Difficult birth and motor outcome in early infancy and at school age van Iersel, Patricia Anna Maria

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1 University of Groningen Difficult birth and motor outcome in early infancy and at school age van Iersel, Patricia Anna Maria IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2016 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): van Iersel, P. A. M. (2016). Difficult birth and motor outcome in early infancy and at school age. [Groningen]: Rijksuniversiteit Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Chapter 1 General Introduction 11

3 General Introduction. In 2014 about children were born in The Netherlands 1 and about worldwide. 2 Part of these births is complicated by perinatal adversities such as preterm birth, being small-for-gestational age or a difficult birth at term (DBAT). DBAT may result in mild to severe perinatal asphyxia. For example, the incidence of perinatal asphyxia is 1/1000 live births in Western industrialized countries. 3 The incidence in low and middle income countries (LMIC) is much higher. Data from hospital-based studies in such settings suggest an incidence of at least 5-10/1000 live births 3. In 2010 nearly a quarter of all neonatal deaths were due to perinatal asphyxia, 95% occurring in LMIC. 4 The incidence of preterm birth has been reported to range from 5% to 7% in industrialized countries, but in LMIC the rates are estimated to be higher. 5 In addition, 8-26% of infants worldwide are born small-for-gestational age (SGA). 6 Infants born with perinatal complications are considered to be at risk for developmental disorders, but it is a complicated matter to predict the outcome of neurodevelopment in individual infants at risk. While major disorders like Cerebral Palsy (CP), epilepsy and mental retardation are usually diagnosed in early childhood, less severe neurological impairments and less severe limitations in mobility (Figure 1), 7 such as Developmental Coordination Disorder (DCD), and behavioural problems, including Attention Deficit Hyperactivity Disorder (ADHD) are often diagnosed much later, for example at school-age, when more complex tasks and more competences are expected from children. 8 And although - especially in industrialized countries - development of neuroimaging techniques has improved the possibilities to identify high risk infants, it is for instance still very difficult to predict at early age the severity of limited mobility. 8 Even more so in LMIC where sophisticated diagnostic tools are often unavailable to determine risks for further development. Predicting minor limitations in mobility is even more problematic in all 12

4 circumstances, as the underlying neural substrate is often not apparent on neuroimaging, such as cranial ultrasonography of the brain and standard magnetic resonance imaging (MRI). 9 Figure 1. International Classification of functioning, Disability and Health for Children and Youth. It is generally assumed that intervention in infants at risk should take place very early, preferably in the period that the plasticity of the brain is at its maximum (2-3 months before until 18 months after term age) Evidence from neurobiology indicates that early intervention is capable of changing the structure and function of the brain Therefore, in general practice, we aim to detect infants at risk as young as possible to achieve optimal results of intervention. Recent reviews about the effects of early interventions report a positive influence on motor and cognitive 13

5 development especially in the preschool years Therefore, it is generally recommended to start interventions with children at risk for developmental problems at early age, when the plasticity of the brain is at its highest. This thesis focuses on developmental outcome of a specific group of infants at risk, i.e., infants with DBAT. It zooms in on infants who had been born in or were admitted to a regional hospital in the Netherlands. In the scientific literature studies in the non-academic setting are underrepresented. However, knowledge acquired in this setting is highly relevant as the vast majority of children all over the world - in LMIC, but also in industrialized countries - are born in non-academic centres. In the non-academic setting paediatricians use only clinical signs to assess developmental risk, because, in general, MRI is not readily available in such a setting. The Assessment of General Movements, a clinical tool to evaluate the integrity of the young nervous system, is increasingly more often used. This method is used in the series of studies of this thesis. It is a cheap, noninvasive method applicable in all hospital settings. 18 The specific objectives of this thesis are: 1. to investigate the neurodevelopmental sequelae of a difficult birth, including milder forms of perinatal asphyxia in term and preterm children admitted to a non-academic centre in the Netherlands; 2. to evaluate in full-term infants the significance of the assessment of General Movements in early infancy as an instrument to predict CP and - in children without CP - milder forms of limited mobility, learning problems and behavioural problems and mild neurological impairment. In the following paragraphs I will first briefly review what is known on the neurodevelopmental sequelae of DBAT, including mild to moderate perinatal asphyxia. Next I will present a short overview of various theories of neurodevelopment and the theoretical background of the Assessment of 14

