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Neurological outcomes following preterm birth
Seminars in Fetal & Neonatal Medicine (2007) 12, 374e382
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Neurological outcomes following preterm birth Joe Fawke* School of Human Development, University of Nottingham, Nottingham, UK
KEYWORDS Infant; Premature birth; Extremely low birth weight; Very low birth weight; Low birth weight; Cerebral palsy; Developmental coordination disorder; Minor neurological dysfunction
Summary Neonatal survival continues to improve; for many years, including throughout the 1990s there have been anxieties that this was at the cost of additional morbidity, most particularly in terms of neurosensory impairments. Recent evidence suggests that rates of neuromotor morbidity, in particular cerebral palsy, may be declining for all but the most immature babies. Severe sensory impairment has a low, but relatively static incidence. High prevalence, low severity motor problems and their inter-relationship with developmental co-ordination disorder, executive dysfunction and cognitive impairment are increasingly recognised and correlated with reduced school performance. Because of difficulties in comparing outcomes across different populations, validated motor and manual function classifications have been developed for children with cerebral palsy and can help to standardise outcome measures. Improved neuro-imaging is helping us understand the types and consequences of neonatal brain injury. The possibility of using composite measures of early motor movement quality, longitudinal use of motor classification systems and volumetric magnetic resonance imaging (MRI) imaging to understand developmental processes needs to be explored. ª 2007 Elsevier Ltd. All rights reserved.
Introduction Preterm birth is increasingly common in Western industrialised societies and more babies are being born at extremely low gestational ages.1,2 After survival, the second question parents may ask a Neonatologist is often about future disability and there is great public and professional interest in the outcome of this vulnerable population. Long term neurological follow up of preterm populations is thus vital to inform discussions with parents, assist children and families, guide practice, service provision, audit, benchmarking and research. From the 1970s with improvements in perinatal care, survival following preterm birth or low birth weight has
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steadily improved;3 this has been demonstrated in many countries with differing philosophies and health care systems including the USA,4,5 Canada,6 Holland,7 New Zealand,8 Australia9 and the UK.10 A review of mortality and morbidity data3 from 20 cohorts of 4116 extremely preterm (26 weeks) and 38 cohorts of 4345 extremely small (800 g) babies, born from 1972 onwards across several countries, demonstrated an annual increase in survival of 2.2% for infants 26 weeks’ gestation from 1980 to 1990 and 2.1% for infants born weighing 800 g from 1976 to 1990. Much of this recent change may be attributed, in part, to the increasingly widespread use of antenatal steroids and postnatal surfactant therapy. In the UK, we have seen steady improvement in survival at very low gestational ages since the mid 1990s, as documented in regional studies (Fig. 1). Worldwide these improvements in survival have been accompanied by concerns that the survivors bore a greater
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Neurological outcomes following preterm birth
375
100
Table 1
90
Percent Survival
80
Trent
70
25w
60
Evolving definitions of cerebral palsy
Author/Year
Proposed definition of cerebral palsy
MacKeith and Polani (1959)12
‘A persisting but not unchanging disorder of movement and posture, appearing in the early years of life and due to a non-progressive disorder of the brain, the result of interference during its development’
Bax et al. (1964)13
‘A disorder of movement and posture due to a defect or lesion in the immature brain.’ Bax added that ‘for practical purposes it is usual to exclude from cerebral palsy those disorders which are 1. of short duration, 2. due to progressive disease, 3. due solely to mental deficiency.’
Mutch et al. (1992)14
‘An umbrella term covering a group of non-progressive, but often changing, motor impairment syndromes secondary to lesions or anomalies of the brain arising in the early stages of development.’
Bax et al. (2004)15
Cerebral palsy (CP) describes a group of disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, cognition, communication, perception, and/or behaviour, and/or by a seizure disorder.
50 24w
40 30 20
23w
10 0
EPICure 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
Calendar Year (mid year of average)
Figure 1 Increasing survival at borderline viability: the EPICure Study, data from March to December 1995 (reprinted with permission from Costeloe et al. (2000)11) and three year rolling average data from 1995 to 2004 for infants born in the Trent Health Region of the UK (reprinted with permission from The Neonatal Survey65).
burden of disability. The trade off between death and disability is hard to define and longitudinal long term studies are uncommon (see the Wilson-Costello chapter in this issue). Furthermore, the interpretation of mortality and morbidity reports is complex as each uses different denominators, defines live birth differently and comes from areas with considerably different policies and philosophies as to the care provided for babies born at what is considered borderline viability, as discussed in the chapter by Draper and Field in this issue. In this chapter the definition of the most frequent important neurological outcome, cerebral palsy (CP), the prevalence and spectrum of less severe but nevertheless important motor disorders and the prevalence of sensory impairment will be discussed.
Definitions and classification systems There have been many assessment schemes for neurological outcome following preterm birth but the outcome measures reported and definitions of disability vary considerably. Most groups report the incidence of ‘cerebral palsy’ but, as demonstrated in Table 1, this concept has been redefined several times and it is difficult to standardise such assessments between observers, particularly in young infants. A diagnosis of CP does not equate to severe disability nor does not having CP mean that no disabilities are present. Functional outcome measures, as embraced in the latest definition15 are important, as they give a richer picture of a child’s abilities. This can be achieved using composite outcome groupings where grades of disability are defined using preset functional criteria that can help to stratify disability in a more relevant way. An example of this is shown in Table 2. Different studies may define these groupings in different ways but the use of standardised tests of cognitive function, behaviour and functional motor assessments
increases the ability to compare outcomes, something that has hampered comparative studies in the past. Recently two new tools have become available for assessing bimanual function and gross motor function in children with CP. The Gross Motor Function Classification System (GMFCS) is a validated scale17,18 providing age appropriate clinical vignettes describing five differing levels of motor function in children with CP. Level 1 defines the mildest disability group and 5 the most severe, with levels 2 and 3 equating to moderate disability. These vignettes have been well validated using both professionals and parents to rate children’s performance. The positive predictive value of the GMFCS at 1e2 years to predict walking by the age of 12 was 0.74 and the negative predictive value was 0.90. Inter-rater reliability (0.93) and test-retest reliability (0.79) were both high. Further information and a copy of the GMFCS can be found at http://www. canchild.ca/Default.aspx?tabid Z 195. The Manual Ability Classification System (MACS) rates bimanual function in relation to daily activities in children
376
Table 2
Example of composite outcome score in middle childhood Definitions
Cognitive
Neuromotor
Vision
Hearing
Behaviour
Other (e.g., medical condition)
Impairment
Problems in body structure or function such as substantial deviation with no loss of function
WASI 90 and 1 or more NEPSY domain <2.5th centile
Abnormal signs with normal function
Unilateral hearing loss, with normal hearing in good ear (passed screen in good ear without hearing aid)
SDQ: One or more abnormal subscores or abnormal total difficulties score
Medical condition that needs medication most days; uses sign language, communicates effectively
Mild disability
Some loss of function but able to function independently
WASI 80e89
GMF level 1 Arms clumsiness of fine movements but independent
Abnormal eye movements (including nystagmus) with VA 7.5 or better in best eye (with glasses if worn), or corrected refractive error with VA 6 or 7.5 VA in best eye (with refractive errors corrected) 6/9 or 6/18
Hearing loss fully corrected with hearing aids, as per most recent hearing assessment
Parent and teacher overall difficulties (Q26) ‘‘Yes’’ and impact score 0e1 parent and 0e1 teacher
Moderate disability
Aids or assistance needed for some tasks. Moderate difficulty in doing some activities
WASI 70e79
GMF level 2e3 Arms: able to feed and dress self, but needs aids, or has some difficulty
VA <6/18e6/60
Hearing loss partly corrected with aids
Parent and teacher overall difficulties (Q26) ‘‘Yes’’ and impact score 2e5 parent and 2 teacher
Severe disability
Unable to undertake activity without aids or assistance most of the time, or completely dependent on carer
WASI 69
GMF level 4e5 Arms: needs assistance to feed and dress
VA <6/60, gross movement/light and dark only or worse
Hearing loss not corrected with aids
Parent and teacher overall difficulties (Q26) ‘‘Yes’’ and impact score 6e10 parent and 3e6 teacher
Chronic medical condition requiring >1 admission per 6 months, or causing growth problems, or requiring special diet; epilepsy with >1 generalised fit/ month; stoma Medical condition needs supervision most of the time or meeting definition of moderate disability Condition needs supervision/aid constantlyincludes continuous home oxygen; communication severely limited.
