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 Difficult birth and motor outcome in early infancy and at school age Patricia van Iersel 1

3 Correspondence to: Patricia van Iersel Trekweg HR Apeldoorn The Netherlands P.A.M. van Iersel, 2016 Difficult birth and motor outcome in early infancy and at school age. Thesis University Medical Centre Groningen. Summary in Dutch. ISBN no: No part of this thesis may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording or any information storage and retrieval system, without permission of the copyright owner. Cover: Maarten Haazebroek Pictures: Maarten Haazebroek Printed by: GVO Drukkers en Vormgevers B.V. Ede 2

4 Difficult birth and motor outcome in early infancy and at school age Proefschrift ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens het besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 15 juni 2016 om uur door Patricia Anna Maria van Iersel geboren op 25 augustus 1949 te Breda 3

5 Promotor Prof. dr. M. Hadders-Algra Beoordelingscommissie Prof. dr. A.F. Bos Prof. dr. P.J.M. Helders Prof. dr. M.W.G. Nijhuis-van der Sanden 4

6 Paranimfen Saskia C.M. Bakker, MD Arnold H.J. Jonker, PT The printing of this thesis was financially supported by the Scientific College Physical Therapy (WCF) of the Royal Dutch Society for Physical Therapy (KNGF) and by the Gelre Hospital Apeldoorn, the Netherlands. 5

7 Het lijkt altijd onmogelijk totdat het gedaan is Nelson Mandela 6

8 Table of Contents. List of abbreviations Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 General Introduction. Quality of general movements in term infants with asphyxia. Early Human Development 2009;85:7-12 Does perinatal asphyxia contribute to neurological dysfunction in preterm infants? Early Human Development 2010;86: Limitations in the activity of mobility at age 6 years after difficult birth at term. A prospective cohort study. Physical Therapy 2015; epub ahead of print Does quality of general movements in full-term infants predict cerebral palsy and milder forms of limited mobility at six years? Submitted for publication General discussion, clinical implications, future Research Summary Nederlandse samenvatting References List of co-authors affiliations Dankwoord (Aknowledgements) About the author 7

9 List of abbreviations ADHD aeeg ASEBA CBCL CP CS DA DBAT DCD GA GMs ICF-CY LMIC MA MABC MND MRI NE NGST NO NPV PLIC PMA PPV PVL REM SDQ Attention Deficit Hyperactivity Disorder Amplitude-integrated Electroencephalography Achenbach System of Empirically Based Assessment Child Behavior Checklist Cerebral Paralysis Caesarian Section Definitely abnormal Difficult Birth At Term Developmental Coordination Disorder Gestational age General Movements International Classification of Functioning, Disability and Health, Children & Youth version Low and Middle Income Countries Mildly abnormal Movement Assessment Battery for Children Minor Neurological Dysfunction Magnetic Resonance Imaging Neonatal Encephalopathy Neuronal Group Selection Theory Normal-optimal Negative Predictive Value Posterior Limb of the Internal Capsule Post Menstrual Age Positive Predictive Value Peri Ventricular Leucomalacia Rapid Eye Movements Strengths and Difficulties Questionnaires 8

10 SGA SO TRF TSCC US WHO Small for Gestational Age Suboptimal Teachers Report Form Trauma Symptom Checklist for Children Ultra Sound World Health Organization 9

11 10

12 Chapter 1 General Introduction 11

13 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

14 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

15 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

16 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

17 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

18 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

19 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

20 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

21 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

22 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

23 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

24 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

25 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

26 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

27 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

28 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

29 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

30 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

31 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

32 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

33 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

34 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

35 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

36 Chapter 2 Quality of general movements in term infants with asphyxia 35

37 QUALITY OF GENERAL MOVEMENTS IN TERM INFANTS WITH ASPHYXIA Patricia AM van Iersel, PT 1, Saskia CM Bakker, MD 2, Arnold JH Jonker, PT 1, Mijna Hadders-Algra, MD, PhD 3 1 Gelre Hospital, Department of Physical Therapy, Apeldoorn, the Netherlands 2 Gelre Hospital, Department of Paediatrics, Apeldoorn, the Netherlands 3 University Medical Center Groningen (UMCG), Department of Neurology - Developmental Neurology, Groningen, the Netherlands Early Human Development 2009;85:

38 Abstract Background: Perinatal asphyxia may result in a developmental disorder. A recently developed non-invasive tool to investigate brain function at early age is the assessment of general movements (GMs). Aim: To evaluate relationships between perinatal risk factors and the quality of GMs in the neonatal period and at 3 months in term newborns with asphyxia in a secondary paediatric setting. Methods: 64 term (>36 weeks postmenstrual age (PMA)) infants with perinatal asphyxia were studied. GMs were assessed at writhing GM age (38 47 weeks PMA) and at fidgety GM age (48 56 weeks PMA). Preand perinatal factors were collected in a standardized way. Results: Multivariate analysis revealed that DA GMs at writhing age mainly correlated with asphyxia related illness. DA GMs at fidgety age correlated in particular with abnormalities on the neonatal ultrasound scan of the brain. Conclusion: In secondary paediatric settings GM-assessment especially around 3 months is a valuable tool for the assessment of the integrity of the nervous system in term infants with asphyxia. 37

39 Introduction Perinatal asphyxia is a well known cause of developmental disorders. 1-2 It may result in the development of cerebral palsy (CP), but most cases of CP are not the result of an interruption of oxygen supply around birth. 3-6 In addition, many children born with perinatal asphyxia develop in a typical way. 7-8 To date it is still unclear which child born with asphyxia will develop neurological impairment and which will not. Recently developed imaging techniques of the newborn brain, such as diffusion weighted MRI and magnetic resonance spectroscopy are promising in this respect, 9-10 but these techniques are not readily available in a secondary paediatric setting. In the more general paediatric setting it remains difficult to predict outcome of perinatal asphyxia. The lack of clinical clarity on prognosis can be explained partially by the variable way in which the term asphyxia is applied. Traditionally the term asphyxia ( being pulseless ) was used for infants with a low Apgar score and/or failure to breath. 3,11 Of course a low Apgar score may be the result of perinatal hypoxia or ischaemia, but it may also have been caused by other problems, for example a congenital disorder of the brain. 12 The term asphyxia is also used for conditions in which indirect parameters such as an abnormal fetal heart rate tracing or acidosis suggest the presence of hypoxia and ischemia. 13 Others suggest to use the term asphyxia only for infants born with indicators of hypoxia-ischaemia who present with neonatal encephalopathy Here it should be realized however, that - in analogy to CP a major part of neonatal encephalopathy is not caused by hypoxic-ischaemic insults The aim of the present study is to analyse the contribution of pre- and perinatal risk factors to the neurological condition at birth and at the age of 3 months in infants with perinatal asphyxia referred to a secondary paediatric department. We included infants with and without neonatal encephalopathy, as this reflects admission practice in the secondary paediatric setting. Neurological condition was assessed by means of the quality of general movements (GMs). The assessment of GMs is a non- 38

40 invasive sensitive method to evaluate the integrity of the young nervous system and as such complementary to the clinical neurological examination of the paediatrician. A previous study indicated that the assessment of GMs was a good indicator of neurological sequelae in term infants with asphyxia referred to a tertiary care centre. 20 In the latter study all subjects had signs of neonatal encephalopathy as indicated by a Sarnatscore Other studies evaluated GM-quality in mixed groups of at risk infants, including term infants with perinatal asphyxia. The studies concluded that the assessment of GMs is a valuable and reliable tool to predict later neurological dysfunction and behavioural problems Subjects and Methods Subjects The study group consisted of term infants presenting with perinatal asphyxia admitted to the regional general hospital, Gelre Hospital in Apeldoorn the Netherlands between January 1999 and July Term birth was defined as birth after 36 completed weeks of gestation. Children were included into the study group, if they fulfilled at least two of the following criteria for asphyxia: 1) abnormal cardiotocogram (CTG), e.g. late decelerations, persistent bradycardia (< 100 beats per minute, or persistent tachycardia (>160 beats per minute)), 2) Apgar score at 5 minutes < 7, 3) umbilical ph < 7.20 and 4) umbilical base excess < -10 mmol/l. Ninety term infants fulfilled the criteria for asphyxia. The parents of 17 infants declined the offer to participate in the study; another 9 infants were not reported to the research team. Therefore, 64 infants were enrolled in the study group. Thirty infants presented with neurological symptoms during the first days after birth (neonatal encephalopathy (NE); Table 1). Clinical characteristics of the study group are listed in Table 1. Infants with visible congenital anomalies, like malformations, dysmorphic features, chromosomal disorders or heriditary syndromes, were excluded from the 39

41 study. The parents of the children gave signed informed consent and the procedures were approved by the Regional Medical Ethical Committee. Methods According to the method of General Movements spontaneous motility in supine position of all infants was video recorded twice during the first postnatal months, i.e., at writhing GM age (38 47 weeks PMA) and at fidgety GM age (48 58 weeks PMA). Care was taken to record at least 5 minutes of spontaneous motility in an awake, active, non-crying state. The GMs were assessed by the first author who was aware of the clinical condition of the infant and by the last author who was blinded to the infant s clinical condition. Movement quality was classified as normal optimal (NO), normal suboptimal (SO), mildly abnormal (MA) or definitely abnormal (DA), according to Hadders-Algra et al. (2004). NO movements are very variable and complex and fluent. SO movements have a sufficient amount of movement variation and complexity, but are not fluent. MA movements are characterized by a limited amount of variation and complexity, and DA movements by a virtual or total absence of movement variation and complexity. 18 Inter-observer agreement between the two assessors (determined on the basis of a random sample of 60 videos for each age period) was good: writhing period: Cohen s κ = 0.78, fidgety period: κ = In case of disagreement classification was discussed till consensus was reached. Data on social class were collected by means of a parental questionnaire. Clinical data and data based on hospital records were collected on standardized forms (table 1). Ultrasound scans of the brain of the asphyxiated infants were made on clinical indication on ages varying from 1 day to 16 days (median: 2 days). In a minority of infants multiple scans had been made. Ultrasound abnormalities were classified according to Daneman et al

42 Table 1. Clinical characteristics of the study group Variables Prenatal and social characteristics Study group n = 64 Male Gender (%) 37(58%) Maternal education: higher education (%)* 17 (27%) Presence of complications during pregnancy: - HELLP/ preeclampsia/hypertension - loss of blood/placenta praevia - placental abruption - Rhesus antagonism - imminent preterm labour - hyperglycaemia Perinatal characteristics 21 (33%) 12 (19%) 3 (4%) 3 (4%) 1 (2%) 1 (2%) 1 (2%) Gestational age at birth in weeks: median (range) 40 (36 43) Breech presentation 3 ( 5%) Duration first stage in hours: median (range) 8.75 (0 24) Duration second stage in minutes: median (range) 21.5 (0 240) Decelerating CTG (%) 41 (64%) Instrumental delivery 39 (61%) Neonatal characteristics Apgar score after 1 minute: median (range) 3 (0 8) Apgar score after 5 minutes: median (range) 6 (2 9) Birthweight, mean ± SD 3387 ± 630 Small for gestational age, birthweight < P10 7 (11%) Cord ph, mean ± SD 7.1 ± 0.2 Cord BE, mean ± SD ± 6.5 EEG: - no EEG performed - normal EEG - abnormal EEG ** Sarnat score : - no signs of neonatal encephalopathy - Grade I - Grade II - Grade III 30 (47%) 18 (28%) 16 (25%) 34 (53%) 16 (25%) 13 (20%) 1 (2%) Clinical seizures 14 (22%) Neonatal Ultrasound (US) scan of the brain: - no US performed - US normal - US abnormal 40 (62%) 10 (16%) 14 (22%) Parenteral feeding > 1 week 8 (13%) Breastfeeding 49 (77%) Organfailure : - kidneyfailure - liverfailure - hypoglycaemia - respiratory problems, no artificial ventilation 8 (13%) 5 ( 8%) 8 (13%) 36 (56%) > 1 organ with failure 16 (25%) Perinatal infection 12 (19%) * : University education or vocational college, ** : Abnormal EEG findings according to Laroia et al : Score according to Sarnat & Sarnat 1976 : Abnormal US findings according to Daneman et al : 1 hour postnatally < 1.6, 3 hours postnatally < 2.7, 24 hours postnatally < 3.0 mmol/liter [ Srinivasan 1986] 41

43 As it is known that abnormalities in the thalamus and basal ganglia may not be visible on ultrasound during the first week of life, we applied the following algorithm for the classification of ultrasound findings: Infants who did not have an ultrasound scan or who had a single assessment with normal findings in the first 6 days of life were classified as having missing ultrasound data. Infants with multiple normal scans or a normal scan after day 6 were classified as having normal scans and the ultrasound finding of those infants who had at least one abnormal ultrasound scan were classified as abnormal (Table 1). Table 2. Quality of General Movements in the neonatal period ( writhing GM age) and around 3 months ( fidgety GM age) Quality of GMs at writhing GM age Quality of GMs at fidgety GM age NO SO MA DA Total NO SO MA DA Total Statistics Statistics were performed with the software package SPSS, version 12. The analysis focused on the influence of ante-, peri-, and neonatal characteristics on the quality of GMs. Besides univariate statistical analyses with Chi-square, Mann Whitney and t-test, logistic regression analysis was applied to determine which early factors were the major determinants of abnormal GMs in infants with asphyxia. Factors were only entered into the model if the association with GM quality reached a p-value < Differences with p-levels < 0.05 were considered statistically significant (two tailed). 42

44 Table 3. Relation between early risk factors and definitely abnormal GMs in infants with asphyxia (n=64). DA GMs at Writhing age DA GMs At Fidgety age Perinatal risk factors Duration first stage > 6 hours Duration second stage > 60 minutes 0.06 Instrumental delivery: vacuum extraction 0.10 Cord ph < CTG decelerations 0.07 Presence of at least 2 of the 4 criteria of asphyxia 0.02* ( AS after 5 min. < 7, ph < 7.20; BE < -15; CTG decelerations) Neonatal risk factors Perinatal infection Sarnat score II or more 0.01** 0.02** Kidneyfailure ** More than one of following signs of organ failure / 0.02* clinical sequelae of asphyxia kidney failure; liver failure; hypoglycaemia; respiratory problems with or without the need of artificial ventilation Parenteral feeding > 1 week 0.02** 0.07 Abnormal EEG (n = 34) 0.05* Abnormal US ( n = 24) ** Numbers indicate p-values; Statistics preformed: * χ², ** Fisher Exact Test. Results Neonatally 22 (34%) infants showed DA GMs and 26 (41%) MA GMs. The quality of GMs had improved at fidgety GM age. At that age 9 (14%) infants had DA GMs and 24 (38%) MA GMs (Table 2). GM-quality of 20 infants (32%) was identical at both ages, it improved in 35 infants (54%) and deteriorated in 9 infants (14%) (Table 2). Univariate analysis indicated that DA GMs at writhing GM age were related to variables which reflected the degree of organfailure as an immediate clinical consequence of the asphyxia. DA GMs at writhing GM age were related to the presence of at least two of the four criteria of asphyxia, the presence of a Sarnat score > 1, kidney and multiple organ failure, the need of parenteral feeding for at least a week and the presence of abnormalities on EEG (Table 3). DA GMs at fidgety GM age were only related to abnormalities on the neonatal ultrasound scan of the brain and to a Sarnat score > 1 (Table 3). 43