6 General Movements (GMs). Finally, I will review the various neurodevelopmental tests used in the series of studies of this thesis. DBAT and perinatal asphyxia Up to the beginning of this century it was general practice to call DBAT, diagnosed on the basis of metabolic acidosis, Apgar score after 5 minutes, clinical signs of neonatal encephalopathy and multi-organ system dysfunction, perinatal asphyxia. Asphyxia literally means without pulse and in general stands for stoppage of breathing or suffocation. Up until today many different definitions for perinatal asphyxia are used in the literature, mostly depending on the medical field from which it is approached. In 1992 the American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG) markers of perinatal asphyxia were: 1) profound metabolic acidosis (ph < 7), 2) Apgar score beyond 5 minutes < 3, 3) neonatal encephalopathy(ne) and 4) multi-organ system dysfunction. The ACOG extended the definition in 2002 with a) base deficit > 12mmol/l, b) CP, c) exclusion of other aetiology, d) sentinel event associated with labour, e) fetal heart rate changes, f) early imaging changes. 19 In 2007 Mc Guire 3 wrote: The clinical diagnosis of perinatal asphyxia is based on several criteria, the two main ones being evidence of cardiorespiratory and neurological depression (defined as an Apgar score remaining less than 7 at 5 minutes after birth) and evidence of acute hypoxic compromise with acidaemia (defined as an arterial blood ph of less than 7 or base excess greater than -12 mmol/l). Although a very low (<5) Apgar score after 5 and 10 minutes still predicts adverse outcome in full-term infants, the Apgar score as a solitary symptom is no longer considered to be a marker for asphyxia or NE Blood gas values prove to be better indicators particularly of severe NE than Apgar scores, but - on the other hand - many infants with a ph < 7 show no signs of NE. 20,22 15

7 Generally the severity of asphyxia was and is classified in Sarnat stages of NE: stage 1 (mild NE), stage 2 (moderate NE) and stage 3 (severe NE). 23 Infants with Sarnat stage 1 often show symptoms for less than 24 hours. Symptoms include hyper alertness, tachycardia, mydriasis, increased deep tendon reflexes, exaggerated primitive reflexes. In general, muscle tone is normal, no seizures occur and the electro-encephalogram (EEG) shows no abnormalities. The duration of Sarnat stage 2 ranges between 2-14 days and is characterised by a lethargic level of consciousness, bradycardia, miosis, (mild) hypotonia, weak primitive reflexes and strong distal flexion. Focal or multifocal seizures are common in this group; EEG shows abnormalities. Sarnat stage 3 is marked by suppression of autonomic and brainstem function, absence of primitive reflexes and frequent seizures. Children in this group are stuporous and flaccid; this stage can last from hours to weeks. 23 From the middle of the twentieth century neuroimaging techniques such as cranial ultrasound (US) and MRI were gradually introduced. As the knowledge on the clinical significance of neuroimaging grew the neonatal cerebral MRI became a standard tool in Western academic centres to determine brain injury in infants with asphyxia resulting in NE. Neuroimaging showed the degree of damage to the cortex, thalamus and basal ganglia, which gave more insight in the expected sequelae. 24 This changed the scientific approach of perinatal asphyxia in the international literature. Currently neonatal MRI and amplitude-integrated electroencephalography (aeeg) are playing a big role in diagnosing brain damage and predicting outcome in infants admitted to tertiary hospitals. 20,24-26 These techniques are however not available in regional hospitals. Regional hospitals in high income countries often have a cerebral ultrasound facility, but this technique as well as the clinical neurological examination have proved to lead to relatively many false positives. 20 In most LMIC settings, however, and also in most regional hospitals in high income countries DBAT, including perinatal asphyxia is still diagnosed by clinical markers in the absence of the more sophisticated techniques. 16

