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AM Beke 1st Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary

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Introduction

The most important questions in case of preterm infants: Will the child survive? If “yes,” what will be the long-term consequences of preterm delivery? They are of great importance, which may influence the life of the family and other medical decisions.

Characteristics of the Central Nervous System in Preterm newborns

The characteristics include morphological and functional immaturity, weak autoregulation (pressure-passive cerebral circulation), immature blood vessels, maturity-dependent injuries (oligodendroglia precursor cells), high plasticity, and uncertain outcome. Developmental risk factors in preterm newborns are immaturity, specific damages, and developmental differences compared with term newborns.

Most Frequent Diseases of the Central Nervous System in Preterm newborns

Periventricular leukomalacia (PVL)

Pathogenetic factors of periventricular white matter lesions are endarteries, immature, pressure-passive circulation, and metabolic dysfunction of glial cells. Inflammation with excessive cytokine production and oxidative stress with increased glutamate excitotoxicity are induced by infectious and/or hypoxic-ischemic mechanisms. PVL affects the white matter of the brain, causing periventricular focal necrosis and cystic formation within the white matter [1]. Frequency of PVL less than 1500 g of birthweight is about 40% of this population. PVL is connected to the development of cerebral palsy (CP), intellectual impairment, as well as visual disturbances. Although cells of the oligodendrocyte lineage are regarded as the primary target in the pathogenesis of PVL, there is increasing evidence that neonatal white matter damage is accompanied by gray matter abnormalities, including neuronal loss, impaired axonal guidance, and altered synaptogenesis. Premature newborns affected by PVL often have smaller cortex and deep gray matter volumes, reduced cortical neurons, and alterations in the orientation of central white matter fiber tracts [2].

Intraventricular haemorrhage (IVH)

In the premature brain, before the 28th gestational week, IVH occurs in 45%–50% of cases. The locus of development is the germinal matrix that exists in the premature brain up to the 32nd week of gestation. Types of intraventricular–periventricular haemorrhage (IVH-PVH) are presented in Figure 1: grade I: subependymal haemorrhage; grade II: IVH without dilatation; grade III: IVH; grade IV: bleeding in parenchymal structures, often coexisting with PVL, as periventricular haemorrhagic infarction.


            Figure 1.
Figure 1.

Intra-periventricular haemorrhage – states, frequencies, and consequences

Citation: Developments in Health Sciences 1, 1; 10.1556/2066.1.2018.09

Perinatal stroke

It occurs more often in term newborns or in late preterm newborns, due to maternal or fetal causes. The pathology consists of arterial embolisation or thrombosis in the cerebral vessels. Perinatal strokes occur most of cases in the cause of hemiparetic CP. During the later developmental period, non-motor outcomes may account for many problems. With CP, many patients may also have intellectual disabilities, behavioural disorders, and epilepsy as well. Sometimes, perinatal stroke is difficult to diagnose having the aforementioned symptoms. Developing methods of rehabilitation and new types of interventions may increase the quality of life and functions of the affected preterm newborns.

Diagnosis

IVH-PVH may be present without early clinical symptoms; therefore, serial check-ups are important to establish the diagnosis. In spite of the fact that the incidence is decreasing in recent times, PVH-IVH still is a major concern with extremely low-birthweight infants (BW < 1000 g).

Clinical signs

Neurological examination of preterm newborns is unsure. The early injury of the brain, followed by an abnormal development, which depends not only on the extent of the lesions, but also on the efficacy of the compensatory mechanisms as well. The prognostic value of early neurological examinations is not high. The most important goal is to differentiate between the immaturity and the injuries of the preterm brain.

Suspicions and neurological symptoms of CP (minor and major abnormalities) include intermittent changes in muscle tone, long-term asymmetry in posture, reflexes, and movements, abnormal muscle tone, persistent tonic reflexes, undeveloped postural and balance reflexes, developmental delay (somatomotor and mental), disturbances in vegetative functions, weak sucking reflex, feeding difficulties, and absence of habituation to light and to sound.