45 Multivariate analyses revealed that DA GMs at writhing age were best explained by the presence of at least two of the criteria of asphyxia in combination with failure of at least one organ (Table 4). DA GMs at fidgety GM age were associated in particular with abnormalities on the neonatal ultrasound scan of the brain and a long duration of the second stage of labour (> 1 hour; Table 4). Table 4. Result of logistic regression analysis of factors contributing to the occurrence of definitely abnormal GM at writhing and fidgety age. Odds Ratio (95%CI ) P-value DA Writhing GMs: explained variance - Presence of at least 2 of the 4 criteria of asphyxia (ph < 7.20; BE < -10; CTG decelerations; AS 5 min.< 7) - More than one of following signs of organ failure / clinical sequelae of asphyxia: kidney failure; liver failure; hypoglycaemia; respiratory problems with or without the need of artificial ventilation 19.3% 4.44 (1.34, 14.76) 5.80 (1.56, 21.50) DA Fidgety GMs: explained variance - Duration second stage of labour > 60 min. - Abnormal ultrasound scan of brain 17.8% 8.81 (1.44, 53.78) (1.75, 64.88) Discussion Our study indicated that in term infants with asphyxia the risk factors for DA GMs in the neonatal period differ from those at the age of 3 months. Early neurological deviancy expressed in the form of DA GMs was associated with acute illness induced by the hypoxic-ischaemic event, whereas neurological morbidity at 3 months was related in particular to neonatal ultrasound scan abnormalities of the brain. The present study was carried out in a regional hospital. The strengths and weaknesses of the study are related to this specific setting. A weakness of the study was the limited access to neuro-imaging. We only had access to the information on the ultrasound scans of the brain. These ultrasound 44

46 scans had been made on indication of the paediatrician and we depended on the radiologist s written report for the details of the findings. The strengths of the study are threefold: 1) evaluation of risk factors for deviant outcome in term infants with asphyxia at birth in a regional hospital, i.e. a non-academic setting, 2) the absence of attrition and 3) the standardized application of a sensitive method to evaluate brain function in young infants. The asphyxiated infants of the present study showed considerably more often abnormal GMs than term infants in the general population. Less than 4% of the 3-month-old full-term infants in the general population show DA GMs and 25% exhibit mildly abnormal GMs, 28 compared to 14% and 38% of our study group of asphyxiated infants. This finding confirms the increased risk for neurological morbidity after perinatal asphyxia at term. 18,20,29-30 Abnormal GMs at writhing age correlated with perinatal factors associated with asphyxia and its immediate consequences such as organ failure. The study of Bos et al 31 indicated that acute systemic illness such as sepsis may induce abnormal GMs. The present data indicate that in infants with asphyxia DA GMs in the neonatal period were more closely related to the acute illness induced by hypoxia-ischaemia than to lesions of the brain. After the neonatal period this changed. Movement quality of a substantial number of infants with DA GMs at writhing age improved at fidgety age, in general to MA GMs (see Table 2). This means that part of the infants with clinical asphyxia suffered from a transient form of dysfunction only. This finding underscores the young brain s intrinsic potential for recovery. This is one of the major reasons that perinatal adversities only infrequently result in permanent neurological damage ( brain sparing phenomenon ). 32 The improvement in the infants with apparently transient dysfunction resulted in the emergence of a clear relationship between abnormalities of the brain detected by means of ultrasound imaging of the newborn brain and DA GMs at fidgety age. The abnormalities on the neonatal ultrasound scans in general consisted of increased signal intensity in the periventricular white matter. This finding fits in with the recently generated hypothesis that abnormal GMs result from 45

47 dysfunction or damage of the cortical subplate or its efferent motor connections which run through the periventricular white matter. 28,33 The data indicated that a duration of the second stage of labour of more than one hour increased the risk for DA GMs at fidgety age. This finding does not correspond to the literature. 34 It still is a matter of dispute whether a prolonged duration of the second stage of labour contributes to adverse neonatal outcome, but a second stage of less than two hours is in general considered as safe In conclusion, the quality of GMs in the neonatal period is mainly related to acute illness of the asphyxiated infant and not to abnormalities on the ultrasound scan of the brain. This finding reflects the sensitivity of the young brain to react to adverse clinical conditions. Fortunately, part of the early neurological deviancy reflects transient dysfunction only. Due to the disappearance of transient dysfunction, GM-assessment at 3 months, which was related to abnormalities on the neonatal ultrasound scan of the brain, seems to have more clinical importance. As GM-assessment is cheap and non-invasive our findings suggest that this method is a valuable tool to be used to evaluate the integrity of the nervous systems of infants, who suffered from perinatal asphyxia. This may be valid in particular in secondary settings where newly developed imaging techniques are not available. It goes without saying that follow up at school age of the infants studied is highly desirable. Acknownledgements: The study was financially supported by the TB Foundation. We kindly acknowledge the cooperation of the Doevedans Midwife Practice in Apeldoorn and the Obstetrical and Paediatric Department of the Gelre Hospital for participating in the intake of the children. MH-A designed the study, PvI and MH-A analyzed and interpreted the results and wrote the report, AJ did the video-editing and assisted in analyzing the videotapes together with colleages B.Coenraads and R.Tegelenbosch. CMB, AJ and Dr. J.M. Smit were involved in the writing of the report. 46

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50 22. Hadders-Algra M. (1999): Quality of general movements in infancy is related to neurological dysfunction, ADHD, and aggressive behaviour. Dev. Med. Child Neurol. 41: Hadders-Algra M.,Mavinkurve-Groothuis A.M.C., Groen S.E., Stremmelaar E.F., Martijn A., Butcher P.R. (2004): Quality of general movements and the development of minor neurological dysfunction at toddler and school age. Clin. Rehabil. 18: Groen S.E., de Blécourt A.C.E., Postema K., Hadders-Algra M. (2005): General movements in early infancy predict neuromotor development at 9 to 12 years of age. Dev. Med. Child Neurol. 47: Daneman A., Epelman M., Blaser S., Jarrin J.R. (2006): Imaging of the brain in full-term neonates: does sonography still play a role? Pediatr. Radiol. 36; Hertzberg B.S., Pasto M.E., Needleman L., Kurtz A.B., Rifkin M.D. (1987): Postasphyxial encephalopathy in term infants. J. Ultrasound Med. 6: Voit T., Lemburg P., Neuen E., Lumenta C., Stork W. (1987): Damage of thalamus and basal ganglia in asphyxiated full-term neonates. Neuropediatrics 18: Hadders-Algra M. (2007): Putative neural substrate of normal and abnormal general movements. Neurosci. Biobehav Rev. 31: Robertson C.M.T., Finer N.N., Grace M.G.A. (1989): School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J.Pediatr. 114: Robertson C.M., Finer N.N. (1993): Long term follow up of term neonates with perinatal asphyxia. Clin. Perinatol. 20: Bos A.F. (1993): Differential effects of brain lesions and sytemic disease on the quality of general movements: a peliminary report. Early Hum. Dev. 34: Scherjon S.A., Oosting H., de Visser B.W., de Wilde T., Zondervan H.A., Kok J.H. (1996): Fetal brain sparing is associated with 49

51 accelerated shortening of visual evoked potential latencies during early infancy. Am J Obstet Gynecol. 175(6): Kostović I., Judaš M. (2007): Transient patterns of cortical lamination during prenatal life: Do they have implications for treatment? Neurosci Biobehav Rev. 31(8): Altman M.R., Lydon-Rochelle M.T. (2006): Prolonged second stage of labour and risk of adverse maternal and perinatal outcomes: a systematic review. Birth 33: Cheng Y.W., Hopkins L.M., Caughey A.B. (2004): How long is too long: Does a prolonged second stage of labor in nulliparous women affect maternal and neonatal outcome? Am. J. Obstet. Gynecol.: 191, Cheng Y.W., Russel K.L. jr.hopkins L.M., Caughey A.B. (2007): Duration of the second stage of labor in multiparous women: maternal and neonatal outcomes. Am. J. Obstet. Gynecol.196: 585.e1-585.e6 37. Laroia N., Guillet R., Burchfiel J., Mc Bride M.C. (1998): EEG background as predictor of electrografic seizures in high-risk neonates. Epilepsia. 39: Srinivasan G. (1986): Plasma glucose values in normal neonates: a new look. J.Pediatr. 109:

52 Chapter 3 Does perinatal asphyxia contribute to neurological dysfunction in preterm infants? 51

53 DOES PERINATAL ASPHYXIA CONTRIBUTE TO NEUROLOGICAL DYSFUNCTION IN PRETERM INFANTS? Patricia AM van Iersel, PT 1, Saskia CM Bakker, MD 2, Arnold JH Jonker, PT 1, Mijna Hadders-Algra, MD, PhD 3 1 Gelre Hospital, Department of Physical Therapy, Apeldoorn, the Netherlands 2 Gelre Hospital, Department of Paediatrics, Apeldoorn, the Netherlands 3 University Medical Center Groningen (UMCG), Department of Paediatrics - Developmental Neurology, Groningen, the Netherlands Early Human Development 2010;86:

54 Abstract Background: Children born preterm are known to be at risk for neurodevelopmental disorders. The role of perinatal asphyxia in this increased risk is still a matter of debate. Aim: To analyze the contribution of perinatal asphyxia in a population of preterm infants admitted to a secondary paediatric setting to neurological dysfunction in the first months after birth and to the development of cerebral palsy. Methods: 17 preterm infants with perinatal asphyxia born before 35 weeks postmenstrual age (PMA) and 34 carefully matched preterm controls without asphyxia were studied. Neuromotor outcome was examined by means of three assessments of the quality of general movements (GM) at preterm (around 34 weeks PMA), writhing (around term age) and fidgety GM age (around 3 months post term). Follow-up until at least 18 months corrected age focused on the presence of cerebral palsy (CP) Results: GM-quality of infants with asphyxia and of those without did not differ. Multivariate analysis revealed that abnormal GMs at preterm age were associated with respiratory problems, those at writhing age with none of the assessed risk factors, and those at fidgety age with the severity of periventricular leukomalacia (PVL) on neonatal ultrasound scan. Perinatal asphyxia was not associated with the development of CP. CP was associated with PVL and the presence of abnormal GMs at fidgety age. Conclusion: Perinatal asphyxia in preterm infants is not associated with an increased risk for neurodevelopmental problems including CP. Respiratory problems during the neonatal period are associated with PVL and adverse neurological outcome. 53

55 Introduction Children born preterm are known to be at risk for developmental problems. Neurodevelopmental sequelae can be as serious as cerebral palsy (CP), but also more moderate motor or behavioural impairments such as minor neurological dysfunction (MND), attention deficit hyperactivity disorder (ADHD) and cognitive deficits and learning disorders occur more often in infants born preterm than in infants born at term. 1-6 It is well known that lesions of the brain diagnosed by neonatal ultrasound or MRI are useful tools to predict neurodevelopmental outcome in these infants. 2,7 Also other risk factors, such as very low birthweight (VLBW), 2 gestational age at birth less than 32 weeks 5-6 or severe (grade 2 or 3) respiratory distress syndrome 8 may assist prediction of development in preterm children. The importance of perinatal asphyxia as a risk factor for poor developmental outcome in preterm children is still a matter of debate. This can be partly explained by the fact that perinatal asphyxia in preterms is difficult to define. For instance, a low Apgar score in preterm infants does not necessarily indicate the presence of asphyxia, 9 it also may reflect a diminished capacity of the child s nervous system to cope with the transition from intrauterine to extra-uterine life due to other factors. The latter may explain why a low Apgar score at 5 minutes in preterm infants is associated with an increased risk for poor motor and psychosocial outcomes. 6 The study of Low et al. 10 in which asphyxia in preterms was defined as the presence of an umbilical arterial bufferbase < 34 mmol/l, indicated that asphyxia was associated with an increased risk of abnormal motor and cognitive outcome at the age of 1 year. Also the study of Westgren et al. 11 suggested a contribution of asphyxia to deviant developmental outcome in preterm infants. They reported an association between late decelerations or pronounced variable decelerations in the fetal heart rate (FHR) and neurodevelopmental abnormalities at two years. On the other hand Hadders-Algra et al. 12 found that the common indicators of perinatal asphyxia (umbilical ph and Apgar score) did not relate to neurological or behavioural outcome of preterms at the age of 6 years. Holmqvist et al

56 reported that fetal acidosis (scalp ph < 7.20) in preterm infants may be an additional factor to explain neurodevelopmental outcome at the age of 6 years. But they also concluded that fetal acidosis as a single factor does not predict outcome. The aim of the present study is to analyse the contribution of perinatal asphyxia in a population of preterm infants born before 35 weeks postmenstrual age (PMA) admitted to a regional hospital to neurological dysfunction in the first months after birth and to the development of cerebral palsy. Neurological condition in early life was assessed by means of the quality of general movements (GMs). The assessment of GMs is a non-invasive sensitive method to evaluate the integrity of the young nervous system. 14 Previous studies indicated that the quality of GMs in preterm infants was related to neurological sequelae in later life Subjects and Methods Subjects The study group consisted of 17 preterm infants born before the 35 th week of gestation presenting with perinatal asphyxia admitted to the regional general hospital, Gelre Hospital in Apeldoorn the Netherlands between June 1999 and June Perinatal asphyxia was defined on the basis of classical parameters, i.e. cord ph < 7.20, base excess < -10 mmol/l, abnormal cardiotocogram (CTG) recording, e.g. late decelerations, persistent bradycardia (< 100 beats per minute, or persistent tachycardia (>160 beats per minute) and an Apgar score after 5 minutes < 7. Children were included into the study group if they fulfilled at least two of these criteria for asphyxia. Seventeen preterm infants fulfilled the criteria for asphyxia. The control group consisted of 34 preterm infants without asphyxia who were recruited at the medium care neonatology ward of the Gelre Hospital. We aimed at matching study and control groups for 1) gestational age, 2) 55

57 gender, 3) educational level of the mother and 4) infants that were small for gestational age (SGA). Matching was successful for all variables. Clinical characteristics of both groups are summarized in table 1. Nine study infants presented with neurological symptoms during the first days after birth. Infants with congenital anomalies were excluded from the study. The parents of the children gave signed informed consent and the procedures were approved by the Medical Ethical Committee of UMC Utrecht. Methods The primary outcome parameter of neurological condition of the infants included into this prospective study was the quality of general movements (GMS). To this end spontaneous motility in supine position of all infants was video recorded three times during the first postnatal months, i.e., at preterm GM age (before 38 weeks PMA), at writhing GM age (38 47 weeks PMA) and at fidgety GM age (48 58 weeks PMA). Care was taken to record at least 5 minutes of spontaneous motility in an awake, active, non-crying state. Movement quality was classified as normal optimal (NO), normal suboptimal (SO), mildly abnormal (MA) or definitely abnormal (DA), according to Hadders-Algra et al. 14 NO movements are very variable and complex and fluent. SO movements have a sufficient amount of movement variation and complexity, but are not fluent. MA movements are characterized by a limited amount of variation and complexity, and DA movements by a virtual or total absence of movement variation and complexity (see Hadders-Algra 14 ). The GMs were assessed by the first author who was aware of the clinical condition of the infant and by the last author who was blinded to the infant s clinical condition. Inter-observer agreement between the two assessors determined on the basis of a random sample of 20 videos for each age period was good: preterm period Cohen s κ = 0.77, writhing period κ = 0.80, fidgety period κ = In case of disagreement classification was discussed until consensus was reached. 56

58 Table 1. Prenatal, social, perinatal, neonatal and clinical characteristics. Variables Study group Control group Prenatal and social characteristics n = 17 n = 34 p-value Maternal age (years), mean ± SD 30 ± ± Maternal education: higher education 5 (29%) 12 (35%) (%) Perinatal characteristics Gestational age at birth in weeks: 32 (28-34) 32 (28-34) median (range) Duration second stage in minutes: 0 (0-22) 9 (0-120) # median (range) Caesarian section 13 (77%)* 13 (38%) Decelerating CTG (%) 14 (82%) 5 (15%) < Umbilical ph, mean ± SD ,14 # ,07 < Umbilical BE, mean ± SD # < Apgar score after 1 minute: median 3 (0-8) # 8 (2-10) < (range) Apgar score after 5 minutes: median 5 (1-9) # 9 (5-10) < (range) Birthweight, mean ± SD SGA < P10 4 (23%) 7(21%) Neonatal characteristics Respiratory problems : - No respiratory problems 2(12%) 14(88%) - Minor respiratory problems 5(26%) 14(74%) Marked respiratory problems 10(63%) 6(37%) IRDS: - no - grade 1 / gr 2 / gr 3 / gr 4 Organfailure : - kidneyfailure - liverfailure - hypoglycaemia - respiratory problems requiring art. Ventilation Neonatal jaundice Neonatal jaundice requiring phototherapy Neonatal Ultrasound scan of the brain : - no US performed - normal / gr 1 / gr 2 / gr 3 / gr 4 9(53%) 3 / 2 / 1 / 2 3(18%) 4(24%) 8(47%) 10(59%)* 11(65%) 7 (41%) 25(74%) 3 / 6 / 0 / (0%) 0(0%) 9(27%) 6(18%) 29 (85%) 25 (74%) * (0%) 2(6%) 7 / 6 / 3 / 1 / 0 16 / 13 / 0 / 2 / Time in hospital (days): median (range) 29 (12-92) 27(15-83) * Chi square Fisher Exact Test # Mann Whitney Chi square for trend Clinical data based on hospital and midwifery records were collected on standardized forms. Data on social class were collected by means of a parental questionnaire. Respiratory problems were categorized as: 1) no respiratory problems (with or without caffeïne treatment), 2) minor respiratory problems e.g. requiring low flow oxygen/cpap, or the presence 57