J. Fawke
Source: Telford et al. (2006).16 WASI, Wechsler Abbreviated Scale of Intelligence; GMF, Gross Motor Function Classification System grade; VA, visual acuity; SDQ, Strengths and Difficulties Questionnaire (available on http://www.sdqinfo.com). Reprinted with permission from Elsevier (The Lancet, 2006, 367, 1080e1085).
Neurological outcomes following preterm birth from 4 to 18 years old with CP over a single 5 level scale covering all ages. It considers the collaborative use of both hands and reflects typical rather than maximal performance. MACS differs from other manual scales in that it considers a ‘gestalt’ or overall functional activity as opposed to specific manual abilities. It is the only system of manual ability classification that has been tested for reliability.19 There are 5 levels of functioning within the scale and the intra-class correlation between therapists was 0.97 and that between parents and therapist was 0.96. A copy of MACS can be downloaded from http://www.macs.nu. As yet the validity or applicability of the scale to children younger than 4 years has not been tested. Validated functional rating systems allow research groups to compare comparable outcomes and could facilitate communication between healthcare professionals and enhance discussions with families. Most neonatal services provide follow up data for high risk children at around 2 years of age. However, it was argued as long ago as 1982 by Nelson and Ellenberg20 that this early assessment of function may be misleading. Rosenbaum21 highlights the difference between slow motor development following a normal developmental profile and motor development following an abnormal trajectory. He argues that some children who were labelled as having CP and appeared to grow out of it were in the former group; thus around 4 years of age appears to be the minimum required to allow investigators to properly distinguish between normal trajectory, slow motor development and abnormal pattern motor development. This has been the practice for some time for data reported from CP registers, for example from Sweden22 and the UK.23,24 The Collaboration of European Cerebral Palsy Registers (SCPE) have also agreed that 4 years appears appropriate as the earliest age to reliably report the type and severity of CP.1 Thus, there is a need for agreement over ages for establishing outcomes. Whereas neonatal services have established outcome evaluations at 18e30 months to provide relatively fast clinical feedback and minimise loss to follow up, it must be understood that the severity and classification of motor outcome may be unreliable, particularly for those with less severe disability. For example, although the EPICure study group found that 86% of children with severe disability at 30 months had moderate-severe disability at 6 years, the presence of other disabilities at 30 months were no more predictive of developmental problems at 6 years than no disability.25 At 30 months, 42 children were classified with CP on the basis of a structured neurological assessment. At 6 years, eight had a normal neurological assessment but a further 13 children were now considered abnormal. Within the cohort assessed at both ages (n Z 236) the prevalence of CP rose slightly from 18 to 20% but only 14% had CP diagnosed at both assessments; these were those children with more severe functional consequences.
Cerebral palsy The prevalence of CP amongst the general population is generally quoted as approximately 2e4/1000 live births. CP is an important neurological outcome following preterm
377 birth and increasing prevalence with decreasing maturity or decreasing birthweight is well described. Of the different patterns of disability, spastic diplegia is that most typically associated with preterm birth, an association first noted by Sigmund Freud in 1897.26 It is generally thought to be the consequence of injury to the internal capsule, in which those fibres supplying the lower limb are more prone to bilateral hypoxia-ischaemia, and is associated with periventricular leucomalacia (PVL).27 Hemiplegia and more complex spastic CP may occur, but less commonly and result from more extensive lesions including the cortex. In particular, hemiplegia may arise following haemorrhagic periventricular infarction, associated with intraventricular haemorrhage (IVH). The most immature children may have very complex motor disability with injury to multiple areas.28 The number of very low gestational age infants being born is increasing in Europe1 and in the USA2 and the chances of these babies surviving have improved.3 Therefore, relative to the whole population with CP, more are of extremely low gestation or birthweight. The prevalence of CP has been used as a marker of the ‘success’ of perinatal services and as the subject of epidemiological study. CP registers of national or regional populations have contributed to our understanding of the demography of the condition. In Sweden, for example, falling neonatal mortality has been associated with an increased frequency of CP.22 Changes in birthweight specific prevalence in the Mersey Region of the UK have been associated with step changes in neonatal service provision: increasing survival at successively low birthweight categories was associated with an initial rise in CP prevalence, presumably because babies were now surviving with disability who would previously have died.23,24 Subsequently the prevalence of CP in each birthweight category levelled off and then decreased implying that experience of caring for these smaller infants was directly related to the prevalence of CP. During the 1990s increased survival of extremely preterm babies appeared to be at the expense of increased morbidity.4 Encouragingly, the collaboration of European Cerebral Palsy Registers (SCPE) has recently reported a fall in CP rates in the most immature groups. Between 1980 and 1996 CP rates dropped from a mean of 60.6 (95% Confidence Interval (95% CI) Z 37.8e91.4) per 1000 liveborn very low birth weight (VLBW) infants to 39.5 (28.6e 53.0), a fall related to a decline in frequency of bilateral spastic CP among infants with a birthweight of 1000e 1499 g.1 In this group, boys had a higher prevalence of CP than girls (61 vs 49.5/1000) but no such gender differences were observed among extremely low birthweight (ELBW) children. Using gestational age revealed similar findings, for infants born between 28 and 31 weeks of gestation overall prevalence fell from 80 to 50/1000 live births. In contrast, CP prevalence for infants aged <28 weeks’ remained static at 40/1000 livebirths from 1980e1996. The decrease in the prevalence of CP was primarily due to there being fewer children with spastic diplegia amongst children born weighing 1000e1499 g or at 28e32 weeks of gestation. Although the prevalence of CP amongst the smallest babies remained static overall it did fall in children born
378 after 1990. This is consistent with a report from a large American single centre29 that showed a rise in spastic CP from 8% (1982e1989) to 13% (1991e1999) before a drop to 5% (2000e2002) and the pattern is consistent with the earlier observations of Pharoah and colleagues.27 Importantly this reduction in CP has occurred despite an increasing incidence of liveborn ELBW infants in Europe and the USA.1,2 Within the EPICure cohort the risk of CP was increased in males, following early neonatal transfer, following long courses of postnatal steroids and in the presence of cavitating brain injuries.30 One major change that occurred over the late 1990s was the reduction in use of postnatal steroids, both in length of course and willingness to use them, following well publicised systematic reviews.31e33 It is tempting to speculate that at least some of the reduction may be due to this. The impact of increasing survival at borderline viability on neuromorbidity since 2000 is unknown, but longitudinal data from two Swedish centres report progressive improvements in survival with encouragingly low morbidity. They reported 66% survival to discharge amongst liveborn 23e25 weeks’ gestation infants with 81% of survivors free of severe IVH (grade 3 or worse), PVL or severe retinopathy of prematurity (ROP: stage 3 or worse).34 A study from a different region of Sweden also implied very low rates of MRI-detected brain injury,35 allowing the speculation that we may, at last, be seeing the results of brain-orientated intensive care first suggested by Ann Stewart and colleagues in 1981.36
Motor development in early infancy ‘dystonias’ The evolution of general movements (GM), seen in early infancy, has been studied extensively by Prechtl.37 GM involve all parts of the body, are complex, variable and generally fluent and are present during fetal life and early infancy, disappearing around 58 weeks post menstrual age (PMA) when goal directed movements supervene. These GM have been split unto 3 phases: firstly a preterm phase (10e38 weeks PMA) characterised by variable complex movements; secondly a writhing phase with slow, forceful movements (36e48 weeks PMA); and finally a fidgety phase (46e58 weeks PMA) with a continual stream of small amplitude movements. Prechtl’s system for analysing the quality of GM considers the complexity, variation and fluency of the movements and the aim of the system was to identify children who would have abnormal patterns of movement that predicted later motor problems. Bos and colleagues38 studied 15 children with chronic lung disease born between 26 and 30 weeks’ gestation. The development of CP was related to the presence of cramped, synchronised movements near term and to the absence of fidgety movements at the age of 3 months after term. None of the children with normal movements developed CP. Cerebral ultrasound appearances were strongly correlated with the extent of the abnormal movements. These findings are supported by Ferrari’s observations, amongst 84 preterm children, that consistently or predominantly cramped synchronised GM evolved into CP.39
