The Journal of Pediatrics
Volume 149, Issue 2 , Pages 152-154, August 2006

Neurodevelopmental impact of low-grade intraventricular hemorrhage in very preterm infants

  • Terrie E. Inder, MBChB, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Dr Terrie E. Inder, One Children’s Place, St Louis Children’s Hospital, Washington University, St Louis, MO 63110.

Associate Professor of Pediatrics, Neurology and Radiology, St Louis Children’s Hospital, Washington University, St Louis, MO

Received 8 May 2006; accepted 30 May 2006.

Article Outline

Abbreviations:  CUS, Cranial ultrasound , IVH, Intraventricular hemorrhage

 

Intraventricular hemorrhage (IVH) remains one of the most common neuropathologies documented in the preterm infant, with rates varying between 15% and 25% and remaining static over the last decade.1, 2 Although neonatal clinicians have readily accepted that high-grade (III to IV) IVH is associated with an increased risk of adverse neurodevelopmental outcome in the preterm infant, there has been more controversy and less clinical anxiety in relation to the low grades (I to II) of IVH.

See related article, p 169

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Does Low-Grade IVH Influence Neurodevelopmental Outcome in the Preterm Infant? 

There have been many reports describing associations between cranial ultrasound (CUS) findings, including low-grade I to II IVH, and neurodevelopmental outcomes over the past three decades, but comparison of these studies is complicated by a variety of factors, including (1) the populations studied included larger preterm infants, (2) the era of neonatal medicine was before the routine administration of antenatal steroids and surfactant, (3) technical issues of timing and quality of acquisition of the CUS, and (4) the duration of time for which subjects were in clinical follow-up with more subtle neurodevelopmental abnormalities not being readily detected at younger ages. The largest, most recent study relating IVH to outcomes is the EPIPAGE study1 of 1954 infants of less than 32 weeks’ gestation. This study found that isolated grade I to II IVH occurred in 319 (16%) infants, with a subsequent rate of cerebral palsy by age 2 years of 5.5%. When the authors included the other noted pathologies of ventricular dilation (n = 98) and cystic or echodense periventricular leukomalacia (PVL) (n = 241), the rates of cerebral palsy increased substantially for grade I IVH (n = 229) to 8.1% and grade II IVH (n = 168) to 12.2%. Notably, cerebral palsy rates with isolated grade I to III IVH also rose with immaturity, from 5% in 31 to 32 weeks to 10% to 15% in 27 to 30 weeks, and 33% in 24 to 26 weeks.

For school-aged outcomes, Sherlock et al3 examined 298 preterm infants (weighing <1000 grams at birth) at age 8 years to determine the impact of IVH in relation to neuromotor and cognitive outcomes. They documented that no IVH was associated with cerebral palsy rates of 6.7%, with no rise in association with grade I IVH (6.4%) but a marked elevation with grade II IVH to 24%. There was no impact of grade I to II IVH on cognitive outcomes.

In this issue of The Journal of Pediatrics, Patra et al4 report that grade I to II IVH was associated with a 2-fold increase in the risk of lower cognitive performance (MDI) and a 2.6-fold increase in the risk of neuromotor abnormalities (cerebral palsy and tone) after controlling for social and neonatal factors (sex, bronchopulmonary dysplasia (BPD), sepsis, necrotising enterocolitis (NEC), maternal marital status, race, and education). There are some weaknesses in the current study, including (1) the cohort spanned a long period of 8 years with neonatal intensive care unit therapy changes; (2) there was no reporting or controlling for the potential confounder of postnatal steroid exposure; and (3) antenatal steroid use was low and differed significantly between the groups without being controlled for in the modeling. It would also have been very useful to have seen the authors present their data distinguishing grade I and II IVH outcomes from each other, as this may have truly assisted in understanding the predictive power and the causal pathways by which low-grade IVH may be associated with poor neurodevelopmental outcomes. The strengths of the study include the high follow-up rate of 91% and the fact that all other potential neuropathologies on CUS (severe PVL, high-grade IVH, ventricular dilation) as well as meningitis were excluded.