59 of apneas and bradycardias, despite caffeïne treatment and 3) marked problems, i.e. requiring mechanical ventilation. Ultrasound scans of the brain were made on clinical indication, the number of scans varied from 1 to 5 (median value 2). The abnormalities were classified according to the grading system for periventricular leucomalacia (PVL) of de Vries et al. (1992), i.e. grade 1: transient periventricular densities persisting for 7 days or longer, grade 2:periventricular densities evolving to small localized fronto-parietal cystic lesions, grade 3: periventricular densities evolving to extensive cystic lesions, grade 4: densities extending into deep white matter evolving to extensive cystic lesions. Four infants had a mild germinal matrix or intraventricular haemorrhage (Papile et al. 1978). Their brain scans were classified according to grade of accompanying PVL. Outcome of all children was assessed with paediatric assessments till the corrected age of 2 years with intervals determined by clinical condition. The assessment included a neurological evaluation according to Touwen (1976). 18 Children were classified as having cerebral palsy (CP) when they exhibited at the corrected age of at least 18 months a classical configuration of neurological signs fitting to the diagnosis, such as - in case of bilateral spastic CP - the combination of a stereotyped posture and motility of the legs, an increased muscle tone and brisk tendon reflexes in the legs and Babinski signs (SCPE). 19 Statistics Statistics were performed with the software package SPSS, version 15. The analysis focused on the influence of asphyxia on the quality of GMs. Next, the relation between other pre-, peri-, and neonatal characteristics and GM-quality was evaluated. Besides univariate statistical analyses with Chisquare, Mann Whitney and t-test, logistic regression analysis was applied to determine which early factors were the major determinants of abnormal GMs. Factors were only entered into the model if the differences between the risk variable and the GM-quality reached a p-level < Subsequently the relation between CP and the severity of PVL on neonatal US and between 58

60 CP and quality of GMs was determined by analysis with Chi square for trend. Differences with p-levels < 0.05 were considered statistically significant (two tailed). Table 2. Quality of General Movements in study and control group Quality of GMs At preterm GM age At writhing GM age At fidgety GM age Study control study control study control Normal optimal 1 (6%) 0 (0%) 0 (0%) 0 (0%) 1 (6%) 3 (9%) Suboptimal 3 (18%) 8 (24%) 4 (24%) 5 (15%) 7 (41%) 9 (26%) Mildly abnormal 10 (59%) 16 (49%) 9 (53%) 16 (49%) 6 (35%) 18 (53%) Definitely abnormal 3 (18%) 9 (27%) 4 (24%) 12 (36%) 3 (18%) 4 (12%) Results Neurological condition during the first postnatal months GM-quality of infants with asphyxia and of those without did not differ (Table 2). A minority of infants had a stable GM quality from preterm to fidgety GM age (study group 3 infants (18%), control group 7 infants (21%)). GM-quality improved in about a third of infants (study group 6 infants (35%), control group 11 infants (32%)), it deteriorated in 18% (study group n=3, control group n=6) and it had a variable course in the remaining infants (study group n=5, control group n=10). This means that GM-quality often changed and equally often in both groups. Table 3: Result of logistic regression analysis of factors contributing to the occurrence of abnormal (MA+DA) GM at preterm age. Odds Ratio (95%CI ) P- value Abnormal (MA + DA) preterm GMs: explained variance - Respiratory problems - Gestational age < 33 weeks 21.1% 6.29 (1.42, 27.76) 0.16 ( 0.02, 1.49)

61 As asphyxia was not related to GM-quality we investigated which of the clinical risk factors did contribute to GM-quality. None of the risk factors of Table 1 was associated with DA GMs at preterm age. The presence of abnormal (MA+DA) GMs was however associated with gestational age below 33 weeks (Fisher exact test, p=0.04) and the presence of respiratory problems (Fisher exact, p= 0.02; Figure 1) and failure of at least one organ (Fisher exact, p=0.007). Multivariate analysis confirmed the association between respiratory problems and abnormal preterm GMs (Table 3). Univariate statistics indicated that DA GMs at writhing age were associated with the presence of IRDS > grade 1 (Fisher exact, p=0.002) and that abnormal (MA+DA) GMs were associated with the presence of hypoglycaemia (Fisher exact, p=0.02). Multivariate analysis could however not confirm these associations. Table 4: Result of logistic regression analysis of factors contributing to the occurrence of definitely abnormal GM at fidgety age. Odds Ratio (95%CI ) P-value DA Fidgety GMs: explained variance - Severity of PVL on ultrasound scan of the brain - Gestational age < 33 weeks 16% 2.37 (1.04, 5.40) 0.29 (0.04, 1.91) At fidgety GM age DA GMs were associated with the presence of neonatal jaundice requiring phototherapy (Fisher exact, p = 0.04) and the severity of PVL on the neonatal ultrasound (Chi square for trend, p = 0.002; Figure 2). Multivariate analysis confirmed the association between abnormal GMs at fidgety GM age and the severity of PVL on the US scan (Table 4). Interestingly, the severity of PVL was related to the presence of respiratory problems, but not to the presence of asphyxia (Table 1). 60

62 Figure 1: Respiratory problems and MA+DA GMs at preterm age. Fisher exact test : p = 0.01 Figure 2: Severity of PVL on neonatal ultrasound and DA GMs at fidgety age. Chi square for trend: p = Cerebral palsy Two of the children with asphyxia (11%) developed a bilateral spastic cerebral palsy. In the control group four children (11%) had CP: two a bilateral and two a unilateral spastic CP. With the exception of the severity of PVL on the neonatal ultrasound scan of the brain none of the perinatal and neonatal risk factors was associated with CP. The severity of PVL, as determined by repeated US scans, showed a clear relationship with the development of CP (Chi square for trend, p = 0.001, Figure 3a). 61

63 Quality of GMs at preterm and writhing GM age were not related to the development of CP but the quality of GMs at fidgety GM age was clearly related to the development of CP (Chi square for trend, p = 0.001). Interestingly, the two children who showed MA GMs at fidgety age (Figure 3b), developed a unilateral spastic CP, the other four, who developed a bilateral spastic CP, showed DA at fidgety age. Figure 3: Severity of PVL on neonatal ultrasound (a) and GM quality at fidgety age (b) and cerebral palsy. Both Chi square for trend: p =

64 Discussion This study indicated that the rates of abnormal GMs and CP of preterm infants with asphyxia were similar to those in preterms without asphyxia. The present study was carried out in a regional hospital. The strengths and weaknesses of the study are related to this specific setting. A weakness of the study was the limited access to neuro-imaging. Inherent to the setting we only had information on the ultrasound scans of the brain. All infants had serial ultrasound scans on indication of the paediatrician. Secondly, the number of infants recruited over a period of eight years that could be studied was small, indicating that preterm infants with asphyxia are not frequently referred to the ward of a neonatal unit in a regional hospital. It is conceivable that perinatal care of preterms with asphyxia changed during this period. The strengths of the study are: 1) evaluation of risk factors for deviant outcome in preterm infants with asphyxia at birth in a regional hospital, i.e. a non-academic setting, 2) the absence of attrition, 3) appropriately matched study and control groups and 4) the standardized application of a sensitive method to evaluate brain function in young infants. Our study indicated that perinatal asphyxia in preterm children was not an additional risk factor for poor neurological outcome during the first postnatal months or for CP. Basically two explanations may be offered for the absent relation. First, it is conceivable that preterm infants tolerate perinatal asphyxia better than full term infants. The higher tolerance may be based on a higher resistance to perinatal asphyxia 20 or on the high plasticity of the brain at preterm age. 21 Secondly, it may be that the effect of perinatal asphyxia is overruled by the effect of other perinatal or neonatal risk factors, such as prenatal or perinatal infection. 22 Neonatal factors which were associated with poor neurological outcome in our study were 1) the presence of respiratory problems, which was associated with outcome at preterm GM age and 2) the severity of PVL on the US scan, which was associated with outcome at fidgety GM age and CP. Janvier et al. 23 and Pillekamp et al. 24 also reported that respiratory problems, expressed in 63

65 terms of severity of apnea and bradycardia, were related to adverse neurodevelopmental outcome. Conceivably postnatal hypoxic ischemic events play a more prominent role in adverse neurological outcome in preterm infants than perinatal asphyxia. 13 Alternatively, respiratory problems may also be regarded as an early expression of brain dysfunction. 23 Both suggestions are supported by our finding that the severity of PVL was associated with the presence of respiratory problems and not with the presence of asphyxia. A remarkable finding was that the four children with a bilateral spastic CP showed DA GMs at fidgety age while the two children with unilateral spastic CP showed MA GMs at fidgety age. One of the latter two children had a right sided unilateral spastic CP due to an asymmetrical PVL grade IV. Retrospective review of her GMs at fidgety age revealed a slight asymmetry. She showed less subtle, segmental distal movements in her right than in her left limbs. Previously Guzzetta et al. 25 had reported that lack of subtle, segmental distal movements could be an early sign of unilateral spastic cerebral palsy. It could be surmised that the presence of a relatively intact hemisphere with the bilateral corticospinal projections characteristic of early age allows for the generation of some degree of movement complexity and variation The other child with unilateral spastic CP was only mildly affected. Her ultrasound scans had been normal. Prospectively we had noted a mild asymmetry in motility at fidgety age, but to the disadvantage of side which was best in later life. In conclusion, perinatal asphyxia in preterm infants is not associated with an increased risk for neurodevelopmental problems including CP. In contrast, respiratory problems during the neonatal period are associated to PVL and adverse neurological outcome. Acknownledgements We kindly acknowledge the cooperation of the Paediatric Department of the Gelre Hospital for participating in the intake of the children and we thank Dr. F. Eggelmeijer and B. Coenraads for their comments on a previous draft of the paper. 64

66 References 1. Cooke RW, Perinatal and postnatal factors in very preterm infants and subsequent cognitive and motor abilities. Arch Dis Child Fetal Neonatal Ed.2005;90:F Schmidhauser J, Rousson V, Bucher U, Largo RH, Latal B. Impaired motor performance and movement quality in very-low-birthweight children at 6 years of age. Dev Med Child Neurol 2006;48: Allen MC, Neurodevelopmental outcomes of preterm infants. Review. Curr Opin Neurol 2008;21: Aarnoudse-Moens CSH, Weisglas-Kuperus N, van Goudoever JB, Oosterlaan J. Meta-analysis of neurobehavioural outcome in very preterm and/or very low birth weight children. Pediatrics 2009;124: van Baar AL, Vermaas J, Knot E, de Kleine MJK, Soons P. Functioning at schoolage of moderately preterm children born at 32 to 36 weeks gestational age. Pediatrics 2009;124: Woodward LJ, Moor S, Hood KM, Champion PR, Foster-Cohen S, Inder TE, Austin NC. Very preterm children show impairments across multiple neurodevelopmental domains by age of 4 years. Arch Dis Child Fetal 2009;Neonatal Ed. 94: Logitharajah P, Rutherford MA, Cowan FM. Hypoxic-ischemic encephalopathy in preterm infants: antecedent factors, brain imaging and outcome. Pediatr Res.2009;66: Piekkala P, Kero P, Silianpää M, Erkkola R. The developmental profile and outcome of 325 unselected preterm infants up to two years of age. Neuropediatrics 1988;9: Goldenberg RL, Huddlestone JF, Nelson KG. Apgar scores and umbilical arterial ph in preterm newborn infants. Am.J.Obstet. Gynecol 1984;149:

67 10. Low JA, Galbraith LS, Muir DW, Killen HL, Pater EA, Karchmar EJ. Mortality and morbidity after intrapartum asphyxia in the preterm fetus. Obstet Gynecol. 1992;80: Westgren LMR, Malcus P, Svenningsen NW. Intrauterine asphyxia and long term outcome in preterm fetuses. Obstet Gynecol. 1986;67: Hadders-Algra M, Huisjes AJ, Touwen BCL. Preterm or small for gestational age infants: Neurological and behavioural development at the age of 6 years. Eur J Pediatr 1988;147: Holmqvist P, Plevén H, Svenningsen NW. Vaginally born low-risk preterm infants: fetal acidosis and outcome at 6 years of age. Acta Paediatr Scand 1988;77: Hadders-Algra M. General Movements: a window for early identification of children at high risk for developmental disorders. J Pediatr 2004;145: Ferrari F, Cioni G. Prechtl HFR. Qualitative changes of general movements in preterm infants with brain lesions. Early Hum Dev 1990; 23: Groen SE, de Blécourt AC, 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: Stahlmann N, Härtel C, Knopp A, Gehring B, Kiecksee H, Thyen U. Predictive value of neurodevelopmental assessment versus evaluation of general movements for motor outcome in preterm infants with birthweights < 1500 g. Neuropediatrics 2007;30: Touwen B. Neurological Development in infancy. Clinics in developmental medicine No 58 London: S.I.M.P. with Heinemann. 19. Surveillance of Cerebral Palsy in Europe Low J, Metabolic acidosis and fetal reserve. Baillieres Clin Obstet Gynaecol 1996;10:

68 21. de Graaf-Peters V, Hadders-Algra M. Ontogeny of the human central nervous system: What is happening when? Early Hum Dev 2006;82: Dammann O, Leviton A. Brain damage in preterm newborns:might enhancement of developmentally regulated endogenous protection open a door for prevention? Pediatrics 1999;104: Janvier A, Khairy M, Kokkotis A, Cormier C, Messmer D, Barrington KJ. Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol 2004;24: Pillekamp F, Hermann C, Keller T, von Gontard A, Kribs A, Roth B. Factors influencing apnea and bradycardia of prematurity implications for neurodevelopment. Neonatology : Guzetta A, Mercuri E, Rapisardi G,Ferrari F, Roversi MF, Cowan F, Rutherford M, Paolicelli PB, Einspieler C, Boldrini A, Dubowitz L, Prechtl HFR, Cioni G. General Movements detect early signs of hemiplegia in term infants with neonatal cerebral infarction. Neuropediatrics 2003; 34: Staudt M. (Re-)organization of the developing human brain following periventricular white matter lesions. Neurosci Biobehav Rev 2007; 31: Eyre J A. Cortical spinal tract development and its plasticity after perinatal injury. Neurosci Biobehav Rev 2007;31:

69 68

70 Chapter 4 Limitations in the activity of mobility at age 6 years after difficult birth at term 69

71 Limitations in the activity of mobility at age 6 years after difficult birth at term. A prospective cohort study Patricia A. M. van Iersel 1, Annechien M. Algra 2, Saskia Bakker 3, Arnold Jonker 1, Mijna Hadders-Algra 2 1 Department of Physical Therapy, Gelre Hospital, Apeldoorn, the Netherlands. 2 Department of Pediatrics Developmental Neurology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 3 Department of Pediatrics, Gelre Hospital, Apeldoorn, the Netherlands. Physical Therapy 2015; epub ahead of print 70