J. Fawke Poor repertoire GM are the most frequently observed abnormal movements during the preterm, term and early post-term period. However, their predictive value for a poor neurological outcome seems less than the presence of cramped, synchronised early movements or the absence of fidgety movements.40 Early motor development may be strongly influenced by a baby’s experience whilst on the neonatal intensive care unit.41 Significant brain injury can lead to abnormal motor development but so can non-neurological factors such as positioning and chronic lung disease. Until the early 1990s the positioning of extremely preterm infants seemed to be a significant factor in the evolution of abnormal early motor signs. Constant prone positioning resulted in shoulder retraction, external hip rotation with shortening of hip adductors, chest flattening and plagiocephaly. The result was a baby who had excess extensor hypertonicity in the trunk and legs, hypertonic hip adductors and delayed supporting responses. Facilitative positioning techniques can reduce external hip rotation markedly and encourage normal postural development.42 Motor development may also be impaired by chronic lung disease, partly as prone positioning is often used to reduce the work of breathing. In addition, accessory muscle use and chronic fixation of the rib cage to optimise the work of breathing contributed to shoulder retraction. Awareness of these issues has undoubtedly reduced the occurrence of abnormal early neurological development but dystonia may also occur without these risk factors. The detail of the progression of dystonia has been investigated. De Groot and colleagues43 described a group of ex-premature children with active and passive muscle tone discrepancies predominantly affecting the extensor muscles of the trunk. These tonal abnormalities were sometimes asymmetrical44 but were usually transient. It has been postulated that transient dystonias lead to a delay in unsupported sitting and rotation towards the end of the first year.45 This impacts on transition between postures and leads to delay in fine motor development. In otherwise normal children, truncal fixation may impair integration of gross motor function with hand function, resulting in changes in early behaviour. Dystonia was described amongst low birth weight infants as early as 197246 by Drillen. She went on to show that those children with ‘transient dystonia’ had an excess of school problems at a mean age of 6.7 years. Improvements in neuroimaging led to the suggestion that dystonia may result from milder forms of PVL47 and, indeed, in longitudinal studies transient ultrasound periventricular echodensities have been associated with dystonia, but not with school age outcomes.48
Neuromotor dysfunction without cerebral palsy Motor problems without overt neurological signs of CP persist beyond infancy and often are considered under a variety of umbrella terms such as developmental coordination disorder (DCD) or minor neurological dysfunction (MND) or similar. Under such terms, a wide variety of deficits of gross and fine motor performance have been
Neurological outcomes following preterm birth Table 3
379
Neurosensory outcomes in preterm populations
Study/author
Cohort
Type
Year born
Age @ follow up
No. in Cohort
% follow up
% blind
% deaf
EPICure Wood et al. (2000)51,a,b Vohr (2005)63,a,b
<26 weeks
Inter-national UK & Eire NICHD Neonatal Research Network Multi-centre USA
1995
30 months
283
92
2
3
1993e94
18 months
665
79.5
2.3
3.4
20 months
716 910 444 538 512 218
90
1.5 1.0 1.4 0.4 0.4 5
2.3 1.8 1.7 0.8 1.8 3
5 years 2 years
467 152 206 461
92 92 99 84
1 1 0.6 0.2
6 1 4 0.8
22e26 weeks
Single Centre USA
1995e96 1997e98 1993e94 1995e96 1997e98 1982e89
National Finland Regional France
1990e99 2000e02 1996e97 1997
27e32 weeks
Wilson-Costello (2007)29,c,d
Mikkola (2005)58,a,b Fily (2006)64 a b c d
500e1000 g
<1000 g <33 weeks
Bilateral blindness. Bilateral or unilateral blindness. Hearing loss requiring amplification. Bilateral or unilateral deafness.
described in older ex-preterm children that persist during childhood and into adolescence associated with subtle or ‘soft’ neurological signs and reduced neuropsychological function.49 As with CP, these may occur in the absence of traditional neonatal neurological or imaging abnormalities. For example, one longitudinal study of ‘apparently normal’ high risk preterm infants found high proportions of fine motor deficits and increasing proportions of gross motor deficits from 18 months to 5 years.50 Fine motor deficits were described in 54% at 18 months, 47% at 3 years and 64% at 5 years; gross motor deficit was observed in 14% at 18 months, 33% at 3 years and 81% at 5 years. Investigators in this area have tended to concentrate on one perspective, leading to a variety of classifications and descriptors. From a neurological perspective the Groningen group have defined two levels of non-CP neurological dysfunction e simple and complex MND, distinguished by the number of clusters of abnormalities found.51 These 6 clusters comprised posture & muscle tone, reflexes, choreiform dyskinesia, coordination & balance, fine manipulative ability and, finally, other rarely occurring dysfunctions. In the Groningen project a substantial proportion of ex-preterm children were found to have mild disabilities, in many cases including minor neurological dysfunctions. The EPICure study group also found a high proportion of minor disabilities following extremely preterm birth.25,52 Continuity of neurological dysfunction from infancy to childhood has been described. The presence of definitely abnormal general movements in infancy during the ‘fidgety’ period (46e58 weeks PMA) is associated with complex MND in toddlers and at school age.53 There is conflicting evidence as to whether this association holds in to adolescence.40,54 An interesting question relates to whether the signs of MND and of CP are part of the same continuum? CP is
associated with a range of brain injuries, many of which are not identified during conventional ultrasound imaging, but are present when children with signs are later investigated with MRI. A significant proportion of VLBW children without CP and at normal schools will have abnormalities detected on MRI scanning, but in associative studies these have not been related to performance over a range of neurological, functional or psychological tests.55e57 Newer MRI techniques relating to brain growth and function may elucidate this relationship more clearly. This interesting group includes spectrums of minor motor problems overlapping with DCD, behavioural problems, attentional and learning difficulties. Perceptuomotor and sensory integration problems have also been reported.49 Complex MND is more strongly associated with the presence of these difficulties than simple MND. The overlap of motor difficulties with attention, cognition and behavioural problems complicates measurements of motor function. Standardised motor tests require the subject to understand the test, maintain concentration on the task and to inhibit other distractors, in addition to having the necessary motor and visuospatial skills. Consequently poor motor performance can occur for a variety of reasons. A Finnish national ELBW cohort, born in 1996e1997, was followed up using the NEPSY battery of standardised tests of attention-executive function, sensorimotor and visuospatial abilities. All scores fell below the test standardised means with sensorimotor and visuospatial domains being the most significantly affected.58 Similar findings have been reported in the EPICure cohort. However, in these extremely preterm 6 year olds in mainstream education, without CP, much of the documented sensorimotor and visuospatial impairment was explained by general cognitive deficit; nevertheless after allowing for cognitive
380
J. Fawke
performance, motor and executive impairments contributed additional impairment to school performance.59
Prevalence of sensory disability Different follow up evaluations have defined blindness or deafness in different ways. There is little consistency as to what is included in reports and formal hearing and visual testing is rarely reported. Despite this there is reasonable agreement as to the prevalence of these problems (Table 3). There is a paucity of research into neonatal hearing loss.60 Universal neonatal hearing screening (UNHS) is now in place in the UK using brainstem auditory evoked responses (BAER) as a supplement to otoacoustic emissions for testing preterm infants. This provides an opportunity to monitor the prevalence of neonatal hearing impairment more accurately. The majority of neonatal hearing impairment is sensorineural in origin but auditory discrimination may also be less good in preterm children compared to term peers.61 Smaller babies who have been septicaemic, had high serum bilirubin levels or received significant doses of ototoxic drugs appear to be at highest risk.60 Recent follow up studies report a prevalence of variably defined severe hearing impairment ranging from 0.8 to 6%. ROP is a significant cause of impaired vision amongst extremely preterm or ELBW infants and may cause serious visual impairment in between 0.3 and 2.3% survivors in recent studies (see the O’Connor and Fielder chapter in this issue), but other visual impairments such as strabismus, refractive error, poor contrast sensitivity and poor stereovision occur more frequently62 and cortical visual impairments complicating complex brain injuries should not be forgotten.