8 Another change in the medical care of infants with asphyxia that occurred at the end of last century, was the introduction of hypothermia treatment in term infants with DBAT with severe to moderate NE in order to minimize neurological sequelae Like neonatal MRI, this technology generally only is available in academic centres in high income countries. During this period it also became clear that infants with DBAT resulting in milder forms of NE did not always suffer from adverse developmental consequences following their difficult extra-uterine start. In addition, it grew clear that the effect of NE following DBAT depends largely on which moment of brain development it strikes. In full-term infants damage frequently occurs in the thalamus, the basal ganglia and in the cerebral cortex. 29 In preterm infants the damage mostly occurs in the periventricular regions. 30 The above illustrates the heterogeneity in terminology in the field. This heterogeneity is also visible in this thesis, which covers work that started in I will use the term DBAT and asphyxia as synonyms and the term NE to describe the presence of neonatal neurological dysfunction after DBAT. The degree of NE is expressed by the classification of Sarnat. DBAT followed by NE previous studies Short and long term outcome of DBAT resulting in severe and moderate NE have been studied both before and after the introduction of advanced neuroimaging and hypothermia treatment. Infants with severe NE die or develop serious neurodevelopmental disabilities The developmental consequences of DBAT resulting in moderate NE are less clear. According to literature developmental outcome in children with moderate NE is heterogeneous group. Since neuroimaging was introduced it became apparent that infants with moderate NE have more often lesions, also in the thalamus, basal ganglia and white matter than initially thought. The consequences of these lesions at later age may vary from mild cognitive impairment to CP. The heterogeneous outcome of infants with moderate NE 17

9 was illustrated well by the study of Carli et al. 34 At the age of one year 23 (52%) of the 42 children studied had a typical neurodevelopmental outcome, 4 (9.5%) had a mild developmental delay without neurological dysfunction, 12(28.5%) had CP (11 severe and 1 mild), 2 children died before the age of one year and one could not be assessed. Long term follow up until 2008 was described in two reviews According to the reviews cognitive performance of the children with NE was within the normal range, but worse than that of comparison children. Moderate NE may be associated with elevated rates of hyperactivity and autism, but whether this is really true is not clear as the different studies used different clinical markers of asphyxia and applied different assessments to evaluate outcome. Neuromotor impairment was found to be fairly uncommon in children with mild to moderate NE More recent studies included also children with moderate to mild NE and pointed towards cognitive, behavioural and specific memory problems in this group, but effects on mobility were addressed to a limited extent only It is remarkable, that the group of infants with DBAT with mild NE or without NE is largely underrepresented in these studies. Nevertheless this population forms a substantial proportion of the infants diagnosed with DBAT in nonacademic settings all over the world. It remains largely unknown what the long term consequences of DBAT are. Therefore it is important to evaluate neurodevelopmental outcome at school age of children born with DBAT resulting in milder forms of NE in order to determine whether they are not at risk for minor neurodevelopmental disorders, including limited mobility, as suggested by literature. 29,35-36,41 Difficult birth in preterm infants. Preterm infants have an increased risk for developmental problems. 30 The dominant pathology in preterm infants is periventricular leucomalacia (PVL), whether or not evolving into cysts (cystic PVL). PVL is often accompanied by neuronal disease, which involves the development of the 18

10 cerebral white matter, the subplate neurons, the thalamus and the basal ganglia. Even the cortex and cerebellum can be affected depending on the severity of PVL and gestational age of the infant. 30,41-42 Many factors may be involved in the aetiology of PVL, including for instance intrauterine infections, hypoglycaemia and being small for gestational age, but also perinatal asphyxia is considered to be one of the factors contributing to PVL In literature only a few follow-up studies of preterm infants are present that a) were designed to determine the effect of perinatal asphyxia in preterm infants or b) paid specific attention to the role of perinatal asphyxia within the context of other risk factors. Four studies aimed at assessing the effects of perinatal asphyxia in preterm infants. Fotopoulos et al. 44 assessed a group of preterms (n=57) born at weeks of gestation of whom 29 suffered from perinatal asphyxia and/or infection, the remaining 28 infants were used as controls. Perinatal asphyxia was defined as progressive fetal heart rate abnormalities, scalp ph < 7.20, very low Apgar scores or the need for resuscitation 3 minutes after birth. Nine of the asphyxiated/infected neonates died, while none of the controls did. Fourteen asphyxiated/infected children (study group) and 12 control children attended the follow-up assessment. At 18 months nine out of 14 study children showed abnormalities on the ultrasound scan of the brain against two out of the 12 control children. This differences corresponded to the clinical situation in both groups: the study children showed more often neurological impairments than the controls (study group: two children with CP, six with other neurological impairments; control group: no neurological impairment). A second study was carried out by Low et al. 45 They performed a matched cohort study in which 30 preterm newborns (< 2000 gr.) with metabolic acidosis (umbilical artery buffer base < 34 mmol/l) were followed up to the age of one year. They found that the incidence of major motor and cognitive deficits was significantly higher than that in the control group of non-asphyxiated newborns. Westgren et al. 46 followed a group of 108 preterm infants (gestational age < 37 weeks) of which 30 infants with 19

