periventricular leukomalacia (cPVL) a well-known predictor of motor deficits and CP.[1,2] cPVL was found in 6% and 4% of the children with grades 1 and 2 IVH and 13% and 25% of those with grades 3 and 4 IVH. The authors neither adjust for this pathology, saying that “cPVL may lie along the causal pathway between IVH and adverse outcomes”, nor do they give evidence to support this statement. Indeed the contribution of cPVL to outcomes is not discussed or mentioned in the abstract. We are not aware of evidence that low grade IVH is in a causal pathway to cPVL, and suggested associations between cPVL and higher grades of IVH were based on studies using infrequent ultrasound protocols and without MRI scanning at term equivalent age. [3,4] We are aware of preterm infants who develop late-onset c-PVL not related to an initial low grade IVH but following (Gram-negative) sepsis or necrotising enterocolitis occurring later in the neonatal period.
Compared to several other studies, a high percentage of infants in this study developed CP (8% with no IVH, and 15, 18, 26 and 75% with grades 1-4 IVH). The higher levels of CP than generally expected for grades 1 and 2 IVH [5,6] may partly be explained by the presence of cPVL. Additionally there may have been non-cystic white matter injury e.g. punctate white matter lesions, cerebellar lesions or strokes that were not detected with the imaging protocol used. The statement "Our study adds to a growing understanding of the negative impact of low grade IVH on motor development" fails to adjust the findings for other lesion(s) known to lead to impaired motor development.
We also find the rates of CP in children with grades 3 and 4 IVH high. These may in part be related to care pathways chosen and the timing of treatment of post-haemorrhagic ventricular dilatation but no information is given about this. One might expect about 50-60% of preterm infants with grade 4 IVH to develop a hemiplegia whilst here it is 75% perhaps influenced by the fact that 25% also had cPVL.
Another unexpected and worrying finding is that the severity of CP was the same in children with lower and higher grades of IVH. This could be due to the inclusion of infants with co-existing c-PVL or other lesions. It is unfortunate that no MRI findings are reported to substantiate the cUS findings particularly in infants with CP following low-grade IVH.
This paper may well be used by neonatologists to give prognoses following IVH in the first week after birth. We are concerned that these data will worry parents unnecessarily, especially those of infants with isolated low-grade IVH. Whilst it is fair to tell parents that other lesions may become apparent or develop we need to distinguish between outcomes due to findings seen at the time of scanning and those related to a potential pathology not yet seen and perhaps developing following unrelated clinical problems.
Frances Cowan, Floris Groenendaal and Linda S de Vries
Prof Frances M Cowan PhD FRCPCH
Dept. of Paediatrics
Imperial College London
W12 0HS, UK
Dr Floris Groenendaal MD PhD and Prof Linda S de Vries MD PhD
Wilhelmina Children’s Hospital,
University Medical Centre Utrecht,
KE 04.123.1, PO Box 85090,
3508 AB Utrecht, Netherlands
1. Martinez-Biarge M, Groenendaal F, Kersbergen KJ, Benders MJNL, Foti F, van Haastert IC, Cowan FM, de Vries LS. Neurodevelopmental Outcomes in Preterm Infants with White Matter Injury Using a New MRI Classification. Neonatology. 2019;116(3):227-235
2. van Haastert IC, Groenendaal F, Uiterwaal CS, Termote JU, van der Heide-Jalving M, Eijsermans MJ, Gorter JW, Helders PJ, Jongmans MJ, de Vries LS. Decreasing incidence and severity of cerebral palsy in prematurely born children. J Pediatr. 2011 Jul;159(1):86-91.e1
3. Kusters CDJ, Chen ML, Follett PL Dammann O. "Intraventricular" hemorrhage and cystic periventricular leukomalacia in preterm infants: How are they related? J Child Neurol 2009; 24:1158-1170.
4. Kuban K, Sanocka U, Leviton A, Allred EN, Pagano M, Dammann O, et al. White matter disorders of prematurity: association with intraventricular hemorrhage and ventriculomegaly. J Pediatr 1999; 134:539-546.
5. Payne AH, Hintz SR, Hibbs AM, Walsh MC, Vohr BR, Bann CM, Wilson-Costello DE; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network: Neurodevelopmental outcomes of extremely low-gestational age neonates with low-grade periventricular intraventricular hemorrhage. JAMA Pediatr 2013;167:451–459.
6. Reubsaet P, Brouwer AJ, van Haastert IC, Brouwer MJ, Koopman C, Groenendaal F, de Vries LS. The Impact of Low-Grade Germinal Matrix-Intraventricular Hemorrhage on Neurodevelopmental Outcome of Very Preterm Infants. Neonatology 2017;112(3):203-210.
7. Leijser LM, Miller SP, van Wezel-Meijler G, Brouwer AJ, Traubici J, van Haastert IC, Whyte HE, Groenendaal F, Kulkarni AV, Han KS, Woerdeman PA, Church PT, Kelly EN, van Straaten HLM, Ly LG, de Vries LS. Posthemorrhagic ventricular dilatation in preterm infants: When best to intervene? Neurology. 2018;90(8):e698-e706
• Contributors: FMC, FD and LdeV contributed equally to the letter
• Funding: The authors have not declared a specific funding agency in the public, commercial or not-for-profit sectors.
• Competing interests: None declared.
• Provenance and peer review: Not commissioned.
• Patient consent for publication: Not required.