Conclusions There is emerging evidence that the prevalence of CP and major focal brain injury amongst the smallest and most vulnerable preterm babies may be decreasing and major sensory disability remains at a low prevalence in recent reports. However, the high frequency of low severity impairments of motor function persists. Although much of the motor and associated executive impairments may be explained by general cognitive deficits these impairments additionally contribute to poor performance in middle childhood. Understanding the origin of these problems may help to conceptualise the evolving problems in brain development found amongst very preterm children.
Practice points After a period of increasing neonatal morbidity, cerebral palsy (CP) rates may now be falling for all but the most immature (<28 weeks), smallest (<1000 g) babies. High prevalence, low severity neurological dysfunction after preterm birth is becoming increasing
recognised. It may serve as a predictor of later cognitive and attentional problems. For children with CP, validated measures of motor (GMFCS) and manual (MACS) function exist. Use of the GMFCS can provide some evidence-based prognostication about future motor function.
Research directions The apparent association between early motor dysfunction, later minor neurological dysfunction and increasingly evident cognitive and attentional problems needs to be defined. The neural origin of these impairments needs to be defined early and interventions defined that may ameliorate later disability.
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infants born at the threshold of viability. Pediatrics 2000; 106(4):659e71. MacKeith RC, MacKenzie ICK, Polani PE. The Little Club Memorandum on the terminology and classification of ‘cerebral palsy’. Cereb Palsy Bull 1959;1:27e35. Bax MCO. Terminology and classification of cerebral palsy. Dev Med Child Neurol 1964;6:295e307. Mutch LW, Albermann E, Hagberg B, Kodama K, Velickovic MV. Cerebral palsy epidemiology: where are we now and where are we going? Dev Med Child Neurol 1992;34:547e55. Bax M, Goldstein M, Rosenbaum P, Leviton A, Paneth N, Dan B, et al. Proposed definition and classification of cerebral palsy, April 2005. Dev Med Child Neurol 2005;47:571e6. Telford K, Waters L, Vyas H, Manktelow BN, Draper ES, Marlow N. Outcome after neonatal continuous negative pressure ventilation: follow up assessment. Lancet 2006; 367(9516):1080e5. Palisano RJ, Rosenbaum PL, Walters SD, Russel D, Wood E, Galuppi B. Development and reliability of system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39:214e23. Wood E, Rosenbaum P. The Gross Motor Function Classification system for cerebral palsy: a study of reliability and stability over time. Dev Med Child Neurol 2000;42:292e6. Eliassson AC, Krumlinde-Sundholm L, Ro ¨sblad B, Beckung E, Arner M, Ohrvall AM, et al. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. Dev Med Child Neurol 2006;48:549e54. Nelson KB, Ellenberg KH. Children who ‘‘outgrew’’ cerebral palsy. Pediatrics 1982;69(5):529e36. Rosenbaum P. Classification of abnormal outcome. Early Hum Develop 2006;82:167e71. Hagberg B, Hagberg G, Beckung E, Uvebrant P. Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991e94. Acta Paediatr 2001;90(3): 271e7. Pharoah PO, Platt MJ, Cooke T. The changing epidemiology of cerebral palsy. Arch Dis Child Fetal Neonatal 1996;75(3):F169e73. Pharoah PO, Cooke T, Johnson MA, King R, Mutch L. Epidemiology of cerebral palsy in England and Scotland 1984e9. Arch Dis Child Fetal Neonatal Ed 1998;79:21e5. Marlow N, Wolke D, Bracewell MA, Samara M, for the EPICure Study Group. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352(1):9e19. Freud S. Die infantile Cerebralla ¨hmung. In: Nothnagel H, editor. Specielle Pathologie und Therapie, Bd IX, Teil, III. Vienna: Holder; 1897. p. 1e327. Volpe JJ. Brain injury in the premature infant: overview of clinical aspects, neuropathology, and pathogenesis. Semin Pediatr Neurol 1998;5(3):135e51. Marlow N, D’Souza SW, Chiswick ML. Neurodevelopmental outcome in babies weighing less than 2001 g at birth. Br Med J Clin Res Ed 1987;294(6587):1582e6. Wilson-Costello D, Friedman H, Minich N, Siner B, Taylor G, Schluchter M, et al. Improved neurodevelopmental outcomes for extremely low birth weight infants in 2000e2002. Pediatrics 2007;119(1):37e45. Wood NS, Costeloe K, Gibson AT, Hennessey EM, Marlow N, Wilkinson ARfor the EPICure Study Group. The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth. Arch Dis Child Fetal Neonatal Ed 2005;90(2): F134e40. Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (<96 h) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;(1):CD001146.