11 ominous fetal heart tracings formed the study group with asphyxia and 78 children with innocuous fetal heart tracings formed the control group. The groups were followed up to 2-4 years of age. The rate of Apgar score under 7 at 1 minute was 73% in the asphyxia groups against 25% in the control group. Of the children with asphyxia 14 (47%) died within two years after birth against 11 (14%) of the non-asphyxiated children. At the age of 2 four (25%) of the sixteen children of the study group and eight (12%) of the 67 controls had developmental or neurological impairments, which suggests that mortality and neurodevelopmental abnormalities are more common in the asphyxia group. Finally, Holmqvist et al. 47 compared two groups of low risk preterms with fetal acidosis with a full-term control group: one preterm group had a gestational age (GA) of weeks and the other preterm group had a GA of weeks. Fetal acidosis was defined as a scalp ph < Fetal acidosis was more common in the group born at week gestational age than in the group born at week. At 6 years 11% of the children in the total preterm group had major neurodevelopmental problems and 38% had minor problems, with no evident differences between the two preterm groups. Only one control child had a neurodevelopmental impairment, it consisted of a minor psychomotor deviation. The study was unable to demonstrate a clear effect of fetal acidosis on neurodevelopmental outcome. Two other studies addressed the effect of perinatal asphyxia as one of the many risk factors which may play a role in the development of preterm children. Piekkala et al. 48 studied the developmental profile and outcome at 2 years of an unselected group of 325 preterms, born during a period of 2 years. In the preterm group, asphyxia (Apgar score after 5 min <8) at birth was associated with non-optimal gross motor development at 3 months and 2 years corrected age. Kerstjens et al. 49 who studied a cohort of 832 moderately preterm children born in , reported that only hypoglycaemia increased the risk of developmental delay at preschool age, while asphyxia did not. 20

12 Overall, this means that it is still unclear whether difficult birth, including perinatal asphyxia affects developmental outcome in preterm infants. It presumably is one of the many factors playing a role in the governing brain injury in preterm infants. 43 Theories on neuromotor development Various theories exist on infant neuromotor development. Up to the middle of the twentieth century neuromotor development was supposed to be an autonomous process. This was described in the Neuromaturation Theory. 50 According to this theory neurodevelopment of an infant follows a predetermined pattern in the central nervous system, which can hardly be influenced by environmental factors. In addition, motor development is considered to be the result of an increasing cortical control over lower reflexes. The motor development of the child follows an ordered sequence of milestones. In the eighties of last century E. Thelen explained neuromotor development with the Dynamic Systems Theory, 51 using the ideas of Kugler et al. In this theory most of the changes during development are being attributed to environmental factors. 52 The Dynamic Systems Theory considers development as a self-organizing process. Various components like body weight, muscle strength, environmental situations, such as the support surface, toys, and also the mood and the motivation of the child produce motor behaviour, leaving only a subordinate role for the nervous system in this process, very much in contrast with the Neuromaturation Theory. 53 More recently the Neuronal Group Selection Theory (NGST) was introduced. 54 This theory may be regarded as a compromise between the neuromaturation theories in which the central nervous system plays a major role and the Dynamic Systems Theory that attributes this role to 21

13 environmental factors, thus introducing a theory in which nature and nurture both play an important role. NGST and typical motor development According to NGST typical motor development starts with primary neuronal repertoires, each repertoire consisting of multiple neuronal groups, which act as functional units. The cells and the gross connectivity of the primary repertoires are determined by evolution and these repertoires exhibit abundant variation (primary variability) to explore all motor possibilities. The phase of primary variability is characterized by variation in motor behaviour, but also by the absence of the ability to adapt motor behaviour to specific situations. 55 After the first phase the nervous system starts to use afferent information produced by experience and behaviour and generates new adaptive motor behaviour by means of selection. This phase is called the secondary (adaptive) variability. At the onset of this phase, movement variation during a specific task is abundant, but this gradually diminishes until the optimal strategy is found. Thus, the motor behaviour gets tuned to the specifics of the situation. Mechanisms underlying the change from the phase of primary into the phase of secondary variability are thus far not understood. The process of selection is based on trial and error experiences that are unique to the individual. The timing of the transition from primary to secondary variability appears at function-specific ages, for example in sucking behaviour the phase of second variability starts already before term age and in postural adjustment it starts after the age of 3 months. So every basic motor function has its own specific moment in development to start with selection and adaptation of its neuronal repertoire to changes and challenges in the environment. This is caused by an ingenious interaction between self-induced motor activities, trial and error - learning and endogenous processes in the brain