72 Abstract Background: A difficult birth at term (DBAT) may manifest as fetal acidosis and low Apgar scores and is often referred to as perinatal asphyxia, especially when infants show signs of neonatal encephalopathy (NE). In contrast to DBAT resulting in moderate to severe NE, which is associated with neurodevelopmental disorders, little is known about prognosis of less severe forms of DBAT, with or without NE. Objective: The objective of this study was to evaluate the ICF-CY activity mobility and other neurodevelopmental sequelae in infants with DBAT at 6 years. Methods: The index cohort (n=62; 35 boys) consisted of consecutive term infants with DBAT based on clinical criteria in a Dutch non-academic hospital, We assessed NE according to the Sarnat grading system and excluded infants with severe NE. The matched reference cohort (n=81; 49 boys) consisted of healthy term infants. Primary outcome at 6 years was limited mobility (Movement ABC 15 th percentile). Secondary outcomes included learning and behavioral problems and the presence of minor neurological dysfunction (MND). Results: Three children developed cerebral palsy and were excluded from analyses. Children with DBAT more often had limited mobility than children without DBAT (RR 2.44, 95%CI ).The risk of limited mobility rose with increasing severity of NE (mild NE RR 3.38, 95%CI ; moderate NE RR 4.00, 95%CI ), and especially manual abilities were affected (RR 4.12, 95%CI ). Learning problems, need for physical therapy and complex MND were more common in children with DBAT than in children without DBAT. Conclusions: Term infants who develop mild or moderate NE following DBAT are at increased risk for limited mobility at 6 years; routine monitoring of neuromotor development in these children is warranted. 71

73 Introduction In industrialized countries one in thousand infants has a difficult birth at term, 1 which may manifest as an abnormal fetal cardiotocogram, fetal acidosis and low Apgar scores. 2-3 In clinical practice, such difficulties are often labeled as perinatal asphyxia. The criteria for perinatal asphyxia in clinical practice vary, i.e., the cut-off of a low Apgar score may be 7 or 6, and that of fetal acidosis may be 7.2, 7.1 or 7.0. Gradually, it became clear that perinatal asphyxia especially has clinical significance when it results in neonatal neurological dysfunction. The Sarnat grading system was introduced to classify the various degrees of neonatal neurological dysfunction following perinatal asphyxia in terms of mild, moderate and severe neonatal encephalopathy (NE; for details on the classification see Table 1). 4 Table 1. Grading of neonatal encephalopathy (NE) according to Sarnat and Sarnat 4 Grade Stage 1: mild NE Stage 2: moderate NE Stage 3: severe NE Signs 1. Hyper alert 2. Overactive stretch reflexes, mild distal flexion, normal muscle tone 3. Strong Moro reaction with low threshold, weak sucking response 4. Sympathetic neural control dominates autonomic function 5. No seizures 6. Signs usually last less than 24 hours 1. Lethargic 2. Overactive stretch reflexes, strong distal flexion, mild hypotonia 3. Weak Moro reaction with a high threshold, weak or absent sucking response,strong tonic neck reflexes 4. Parasympathetic neural control dominates autonomic function 5. Seizures common 6. Signs usually last 2 to14 days 1. Stuporous 2. Decreased or absent stretch reflexes, intermittent decerebration posture, severe hypotonia 3. Absent Moro reaction, absent sucking response, absent tonic neck reflexes 4. Sympathetic and parasympathetic systems depressed 5. Seizures uncommon (EEG: early phase periodic pattern followed by isopotentially EEG) 6. Signs last hours to weeks 72

74 Most evidence on developmental outcome following perinatal asphyxia is based on follow-up of infants who suffered moderate to severe perinatal asphyxia. Since these infants have a high risk for death or disability, they are often admitted or transferred to academic centers, where intensive treatment, including hypothermia, 5 and brain monitoring with magnetic resonance imaging (MRI) belong to the possibilities. 6-9 In contrast, longterm neurodevelopmental functioning of children with a difficult birth at term resulting in milder forms of perinatal asphyxia, with or without NE, has received relatively little attention. Most reviews that included children with mild forms of perinatal asphyxia suggested that impairment is uncommon in these children. 6-9 Nevertheless, more recent studies suggest that these children may be at increased risk for problems in learning, behavioral and memory domains So far, knowledge on long-term motor outcome, in particular in terms of limitations in activities covered by the chapter mobility of the International Classification of Functioning, Disability and Health, Children & Youth version (ICF-CY; WHO 2007), 13 in infants with milder forms of perinatal asphyxia, is lacking. The activity of mobility in the ICF-CY includes the skill to move around from one place to another and arm and hand use, such as the manipulation of objects and catching and throwing a ball. 13 We therefore studied long-term limitations in mobility and other neurodevelopmental outcomes in term infants born in a non-academic setting who had a difficult birth. The presence of a difficult birth at term (DBAT) was based on the presence of at least two of the commonly applied clinical markers of DBAT, i.e., an abnormal fetal cardiotocogram (CTG), a low Apgar score at five minutes and fetal acidosis, expressed as a low value of the ph and a high value of the base excess of the umbilical blood. After birth, the degree of NE was assessed. Outcome at the age of 6 years of the infants with DBAT was compared to that of infants without DBAT, using standardized tools to measure long-term limitations in mobility and other neurodevelopmental outcomes. 73

75 The primary aim of this study was to evaluate whether DBAT is associated with limited mobility at 6 years. Secondary aims were to evaluate associations between DBAT and academic achievement, behavior and neurological condition at the age of 6 years. We added the secondary aims as information on academic achievement and behavior is relevant because limited academic achievement and behavioral problems often are co-morbid conditions of limited mobility The information on neurological condition would allow us to gain insight in the neural mechanisms underlying a potentially limited mobility. Special attention was paid to the predictive value of the presence and severity of NE for limited mobility, in the absence of CP. Participants and Methods In order to understand the nature of our study group, we first summarize the Dutch healthcare system for obstetrical guidance, as it is different from that in most other industrialized countries Women with an uncomplicated pregnancy either deliver at home or in the out-patient clinic of a regional hospital under the guidance of a midwife. In case of imminent complications, women are admitted to clinical obstetrical care under surveillance of a gynecologist. If DBAT occurs and results in a severe form of asphyxia, the infant is referred to an academic center with MRI-scanning and hypothermia treatment facilities; if DBAT results in less severe asphyxia the infant is admitted to the pediatric department of the regional hospital. In an index cohort, we recruited all consecutive DBAT infants who were admitted to the neonatal unit of the Gelre Regional Hospital Apeldoorn, Netherlands between January 1, 1999 and July 1, Infants were eligible for the index cohort if they were born at term (i.e., birth after 36 completed weeks of gestation), in hospital (referrals from midwife practices or outpatient hospital delivery), and if they fulfilled at least two of the following clinical criteria for DBAT: 1) abnormal CTG, i.e., late decelerations, persistent bradycardia or persistent tachycardia; 2) Apgar score at five 74

76 minutes <7; 3) umbilical ph <7.20; and 4) umbilical base excess <-10 mmol/l. 3,6,21 Infants with severe NE and with major congenital malformations were not eligible. Eighty infants presented with DBAT to the neonatal unit. The pediatrician (SB) determined within the first 24 hours after delivery on the basis of neurological parameters the degree of NE according to the grading of Sarnat (Table 1). 4 Seventeen infants were not included because parents declined participation, resulting in an index cohort of 63 infants (Figure 1). Infants who did (n=63) and did not (n=17) participate were similar in terms of inclusion criteria and severity of NE. Figure 1: Flow diagram: intake of study group with DBAT and reference group. In a reference cohort, we recruited healthy term infants at the Gelre Hospital and nearby midwife practices during the same period ( ). Again, infants with major congenital anomalies were not eligible. We matched infants in the reference cohort with the index cohort for sex, gestational age, birth weight and caesarean section. We recruited the healthy term infants a) at home or in an out-patient clinic under the 75

77 guidance of a midwife (n=63), or b) from infants born in the hospital after caesarian section (n=21). In the latter infants caesarian section was applied either because the mother previously had had a caesarian section, or because delivery was not progressing. If the latter was the case, it still had resulted in the birth of a healthy neonate without signs of DBAT. In total, the reference cohort consisted of 84 term infants (Figure 1). The parents of the participants gave signed informed consent and the procedures were approved by the Medical Ethical Committee of University Medical Centre Utrecht (project number ). Clinical assessments (i.e., Apgar scores, CTG, umbilical ph and base excess) were performed in all infants presenting with DBAT as part of standard clinical care. Children from both cohorts were invited for follow-up at 6 years. In the index cohort one child with moderate NE had died, and in the reference cohort three children belonged to families who declined participation, either because of assessment burden (n=2) or logistical reasons (n=1; Figure 1). The assessment at 6 years consisted of a motor and neurological assessment, and behavioral and academic evaluation by means of parental and teachers questionnaires. In addition, parents completed a questionnaire on the child s medical history, including information on the use of paramedical care (speech therapy, physical therapy, or occupational therapy). We assessed mobility with the Movement Assessment Battery for Children (MABC, version I). 22 The MABC has been developed to identify and evaluate children with mild to moderate limitations in activities, covered by the chapter mobility of the ICF-CY. 13,22-23 The test consists of four age bands each with eight functional motor tasks representing a) manual dexterity (in terms of ICF-CY codes: fine hand use, d440); b) ball skills (hand and arm use, d445); and c) static and dynamic balance skills (changing basic body position and moving around, d410 and d455). 13,22 76

78 Table 2. Characteristics of the study population at baseline and at 6 years Children with DBAT Children without DBAT P-value* Perinatal n=59 characteristics, n (%) n=81 General Male gender 33 (56%) 49 (61%) # Birth weight (grams) 3382 ± ± # GA at birth (weeks) 40 (36-43) 40 (37-43) # Maternal age 31 (±4.2) 32 (±4.2) Caesarian section 19 (32%) 21 (26%) # Smoking 9 (22%) 13 (11%) Clinical DBAT parameters Decelerating CTG 38 (64%).. Cord ph 7 05 ± Cord BE ± AS after 1 minute 3 (0-7) 9 (6-10) <0.001 AS after 5 minutes 6 (2-9) 10 (8-10) <0.001 Sarnat classification No NE 34 (58%).. Mild NE (Sarnat grade 1) 16 (27%).. Moderate NE (Sarnat grade 2) 9 (15%).. Characteristics at 6 years** Age at follow-up in (75-83) 76 (74-81) months Family adversities 18 (31%) 18 (22%) Maternal education (27%) 35 (43%) (high) Standing height (cm) 123 ( ) 121 ( ) Body weight (kg) 24 (17-36) 23 (17-38) Head circumference (49-56) 53 (50-58) (cm) Data presented as mean ± SD; Data presented as medium (range)...=not available. AS=Apgar Score; BE=base excess; CTG=cardiotocogram; GA=gestational age. NE=neonatal encephalopathy. Smoking=maternal smoking during pregnancy. Family adversities=presence of one of the following: situation after parental divorce, foster care, adoption, unemployment of breadwinner, serious illness or death of close relatives (first/second grade) in the family. Maternal education=high if university education or vocational college. * Tests used: Pearson s correlation and Chi 2 ** Information obtained from interviews and measurements at 6-year follow-up. # Information on confounding variabels 77

79 Quantitative performance of each test-item is scored from 0 (best) to 5 (worst). Item scores are added up producing three subscores, i.e., 1) manual abilities; 2) ball skills; 3) static and dynamic balance, and a total score. Performance on the total MABC is typical if >15th percentile (P15), borderline if P5 score P15, or definitely impaired if <P5. 24 In the present study we chose to dichotomize outcome on the total MABC into typical (>P15) and limited ( P15). Performance in the three domains (manual abilities, ball skills and balance) was considered as typical if 5 th percentile (P5) and limited if <P5. The chosen cut-offs for the total score and the domain scores are recommended by the European Academy of Childhood Disability and the Dutch National DCD Committee to use in the diagnostics of Developmental Coordination Disorder. 16 The MABC-I has a good test-retest and inter-rater reliability, a moderate concurrent validity lacking a suitable gold standard, and a good construct validity The validity of the subscale scores is satisfactory. 24,27 In order to evaluate behavior, we asked the parents and teachers of all children to fill out the Achenbach s ASEBA questionnaires, which includes the Child Behavioral Checklist (CBCL; parents) and Teachers Report Form (TRF; teachers) For both questionnaires, we dichotomized the resulting scale and total scores on the basis of the T-scores into typical (score <95 th percentile (P95)) and behavioral problems (score P95; including both borderline and clinical scores). The reliability of the CBCL and TRF is good. 30 The concurrent validity of the CBCL and TRF based on correlations with outcome of related checklists and questionnaires is also good The TRF also comprises open questions about academic achievement, school grades, extra educational assistance, repetition of class, and attendance of a special school. Attendance of a special school in the Netherlands is based on the presence of physical, cognitive and behavioral impairment, often a combination of these impairments. On the basis of this information we defined the presence of learning problems as the presence of special 78

80 assistance or special education, or being in an inappropriate grade for age To assess neurological condition we used the standardized, age specific and criterion referenced examination of the child with minor neurological dysfunction (MND). 34 This examination assesses the presence of MND in eight domains, i.e.: 1) dysfunctional posture and muscle tone regulation; 2) dysfunctional reflex activity; 3) mild dyskinesia, e.g., choreiform or athetotiform movements; 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. Important is that a single sign has no clinical significance. Signs obtain significance if they cluster in a domain; for each domain the criteria for dysfunction have been determined. 34 At school age, the assessment results in the following classification: a) neurologically normal, implying the absence of dysfunctional domains or isolated dysfunction in the domain reflexes ; b) simple MND, denoting the presence of dysfunction in one or two domains; c) complex MND, denoting the presence of dysfunction in at least three domains; and d) neurologically abnormal, implying the presence of a clear neurological disorder, such as CP. 34 The diagnosis CP implied the presence of a classical configuration of neurological signs as specified by the Surveillance of Cerebral Palsy in Europe network. 35 Simple MND is considered to reflect typical, but non-optimal brain function; complex MND is regarded as the clinically relevant form of MND, as it is clearly associated with motor, learning and behavioral problems. 34,36 All children were independently assessed by two authors. The first author (PI), who was aware of the clinical condition of the children, performed the initial neurological examination. The last author (MH-A), who is a neurodevelopmental expert and was masked to all details of the child assessed neurological condition on the basis of a video recording of the assessment of the first author. In case of disagreement between the authors the findings of the expert were used. The MND-assessment has a good intra-rater, inter-rater and test-retest reliability (κ = ). 34,36-38 The 79

81 construct validity, based on the relationship of MND with pre- and perinatal adversities, is good. 34,39-40 The predictive validity is also good: severity of MND at 9 years is related to the risk of MND at 12 and 14 years and that of learning and behavioral problems at 9 and 14 years of age. 34,40-41 The primary outcome measure was limited mobility (Movement ABC 15 th percentile) at 6 years. Secondary outcome measures included presence of minor neurological dysfunction (MND), whether or not the child had received physical therapy, and learning and behavioral problems assessed with the CBCL and TRF at 6 years of age. Data analysis Power calculations based on the Dutch norms of the MABC (mean 4.4, standard deviation 4.3) 22 demonstrated that for detection of a difference of at least 2.5 points in total MABC score with 95% power (α=0.05) at least 65 children had to be included per group. The frequencies of primary and secondary outcomes were compared among index and reference cohort with risk ratio s (RR s) and 95% confidence intervals (95%CI). To this end we used Poisson regression. In a first model (model A), we adjusted for those factors for which we initially matched the index and reference children (i.e., sex, gestational age, birth weight and caesarean section). In a second model (model B), we adjusted for matching factors and those factors that changed the crude risk ratios by more than 5%. Finally, we did subgroup analyses according to severity of NE for motor, neurological and behavioral outcomes. Outcomes are expressed in RRs with their 95% confidence intervals (95% CIs). P-values of less than 0.05 were considered statistically significant. Results In the index cohort, three children, who had experienced DBAT with moderate NE, had CP. We excluded them from the analyses because they 80