381 32. Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7e14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;(1):CD001144. 33. Halliday HL, Ehrenkranz RA, Doyle LW. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;(1):CD001145. ˚, Ha 34. Serenius F, Ewald U, Farooqi A, Holmgren P-A ˚kansson S, Sedin G. Short-term outcome after active perinatal management at 23e25 weeks of gestation. A study from two Swedish perinatal centres. Part 3 Neonatal morbidity. Acta Pædiatr 2004;93:1090e7. 35. Horsch S, Hallberg B, Leifsdottir K, Skio ¨ld B, Nagy Z, Mosskin M, et al. Brain abnormalities in extremely low gestational age infants: a Swedish population based MRI study. Acta Paediatrica 2007;96(7):979e84. 36. Stewart AL, Reynolds EO, Lipscomb AP. Outcome for infants of very low birthweight: survey of world literature. Lancet 1981; 1(8228):1038e40. 37. Einspieler C, Prechtl HF. Pretchl’s assessment of general movements: a diagnostic tool for the functional assessment of the nervous system. Ment Retard Devel Disabil Res Rev 2005;11(1):61e7. 38. Bos AF, Martijn A, van Asperen RM, Hadders-Algra M, Okken A, Prechtl HF. Qualitative assessment of general movements in high-risk preterm infants with chronic lung disease requiring dexamethasone therapy. J Pediatr 1998;132:300e6. 39. Ferrari F, Cioni G, Einspieler CR, Roversi MF, Bos AF, Paolicelli PB, et al. Cramped synchronized general movements in preterm infants as an earlier marker for Cerebral Palsy. Arch Pediatr Adolesc Med 2002;156(5):460e7. 40. Einspieler C, Marschik PB, Milioti S, Nakajima Y, Bos AF, Prechtl HF. Are abnormal fidgety movements an early marker for complex minor neurological dysfunction at puberty? Early Hum Dev 2007; 83(8):521e5. 41. Bracewell M, Marlow N. Patterns of motor disability in very preterm children. Ment Retard Dev Disab Res Rev 2002;8: 241e8. 42. Downs JA, Edwards AD, McCormick DC, Roth SC, Stewart AL. Effect of intervention on development of hip posture in very preterm babies. Arch Dis Child 1991;66:797e801. 43. Groot De, Hopkins B, Touwen B. Muscle power, sitting unsupported and trunk rotation in preterm infants. Early Hum Dev 1995;43:37e46. 44. Groot De, Hopkins B, Touwen B. Motor asymmetries in preterm infants at 18 weeks corrected age and outcomes at one year. Early Hum Dev 1997;48:35e46. 45. De Groot L, de Groot CJ, Hopkins B. An instrument to measure independent walking: are there differences between preterm and full term infants? J Child Neurol 1997;12:37e41. 46. Drillien CM. Abnormal neurologic signs in the first year of life in low birth weight infants: possible prognostic significance. Dev Med Child Neurol 1972;22:26e47. 47. De Vries LS, Regev R. Ultrasound evolution and later outcome of infants with periventricular densities. Early Hum Dev 1988; 16:225e33. 48. Jongmans M, Mercuri E, de Vries L, Dubowitz L, Henderson SE. Minor neurological signs and perceptual-motor difficulties in prematurely born children. Arch Dis Child Fetal Neonatal Ed 1997;76:F9e14. 49. Allin M, Rooney M, Griffiths T, Cuddy M, Wyatt J, Rifkin L, et al. Neurological abnormalities in young adults born preterm. J Neurol Neurosurg Psychiatry 2006;77(4):495e9. 50. Goyen T-A, Lui K. Longitudinal motor development of ‘‘apparently normal’’ high risk infants at 18 months, 3 and 5 years. Early Hum Dev 2002;70:103e15. 51. Hadders-Algra M. Two distinct forms of neurological dysfunction: perspectives emerging from a review of data from the
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53.
54.
55.
56.
57.
58.
J. Fawke Groningen Perinatal Project. Dev Med Child Neurol 2002;44: 561e71. Wood N, Marlow N, Costeloe K, Gibson AT, Wilkinson AR. Neurologic and developmental disability after extremely preterm birth. N Engl J Med 2000;343(6):378e84. Hadders-Algra M, Mavinkurve-Groothuis AMC, Groen S, Stremmelaar EF, Martijn A, Butcher P. Quality of general movements and the development of minor neurological dysfunction at toddler and school age. Clin Rehabil 2004;18: 287e99. Groen S, de Ble ´court ACE, Postema K, Hadders-Algra M. General movements in early infancy predict neuromotor development at 9 to 12 years of age. Dev Med Child Neurol 2005;47: 731e8. Cooke RW, Abernethy LJ. Cranial magnetic resonance imaging and school performance in very low birth weight infants in adolescence. Arch Dis Child Fetal Neonatal Ed 1999;81(2): F116e21. Stewart A, Rifkin L, Amess PN, Kirkbride V, Townsend JP, Miller DH, et al. Brain structure and neurocognitive and behavioural function in adolescents who were born very preterm. Lancet 1999;353(9165):1653e7. Abernethy LJ, Palaniappan M, Cooke RW. Quantitative magnetic resonance imaging of the brain in survivors of very low birth weight. Arch Dis Child 2002;87(4):279e83. Mikkola K, Ritari N, Tommiska V, Salokorpi T, Lehtonen L, Tammela O, et al. Neurodevelopmental outcome at 5 years of age of a national cohort of extremely low birth weight
*59.
60.
61.
62.
63.
64.
65.
infants who were born in 1996e1997. Pediatrics 2005; 116(6):1391e400. Marlow N, Hennessy E, Wolke D., Motor and executive function at 6 years of age following extremely preterm birth. Pediatrics [In Press]. Marlow ES, Hunt LP, Marlow N. Sensorineural hearing loss and prematurity. Arch Dis Child Fetal Neonatal Ed 2000;82(2): F141e4. Therien JM, Worwa CT, Mattia FR, de Regnier RO. Altered pathways for auditory discrimination and recognition memory in preterm infants. Dev Med Child Neurol 2004;46(12): 816e24. Powls A, Botting N, Cooke RW, Stephenson G, Marlow N. Visual impairment in very low birthweight children. Arch Dis Child Fetal Neonatal Ed 1997;76(2):F82e7. Vohr BR, Wright LL, Poole K, McDonald SAfor the NICHD Neonatal Research Network Study Group. Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks gestation between 1993 and 1998. Pediatrics 2005;116(3):635e43. Fily A, Pierrat V, Delporte V, Breart G, Truffert Pon behalf of the EPIPAGE Nord-pas-de-Calais Study Group. Factors associated with neurodevelopmental outcome at 2 years after very preterm birth: The Population-Based Nord-Pas-de-Calais EPIPAGE Cohort. Pediatrics 2006;117:357e66. The Neonatal Survey; University of Leicester Annual Reports 1996e2003. * Key references are annotated with an asterisk.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Neurological outcomes following preterm birth Joe Fawke* School of Human Development, University of Nottingham, Nottingham, UK
KEYWORDS Infant; Premature birth; Extremely low birth weight; Very low birth weight; Low birth weight; Cerebral palsy; Developmental coordination disorder; Minor neurological dysfunction
Summary Neonatal survival continues to improve; for many years, including throughout the 1990s there have been anxieties that this was at the cost of additional morbidity, most particularly in terms of neurosensory impairments. Recent evidence suggests that rates of neuromotor morbidity, in particular cerebral palsy, may be declining for all but the most immature babies. Severe sensory impairment has a low, but relatively static incidence. High prevalence, low severity motor problems and their inter-relationship with developmental co-ordination disorder, executive dysfunction and cognitive impairment are increasingly recognised and correlated with reduced school performance. Because of difficulties in comparing outcomes across different populations, validated motor and manual function classifications have been developed for children with cerebral palsy and can help to standardise outcome measures. Improved neuro-imaging is helping us understand the types and consequences of neonatal brain injury. The possibility of using composite measures of early motor movement quality, longitudinal use of motor classification systems and volumetric magnetic resonance imaging (MRI) imaging to understand developmental processes needs to be explored. ª 2007 Elsevier Ltd. All rights reserved.
Introduction Preterm birth is increasingly common in Western industrialised societies and more babies are being born at extremely low gestational ages.1,2 After survival, the second question parents may ask a Neonatologist is often about future disability and there is great public and professional interest in the outcome of this vulnerable population. Long term neurological follow up of preterm populations is thus vital to inform discussions with parents, assist children and families, guide practice, service provision, audit, benchmarking and research. From the 1970s with improvements in perinatal care, survival following preterm birth or low birth weight has
* Tel.: þ44 0115 823 0607; fax: þ44 0115 823 0626. E-mail address: [email protected]
steadily improved;3 this has been demonstrated in many countries with differing philosophies and health care systems including the USA,4,5 Canada,6 Holland,7 New Zealand,8 Australia9 and the UK.10 A review of mortality and morbidity data3 from 20 cohorts of 4116 extremely preterm (26 weeks) and 38 cohorts of 4345 extremely small (800 g) babies, born from 1972 onwards across several countries, demonstrated an annual increase in survival of 2.2% for infants 26 weeks’ gestation from 1980 to 1990 and 2.1% for infants born weighing 800 g from 1976 to 1990. Much of this recent change may be attributed, in part, to the increasingly widespread use of antenatal steroids and postnatal surfactant therapy. In the UK, we have seen steady improvement in survival at very low gestational ages since the mid 1990s, as documented in regional studies (Fig. 1). Worldwide these improvements in survival have been accompanied by concerns that the survivors bore a greater
1744-165X/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2007.06.002
Neurological outcomes following preterm birth
375
100
Table 1
90
Percent Survival
80
Trent
70
25w
60
Evolving definitions of cerebral palsy
Author/Year
Proposed definition of cerebral palsy
MacKeith and Polani (1959)12
‘A persisting but not unchanging disorder of movement and posture, appearing in the early years of life and due to a non-progressive disorder of the brain, the result of interference during its development’
Bax et al. (1964)13
‘A disorder of movement and posture due to a defect or lesion in the immature brain.’ Bax added that ‘for practical purposes it is usual to exclude from cerebral palsy those disorders which are 1. of short duration, 2. due to progressive disease, 3. due solely to mental deficiency.’