14 The self-generated activity during the phase of primary variability is best illustrated by the General Movements. 10 The concept General Movements (GMs) was introduced by Heinz Prechtl who described these movements as the most important during the first postnatal months of the newborn infant. 56 I will describe this concept in the paragraph Background on specific assessment tools used in this thesis. NGST and atypical motor development Atypical motor development may be caused by adversities occurring during an early stage of brain development, resulting in damage of the brain. In terms of NGST this may lead to a decrease in primary neuronal repertoires. 10 Consequently this leads to a reduction of the repertoires during the phases of primary and secondary variability, implying less variation and more stereotyped motor behaviour. In the phase of secondary variability an early lesion may result in a) a reduction of the number of strategies, and b) difficulties in selecting the appropriate strategy because of problems with the processing of afferent information. 55 Atypical motor development Two important motor developmental disorders exist: CP and Development Coordination Disorder (DCD). In the following paragraphs I will give a short overview of both disorders. Cerebral Palsy CP is a disorder of the development of movement and posture, causing activity limitations attributed to non-progressive disturbances of the fetal or infant brain which may also affect sensation, perception, cognition, communication, and behaviour. 57 Worldwide, the incidence of CP is 1 in 500 births. There are currently 17 million people in the world who have CP

15 The severity of CP varies largely. This severity is often indicated with the Gross Motor Function Classification System (GMFCS). The GMFCS has five levels, ranging from level I, implying independent mobility with decreased speed, balance and coordination, to level V denoting serious impairments in maintaining antigravity postures and in need power mobility. 59 CP has a complex and multifactorial aetiology. Risk factors for CP are: a) intrauterine exposure to infections, b) congenital brain malformation or abnormal brain development, c) periventricular leucomalacia (PVL), d) intraventricular, intracranial haemorrhage, e) interruption of oxygen supply ( asphyxia ), f) traumatic brain injury by birth process or g) trauma and infection (meningitis) in later life. Generally infants with a very low birth weight either by very premature birth (< 32 weeks GA), or because they are small for gestational age (or both) have the largest risk for CP. 8,60-61 The neuropathology underlying CP may include: white-matter injury, germinal matrix haemorrhage with or without intraventricular extension, and also injury to the cortex, thalamus, basal ganglia and internal capsula depending on the seriousness of the CP. 9,29,60-61 According to the NGST children with severe forms of CP, who have extensive damage of the brain show virtually no variation in their movements. Hence, their movements are very stereotyped. Also children with mild to moderate CP show stereotypical movements. Their repertoires are reduced (limited variation) and they have difficulties in the adaptation of motor behaviour, due to impaired sensory processing (limited variability). 10 Developmental Coordination Disorder DCD is characterized by limited mobility that interferes with the child's activities of daily living and academic achievement. 62 Criteria to diagnose DCD are given in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); 63 the clinical implementation of the diagnostics has 24

16 been described in the recommendations of the European Academy of Childhood Disability (EACD). 64 The current prevalence of DCD is estimated to be between 5% and 8% of all school-aged children, with boys being more often affected than girls. 62 The aetiology of DCD is unknown, but in part of the children it may be associated with an altered development of the central nervous system. 65 DCD may co-occur with other neurodevelopmental and neurobehavioural disorders, but evidence suggests that DCD is an unique and separate neurodevelopmental disorder. 64 Although criterion D from DSM-5 excludes neurological conditions such as CP or muscular dystrophy as a cause of the motor problems, it has been shown that children with DCD may exhibit minor neurological dysfunction (MND) Our knowledge on the neural substrate of DCD is scarce. Only a few studies have addressed this subject, as was recently reviewed by Peters et al. 69 Evidence from these studies has thus far indicated that multiple areas of the brain may be involved in children with limited mobility, such as DCD, after perinatal adversities, i.e., white matter lesions in the periventricular region, lesions in the cerebellum, the corpus callosum, the basal ganglia and posterior limb of the internal capsule. 69 These findings may support the hypothesis that the neural substrate of CP is similar to that of DCD. The finding that DCD is associated in particular with the complex form of MND points into the same direction Nevertheless, it is important to realize that the origin of DCD is multifactorial, and that children may have limited mobility in the absence of a lesion of the brain, and that children with a minor lesion of the brain may have typical mobility. More research in this field is urgently needed. Background on specific assessment tools used in this thesis. Assessment of General Movements At the end of last century Professor Heinz Prechtl discovered that te quality of GMs may provide information about the integrity of the young nervous 25