Clinical signs of the central nervous system injury are mostly the symptoms of CP. That is, in 35%–40% of the preterm newborns, no early symptoms of CP are detected, and there may be mild muscle tone disorders and behavioural problems. Note that the muscle tone in the preterm newborn population is normally weaker than in term newborns. Late symptoms (after 6 months) show the spastic form of CP, such as diplegia, tetraparesis, as well as disorders in coordination and in fine motor functions. The other associated problems are sensory deficits, epilepsy, intellectual deficits, mental retardation, and posthemorrhagic hydrocephalus followed by ventriculoperitoneal shunt.

Diagnostic value of imaging techniques

Ultrasound (US)

US examination is the first choice in the neonatal intensive care unit and in early infancy until the fontanelle is present. Different types of bleeding, congenital cerebral malformations, and some white matter lesions can be detected by the US. The diffuse form of PVL is not detectable by the US. Exact diagnosis is not possible by the US, where only large cysts are visible and therefore magnetic resonance (MR) investigation is considered the basis of diagnosis [3].

MR investigation

Abnormal myelination of posterior limb of internal capsule (PLIC) in MR in preterm-born children with IVH and unilateral parenchymal infarction at 44th gestational week predicts CP. Children with normal symmetrical PLIC myelination have normal neuromotor outcome. Normal MR at term is a strong indicator of normal neuromotor development [4].

MR signs in school years are decreased cerebral tissue, regional differences, decreased complexity of cortical structure, injured comprehensive, and visual functions.

Outcome of Early Cerebral Lesions in the Preterm Brain

The most sensitive period of cerebral development is between 22nd and 25th weeks of gestation. In this period, neurogenesis, migration, maturation, apoptosis, and synaptogenesis are very active and therefore very vulnerable. Periventricular white matter lesions are followed by cerebral atrophy, lesions of temporal and visual cortex, and irregular cerebral growth. Long-term effects include decreased sensorimotor and medial temporal cortex volume that leads to lower performance and verbal IQ levels [5]. Outcome in the preterms who are at the threshold of viability, born in the 22nd–26th weeks of gestation, with a birthweight lower than 1000 g, CP occurs in 19%, in the group born between 27th and 32nd weeks and with a birthweight more than 1000 g, frequency of CP is 12% [6]. Others found similar results in the outcomes in the highest-risk group of newborns (gestational weeks less than 24 weeks, birthweight less than 750 g, Apgar score: ≤3) with motor deficit, such as CP: 30% and other neurodevelopmental disabilities: 30% [7]. Among preterm newborns with a birthweight less than 1500 g, 10% of survivors show motor deficits, and 25%–50% still have cognitive, sensory, and behavioural deficits [8, 9].

Conclusions

Follow-up studies would be (should be) continued to detect the transitional or long-term disabilities in preterm newborns. The early developmental therapies, such as neurohabilitation and other early interventions, are effective in the prevention and moderation of long-term consequences of prematurity and early detected cerebral injuries. Individual therapeutic and developmental programmes should be organised by a team of developmental neurologists, psychologists, conductors, physiotherapists, and special educators. The key of success is to help the families to reduce anxiety and to be partners in the development of the handicapped children. The role of the family is a very important supportive factor in the late outcome of preterm newborns [10]. The complex effect of prematurity is observed in Figure 2.


          Figure 2.
Figure 2.

Prematurity, as a developmental risk – transactional model

Citation: Developments in Health Sciences 1, 1; 10.1556/2066.1.2018.09

The maternal role (anxiety, acceptance, and competence deficit) and the child’s special development influence each other in a transactional way. The therapeutic team can help in the reinforcement of the mother–child relationship together with the development of the preterm newborns.

Abbreviations

NICU

neonatal intensive care unit

IVH

intraventricular haemorrhage

PVL

periventricular leukomalacia

CP

cerebral palsy

MR

magnetic resonance

PVH

periventricular haemorrhage

PVHI

periventricular haemorrhagic infarction

PLIC

posterior limb of internal capsule

IQ

intelligence quotient

Acknowledgements

The author would like to thank Professor János Rigó for the invitation of the symposium presentation and Géza Erdős for the technical help.

References

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  • 2.

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    • Crossref
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  • 3.