Mutch et al. (1992)14
‘An umbrella term covering a group of non-progressive, but often changing, motor impairment syndromes secondary to lesions or anomalies of the brain arising in the early stages of development.’
Bax et al. (2004)15
Cerebral palsy (CP) describes a group of disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, cognition, communication, perception, and/or behaviour, and/or by a seizure disorder.
50 24w
40 30 20
23w
10 0
EPICure 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
Calendar Year (mid year of average)
Figure 1 Increasing survival at borderline viability: the EPICure Study, data from March to December 1995 (reprinted with permission from Costeloe et al. (2000)11) and three year rolling average data from 1995 to 2004 for infants born in the Trent Health Region of the UK (reprinted with permission from The Neonatal Survey65).
burden of disability. The trade off between death and disability is hard to define and longitudinal long term studies are uncommon (see the Wilson-Costello chapter in this issue). Furthermore, the interpretation of mortality and morbidity reports is complex as each uses different denominators, defines live birth differently and comes from areas with considerably different policies and philosophies as to the care provided for babies born at what is considered borderline viability, as discussed in the chapter by Draper and Field in this issue. In this chapter the definition of the most frequent important neurological outcome, cerebral palsy (CP), the prevalence and spectrum of less severe but nevertheless important motor disorders and the prevalence of sensory impairment will be discussed.
Definitions and classification systems There have been many assessment schemes for neurological outcome following preterm birth but the outcome measures reported and definitions of disability vary considerably. Most groups report the incidence of ‘cerebral palsy’ but, as demonstrated in Table 1, this concept has been redefined several times and it is difficult to standardise such assessments between observers, particularly in young infants. A diagnosis of CP does not equate to severe disability nor does not having CP mean that no disabilities are present. Functional outcome measures, as embraced in the latest definition15 are important, as they give a richer picture of a child’s abilities. This can be achieved using composite outcome groupings where grades of disability are defined using preset functional criteria that can help to stratify disability in a more relevant way. An example of this is shown in Table 2. Different studies may define these groupings in different ways but the use of standardised tests of cognitive function, behaviour and functional motor assessments
increases the ability to compare outcomes, something that has hampered comparative studies in the past. Recently two new tools have become available for assessing bimanual function and gross motor function in children with CP. The Gross Motor Function Classification System (GMFCS) is a validated scale17,18 providing age appropriate clinical vignettes describing five differing levels of motor function in children with CP. Level 1 defines the mildest disability group and 5 the most severe, with levels 2 and 3 equating to moderate disability. These vignettes have been well validated using both professionals and parents to rate children’s performance. The positive predictive value of the GMFCS at 1e2 years to predict walking by the age of 12 was 0.74 and the negative predictive value was 0.90. Inter-rater reliability (0.93) and test-retest reliability (0.79) were both high. Further information and a copy of the GMFCS can be found at http://www. canchild.ca/Default.aspx?tabid Z 195. The Manual Ability Classification System (MACS) rates bimanual function in relation to daily activities in children
376
Table 2
Example of composite outcome score in middle childhood Definitions
Cognitive
Neuromotor
Vision
Hearing
Behaviour
Other (e.g., medical condition)
Impairment
Problems in body structure or function such as substantial deviation with no loss of function
WASI 90 and 1 or more NEPSY domain <2.5th centile
Abnormal signs with normal function
Unilateral hearing loss, with normal hearing in good ear (passed screen in good ear without hearing aid)
SDQ: One or more abnormal subscores or abnormal total difficulties score
Medical condition that needs medication most days; uses sign language, communicates effectively
Mild disability
Some loss of function but able to function independently
WASI 80e89
GMF level 1 Arms clumsiness of fine movements but independent
Abnormal eye movements (including nystagmus) with VA 7.5 or better in best eye (with glasses if worn), or corrected refractive error with VA 6 or 7.5 VA in best eye (with refractive errors corrected) 6/9 or 6/18
Hearing loss fully corrected with hearing aids, as per most recent hearing assessment
Parent and teacher overall difficulties (Q26) ‘‘Yes’’ and impact score 0e1 parent and 0e1 teacher
Moderate disability
Aids or assistance needed for some tasks. Moderate difficulty in doing some activities
WASI 70e79
GMF level 2e3 Arms: able to feed and dress self, but needs aids, or has some difficulty
VA <6/18e6/60
Hearing loss partly corrected with aids
Parent and teacher overall difficulties (Q26) ‘‘Yes’’ and impact score 2e5 parent and 2 teacher
Severe disability
Unable to undertake activity without aids or assistance most of the time, or completely dependent on carer
WASI 69
GMF level 4e5 Arms: needs assistance to feed and dress
VA <6/60, gross movement/light and dark only or worse
Hearing loss not corrected with aids
Parent and teacher overall difficulties (Q26) ‘‘Yes’’ and impact score 6e10 parent and 3e6 teacher
Chronic medical condition requiring >1 admission per 6 months, or causing growth problems, or requiring special diet; epilepsy with >1 generalised fit/ month; stoma Medical condition needs supervision most of the time or meeting definition of moderate disability Condition needs supervision/aid constantlyincludes continuous home oxygen; communication severely limited.
J. Fawke
Source: Telford et al. (2006).16 WASI, Wechsler Abbreviated Scale of Intelligence; GMF, Gross Motor Function Classification System grade; VA, visual acuity; SDQ, Strengths and Difficulties Questionnaire (available on http://www.sdqinfo.com). Reprinted with permission from Elsevier (The Lancet, 2006, 367, 1080e1085).
Neurological outcomes following preterm birth from 4 to 18 years old with CP over a single 5 level scale covering all ages. It considers the collaborative use of both hands and reflects typical rather than maximal performance. MACS differs from other manual scales in that it considers a ‘gestalt’ or overall functional activity as opposed to specific manual abilities. It is the only system of manual ability classification that has been tested for reliability.19 There are 5 levels of functioning within the scale and the intra-class correlation between therapists was 0.97 and that between parents and therapist was 0.96. A copy of MACS can be downloaded from http://www.macs.nu. As yet the validity or applicability of the scale to children younger than 4 years has not been tested. Validated functional rating systems allow research groups to compare comparable outcomes and could facilitate communication between healthcare professionals and enhance discussions with families. Most neonatal services provide follow up data for high risk children at around 2 years of age. However, it was argued as long ago as 1982 by Nelson and Ellenberg20 that this early assessment of function may be misleading. Rosenbaum21 highlights the difference between slow motor development following a normal developmental profile and motor development following an abnormal trajectory. He argues that some children who were labelled as having CP and appeared to grow out of it were in the former group; thus around 4 years of age appears to be the minimum required to allow investigators to properly distinguish between normal trajectory, slow motor development and abnormal pattern motor development. This has been the practice for some time for data reported from CP registers, for example from Sweden22 and the UK.23,24 The Collaboration of European Cerebral Palsy Registers (SCPE) have also agreed that 4 years appears appropriate as the earliest age to reliably report the type and severity of CP.1 Thus, there is a need for agreement over ages for establishing outcomes. Whereas neonatal services have established outcome evaluations at 18e30 months to provide relatively fast clinical feedback and minimise loss to follow up, it must be understood that the severity and classification of motor outcome may be unreliable, particularly for those with less severe disability. For example, although the EPICure study group found that 86% of children with severe disability at 30 months had moderate-severe disability at 6 years, the presence of other disabilities at 30 months were no more predictive of developmental problems at 6 years than no disability.25 At 30 months, 42 children were classified with CP on the basis of a structured neurological assessment. At 6 years, eight had a normal neurological assessment but a further 13 children were now considered abnormal. Within the cohort assessed at both ages (n Z 236) the prevalence of CP rose slightly from 18 to 20% but only 14% had CP diagnosed at both assessments; these were those children with more severe functional consequences.