17 system. 18,55,70 Since that time the assessment of GMs has been further developed and is considered a valuable, cheap and non-invasive tool to evaluate the young nervous system. GMs consist of spontaneous gross movements which vary in speed and amplitude. They involve all parts of the body but they lack distinctive sequencing. 18 The first movements of the foetus start around 7 weeks and initially show little variation, amplitude and speed. However at 9-10 weeks postmenstrual age (PMA) GMs, consisting of movements in which all body parts take part, show a substantial degree of variation in time and space. 68 GMs reflect the properties of the primary repertoire (NGST) and are present till about 4 months post-term when they are gradually replaced by goal directed movements. 54,68,70 GMs show age specific characteristics: GMs before 38 weeks PMA show abundant variation in the movements of all body parts and are called preterm GMs. GMs at age 38 to 47 weeks PMA are forceful, have a writhing character, seem to be a little bit slower than preterm GMs, and trunk and pelvis are a less involved. These GMs are called writhing GMs. The GMs at the age of 48 to 58 weeks PMA, i.e., 2 to 4 months post-term, show a continuous stream of tiny and elegant movements, which have a dancing character. They are called fidgety GMs. 18 The basic characteristics of GMs during typical development are identical at all three GM-ages: typical GMs are characterized by variation, complexity and fluency. Abnormal GMs lack these properties or have them to a lesser extent; they are more stereotyped and not fluent. The quality of GMs may be classified as: a) normal-optimal (NO): these GMs are very variable and complex and they are fluent; b) suboptimal (SO) GMs: they have a sufficient amount of movement variation and complexity, but are not fluent, c) mildly abnormal (MA) GMs show only a limited amount of variation and complexity and d) definitely abnormal (DA) GMs are characterized by a virtual or total absence of movement variation and complexity

18 The quality of GMs is assessed on the basis of a video recording of at least 5 minutes. For the recording of GMs the children are placed in supine position on a flat surface, and preferably they are in an awake, active, noncrying behavioural state (Prechtl s state 4, Table 1). 71 Crying changes the character of the GMs, the movements become more stereotyped and less fluent. If the child is crying, it can be calmed by a pacifier or by interaction with parents or by toys, but this is not allowed during recording or assessing, as sucking or interaction with parents or toys affects the character of the GMs. REM sleep or REM-sleep-like conditions (in infants aged < 36 weeks GA) do not affect movement complexity and variation, but as GMs during REM sleep are often short-lasting, abrupt and have a jerky onset, Prechtl s state 4 is certainly preferred to sleeping for GMassessment. 72 The child preferably only wears a onesie, and the surrounding temperature should be comfortably warm. 18 Table 1. State of the infant, according to Prechtl. State 1 Eyes closed, regular respiration, no movements State 2 Eyes closed, irregular respiration, no gross movements State 3 Eyes open, no gross movements State 4 Eyes open, gross movements, no crying State 5 Eyes open or closed, crying State 6 Other state describe - (e.g. coma) The GMs must be assessed by a trained and experienced observer. Inter-and intraobserver reliability are good, between 89% and 93% (or κ > 0.75). 73 In several recent reviews the predictive validity of GMs has been studied First of all the reviews agreed on the good predictive value for CP in high-risk infants. Three reviews showed that prediction of 27

19 developmental outcome on the basis of the quality of general movements is best when a longitudinal series of GM recordings is made, but as a single assessment the assessment at fidgety age is most predictive Recording of General Movements Noble et al. 76 concluded that the prediction was generally good, but Zuk et al. 73 mentioned especially the predictive validity for Attention Deficit Hyper Activity Disorder (ADHD), MND and behavioural problems in high and low risk children. However Darsaklis et al. 75 indicated that it was too early for this conclusion. They suggested that more research was needed to provide more high quality evidence from larger, heterogeneous, more representative populations, and the use of standardized skill-based outcome assessments. It should be noted that the large majority of infants 28