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What Are the Potential Neuropathological Mechanisms by Which Low-Grade IVH May Lead to Poor Neurodevelopmental Outcome? 

There are multiple potential mechanisms of brain injury in the preterm infant with low-grade IVH, but principally they relate to two key sites of pathology: the cerebral white matter and the destruction of the germinal matrix. Injury to the developing cerebral white matter may occur either before, directly in association with, or as a result of the IVH by the following mechanisms: (1) hypoxic-ischemic injury that may precede and/or be concurrent with the IVH; (2) free radical–mediated white matter injury resulting from elevations of available iron with subsequent catalytic production of the highly reactive hydroxyl radical by the Fenton reaction. An elevation in free iron in the cerebrospinal fluid has been demonstrated in association with IVH.5 Such accelerated free radical activity is injurious to the immature oligodendroglia, which were shown to be exquisitely sensitive to free radicals,6, 7 leading to impaired myelination; and finally (3) vasospasm has been suggested,8, 9 although the absence of a muscularis in the extremely preterm infant make this less likely.7 The second site of pathology in association with low-grade IVH is direct injury and destruction of the germinal matrix. The germinal matrix contains the glial precursor cells, which are destined to give rise to oligodendroglia and astrocytes. The immature oligodendroglia have a critical role in postnatal myelination, and impairment in myelin production would be associated with subsequent motor impairments. However, the strong independent association of the presence of IVH with white matter injury (as described above) makes distinguishing the loss of such precursor cells alone as a cause of impaired motor functioning almost impossible. Studies of preterm infants by quantitative MRI techniques do not support that isolated IVH alone is associated with impaired myelination.10 Finally, the destruction of the germinal matrix may impair the development of astrocytes that were destined for the supragranular (upper) cortical layers assisting in cortical organization.11 Loss of cortical organization and growth may be reflected by a loss of gray matter volume12 and impaired cognitive outcomes.

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Why the Differences in the Studies, and What Is the Real Answer? Is Isolated Low-Grade IVH Associated With Poor Neurodevelopmental Outcome? 

Although the studies do differ in their findings, the more recent contemporaneous studies of similar populations of very preterm infants demonstrate similar rates of cerebral palsy, with grade I to II IVH approximating a 10% risk, clearly double that of no IVH. It is not, however, clear if this risk is elevated with grade I IVH alone or if there is any elevated risk for subsequent cognitive deficit. The major limitation of these studies is the inability to truly distinguish the key neuropathologies that may be leading to the subsequent impairment in neurodevelopmental outcome. Cranial ultrasound has very poor diagnostic utility for diffuse white matter injury,13 which occurs in up to 75% of preterm infants.14, 15 The cerebral white matter is also the most common site of neuropathological impact for IVH, as described above. In such a manner, low-grade IVH may be merely a visible marker on cranial ultrasound for the true neuropathology of cerebral white matter injury, which, on MRI, is highly predictive of both motor and cognitive deficits.16 Of note, the elevation of risk for poor outcomes with low-grade IVH with increasing immaturity suggests an independent role for the loss of the astrocytic and glial precursors from the immature germinal matrix. An answer to this would be assisted with documentation of an impact of grade I IVH both with and without white matter injury.

In conclusion, the study by Patra et al4 has highlighted to the neonatal clinician that grade I to II IVH should not be disregarded in terms of neurodevelopmental consequences. Definitive neuroimaging with MRI in any infant with any grade of IVH before discharge would further assist in defining both the nature and extent of cerebral injury and/or impaired cerebral development. One key question for the future is, “Does low-grade IVH lead to adverse neurodevelopmental outcomes via white matter injury alone, or is there an additional impact on neural progenitor cells limiting plasticity and development?” Regardless of the answer, our aim of continuing to reduce the incidence of IVH must be encouraged.