Cerebral palsy The prevalence of CP amongst the general population is generally quoted as approximately 2e4/1000 live births. CP is an important neurological outcome following preterm
377 birth and increasing prevalence with decreasing maturity or decreasing birthweight is well described. Of the different patterns of disability, spastic diplegia is that most typically associated with preterm birth, an association first noted by Sigmund Freud in 1897.26 It is generally thought to be the consequence of injury to the internal capsule, in which those fibres supplying the lower limb are more prone to bilateral hypoxia-ischaemia, and is associated with periventricular leucomalacia (PVL).27 Hemiplegia and more complex spastic CP may occur, but less commonly and result from more extensive lesions including the cortex. In particular, hemiplegia may arise following haemorrhagic periventricular infarction, associated with intraventricular haemorrhage (IVH). The most immature children may have very complex motor disability with injury to multiple areas.28 The number of very low gestational age infants being born is increasing in Europe1 and in the USA2 and the chances of these babies surviving have improved.3 Therefore, relative to the whole population with CP, more are of extremely low gestation or birthweight. The prevalence of CP has been used as a marker of the ‘success’ of perinatal services and as the subject of epidemiological study. CP registers of national or regional populations have contributed to our understanding of the demography of the condition. In Sweden, for example, falling neonatal mortality has been associated with an increased frequency of CP.22 Changes in birthweight specific prevalence in the Mersey Region of the UK have been associated with step changes in neonatal service provision: increasing survival at successively low birthweight categories was associated with an initial rise in CP prevalence, presumably because babies were now surviving with disability who would previously have died.23,24 Subsequently the prevalence of CP in each birthweight category levelled off and then decreased implying that experience of caring for these smaller infants was directly related to the prevalence of CP. During the 1990s increased survival of extremely preterm babies appeared to be at the expense of increased morbidity.4 Encouragingly, the collaboration of European Cerebral Palsy Registers (SCPE) has recently reported a fall in CP rates in the most immature groups. Between 1980 and 1996 CP rates dropped from a mean of 60.6 (95% Confidence Interval (95% CI) Z 37.8e91.4) per 1000 liveborn very low birth weight (VLBW) infants to 39.5 (28.6e 53.0), a fall related to a decline in frequency of bilateral spastic CP among infants with a birthweight of 1000e 1499 g.1 In this group, boys had a higher prevalence of CP than girls (61 vs 49.5/1000) but no such gender differences were observed among extremely low birthweight (ELBW) children. Using gestational age revealed similar findings, for infants born between 28 and 31 weeks of gestation overall prevalence fell from 80 to 50/1000 live births. In contrast, CP prevalence for infants aged <28 weeks’ remained static at 40/1000 livebirths from 1980e1996. The decrease in the prevalence of CP was primarily due to there being fewer children with spastic diplegia amongst children born weighing 1000e1499 g or at 28e32 weeks of gestation. Although the prevalence of CP amongst the smallest babies remained static overall it did fall in children born
378 after 1990. This is consistent with a report from a large American single centre29 that showed a rise in spastic CP from 8% (1982e1989) to 13% (1991e1999) before a drop to 5% (2000e2002) and the pattern is consistent with the earlier observations of Pharoah and colleagues.27 Importantly this reduction in CP has occurred despite an increasing incidence of liveborn ELBW infants in Europe and the USA.1,2 Within the EPICure cohort the risk of CP was increased in males, following early neonatal transfer, following long courses of postnatal steroids and in the presence of cavitating brain injuries.30 One major change that occurred over the late 1990s was the reduction in use of postnatal steroids, both in length of course and willingness to use them, following well publicised systematic reviews.31e33 It is tempting to speculate that at least some of the reduction may be due to this. The impact of increasing survival at borderline viability on neuromorbidity since 2000 is unknown, but longitudinal data from two Swedish centres report progressive improvements in survival with encouragingly low morbidity. They reported 66% survival to discharge amongst liveborn 23e25 weeks’ gestation infants with 81% of survivors free of severe IVH (grade 3 or worse), PVL or severe retinopathy of prematurity (ROP: stage 3 or worse).34 A study from a different region of Sweden also implied very low rates of MRI-detected brain injury,35 allowing the speculation that we may, at last, be seeing the results of brain-orientated intensive care first suggested by Ann Stewart and colleagues in 1981.36
Motor development in early infancy ‘dystonias’ The evolution of general movements (GM), seen in early infancy, has been studied extensively by Prechtl.37 GM involve all parts of the body, are complex, variable and generally fluent and are present during fetal life and early infancy, disappearing around 58 weeks post menstrual age (PMA) when goal directed movements supervene. These GM have been split unto 3 phases: firstly a preterm phase (10e38 weeks PMA) characterised by variable complex movements; secondly a writhing phase with slow, forceful movements (36e48 weeks PMA); and finally a fidgety phase (46e58 weeks PMA) with a continual stream of small amplitude movements. Prechtl’s system for analysing the quality of GM considers the complexity, variation and fluency of the movements and the aim of the system was to identify children who would have abnormal patterns of movement that predicted later motor problems. Bos and colleagues38 studied 15 children with chronic lung disease born between 26 and 30 weeks’ gestation. The development of CP was related to the presence of cramped, synchronised movements near term and to the absence of fidgety movements at the age of 3 months after term. None of the children with normal movements developed CP. Cerebral ultrasound appearances were strongly correlated with the extent of the abnormal movements. These findings are supported by Ferrari’s observations, amongst 84 preterm children, that consistently or predominantly cramped synchronised GM evolved into CP.39
J. Fawke Poor repertoire GM are the most frequently observed abnormal movements during the preterm, term and early post-term period. However, their predictive value for a poor neurological outcome seems less than the presence of cramped, synchronised early movements or the absence of fidgety movements.40 Early motor development may be strongly influenced by a baby’s experience whilst on the neonatal intensive care unit.41 Significant brain injury can lead to abnormal motor development but so can non-neurological factors such as positioning and chronic lung disease. Until the early 1990s the positioning of extremely preterm infants seemed to be a significant factor in the evolution of abnormal early motor signs. Constant prone positioning resulted in shoulder retraction, external hip rotation with shortening of hip adductors, chest flattening and plagiocephaly. The result was a baby who had excess extensor hypertonicity in the trunk and legs, hypertonic hip adductors and delayed supporting responses. Facilitative positioning techniques can reduce external hip rotation markedly and encourage normal postural development.42 Motor development may also be impaired by chronic lung disease, partly as prone positioning is often used to reduce the work of breathing. In addition, accessory muscle use and chronic fixation of the rib cage to optimise the work of breathing contributed to shoulder retraction. Awareness of these issues has undoubtedly reduced the occurrence of abnormal early neurological development but dystonia may also occur without these risk factors. The detail of the progression of dystonia has been investigated. De Groot and colleagues43 described a group of ex-premature children with active and passive muscle tone discrepancies predominantly affecting the extensor muscles of the trunk. These tonal abnormalities were sometimes asymmetrical44 but were usually transient. It has been postulated that transient dystonias lead to a delay in unsupported sitting and rotation towards the end of the first year.45 This impacts on transition between postures and leads to delay in fine motor development. In otherwise normal children, truncal fixation may impair integration of gross motor function with hand function, resulting in changes in early behaviour. Dystonia was described amongst low birth weight infants as early as 197246 by Drillen. She went on to show that those children with ‘transient dystonia’ had an excess of school problems at a mean age of 6.7 years. Improvements in neuroimaging led to the suggestion that dystonia may result from milder forms of PVL47 and, indeed, in longitudinal studies transient ultrasound periventricular echodensities have been associated with dystonia, but not with school age outcomes.48
Neuromotor dysfunction without cerebral palsy Motor problems without overt neurological signs of CP persist beyond infancy and often are considered under a variety of umbrella terms such as developmental coordination disorder (DCD) or minor neurological dysfunction (MND) or similar. Under such terms, a wide variety of deficits of gross and fine motor performance have been
Neurological outcomes following preterm birth Table 3
379
Neurosensory outcomes in preterm populations
Study/author
Cohort
Type
Year born
Age @ follow up
No. in Cohort
% follow up
% blind
% deaf
EPICure Wood et al. (2000)51,a,b Vohr (2005)63,a,b
<26 weeks
Inter-national UK & Eire NICHD Neonatal Research Network Multi-centre USA
1995
30 months
283
92
2
3
1993e94
18 months
665
79.5
2.3
3.4
20 months
716 910 444 538 512 218
90
1.5 1.0 1.4 0.4 0.4 5
2.3 1.8 1.7 0.8 1.8 3
5 years 2 years
467 152 206 461
92 92 99 84
1 1 0.6 0.2
6 1 4 0.8
22e26 weeks
Single Centre USA
1995e96 1997e98 1993e94 1995e96 1997e98 1982e89
National Finland Regional France
1990e99 2000e02 1996e97 1997
27e32 weeks
Wilson-Costello (2007)29,c,d
Mikkola (2005)58,a,b Fily (2006)64 a b c d
500e1000 g
<1000 g <33 weeks
Bilateral blindness. Bilateral or unilateral blindness. Hearing loss requiring amplification. Bilateral or unilateral deafness.