82 were unable to perform the MABC. In total, 59 children in the index cohort and 81 children in the reference cohort were included in the analyses (Figure 1). Cohorts were similar in terms of matching factors and social and anthropometric characteristics at 6 years (Tab. 2). Of the 59 children with DBAT, 9 had moderate NE, 16 had mild NE and 34 showed no signs of NE (Tab. 2). Results are presented as crude RR s and 95%CI s, since adjustment for matching factors or other potential confounders did not influence the RR s (Supplementary material S1). Children with DBAT more often had limited mobility (total MABC P15) than children without DBAT (RR 2.44, 95%CI , p=0.019; Tab. 3), which was mainly explained by limited manual abilities (RR 4.12, 95%CI , p=0.010), and to a lesser extent by limited balance skills (RR 1.77, 95%CI , p=0.069; Tab. 3). Table 4 shows the RR s for limited mobility (MABC P15) and limited manual abilities, ball skills and balance skills by severity of NE. For limited mobility and limited manual abilities risk rose with severity of NE (Figure 2); this trend was not present for limited balance and ball skills. Children with DBAT, but without NE were not at increased risk for limited mobility (Tab. 4). Table 3: Crude risk ratios for limited mobility at 6 years in children with or without DBAT by mobility domains. DBAT n=59 No DBAT n=81 Crude RR(95%CI) P-value Limited mobility Total MABC P15 16(27) 9(11) 2.44 ( ) Manual abilities < P5 12(20) 4(5) 4.12 ( ) Ball skills < P5 11(19) 19(24) 0.79 ( ) Balance skills < P5 18(31) 14(17) 1.77 ( )

83 Table 4: Crude risk ratios for limitations in total MABC, manual abilities, ball skills and balance skills at 6 years in children with and without DBAT by Sarnat stage. Total MABC P15 Children without DBAT Children with DBAT No signs of NE Mild NE ( Sarnat stage 1) Moderate NE (Sarnat stage 2) Total Children affected n (%) 9 (11) 6 (18) 6 (38) 4 (44) Crude RR (95%CI) Reference 1.59 ( ) 3.38 ( ) 4.00 ( ) P-value Manual abilities < P5 Children without DBAT 81 4 (5) Reference.. Children with DBAT No signs of NE 34 5 (15) 2.98 ( ) Mild NE (Sarnat stage 1) 16 3 (19) 3.80 ( ) Moderate NE (Sarnat stage 2) 9 4 (44) 9.00 ( ) < Ball skills < P5 Children without DBAT (24) Reference.. Children with DBAT No signs of NE 34 5 (15) 0.63 ( ) Mild NE +(Sarnat stage 1) 16 3 (19) 0.80 ( ) Moderate NE (Sarnat stage 2) 9 3 (33) 1.42 ( ) Balance skills < P5 Children without DBAT (17) Reference.. Children with DBAT No signs of NE 34 9 (27) 1.53 ( ) Mild NE (Sarnat stage 1) 16 5 (31) 1.81 ( ) Moderate NE (Sarnat stage 2) 9 4 (44) 2.57 ( ) Data are number (%) or crude risk ratio s (95% CI);..=not available. NE=neonatal encephalopathy. Children with DBAT had more often complex MND (RR 1.94, 95%CI , p=0.048) and learning problems (RR 2.75, 95%CI , p=0.001), and received more frequently physical therapy (RR 2.86, 95%CI , p=0.001) than children without DBAT, but rates of simple MND and behavioral problems were similar in children with and without DBAT (Tab. 5). The risk for complex MND rose with the severity of NE; the association with; learning problems and physical therapy guidance was independent of the degree of NE (Supplementary Material S2). 82

84 Table 5: Crude risk ratios for secondary outcomes at 6 years in children with or without DBAT. Secondary outcomes, n (%) DBAT No n=59 DBAT n=81 Therapeutic guidance Physical therapy Occupational therapy 25 (42) 12(15) 1 (2) 1 (1) Crude RR (95%CI) 2.86 ( ) 1.37 ( ) P-value Learning problems Any learning problem 24 (41) 12(15) 2.75 ( ) Behavioral problems Total CBCL P95 Total TRF P95 Neurological condition Simple MND Complex MND 8 (14) 8(10) 10 (17) 10(12) 20 (34) 26(32) 17 (29) 12(15) 1.37 ( ) 1.40 ( ) 1.06 ( ) 1.94 ( ) Data are number (%) or risk ratio (95% CI);..=not available. MND=minor neurological dysfunction. CBCL=Child Behavior Checklist; TRF=Teachers Report Form. Total CBCL/total TRF=scores 95 th percentile include borderline and clinical abnormal scores. Any learning problem=children with learning problems are defined as those who need special assistance or special education, or who are in an inappropriate grade for age. Discussion Our study shows that children with DBAT diagnosed in a non-academic setting more often have limitations in the activity of mobility at 6 years than children without DBAT. The association is dependent on severity of NE following DBAT, and is mainly explained by limited manual skills. The association between severity of NE and limited mobility was supported by a similar association between severity of NE and complex MND. Finally, we found that, independent of severity of NE, children with DBAT are at risk for learning problems and more often receive physical therapy. Our finding of an increased risk for adverse neurodevelopmental outcome in children with moderate NE following DBAT is consistent with previous reviews addressing long-term neurodevelopmental outcomes in children with mild to moderate NE. 3,6-7,10-12,21 83

85 Figure 2: Rate of children with limited mobility ( MABC P15 ) at 6 years in children with and without DBAT by severity of NE. In the current study we demonstrate that the increased risk for adverse neurodevelopmental outcome is not restricted to children with moderate NE: also children with mild NE after DBAT are at increased risk for adverse neurodevelopmental outcomes, i.e., for limited mobility, learning problems and complex MND. This finding is at variance with most previous reviews, 3,6-7,21 but in line with more recent work which looked at different neurodevelopmental domains separately Moreover, in one of these studies, which focused on the pathology of the corpus callosum, it was shown that children with mild and moderate NE scored significantly worse on the MABC than controls. 7 Our study focused on the outcome limited mobility and was thereby able to show that the increased risk for limited mobility after DBAT was dependent on the presence and severity of NE and that children with DBAT, but without NE are not at risk for limited mobility. 84

86 There are several possible explanations why we found an effect of mild NE on developmental outcome whereas most other studies did not. First, due to the origin of our population - children with DBAT recruited in a regional hospital - the rate of children with mild NE in our study was higher than in previous studies. Second, the present study focused on limited mobility assessed with a standardized tool, whereas other studies addressed other developmental domains. Finally, we assessed children at 6 years. In previous reviews, the length of follow-up differed substantially between studies, but it was generally shorter than in our study. 3,6,21 Since it takes time for specific motor and cognitive functions to develop, some deficits may not have had sufficient developmental time to manifest themselves ( growing into deficit phenomenon). 42 The finding that an increased risk for limited mobility in children with DBAT depends on the presence and severity of NE was supported by the data on neurological impairment. Also the complex form of MND was dependent on the presence and severity of NE. Previously, it has been shown that the presence of complex MND is associated with a substantially increased risk for DCD. 43 Children with DBAT without NE were not at increased risk for limited mobility and neurological impairment. Interestingly, all children with DBAT, irrespective the presence and severity of NE, were at risk for learning problems (defined as the presence of special assistance or special education, or being in an inappropriate grade for age) and the use of physical therapy. This suggests that the pathways underlying learning problems and the use of physical therapy differ from those of limited mobility and neurological impairment measured with standardized tests. Presumably, the limited mobility can be largely attributed to impaired neurological integrity due to perinatal adversities. For the learning problems and the use of physical therapy two explanations may be offered. First, the use of educational and physical therapy guidance may indicate that the child s DBAT history generated parental concern over the child s development which in turn resulted in a higher request for developmental guidance. 44 Second, DBAT may reflect a generally reduced capacity to cope 85

87 with heterogeneous conditions, i.e., at birth, during motor development and at school. The strengths of our study are the focus on the effect of DBAT accompanied by milder forms of NE on limited mobility, the use of standardized tools for outcomes and the minimal attrition during follow-up. This means that our results may be generalized to similar settings. Also by applying standardized tools such as the MABC, we were able to measure more subtle components of mobility than most former studies did. Our study has limitations. First, we suspect that, despite matching and multivariable analyses for known potential confounders, selection in the reference cohort might have influenced outcome. Indeed, in our study the rate of simple MND in the reference cohort was higher than expected, 34 which may have underestimated the true effect of DBAT on neurodevelopmental outcomes. Second, we assessed learning problems - a secondary outcome - with the TRF This tool provides a global estimation of learning problems, but does not allow for a specification of underlying cognitive deficits and third, subgroup analyses should be interpreted with caution. Nevertheless, the finding that the risk of limited mobility rose with increasing severity of NE strengthens our results. The non-academic setting of our study can be regarded as a limitation as well as strength of the cohort. Studying DBAT in a regional hospital meant that neonatal MRI findings were conspicuous by their absence. Nowadays, MRI has proven to be of additional value with regard to diagnosis and prognosis of DBAT resulting in moderate to severe NE. 5 The size and the site of moderately to severe brain lesions predict developmental outcome well. 7,45-48 However, the relationship between mild or non-localized brain lesions and limited mobility is less well understood. 15 Apart from concerns regarding the usefulness of MRI in infants with milder variants of NE, MRI is not ubiquitous available for high risk infants in non-academic settings, including those in lower and middle income countries. In these settings simple clinical parameters of DBAT and NE may help local staff to identify children with DBAT in need of continued monitoring

88 Another difficulty of our study was the inclusion of both in- and outhospital born infants. Although imbalances between index and reference cohort could have potentially influenced our results, this mix was inherent to our aim to include milder forms of DBAT and the way Dutch healthcare is organized Finally, it may be considered a limitation that our study evaluated perinatal care provided in Perinatal care has changed since that time, including the introduction of hypothermia treatment. This treatment is applied in academic hospitals, especially in infants with severe NE, but increasingly often also in infants with moderate NE It is conceivable that hypothermia treatment has an effect on long-term neurodevelopmental outcome. This needs to be addressed in future studies. Our findings have implications for clinical practice and future research. First, children with DBAT not resulting in NE are not at risk for limited mobility. Parents of these children may be reassured. Second, children with DBAT resulting in mild and moderate NE are at risk for limited mobility. We therefore recommend routine monitoring of neuromotor development of all children with DBAT resulting in NE, who did or did not receive hypothermia treatment. Early detection of impairments and limitations offers a means for the provision of early intervention, which may assist the prevention of limitations in mobility in later life The frequency of monitoring during infancy may be guided by the clinical signs of the infant; after infancy a biannual assessment is recommended. Conclusion This study shows that children with mild or moderate NE following DBAT are at risk for limited mobility, in particular for limited manual abilities. The risk of limited mobility is dependent on the presence and severity of NE, whereby children with DBAT without NE are not at risk for limited mobility. Further studies in children with DBAT are warranted to confirm our findings. In the meantime, clinicians are encouraged to monitor development of all children with NE following DBAT, ensuring that children with limited mobility are detected in an early stage. 87

89 Acknowledgments We thank Ale Algra (UMC Utrecht) for his critical comments, Anneke Kracht (UMC Groningen) for technical assistance and Elisa Hamer and Nienke Devlin for critical remarks on a previous draft of the manuscript. References 1. Mc Guire W. Perinatal asphyxia. BMJ Clinical Evidence 2007;11: Hafström M, Ehnberg S, Blad S, Norén H, Renman C,Rosen KG, Kjellmer I. Developmental outcome at 6.5 years after acidosis in term newborns: A population-based study. 2012;129: Pin TW, Eldridge B, Galea MP. A review of developmental outcomes of term infants with post-asphyxia neonatal encephalopathy. Eur J Paediatr Neurol 2009;13: Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. Arch Neurol 1976;33: Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013;1:CD Dilenge ME, Majnemer A, Shevell MI. Long-term developmental outcome of asphyxiated term neonates. J Child Neurol 2001;16: van Kooij BJM, van Handel M, Uiterwaal CSPM, Groenendaal F, Nievelstein RA, Rademaker KJ, Jongmans MJ, De Vries LS. Corpus Callosum size in relation to motor performance in 9-10 year old children with neonatal encephalopathy. Pediatr Res 2008;63: de Vries LS, Jongmans MJ. Long term outcome after neonatal hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2010;95: F

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95 Supplementary Material S1: Adjusted risk ratios for MABC P15 at 6 years in children with or without DBAT. MABC P15 n/n (%) 25/140 (18) Unadjusted 2.44 ( ) Sex Birth weight GA at birth Caesarian Section (CS) Maternal age 2.42 ( ) 2.54 ( ) 2.44 ( ) 2.37 ( ) 2.56 ( )* Maternal education 2.50 ( ) Family adversities 2.48 ( ) Smoking 2.49 ( ) 4 factors (model A) 5 factors (model B) 2.45 ( ) 2.62 ( ) Data are number (%) or risk ratio (95% CI). GA=gestational age. Maternal education=high if university education or vocational college. Family adversities=presence of one of the following: situation after parental divorce, foster care, adoption, unemployment of breadwinner, serious illness or death of close relative (first- or seconddegree family member). Smoking=scored as none, 5 cigarettes/day or >5 cigarettes/day (during pregnancy). in this model matching factors (sex, gestational age, birth weight and caesarean section) were included. In this model matching factors and factors that changed the crude risk ratio by more than 5% were included (italic*). S2-S5: Crude risk ratios for different developmental outcomes at 6 years in children with and without DBAT and severity of NE. Limited mobility (S2) Total MABC 15 Crude RR P-value (%) (95%CI) Children without DBAT 81 9 (11) Reference.. Children with DBAT No signs of NE Mild NE (Sarnat stage 1) Moderate NE (Sarnat stage 2) (18) 6(38) 4(44) 1.59 ( ) 3.38 ( ) 4.00 ( ) Data are number (%) or risk ratio (95% CI);..=not available. NE=neonatal encephalopathy. 94

96 Physical therapy and learning problems (S3) Total Physical therapy (%) Crude RR (95%CI) P- value Learning problems (%) Crude RR (95%CI) Children without DBAT (15) Reference.. 12 (15) Reference.. Children with DBAT No signs of NE (41) 2.78 ( ) (38) 2.58 ( ) Mild NE (Sarnat stage 1) 16 3 (31) 2.11 ( ) (38) 2.53 ( ) Moderate NE 9 3 (67) 4.50 ( ) (56) 3.75 ( ) (Sarnat stage 2) Data are number (%) or risk ratio (95% CI);..=not available. NE=neonatal encephalopathy. P- value Behavioral problems (S4) Total Behavioral problems Total CBCL (%) Crude RR (95%CI) P- value Behavioural problems Total TRF (%) Crude RR (95%CI) Children without DBAT 81 8 (10) Reference.. 10 (12) Reference.. Children with DBAT No signs of NE 34 4 (12) 1.19 ( ) (9) 0.74 ( ) Mild NE (Sarnat stage 1) 16 2 (13) 1.27 ( ) (3) 2.03 ( ) Moderate NE 9 2 (22) 2.25 ( ) (33) 2.70 ( ) (Sarnat stage 2) Data are number (%) or risk ratio (95% CI);..=not available. NE=neonatal encephalopathy. CBCL=Child Behavior Checklist. TRF=Teachers Report Form. P- value 95

97 Neurological condition (S5) Total Simple MND (%) Crude RR (95%CI) P- value Complex MND (%) Crude RR (95% CI) Children without DBAT (32) Reference.. 12 (15) Reference.. Children with DBAT No signs of NE (41) 1.28 ( ) (18) 1.29 ( ) Mild NE (Sarnat stage 1) 16 3 (19) 0.58 ( ) (38) 2.53 ( ) Moderate NE (Sarnat 9 3 (33) 1.04 ( ) (56) 3.75 ( ) stage 2) Data are number (%) or risk ratio (95% CI);..=not available. NE=neonatal encephalopathy. MND=minor neurological dysfunction. P- value 96

98 Chapter 5 Does quality of general movements in full-term infants predict cerebral palsy and milder forms of limited mobility at six years? 97