20 included in the studies of the reviews, were preterm infants. Studies including groups of mainly full-term infants are scarce. They consist of studies on infants with severe perinatal asphyxia and infants of the general population. 8,80-81 This means that we know little about the predictive value of GMs in full-term infants. In addition, as Darsaklis et al. mentioned, up until now most studies focused on serious developmental disorders and only occasionally on minor developmental disorders. In conclusion the assessment of GMs has proven to be a valuable, non-invasive and cheap clinical tool to evaluate the integrity of the nervous system in high risk newborns. This is especially true in situations where expensive neuroimaging is not available, like in many regional hospitals all over the world. However more studies are needed on the prediction of minor developmental disorders. Movement Assessment Battery for Children The Movement ABC (MABC) is a test specifically developed to identify and evaluate children with mild to moderate forms of limited mobility. This test was first described as the Test of Motor Impairment in 1972 and has been revised and re-standardized on a regular basis. In 1992 the MABC, version 1 was published by Henderson and Sugden. 82 It was designed for children aged 4 to 12 years. This version was standardized for the Dutch population by Bouwien Smits-Engelsman in In 2007, another revised version (MABC, version 2) has been published, applicable for children up to 16 years of age. The Dutch version of the MABC, version 2 was published in 2010, i.e., after the onset of the 6-years assessment of this thesis. Therefore we used the MABC, version 1 in the studies of the thesis. The MABC, version 1 contains two components: a) a standardized performance test, and b) a behaviour checklist. In this study we only used the performance test. This test comprises an evaluation in three domains: a) manual dexterity, consisting of three items, b) ball skills, consisting of 29

21 two items and c) static and dynamic balance, consisting of three items. The items are adjusted to the functional motor abilities of children within four age bands, i.e., 4-6 years, 7-8 years, 9-10 years and years. Quantitative performance of each item is scored from 0 (best) to 5 (worst). In addition, qualitative aspects may be recorded on a standardized list. The scores of the quantitative performance items are added up producing three subscores and a total score. These scores are compared to a normative table to determine if performance is typical (> 15 th percentile (> P15)), borderline (P5 score P15), or definitely limited (< P5). 83 The MABC 1 has a good test-retest and interrater reliability, a moderate concurrent validity lacking a suitable gold standard 83,85,87 and a good construct validity. 81,85 Both versions of the MABC can be used as a screening instrument, as a descriptive instrument and also to evaluate effects of interventions. 83,88 The M-ABC is not time consuming and is widely used in many countries. The Child Behavior Checklist and the Teachers Report Form The Child Behavioral Checklist (CBCL) and the Teachers Report Form (TRF) are standardized questionnaires on the child s behavioural and emotional competences. 89 They were developed by Achenbach in 1991 to identify problem behaviour in children from 4 to 18 years and are also known as the Achenbach System of empirically based Assessment (ASEBA). 90 With the CBCL and TRF problem behaviour can be classified in two different ways: a) in scales oriented on the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association, and b) in eight syndrome scales i.e., anxious/depressed behaviour, withdrawn/depressed behaviour, somatic complaints, social problems, thought problems, attention problems, rulebreaking behaviour and aggressive behaviour. In this study we used the latter form of classification, including their compound scores that are labelled internalizing and externalizing behaviour

22 The parents of the child are asked to complete the CBCL questionnaire and the teacher is asked to complete the TRF list. Both lists contain roughly the same questions, so the child s behaviour can be compared in different surroundings and situations. The TRF also provides general information on learning problems. The raw scores of the questionnaire may be expressed as percentile scores, percentile scores for the various scales and for the total score. Scores below the 95 th percentile (P95) are considered to be within the normal range, scores between P95 and P98 are regarded as borderline scores and scores P98 imply a clinical score, i.e., the presence of considerable risk for serious behavioural if not psychiatric disorders. 89 The reliability of the CBCL and TRF is good ranging from κ=0.72 to ,91-92 The concurrent validity of the CBCL and TRF based on correlations with outcome of the Trauma Symptom Checklist for Youth (TSCC 93), the Youth Self Report (ASEBA) and the Strenghts and Difficulties Questionnaire (SDQ 94 ) is good. 95 Neurological Examination of the Child with Minor Neurological Dysfunction. The Neurological Examination of the child with Minor Neurological Dysfunction (MND) is a criterion referenced assessment of the neurological condition of the child. 96 The minimum age for this test is 4 years - with some adjustments for this early age - and there is no upper age limit. 96 Initially this neurological examination of MND was described by Prof. B. Touwen and Prof H. Prechtl. 97 In 1979, a second edition was published by Touwen. 98 He wrote that a special test for children was needed, because the child s nervous system is qualitatively different from that of an adult. The child s nervous system is rapidly developing, while the nervous system of an adult has reached a relatively stable phase of development. The assessment pays special attention to minor neurological deviations, but it of course does also allow for the assessment of frank neurological 31