described in older ex-preterm children that persist during childhood and into adolescence associated with subtle or ‘soft’ neurological signs and reduced neuropsychological function.49 As with CP, these may occur in the absence of traditional neonatal neurological or imaging abnormalities. For example, one longitudinal study of ‘apparently normal’ high risk preterm infants found high proportions of fine motor deficits and increasing proportions of gross motor deficits from 18 months to 5 years.50 Fine motor deficits were described in 54% at 18 months, 47% at 3 years and 64% at 5 years; gross motor deficit was observed in 14% at 18 months, 33% at 3 years and 81% at 5 years. Investigators in this area have tended to concentrate on one perspective, leading to a variety of classifications and descriptors. From a neurological perspective the Groningen group have defined two levels of non-CP neurological dysfunction e simple and complex MND, distinguished by the number of clusters of abnormalities found.51 These 6 clusters comprised posture & muscle tone, reflexes, choreiform dyskinesia, coordination & balance, fine manipulative ability and, finally, other rarely occurring dysfunctions. In the Groningen project a substantial proportion of ex-preterm children were found to have mild disabilities, in many cases including minor neurological dysfunctions. The EPICure study group also found a high proportion of minor disabilities following extremely preterm birth.25,52 Continuity of neurological dysfunction from infancy to childhood has been described. The presence of definitely abnormal general movements in infancy during the ‘fidgety’ period (46e58 weeks PMA) is associated with complex MND in toddlers and at school age.53 There is conflicting evidence as to whether this association holds in to adolescence.40,54 An interesting question relates to whether the signs of MND and of CP are part of the same continuum? CP is
associated with a range of brain injuries, many of which are not identified during conventional ultrasound imaging, but are present when children with signs are later investigated with MRI. A significant proportion of VLBW children without CP and at normal schools will have abnormalities detected on MRI scanning, but in associative studies these have not been related to performance over a range of neurological, functional or psychological tests.55e57 Newer MRI techniques relating to brain growth and function may elucidate this relationship more clearly. This interesting group includes spectrums of minor motor problems overlapping with DCD, behavioural problems, attentional and learning difficulties. Perceptuomotor and sensory integration problems have also been reported.49 Complex MND is more strongly associated with the presence of these difficulties than simple MND. The overlap of motor difficulties with attention, cognition and behavioural problems complicates measurements of motor function. Standardised motor tests require the subject to understand the test, maintain concentration on the task and to inhibit other distractors, in addition to having the necessary motor and visuospatial skills. Consequently poor motor performance can occur for a variety of reasons. A Finnish national ELBW cohort, born in 1996e1997, was followed up using the NEPSY battery of standardised tests of attention-executive function, sensorimotor and visuospatial abilities. All scores fell below the test standardised means with sensorimotor and visuospatial domains being the most significantly affected.58 Similar findings have been reported in the EPICure cohort. However, in these extremely preterm 6 year olds in mainstream education, without CP, much of the documented sensorimotor and visuospatial impairment was explained by general cognitive deficit; nevertheless after allowing for cognitive
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performance, motor and executive impairments contributed additional impairment to school performance.59
Prevalence of sensory disability Different follow up evaluations have defined blindness or deafness in different ways. There is little consistency as to what is included in reports and formal hearing and visual testing is rarely reported. Despite this there is reasonable agreement as to the prevalence of these problems (Table 3). There is a paucity of research into neonatal hearing loss.60 Universal neonatal hearing screening (UNHS) is now in place in the UK using brainstem auditory evoked responses (BAER) as a supplement to otoacoustic emissions for testing preterm infants. This provides an opportunity to monitor the prevalence of neonatal hearing impairment more accurately. The majority of neonatal hearing impairment is sensorineural in origin but auditory discrimination may also be less good in preterm children compared to term peers.61 Smaller babies who have been septicaemic, had high serum bilirubin levels or received significant doses of ototoxic drugs appear to be at highest risk.60 Recent follow up studies report a prevalence of variably defined severe hearing impairment ranging from 0.8 to 6%. ROP is a significant cause of impaired vision amongst extremely preterm or ELBW infants and may cause serious visual impairment in between 0.3 and 2.3% survivors in recent studies (see the O’Connor and Fielder chapter in this issue), but other visual impairments such as strabismus, refractive error, poor contrast sensitivity and poor stereovision occur more frequently62 and cortical visual impairments complicating complex brain injuries should not be forgotten.
Conclusions There is emerging evidence that the prevalence of CP and major focal brain injury amongst the smallest and most vulnerable preterm babies may be decreasing and major sensory disability remains at a low prevalence in recent reports. However, the high frequency of low severity impairments of motor function persists. Although much of the motor and associated executive impairments may be explained by general cognitive deficits these impairments additionally contribute to poor performance in middle childhood. Understanding the origin of these problems may help to conceptualise the evolving problems in brain development found amongst very preterm children.
Practice points After a period of increasing neonatal morbidity, cerebral palsy (CP) rates may now be falling for all but the most immature (<28 weeks), smallest (<1000 g) babies. High prevalence, low severity neurological dysfunction after preterm birth is becoming increasing
recognised. It may serve as a predictor of later cognitive and attentional problems. For children with CP, validated measures of motor (GMFCS) and manual (MACS) function exist. Use of the GMFCS can provide some evidence-based prognostication about future motor function.
Research directions The apparent association between early motor dysfunction, later minor neurological dysfunction and increasingly evident cognitive and attentional problems needs to be defined. The neural origin of these impairments needs to be defined early and interventions defined that may ameliorate later disability.
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