99 Does quality of general movements in full-term infants predict cerebral palsy and milder forms of limited mobility at six years? An observational study Patricia AM van Iersel, PT 1, Saskia CM Bakker, MD 2, Arnold JH Jonker, PT 1, Mijna Hadders-Algra, MD, PhD 3 1 Gelre Hospital, Department of Physical Therapy, Apeldoorn, the Netherlands 2 Gelre Hospital, Department of Paediatrics, Apeldoorn, the Netherlands 3 University Medical Center Groningen (UMCG) and University of Groningen, Department of Paediatrics Developmental Neurology Groningen, the Netherlands. Submitted for publication 98

100 Abstract. Aim: To evaluate in full-term infants associations between quality of General Movements (GMs) and developmental outcome at 6 years in terms of cerebral palsy (CP) and limited mobility in children without CP. Methods: Participants of this prospective study were 145 full-term infants (86 boys). Their GM-quality was assessed at writhing and fidgety GM-age (3 and 13 weeks post-term). The assessment at 6 years consisted of a neurological examination, including assessment of minor neurological dysfunction (MND), evaluation of mobility with the Movement ABC (MABC), and of behaviour and learning problems with questionnaires. Results: Definitely abnormal (DA) GMs at writhing age were not associated with CP, DA GMs at fidgety age were: sensitivity 60%; specificity 91%; positive predictive value 19%, negative predictive value 98%. In children without CP GM-quality was not associated with limited mobility, but it was associated to a minor extent to mild dysfunctions in muscle tone. Interpretation: In full-term infants DA GMs at fidgety age do predict CP, but with lower accuracy than in preterm infants. GM-quality does not predict limited mobility in children without CP. The study supports suggestions that predictive value of GM-assessment in full-term infants is lower than that in preterm infants. 99

101 Introduction Evidence suggests that infants at risk for neurodevelopmental disorders may benefit from early intervention. 1 Therefore it is important to detect these infants as early as possible. The assessment of the quality of General Movements (GMs) is one of the tools which assists the detection of infants at risk. 2-3 GMs are spontaneous movement patterns present up until 3 to 4 months post-term, which involve the whole body. The quality of GMs - in particular the degree of variation and complexity - is used to evaluate the integrity of the central nervous system. Two reviews concluded that the sensitivity and specificity of GM-assessment to predict cerebral palsy (CP) in high risk populations is high. 2-3 This holds true in particular for GMassessment around 3 months corrected age (CA). However, the reviews also noted that the large majority of subjects included in these studies were preterm infants. Only a few studies comprised predominantly full-term infants. The studies of Prechtl et al. 4 and Ferrari et al. 5 demonstrated that the predictive value of GMs in asphyxiated full-term infants was excellent and similar to that of EEG and neuroimaging. However both study groups consisted of infants with moderately to severe forms of asphyxia who were at very high risk for major neurodevelopmental disorder, and therefore not representative for all full-term infants. A more recent study 6 showed that prediction of CP in the general population was substantially worse than that in high risk populations as it predicted serious neurodevelopmental disorders including CP to a limited extent. Relatively little is known on the association between GM-quality during early infancy and other developmental problems such as milder forms of limited mobility. Limited mobility, that may result in Developmental Co-ordination Disorder (DCD), and specific learning problems often first emerge at school age. The activity of mobility in the International Classification of Functioning, Disability and Health, Children & Youth version (ICF-CY) 7 covers the skill to move around from one place to another and arm and hand use, such as manipulation of objects and catching and 100

102 throwing a ball. Four studies that addressed relationships between GMquality and minor developmental disorders used relatively small and heterogeneous groups of at risk infants. The studies suggested that an abnormal quality of GMs around 3 months CA is associated with minor neurological dysfunction (MND), ADHD and aggressive behaviour at school age, but not with measures of intelligence Another small study of preterm infants indicated an association between abnormal GMs and motor performance at school age. 11 Bennema et al. 12 recently studied the predictive value of GMs in a group of low risk infants and reported that definitely abnormal GMs at 2 weeks of age were associated with MND at 18 months and behavioural problems at 4 years. GM-quality at 3 months did not predict developmental outcome at preschool age. The primary aim of this study is to evaluate to what extent the quality of GMs in the first postnatal months in children born full-term with low to moderate risk for developmental disorders predicts a) serious neurological disorder such as CP, and in children without CP - b) milder forms of limited mobility at the age of six years. To this end, we used the data available from a prospective cohort study on neuromotor outcome at six years in children with a difficult birth at term (DBAT), that included both children with and without DBAT. 13,14 The presence of limited mobility was determined with the Movement ABC (MABC). 14,15 In addition, we evaluated in children without CP - associations between GM-quality in the first postnatal months and the use of physical therapy, the presence of learning and behaviour problems and of MND at school age. The evaluation of the association between GM-quality and MND was added to gain insight into the neurological substrate of the associations between GM-quality and functioning in daily life at school age. 101

103 Methods Participants Participants took part in a project on the effect of DBAT on developmental outcome at 6 years. Included in the study were a) 64 term infants admitted because of DBAT to the neonatal ward of the regional general hospital, Gelre Hospital in Apeldoorn the Netherlands between January 1999 and July 2005 (for details see Van Iersel et al. 13 ) and b) 84 healthy term infants without DBAT who were recruited at the obstetrical ward of the same hospital (n=25) or from nearby midwife practices (n=59). DBAT was defined as fulfilling at least two of the following criteria: 1) abnormal cardiotocogram (CTG), 2) Apgar score at 5 minutes < 7, 3) umbilical ph < 7.20 and 4) umbilical base excess < -10 mmol/l. Infants with visible congenital anomalies were excluded. All infants were assessed twice during the first three months. At the age of 6 years five children could not be reassessed: two children of the study group had died and families of three control children declined participation (assessment burden (n=2), logistical reasons (n=1)). The two children who died had been diagnosed with severe CP (Gross Motor Function Classification System (GMFCS) level V) 16, they died at the ages of 2 and 4 years. The data of these two children are included in the evaluation of the predictive value of GM-quality for CP. The perinatal, social and anthropometric characteristics of the studied population are presented in Table 1 (for details see 13,14 ). The parents of the children gave signed informed consent and the procedures were approved by the Medical Ethical Committee of University Medical Centre in Utrecht. 102

104 Table 1. Perinatal characteristics, GM-quality and neurodevelopmental outcome at 6 years. PERINATAL CHARACTERISTICS N=145 Male gender, n (%) 86 (59%) GA at birth in weeks, median (range) 40 (36-43) Birthweight (mean ± SD) 3454 ± 601 Sarnat score: (10%) 18 (12%) 113 (78%) GENERAL MOVEMENTS Writhing GMs: NO/SO/MA/DA 5 (4%) / 46 (32%) / 59 (40%) / 35 (24%) Fidgety GMs: NO/SO/MA/DA 9 (6%) / 60 (41%) / 60 (41%) / 16 (12%) Diagnosed CP at 2 years 5 (3%) GENERAL CHARACTERISTICS AT SIX YEARS N=140 (children without CP assessed at 6 years) Age at follow-up in months, median (range) 77.5 (75-83) Maternal high education, n (%)* 51 (36%) OUTCOME AT 6 YEARS Total MABC P15 25 (18%) - Manual abilities P5 3 (2%) - Balance skills P5 16 (11%) - Ball skills P5 10 (7%) Physical therapy between birth and 6 years 37 (26%) Learning problems # 36 (26%) Behavioural problems - CBCL Total score P95 16 (11%) - CBCL Internalizing behaviour P95 22 (16%) - CBCL Externalizing behaviour P95 17 (12%) - TRF: Total score P95 20 (14%) - TRF Internalizing behaviour P95 27 (19%) - TRF Externalizing behaviour P95 17 (12%) Neurological classification: N/sMND/cMND 65 (46%) / 46 (33%) / 29 (21%) - Dysfunctional posture and muscle tone 22 (16%) - Dysfunctional reflexes 79 (56%) - Involuntary movements 6 (4%) - Coordination problems 60 (43%) - Fine manipulative disability 33 (24%) - Exces of associated movements 1 (1%) - Sensory deficits 0 (0%) - Impaired cranial nerve function 0 (0%) CBCL = Child Behavior CheckList, cmnd = complex Minor Neurological Dysfunction, CP = cerebral palsy, CTG = cardiotocogram, GA = gestational age, N = normal, SD = standard deviation, smnd = simple Minor Neurological Dysfunction, TRF = Teacher Report Form. *Social class according to maternal education: high = university education/vocational colleges. # Any learning problem = need of special assistance or special education, or being in an inappropriate grade for age. Assessment of GM-quality GM-quality in supine position was assessed twice during the first postnatal months, i.e., at writhing GM age (38 47 weeks postmenstrual age (PMA); 103

105 median age 3 weeks corrected age (CA) and at fidgety GM age (48 58 weeks PMA; median age 13 weeks CA). To this end spontaneous motility in supine position was video-recorded for at least 5 minutes in an awake, active, non-crying state. The GMs were assessed by the first author who was aware of the perinatal clinical condition of the infant and by the last author, who was blinded to the infant s perinatal clinical condition. Interobserver agreement between the two assessors was good. 13 Both assessors were unaware of the infant s developmental outcome. Movement quality was classified as normal optimal (NO), normal suboptimal (SO), mildly abnormal (MA) or definitely abnormal (DA), according to Hadders-Algra et al. 17 NO movements are very variable and complex and fluent. SO movements have a sufficient amount of movement variation and complexity, but are not fluent. MA movements are characterized by a limited amount of variation and complexity, and DA movements by a virtual or total absence of movement variation and complexity. Clinical data based on hospital and midwifery records were collected on standardized forms. Data on social class were collected by means of a parental questionnaire. Neurodevelopmental assessments at 6 years. The assessment at 6 years consisted of a neurological examination, an assessment of mobility, and an evaluation of received physical therapy, academic achievement and behaviour by means of parental and teachers questionnaires. 14 Neurological condition was assessed with the neurological examination of the child with MND. 18 This assessment does not only allow to diagnose neurological disorders such as CP, but it also permits a standardized assessment of MND. MND is assessed in eight domains such as posture and muscle tone, dyskinesia, coordination and fine manipulative ability. 18 The children are classified as a) neurologically normal if they do not show 104

106 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 dysfunction is present in at least three domains and d) neurologically abnormal in case of a clear neurological disorder, such as CP. Simple MND implies the presence of typical but non-optimal brain function; it has a relatively high prevalence. Complex MND is regarded as the clinically relevant form of MND; it is known to be strongly correlated with pre- and perinatal adversities. 18 The neurological examination of the child with MND has a good reliability and construct and concurrent validity. 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. 18 In children with CP Gross Motor Function Classification System (GMFCS) and Manual Ability Classification System (MACS) were determined. 16,19 Mobility was assessed with the MABC, which is a test specifically developed to identify and evaluate children aged 4 to 12 years with mild to moderate forms of limited mobility. 15 It evaluates four age bands, each with eight age-appropriate functional motor tasks representing manual dexterity, ball skills and balance skills. Outcome is summarized in three subscores and a total score. In the present study we dichotomized outcomes of the total score by using the 15 th percentile (P15) of the total score as a cut-off into typical (> P15) and atypical ( P15) and the three domain scores manual dexterity, ball skills and balance skills by using the P5 as a cut-off into typical (>P5) and atypical ( P5). The MABC has been standardized for Dutch children. It has a good test-retest and interrater reliability and a good construct validity but a moderate concurrent validity lacking a suitable gold standard. 15 Parents filled out a standardized questionnaire on the child s medical history up until the age of 6 years, including questions on received physical therapy. Behavioural and emotional competences were measured by the Child Behavioral Checklist (CBCL) and the Teachers Report Form (TRF)

107 We used the CBCL and TRF versions for children from 6 to18 years. The behavioural scores of both lists may be summarized with a total score and scores of internalizing and externalizing behaviour. The reliability and the validity of the CBCL and TRF are well confirmed. We dichotomized these three scores into typical implying a score up to the 95 th percentile (P95) and behavioural problems indicating a score P95. The latter includes borderline scores (P95-P98) and clinical scores (>P98). The TRF also furnished information on academic achievement. The presence of learning problems was defined as the need of special educational assistance or special education, or being in an inappropriate grade for age. Statistical analysis Statistics were performed with the software package of SPSS, version 20. At first univariable analyses were applied to evaluate differences in outcome at six years between children with abnormal and normal GMs with the Mann Whitney U test, Chi-square and Fisher Exact Test where appropriate. Next, multivariable logistic regression analysis was applied. Potential confounders adjusted for in the multivariate logistic regression were the presence of perinatal asphyxia, sex and maternal education. Differences with p-levels < 0.05 were considered statistically significant (two tailed). Results GMs-quality and diagnosis of CP At writhing GM-age 35 out of 145 infants (24%) had DA GMs and 94 infants (65%) had abnormal (MA or DA) GMs. At fidgety GM-age 16 infants (12%) had DA GMs and 76 infants (52%) showed abnormal GMs (Table 1). 106

108 Five children had been diagnosed with CP. Three had bilateral spastic CP, two with GMFCS level V (they died at preschool age), and one with GMFCS level IV. The other two children had unilateral CP, one with a relatively severe form (MACS level IV, GMFCS level II), the other with a mild form (MACS and GMFCS levels I). Table 2. General Movements (GMs) and cerebral palsy. GM quality No CP CP Total p-value Writhing age Non-DA GMs 108 (98%) 2 (2%) * DA GMs 32 (91%) 3 (9%) 35 Total Fidgety age Non-DA GMs 127 (98%) 2 (2%) # * DA GMs 13 (81%) 3 (19%) 16 Total CP = cerebral palsy, DA = definitely abnormal * tested with Fisher exact test # 1 bilateral CP (GMFCS, level V) with MA GMs at fidgety age, 1 unilateral CP (GMFCS level I, MACS level I) with SO GMs at fidgety age. The GM-quality of these two children has been confirmed by multiple masked colleagues. 2 bilateral CP (GMFCS, level V), 1 unilateral CP (GMFCS level II, MACS level IV) The presence of DA GMs at writhing age was not associated with the diagnosis CP. Yet, DA GMs at fidgety age showed a statistically significant association with CP (Table 2). The sensitivity of DA GMs at fidgety age to predict CP was 60%; their specificity was 91%. The positive predictive value was 19% and the negative predictive value was 98% (Table 3). Two children with CP had not shown DA GMs at fidgety age. One child presented with a mild unilateral CP, he had shown SO GMs, a normal neonatal EEG and a normal ultrasound scan of the brain. The other child had a severe bilateral CP (GMFCS level IV); she had DA GMs at writhing age and MA GMs at fidgety age. At neonatal age she presented with seizures and the ultrasound scan of her brain showed widespread cortical lesions. 107

109 Quality of writhing GMs and developmental outcome at 6 in children without CP. Details on neurodevelopmental outcome at 6 years are presented in Table 1. Twenty five children (18%) had limited mobility (MABC P15), 37 (26%) had received physical therapy at some point during their life, and 29 children (21%) had complex MND. DA GMs at writhing age were not associated with neurodevelopmental outcome in children without CP. Also abnormal (MA and DA) GMs at writhing age were not associated with limited mobility, the use of physical therapy and behavioural problems (Table 4). However, infants with abnormal writhing GMs had more often learning problems at 6 years than infants with normal GMs (34% vs. 12%; adjusted OR: 3.07; 95%CI ). Abnormal writhing GMs were also associated with a higher risk of a nonnormal neurological condition (presence of simple MND or complex MND; 62% vs 39%; adjusted OR: 2.38; 95%CI ). This association was brought about in particular by the association between abnormal GMs and dysfunctional posture and muscle tone regulation (Table 4). Table 3. Prediction of DA GMs at fidgety age for CP and for dysfunctional posture and muscle tone regulation at 6 years in children without CP. Cerebral Palsy Total group: n=145 Dysfunction in posture and tone Total group: n=140 Prevalence 3% 16% Sensitivity 60% 23% Specificity 91% 93% Positive Predictive Value 19% 38% Negative Predictive Value 98% 86% CP = cerebral palsy, DA = definitely abnormal Quality of fidgety GMs and developmental outcome at 6 years in children without CP. GM-quality at fidgety age was associated only to a limited extent to developmental outcome at 6 years. Only the presence of DA GMs was 108