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References 

  1. Ancel PY , Livinec F , Larroque B , Marret S , Arnaud C , Pierrat V , et al.   Cerebral Palsy Among Very Preterm children in relation to gestational age and neonatal ultrasound abnormalities (the EPIPAGE Cohort Study) . Pediatrics . 2006;117:828–835
  2. Horbar J. Vermont Oxford Network Database Summary 2004.
  3. Sherlock RL , Anderson PJ , Doyle LW . Neurodevelopmental sequelae of intraventricular haemorrhage at 8 years of age in a regional cohort of ELBW very preterm infants . Early Hum Dev . 2005;81:909–916
  4. Patra K , Wilson-Costello D , Taylor HG , Mercuri-Minich N , Hack M . Grades I to II intraventricular hemorrhage in extremely low birth weight infants (effects on neurodevelopment) . J Pediatr . 2006;149:169–173
  5. Savman K , Nilsson UA , Blennow M , Kjellmer I , Whitelaw A . Non-protein-bound iron is elevated in cerebrospinal fluid from preterm infants with posthemorrhagic ventricular dilatation . Pediatr Res . 2001;49:208–212
  6. Back SA , Gan X , Li Y , Rosenberg PA , Volpe JJ . Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion . J Neurosci . 1998;18:6241–6253
  7. Volpe JJ . Neurology of the Newborn . 4th edition. Philadelphia, PA: WB Saunders; 2001;
  8. Dull C , Torbey MT . Cerebral vasospasm associated with intraventricular hemorrhage . Neurocrit Care . 2005;3:150–152
  9. Lou HC . Perinatal hypoxic-ischemic brain damage and intraventricular hemorrhage (a pathogenetic model) . Arch Neurol . 1980;37:585–587
  10. Inder TE , Warfield SK , Wang HX , Huppi PS , Volpe JJ . Abnormal cerebral structure at term in premature infants . Pediatrics . 2005;115:286–294
  11. Gressens P , Richelme C , Kadhim HJ , Gadisseux JF , Evrard P . The germinative zone produces the most cortical astrocytes after neuronal migration in the developing mammalian brain . Biol Neonate . 1992;62:4–24
  12. Vasileiadis GT, Gelman N, Han VK, Williams LA, Mann R, Bureau Y, et al. Uncomplicated intraventricular hemorrhage is followed by reduced cortical volume at near-term age . Pediatrics . 2004;114:e367–e372
  13. Inder TE , Anderson NJ , Spencer C , Wells S , Volpe JJ . White matter injury in the preterm infant (a comparison between serial cranial sonographic and MR findings at term) . Am J Neuroradiol . 2003;24:805–809
  14. Inder TE , Wells S , Mogridge N , Spencer C , Volpe JJ . Defining the nature of the cerebral abnormalities in the premature infant (a qualitative magnetic resonance imaging study) . J Pediatr . 2003;143:171–179
  15. Maalouf EF , Duggan PJ , Rutherford MA , Counsel SJ , Fletcher AM , Battin M , et al.   Magnetic resonance imaging of the brain in a cohort of extremely preterm infants . J Pediatr . 1999;135:351–357
  16. Woodward LJ , Anderson PA , Austin NC , Howard K , Inder TE . Cerebral abnormalities on neonatal magnetic resonance imaging and neurodevelopmental outcomes in preterm infants . N Engl J Med . 2006; (in press)

PII: S0022-3476(06)00494-X

doi:10.1016/j.jpeds.2006.05.046

Refers to article:

  • Grades I-II intraventricular hemorrhage in extremely low birth weight infants: Effects on neurodevelopment

    Kousiki Patra, Deanne Wilson-Costello, H. Gerry Taylor, Nori Mercuri-Minich, Maureen Hack
    The Journal of Pediatrics August 2006 (Vol. 149, Issue 2, Pages 169-173)

The Journal of Pediatrics
Volume 149, Issue 2 , Pages 152-154, August 2006

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