    Mirmiran M , Barnes PD , Keller K , et al. Neonatal brain magnetic resonance imaging before discharge is better than serial cranial ultrasound in predicting cerebral palsy in very low birth weight preterm infants. Pediatrics. 2004;114(4):99298.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    De Vries LS , Groenendaal F , van Haastert IC , Eken P , Rademaker RJ , Meiners LC . Asymmetrical myelination of the posterior limb of the internal capsule in infants with periventricular haemorrhagic infarction: an early predictor of hemiplegia. Neuropediatrics. 1999;30(6):31419.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Woodward LJ , Anderson PJ , Austin NC , Howard K , Inder TE. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med. 2006;355(7):68594.

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    • Search Google Scholar
    • Export Citation
  • 6.

    Hack M , Wilson-Costello D , Friedman H , Taylor GH , Schluchter M , Fanaroff AA. Neurodevelopment and predictors of outcomes of children with birth weights less than 1000 g: 1992–1995. Arch Pediatr Adolesc Med. 2000;154(7):72531.

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  • 7.

    Shankaran S , Johnson Y , Langer JC , et al. Outcomes of extremely-low-birth-weight infants at highest risk: gestational age < or =24 weeks, birth weight < or =750 g, and 1-minute Apgar < or =3. Am J Obstet Gynecol. 2004;191(4):108491.

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  • 8.

    Vohr BR , Wright LL , Poole WK , McDonald SA. Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks’ gestation between 1993 and 1998. Pediatrics. 2005;116(3):63543.

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  • 9.

    Msall ME , Park JJ. The spectrum of behavioral outcomes after extreme prematurity: regulatory, attention, social, adaptive dimensions. Semin Perinatol. 2008;32(1):4250.

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    • Search Google Scholar
    • Export Citation
  • 10.

    Potharst ES , Houtzager BA , van Sonderen L , Tamminga P , Kok JH , Last BF , van Wassenaer AG. Prediction of cognitive abilities at the age of 5 years using developmental follow-up assessments at the age of 2 and 3 years in very preterm children. Dev Med Child Neurol. 2012;54(3):2406.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 1.

    Volpe JJ. Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res. 2001;50(5):55362.

  • 2.

    Pierson CR , Folkerth RD , Billards SS , et al. Gray matter injury associated with periventricular leukomalacia in the premature infant. Acta Neuropathol. 2007;114:61931.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Mirmiran M , Barnes PD , Keller K , et al. Neonatal brain magnetic resonance imaging before discharge is better than serial cranial ultrasound in predicting cerebral palsy in very low birth weight preterm infants. Pediatrics. 2004;114(4):99298.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    De Vries LS , Groenendaal F , van Haastert IC , Eken P , Rademaker RJ , Meiners LC . Asymmetrical myelination of the posterior limb of the internal capsule in infants with periventricular haemorrhagic infarction: an early predictor of hemiplegia. Neuropediatrics. 1999;30(6):31419.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Woodward LJ , Anderson PJ , Austin NC , Howard K , Inder TE. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med. 2006;355(7):68594.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Hack M , Wilson-Costello D , Friedman H , Taylor GH , Schluchter M , Fanaroff AA. Neurodevelopment and predictors of outcomes of children with birth weights less than 1000 g: 1992–1995. Arch Pediatr Adolesc Med. 2000;154(7):72531.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Shankaran S , Johnson Y , Langer JC , et al. Outcomes of extremely-low-birth-weight infants at highest risk: gestational age < or =24 weeks, birth weight < or =750 g, and 1-minute Apgar < or =3. Am J Obstet Gynecol. 2004;191(4):108491.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Vohr BR , Wright LL , Poole WK , McDonald SA. Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks’ gestation between 1993 and 1998. Pediatrics. 2005;116(3):63543.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Msall ME , Park JJ. The spectrum of behavioral outcomes after extreme prematurity: regulatory, attention, social, adaptive dimensions. Semin Perinatol. 2008;32(1):4250.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Potharst ES , Houtzager BA , van Sonderen L , Tamminga P , Kok JH , Last BF , van Wassenaer AG. Prediction of cognitive abilities at the age of 5 years using developmental follow-up assessments at the age of 2 and 3 years in very preterm children. Dev Med Child Neurol. 2012;54(3):2406.

    • Crossref
    • Search Google Scholar
    • Export Citation
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