110 Table 4. Association between abnormal (MA and DA) writhing GMs and definitely abnormal (DA) fidgety GMs and outcome at 6 in children without CP. ABNORMAL (MA AND DA) WRITHING GMS N = 140 DEFINITELY ABNORMAL (DA) FIDGETY GMS N=140 OUTCOME AT 6 YEARS UNADJUSTED OR (95% CI) ADJUSTED OR (95% CI) a UNADJUSTED OR (95% CI) ADJUSTED OR (95% CI) a Movement ABC - Total score: < P ( ) 1.89 ( ) 0.36 ( ) 0.32 ( ) - Manual abilities < P ( ) 1.92 ( ) 0.19 ( ) Ball skills < P ( ) 0.37 ( ) - Balance skills < P ( ) 0.43 ( ) 1.61 ( ) 2.07 ( ) Physical therapy 3.20 ( ) 2.48 ( ) 1.27 ( ) 1.29 ( ) Learning problems 3.81 ( ) 3.07 ( ) 1.94 ( ) 2.02 ( ) Behavioural problems: - CBCL total score P ( ) 0.59 ( ) 0.62 ( ) 0.57 ( ) - internalizing behaviour P ( ) 1.12 ( ) 0.97 ( ) 0.94 ( ) - externalizing behaviour P ( ) 0.62 ( ) 1.35 ( ) 1.13 ( ) - TRF total score P ( ) 1.15 ( ) 1.92 ( ) 1.86 ( ) - internalizing behaviour P ( ) 1.10 ( ) 0.74 ( ) 0.68 ( ) - externalizing behaviour P ( ) 0.51 ( ) 0.57 ( ) 0.50 ( ) Neurological condition - Normal * 0.40 ( ) 0.42 ( ) 0.70 ( ) 1.28 ( ) - Simple MND 1.48 ( ) 1.49 ( ) 1.86 ( ) 1.84 (0.58-5,86) - Complex MND 2.61 ( ) 2.38 ( ) 0.67 ( ) 0.62 ( ) - Simple + complex MND 2.64 ( ) 2.38 ( ) 1.57( ) 1.50 ( ) Neurological domains: - dysfunctional posture and 4.34 ( ) 3.88 ( ) 4.04 ( ) 4.98 ( ) tone - coordination problems 2.14 ( ) 2.01 ( ) 0.56 ( ) 0.51 ( ) - fine manipulative disability 1.72 ( ) 1.52 ( ) 0.56 ( ) 0.52 ( ) * OR: normal vs non-normal (i.e. simple MND, complex MND and CP) OR: simple MND vs normal neurological condition OR: complex MND vs normal neurological condition and simple MND OR: non-normal vs normal a Adjusted for gender, social economic status and presence of asphyxia Bold values indicate statistically significant difference. 109

111 related to some of the outcome parameters (Table 4). DA GMs were not associated with limited mobility, the use of physical therapy, learning and behavioural problems. A minor association was found between DA GMs and neurological condition, i.e., infants with DA fidgety GMs more often showed dysfunctional posture and muscle tone regulation than infants with non-da GMs (adjusted OR: 4.98;95% CI ,Table 4). The sensitivity of DA GMs at fidgety age to predict dysfunctional posture and tone was 23%; their specificity was 93%. The positive predictive value was 38% and the negative predictive value was 86% (Table 3). Discussion The present study demonstrated that abnormal GMs at writhing age did not predict CP or milder forms of limited mobility, but they were associated with an increased risk of learning problems and minor dysfunction of muscle tone regulation. DA GMs at fidgety age did predict CP and were - in children without CP also associated with an increased risk for mild dysfunctions in muscle tone regulation. The high specificity and negative predictive value of DA GMs at fidgety age to predict CP match the values of the review of Bosanquet et al, 2 but low sensitivity and positive predictive value contrasts with the values of the studies mainly based on preterm infants. 2,11,24 Conceivably, our different results may be attributed to the different composition of our study group. Our group consisted of full-term infants only. It is well known that the nature of brain lesions in preterm infants differs from that of full-term infants. 21 Preterm infants have a specific vulnerability of the periventricular white matter, whereas in full-term infants the cortical areas and the basal ganglia and thalamus are known predilection sites for injury. 5,21 Recent evidence suggests that an abnormal quality of GMs, i.e., a reduction in movement complexity and variation especially is associated with pathology of the periventricular white matter This suggests that the quality of 110

112 GMs may reflect especially the integrity of subcortical grey and white matter structures. The two children with CP that did not present with DA fidgety GMs may support this hypothesis: one had severe CP due to widespread cortical pathology, the other one a mild unilateral CP, that may have been caused by a small cortical lesion. If GM-quality is related in particular to the integrity of subcortical structures, this would explain why GM-quality predicts developmental outcome of preterm infants better than that of fullterm infants. Our results on the predictive value of fidgety GMs in full-term infants corresponds to those of Bouwstra et al. 6 in the general population. In children without CP GM quality predicted developmental outcome to a minor extent only: GM quality was not related to limited mobility, use of physical therapy or behavioural problems. The latter contrasts with the study of Bennema et al. who found an association between GM-quality at writhing age and behaviour at 4 years. 12 In the present study abnormal movements at writhing age were associated with learning problems, and the most consistent association was the one between abnormal GM quality and dysfunctional posture and muscle tone. The latter association differs from the one that was previously reported in a group of high risk mainly preterm infants, where abnormal GMs especially were associated with fine manipulative dysfunction and coordination problems. 9 This once again supports the notion that the associations between GM-quality and developmental outcome in full-term infants differ from those in preterm infants. 25 The major strength of the study is that it addresses for the first time the associations between GM-quality and developmental outcome at school age in terms of CP and minor developmental problems in a substantial group of infants born at term. An additional strength is the minimal attrition during follow-up. A limitation of the study is that half of the study infants had DBAT. Hence we studied a selective population implying that the findings cannot be extrapolated to the general population. 111

113 In conclusion, in our group of full-term infants GM-quality at writhing age did not predict CP nor limited mobility. Abnormal (MA and DA) writhing GMs were only associated with a mildly increased risk for learning problems and dysfunctional posture and muscle tone regulation. However, DA GMs at fidgety age did predict CP, but with considerably lower sensitivity and positive predictive value than in populations of preterm infants. DA fidgety GMs were also associated with an increased risk of mild dysfunction in posture and muscle tone regulation. In other words, our study supports previous suggestions 6,12 that the predictive value of GM-assessment in fullterm infants is less than that in preterm infants, stressing the need for further development of non-invasive and easily applicable tools for the evaluation of developmental outcome in infants born at term. Acknowledgements We kindly acknowledge the cooperation of the Doevedans Midwife Practice in Apeldoorn and the Obstetrical and Paediatric Department of the Gelre Hospital for participating in the intake of the children. We thank the Department of Medical Photography of the Gelre Hospital for the continuous photo-technical support and we thank F. Eggelmeijer and N. Devlin for their comments on a previous draft of the paper. Literature 1. Spittle A, Orton J, Anderson P, Boyd R, Doyle LW. Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants. Cochrane Database Syst Rev 2015: CD Bosanquet M, Copeland L, Ware R, Boyd R. A systematic review of tests to predict cerebral palsy in young children. Dev Med Child Neurol 2013;55: Hadders-Algra M. Early diagnosis and early intervention in cerebral palsy. Front Neurol 2014;5: Prechtl HFR, Ferrari F, Cioni G. Predictive value of general movements in asphyxiated fullterm infants. Early Hum Dev 1993;35:

114 5. Ferrari F, Todeschini A, Guidotti I, Martinez-Biarge M, Roversi MF, Berardi A, Ranzi A, Cowan FM, Rutherford MA. General movements in full-term infants with perinatal asphyxia are related to basal ganglia and thalamic lesions. J Pediatr 2011;158: Bouwstra H, Dijk-Stigter GR, Grooten HMJ et al, Predictive value of definitely abnormal general movements in the general population. Dev Med Child Neurol 2010;52: WHO. International classification of functioning, disability and health: children & youth version ICF-CY WHO Library Cataloguing-in- Publication Data, ISBN Hadders-Algra M, Groothuis AMC. Quality of general movements in infancy is related to neurological dysfunction, ADHD, and aggressive behaviour. Dev Med Child Neurol 1999;41: Groen SE, de Blécourt 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: Butcher PR, van Braeckel K, Bouma A, Einspieler C, Stremmelaar EF, Bos AF. The quality of preterm infants spontaneous movements: an early indicator of intelligence and behaviour at school age.j Child Psychol Psychiatry 2009;50: Sustersic B, Sustar K, Paro-Panjan D. General Movements of preterm infants in relation to their motor competence between 5 and 6 years. Eur J Paediatr Neurol 2012;16: Bennema AN, Schendelaar P, Seggers J, Haadsma ML, Heineman MJ, Hadders-Algra M. Predictive Value of general movements quality in low-risk infants for minor neurological dysfunction and behavioural problems at preschool age. Early Hum Dev 2016, accepted for publication 13. Van Iersel PAM, Bakker CM, Jonker AJH, Hadders-Algra M. Quality of general movements in term infants with asphyxia. Early Hum Dev 2009;85:

115 14. Van Iersel PAM, Algra AM, Bakker CM, Jonker AJH, Hadders-Algra M. Limitations in the activity of mobility at age 6 years after difficult birth at term. A prospective cohort study. Phys Ther 2016, accepted for publication 15. Smits-Engelsman BCM. Movement assessment battery for children. Dutch version by Swets test Publishers. 16. Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39: Hadders-Algra M. General Movements: a window for early identification of children at high risk for developmental disorders. J Pediatr 2004;145: Hadders-Algra M. The neurological examination of the child with minor neurological dysfunction. London: Mc Keith Press, Eliasson AC, Krumlinde Sundholm L, Rösblad B, Beckung E, Arner M, Öhrvall AM, Rosenbaum P. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability Developmental Medicine and Child Neurology 2006;48: Achenbach TM. Manual for the child behavior checklist 4-18 and profile. Burlington, VT: University of Vermont, Department of Psychiatry, Volpe JJ. Neurology of the newborn. 5 th ed. Philadelphia: Saunders Elsevier, Hadders-Algra M. Putative neural substrate of normal and abnormal general movements. Neurosci Biobehav Rev 2007;31: Spittle AJ, Brown NC, Doyle NW et al. Quality of general movements is related to white matter pathology in very preterm infants. Pediatrics 2008;121: Spittle AJ, Boyd RN, Inder TE, Doyle LW. Predicting motor development in very preterm infants at 12 months corrected age: the 114

116 role of qualitative magnetic resonance imaging and general movement assessments. Pediatrics 2009;123: Spittle AJ, Spencer Smith MM, Cheong JL, Eeles AL, Lee KJ, Anderson PJ, Doyle LW. General Movements in very preterm children and neurodevelopment at 2 and 4 years. Pediatrics 2013:132;

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118 Chapter 6 General discussion Clinical implications Future research 117

119 General discussion The discussion of this thesis starts with the objectives and main findings of the study. Next, I address terminology used and methodological issues. Thereafter the potential neurodevelopmental sequelae of a difficult birth in term and preterm infants and the predictive value of GMs are discussed. The discussion concludes with suggestions for clinical practice and for future research. Objectives and main findings of the study The objectives of this thesis were twofold. The first objective was 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. The second objective was to evaluate the significance of the assessment of General Movements in young term infants as an instrument to predict CP and in children without CP mild neurodevelopmental disorders at school-age. The studies revealed the following: 1) Infants with a difficult birth at term showed more often abnormal GMs at the age of 3 months than term infants in the general population. Definitely abnormal (DA) GMs in the neonatal period were associated with neonatal illness; DA GMs at 3 months were related to abnormalities on the ultrasound scan of the brain, not to the degree of NE. (study 1) 2) Infants with a difficult birth at term resulting in mild or moderate NE showed an increased prevalence of limited mobility at the age of 6 years. The risk was larger in children who had suffered from moderate NE, than in those who had had mild NE. (study 3) 3) Difficult birth in preterm infants was not associated with an increased rate of abnormal GMs nor with the diagnosis cerebral palsy (CP) at the age of 18 months. Abnormal GMs in the preterm period were associated 118

120 with respiratory morbidity in the preterm period; abnormal GMs at 3 months with periventricular leucomalacia (PVL). (study 2) 4) For full-term infants with a difficult birth in a regional hospital setting GM-assessment is a valuable tool to evaluate the integrity of the nervous system during the first three months of life. Definitely abnormal GMs at 3 months do predict CP, but with lower accuracy than in preterm infants. However, GM-quality of full-term infants does not predict limited mobility at the age of 6 years in children without CP. This finding underlines the notion that the power of GM-quality to predict developmental outcome may differ for term and preterm infants. (study 1 and 4) 119

121 Terminology: difficult birth versus perinatal asphyxia Traditionally the term perinatal asphyxia was widely used for infants with a low Apgar score and with hypoxia-ischaemia at birth. The term was applied in infants in largely varying clinical conditions, i.e., from infants who only were mildly affected up to those who suffered severely. From the seventies onwards the staging of Sarnat was increasingly more often used to describe disease severity in infants with a difficult birth, 23,109 whereas during the last decade increasingly more sophisticated neuroimaging techniques have been applied to characterize the severity of asphyxia. 20,25,29,32,40 Nevertheless in non-academic centres milder forms of asphyxia, diagnosed on the basis of clinical signs are often still labelled as perinatal asphyxia. As the term asphyxia increasingly more often results in misunderstanding and confusion we introduced the term difficult birth in the later years of the work on this thesis. For term infants we introduced DBAT (Difficult Birth At Term). Methodological considerations The most characteristic feature - and at the same time an important strength of the studies of this thesis - is the setting in a regional hospital in the Netherlands. Studies in non-academic settings are underrepresented in scientific research, while the majority of patients worldwide are treated in regional hospitals, in LMIC as well as in industrialized countries. 3-4 Nonacademic centres are visited by patients, who might not need the extensive and specialized care available in academic centres. Nevertheless they represent the major part of hospital populations all over the world. The nonacademic hospital populations present with a large variety of diseases and impairments that need and deserve scientific research for a better understanding of risks, diagnostics and treatment. Additional strengths of the studies included in the thesis are: 120

122 a) The remarkably low attrition, which makes the results more reliable and enhances its potential to generalize. b) The use of standardized tools to assess outcomes, which facilitates the understanding of the results and their comparison with the results of other studies. These tools also enabled us to measure more subtle components of neurological condition and mobility than most former studies did. The tools included the standardized application of the method Assessment of General Movements to evaluate brain function in a young infant. Many studies demonstrated the predictive power of the assessment of GMs in academic high risk populations c) The focus on the effect of DBAT accompanied by milder forms of NE on limited mobility at school age, i.e., motor performance during daily life activities, instead of motor impairments such as deviant muscle tone and abnormal reflexes. d) The inclusion of the MND-assessment allowing the evaluation of the neurological substrate underlying limited mobility. Nevertheless the specific setting of a non-academic hospital is also associated with some limitations: a) Imaging of the lesions of the brain of the study groups was restricted, due to the limited access in the regional hospital setting to magnetic resonance imaging (MRI) of the brain. It should be realized, however, that brain lesions occurring in referrals to a non-academic hospital presumably are the minor ones and that the predictive value of mild and non-localised brain lesions by MRI is not yet well understood. 67 b) Both study groups, i.e., the group of infants born at term and the group of infants born preterm, were recruited over a period of 6 to 8 years. Within such a long intake period medical care for infants with a difficult birth at term or at preterm age presumably has changed, which may have affected the outcome. We evaluated whether year of birth did affect neurodevelopmental outcome in any of our studies. It did not (data not presented). 121