23 pathology, such as CP. The latest major revision was realized and published by Prof. M. Hadders-Algra in The examination includes traditional neurological signs as well as developmental items. Important is that a single sign has no clinical significance. Signs obtain significance if they cluster in a domain. According to this assessment there are eight domains of dysfunction i.e.: 1) dysfunctional posture and muscle tone regulation, 2) dysfunctional reflex activity, 3) mild dyskinesia e.g. choreiform or athetotiform, 4)mild problems in coordination, 5) mild problems in fine manipulative ability, 6) excessive associated movements, 7) mild cranial nerve dysfunction and 8) mild sensory dysfunction. 96 On the basis of the assessment children who have not yet reached puberty are classified as: a) neurologically normal if they do not show dysfunction in any of the domains or isolated dysfunction in the domain reflexes ; b) simple MND if they show dysfunction in one or two domains; c) complex MND if their dysfunction is present in at least three domains and d) neurologically abnormal in case of a clear neurological disorder, such as CP. After the onset of puberty children the criteria for normal and abnormal are identical to the ones before the onset of puberty. The criteria for the two forms of MND, however, are different: simple MND denotes the isolated presence of dysfunctional posture and tone regulation, choreiform dyskinesia, excessive associated movements, mild sensory dysfunction or mild cranial nerve dysfunction; complex MND the presence of mild coordination problems or fine manipulative disability, with or without other domains of dysfunction. 96 There is a distinct difference between the two basic forms of MND. Simple MND implies the presence of typical but non-optimal brain function and could also be called minimal neurological difference. It has a relatively high prevalence of 15 to 20%. This type of MND is only weakly associated with pre- and perinatal factors such as intrauterine growth retardation and preterm birth. 99 Complex MND is the clinically relevant form of MND, with a 32

24 prevalence of about 5%. This form is clearly associated with pre and perinatal adversities and with other developmental disorders, like ADHD, DCD, autism spectrum disorders, dysgraphia and dyslexia. 69, The assessment of the developmental items is not time-based, but based on the Gestalt evaluation of quality of performance. This demands sufficient knowledge of the assessor about age-adequate performance. The neurological examination of the child with MND has a good intra-rater, interrater and test-retest reliability (κ = ). 96, The construct validity, based on the relationship of MND with pre- and perinatal adversities, 96, is good. In the domain of MND no criterion standard is available, but concurrent validity, based on relationships with learning and behavioural disorders is good. Also poor performance on the MABC and the presence of dysgraphia is associated with the presence of MND, especially to minor dysfunction in the domains of coordination and fine manipulative ability. 97, Predictive validity of the presence of complex MND is satisfactory, as it is associated with clinically relevant forms of MND and learning and behavioural problems at later age. 94, Outline of the thesis Chapter 2 (study 1) and Chapter 3 (study 2) of this thesis address the short term effect on neurological condition of perinatal asphyxia in infants born in a regional hospital. Chapter 2 addresses the effect of perinatal asphyxia in infants born at term, Chapter 3 the effects in infants born preterm. The outcome is measured by means of the Assessment of General Movements Chapter 4 (study 3) examines the effect of DBAT resulting in no, mild or moderate NE on neurodevelopmental outcome at the age of 6 years, with special attention to the presence of limited mobility. 33

25 Chapter 5 (study 4) addresses the predictive value of the Assessment of General Movements in full-term infants for CP, and in children without CP - for milder forms of limited mobility, and other neurodevelopmental problems at the age of 6 years. Chapter 6 consists of a general discussion, the clinical implications of the study and recommendations for further research. Chapter 7 summarizes the results of the studies in English and in Dutch. 34