123 c) The study group of infants with a difficult birth at preterm age (28-34 weeks postmenstrual age (PMA)) was small (n=17). This small number most likely reflects health care: preterm infants with a difficult birth, i.e., preterm infants with perinatal asphyxia, are not frequently admitted to the neonatal ward of a regional hospital. Instead they are usually referred to the more extensive facilities of the academic centres. This holds true for infants with an unexpected preterm delivery with neonatal morbidity needing academic facilities who are referred postnatally. From 2005 onwards, it also holds true for fetuses younger than 32 weeks PMA and from 2010 onwards for fetuses younger than 24 weeks PMA - with a compromised condition, who are transferred intra-uterinely to an academic center. 110 The small number of preterm infants in our study resulted in a low power of the study. Nevertheless the study allowed for the conclusion that the effect of a difficult birth in preterm infants on neurodevelopmental outcome was smaller than the effect of a) neonatal respiratory problems like apnea and bradycardia, respiratory failure because of asphyxia, infant respiratory distress syndrome with or without artificial ventilation and b) the effect of PVL. d) The reference cohort of the full-term study group consisted of a mix of infants born inside and outside the hospital. The mix was induced by the matching procedure: infants delivered by caesarean section (CS) are born in the hospital, but in the Netherlands low risk infants born without CS are usually born at home The mix of infants born at home and in the hospital means that our reference group is not representative for the general population. This is reflected by the prevalence of abnormal movements at 3 months: 14% of infants showed DA GMs, and 38% of infants MA GMs. These prevalences are higher than those reported for the general population (DA GMs less than 4%; MA GMs 25%). 81 The high prevalence of the clinically relevant DA GMs in the reference group precluded its use in the infant study. At 6 years the difference between the reference group and the general 122

124 population had decreased. At this age only the prevalence of the clinically not-relevant form of minor neurological dysfunction deviated from that of the general population (simple MND: reference group 32%, general population 20% 97 ). Therefore we decided to include the reference group in the follow-up study at 6 years. The fact that the reference group was a non-representative selection from the general population implies that we may have underestimated the true effect of DBAT on neurodevelopmental outcomes at 6 years. Two additional limitations are: e) Cognitive function was only evaluated in a very global way, i.e., only in terms of limited academic achievement, not in terms of specific cognitive deficits. Limited academic achievement may not only be the result of cognitive deficits, it may also be a consequence of sensory deficits like minor, not yet detected hearing or visual impairments, or environmental factors, such as limited family support or excessive parental concern f) Limited mobility was based on a MABC total score < P15. Although the MABC has been recommended by the EACD to evaluate children with DCD with respect to mild to moderate limitations in activities of mobility, the diagnosis DCD cannot be established on the basis of the MABC alone. The diagnosis of DCD also requires that limited mobility interferes with activities of daily life. 64 Nevertheless, the MABC provides an objective measure of the child s capacities in the mobility domain. Difficult birth in term infants Until recently most evidence on long term developmental outcome following DBAT focused on infants with moderate to severe NE, who needed intensive treatment in academic centres. 25,29,32,40,116 These infants have a high risk 123

125 for death or disability. Although the introduction of hypothermia treatment reduced the incidence of poor neuromotor outcome of perinatal asphyxia from 60% to 45%, outcome after perinatal asphyxia is still a reason for concern. 20,117 In addition, long-term outcome of children with milder forms of DBAT has always received relatively little attention. These milder forms of DBAT may or may not be followed by NE. The reviews including children with moderate to mild forms of DBAT suggested that limitations in mobility are uncommon in these children Nevertheless, more recent studies suggest that these children may have an increased risk for problems in learning, behavioural and memory domains The present study demonstrated that DBAT resulting in mild and moderate NE is associated with an increased risk for limited mobility at the age of 6, the risk for complex MND rising with the severity of NE. Interestingly, the severity of the NE was not associated with neurological outcome at 3 months, i.e., with the quality of general movements. Two explanations may be offered for the discrepancy between the absent association of severity of NE with outcome in infancy and the present association between degree of NE and outcome at 6 years. First, the discrepancy may be partially attributed to the presence of a reference cohort at the age of 6, enlarging the possibility of associations between severity of NE and outcome. Second, the discrepancy may also be explained by the developmental characteristics of the brain: the nervous system of a six year old differs considerably from that of a 3-month-old. The data suggest that the child with DBAT gradually grows into the deficits associated with NE. This suggestion corresponds to another finding of this thesis, i.e., that the predictive power of the quality of GMs in infants with DBAT is not perfect. Our study also demonstrated that children born with DBAT not resulting in NE did not have an increased risk for limited mobility. In our study we were also able to find the associations between mild NE and outcome a) because it was performed in a regional hospital, where relatively more children with milder forms of DBAT are admitted and treated than in an academic centre; and b) because we used standardized tests to measure 124

126 limited mobility instead of testing neurological symptoms and impairments. Note that we measured limited mobility (with a standardized instrument) and not the prevalence of DCD. 64 Our study indicates that in a non-academic setting with restricted neuroimaging facilities the evaluation of the clinical signs of NE graded according to Sarnat is a useful tool to detect in infants with DBAT those at risk for limited mobility. In addition, it should be realized that the capacity of (neonatal) neuroimaging to detect children at risk for milder forms of limited mobility is limited. 69 The value of the assessment of the quality of GMs in infants with DBAT is discussed in a following paragraph. Difficult birth in preterm infants Relatively few studies have been carried out to evaluate the effect of difficult birth on neurodevelopmental outcome in preterm children. The results of these studies are inconclusive. This inconclusiveness may be partly explained by the fact that perinatal asphyxia or difficult birth in preterm infants is difficult to define. Most studies addressing the effect of difficult birth in preterm infants defined difficult birth by Apgar score or the presence of fetal acidosis ,47,118 However, the studies of Goldenberg et al. and Hüseman et al. indicated that Apgar scores and laboratory markers of perinatal acidosis are not appropriate indicators for the risk of perinatal insult to the preterm infant brain The fact that studies on the effect of difficult birth in preterm infants were unable to demonstrate an evident adverse effect of difficult birth in these children, may also be due to the fact that difficult birth is only one of the many conditions that may result in a lesion of the preterm brain. In preterm infants periventricular leucomalacia (PVL) is the major neuropathologic form of brain injury. The main mechanisms causing PVL are a) ischaemia or haemorrhage due to the age dependent vascular supply 125

127 of the brain with its immature regulatory mechanisms, b) maturationdependent vulnerability of brain cells and c) inflammation, often due to maternal intrauterine infection or postnatal sepsis. Most likely, DBAT is only one of the factors that contribute to this myriad of pathogenetic processes. 121 We applied in our study on the effect of difficult birth in preterm infants the same inclusion criteria that we used in the full-term group. The results of the study indicated that difficult birth in preterm children was not an additional risk factor for abnormal GMs or for CP. Adverse neurological outcome was especially associated with a) respiratory problems and b) PVL. It is well-known that PVL is associated with a high risk of adverse neurological outcome. 30,43, Respiratory problems in preterm infants, especially the combination of repeated apnea and bradycardia, are known to have a negative influence on cerebral oxygenation, and this in turn may be associated with less favourable neurodevelopmental outcome. Indeed other studies demonstrated that respiratory problems are associated with worse developmental outcome The present study suggests that in preterm infants postnatal respiratory events may play a more prominent role in adverse neurological outcome than DBAT. However, an alternative explanation for the association between respiratory problems and worse GM-quality may be that respiratory problems may also be regarded as an early expression of brain dysfunction. The same may be said of the association we observed between respiratory problems and PVL. Predictive value of GMs In the nineties of last century the assessment of GMs had been developed as a new method to assess the integrity of the young nervous system especially in high risk populations. The predictive value of the assessments of GMs was reported as being very high in high risk preterm infants and high risk full-term infants. 78, Later studies included more heterogeneous populations

128 Preterm infants Nowadays the predictive value of GMs, in particular for preterm infants, is well established, especially the predictive value of GMs around 3 month post-term. 74, The findings in our small sample of preterm infants are in agreement with the literature: the presence of DA GMs around 3 months was associated with PVL on the ultrasound scan of the brain and with the diagnosis of CP at the age of 18 months. Term infants Much less is known on the predictive value of GMs in full-term infants. Prechtl et al. 78 and Ferrari et al. 79 found a high association between abnormal GMs and adverse neurodevelopmental outcome at 18 months and 2 years. The infants in their study group consisted of a special selection of term infants, i.e., high risk infants, admitted to a tertiary centre with DBAT resulting in moderate to severe NE. The predictive power of GM-quality in these studies differed from the results in the study of Bouwstra et al. 81 The latter study showed that the good predictive value of GMs in high risk populations cannot be generalized to the general population. The Bouwstra et al. study indicated that DA GMs at 3 months are associated with an increased risk for neurodevelopmental impairment. But the study also showed that not all serious neurodevelopmental impairments manifested themselves at early age in the form of DA GMs. As a result the study of Bouwstra et al. showed a moderate sensitivity (67%), a good specificity (97%), a poor positive predictive value (PPV; 12%), and a high negative predictive value (NPV; 99%) in predicting CP. The results of the current study are more in line with those of the Bouwstra-study than with those of the studies in full-term infants with DBAT resulting in moderate to severe NE. In our study DA GMs around 3 months predicted CP to the same extent as they did in the Bouwstra-study, i.e., the predictive values were: sensitivity 60%; specificity 91%; PPV 19% and NPV 127

129 98%. The association of abnormal GMs during the first 3 months after term age with milder forms of limited mobility was weak. Infants with abnormal GMs in the first weeks post-term, i.e., in the writhing GM period, had more often learning problems at 6 years than infants with normal GMs. Abnormal writhing GMs were also related to a higher risk of MND. This association was brought about in particular by the association with dysfunctional posture and muscle tone regulation. An association between abnormal GM quality and MND albeit at 18 months - was also found by Bennema et al., 132 who recently studied a group of mainly low-risk full-term infants. In addition this study reported an association between GM-quality at writhing age and behaviour at 4 years. Bennema et al. also found that GM-quality at 3 months did not predict developmental outcome at preschool age. In the current study DA GMs at 3 months were only related to dysfunctional posture and muscle tone. The findings of this thesis are in agreement with other studies that indicated that GM-quality predicts serious neurological impairments, such as CP, better than milder impairments. 77, A possible explanation of the finding that GMs predict outcome better in preterms than in full-terms may be the difference in the type and location of brain lesions in preterm and full term infants. 8,29-30,43 Brain lesions in preterm infants are often bilateral and frequently found in the periventricular white matter. 30,43 It has been hypothesized that variation and complexity of GMs are generated by the cortical subplate and its efferent connections in the periventricular white matter. 55,70 In full-term infants lesions of the brain are more heterogeneous and either localized in particular in the cerebral cortex, uni- or bilaterally, or, especially in more severe cases, have a more generalized nature and may involve the brainstem. When pathology is restricted to the cortex it is conceivable that these lesions are not reflected in the quality of GMs. In other words, the differences in location of brain lesions between preterm and full-term infants may underlie the finding that GM-quality predicts developmental outcome better in preterm infants than in full-term infants. Differences in 128

130 the site of the brain lesion may also explain why GM assessment predicts outcome better in term infants with DBAT resulting in severe to moderately NE than in term infants with milder forms of DBAT. In conclusion: Our data suggest that the predictive power of GMassessment in full-term infants, especially in those full-terms who did not suffer from moderate to severe NE, is modest and less strong than that in preterm infants. Implications for clinical practice Considering the results and the conclusions of this thesis I have the following suggestions. Suggestions concerning the use of the assessment of GMs: GM assessment is an appropriate short term developmental outcome tool to evaluate in clinical practice perinatal care in preterm as well as in full-term infants. In preterm infants GM assessment is an excellent tool to predict neurodevelopmental outcome, especially when GMs are assessed around 3 months, i.e., in the fidgety GM period. Similarly, GM assessment is also an appropriate tool to assess risk for CP or other serious neurodevelopmental disorders in full-term infants. Yet, in full-term infants, the predictive value of GM assessment for minor developmental disorders is modest at best. Suggestions for full-term infants with DBAT Our study on developmental outcome of full-term children with DBAT stresses that not only children with DBAT resulting in severe and moderate 129

131 NE, but also those with mild NE are at risk for long-term limited mobility and other developmental problems. Therefore: I recommend biannual monitoring of mobility and neurodevelopment until at least the age of 6 years in infants with DBAT resulting in NE. I advocate standardized assessment of mobility and neurodevelopmental outcome, using the same validated tools in all settings to test limitations in mobility and the presence of simple or complex MND. Suggestions for future research Further research on the functional sequelae, especially in the domains of mobility, learning and applying knowledge, of DBAT resulting in milder forms of NE are important. I recommend that such studies use clinical neurological signs, such as the degree of neonatal NE and a standardized neurological assessment including the evaluation of minor neurological dysfunction, in combination with advanced neuroimaging, like Diffusion Tensor Imaging (DTI), and/or somatosensory evoked potentials (SEP). 141 This combined approach offers the optimal means to detect milder forms of NE at an early stage, allowing for an early start of adequate intervention and optimal developmental outcome in these children. 130

132 Chapter 7 Summary Nederlandse samenvatting 131

133 Summary In 2014 about 175,000 children were born in The Netherlands and about 143,300,000 worldwide. Part of these births is complicated by perinatal adversities such as preterm birth, perinatal asphyxia, and being small-forgestational age. Perinatal asphyxia is a well-known complication and refers to the fact that the infant had difficulties at birth. However, it is a concept with varying definitions. The developmental sequelae of perinatal asphyxia have been studied especially in infants born at term. This thesis refers to these infants as infants being born after a difficult birth at term (DBAT). Gradually, it was realized that the risk of developmental disorders in infants with DBAT especially is determined by the degree of the resulting neonatal encephalopathy (NE). During the last decades sophisticated neuroimaging techniques to determine the extent of NE, such as neonatal MRI, became standard tools in Western academic centres. These imaging techniques and the introduction of hypothermia treatment to minimize the neurological sequelae of NE have substantially changed the clinical approach of children with DBAT. However in low and middle income countries and also in nonacademic hospitals in industrialized countries, these techniques usually are not available. Also in these settings it is important to assess the risk of adverse outcome as early as possible, as early detection of high risk offers the possibility of intervention early in life, when the plasticity of the brain is at its peak. The Assessment of General Movements (GMs) is a clinical and cheap tool that can be applied in any setting. It is a tool with high predictive power of developmental outcome including cerebral palsy (CP) in high risk infants in academic settings. Especially definitely abnormal GMs around 3 months (the fidgety GM-phase) are associated with the development of CP. The current studies (studies 1-4) evaluated neurodevelopmental outcome after mild to moderate asphyxia in preterm and especially - full-term infants. Outcome was studied neonatally and at the age of 3 months corrected age with the help of the Assessment of GMs (studies 1 and 2). Outcome of the term infants with DBAT was studied again at the age of 6 132

134 years with a focus on activities in the mobility domain according to International Classification of Functioning, Disability and Health: Children and Youth version (study 3). The long-term follow-up also allowed for an evaluation of the predictive power of the Assessment of General Movements to predict CP and mild forms of limited mobility in children without CP at the age of 6 years (study 4). Study 1:Quality of general movements in term infants with DBAT. In this study we assessed the contribution of perinatal risk factors to neurological condition in the neonatal period and at the age of 3 months in 64 term infants with DBAT born in a regional hospital in the Netherlands. Infants were considered having DBAT when they met at least two of the following clinical criteria: abnormal cardiotocography, Apgar score at 5 min < 7, umbilical ph < 7.20 and umbilical base excess < -10mmol/liter. The results revealed that the infants with DBAT more often showed abnormal GMs at 3 months than infants in the general population (mildly abnormal GMs: 38% vs. 25%; definitely abnormal (DA) GMs: 14% vs. 4%). DA GMs in the neonatal period (writhing GM-age) were mainly associated with DBAT related neonatal illness. DA GMs at 3 months (fidgety GM-age) were correlated especially with abnormalities on the neonatal ultrasound scan of the brain, not with severity of NE. We concluded that in secondary paediatric settings GM-assessment especially around 3 months is a valuable tool for the assessment of the integrity of the nervous system in term infants with DBAT. Study 2: Does perinatal asphyxia contribute to neurological dysfunction in preterm infants? Children born preterm are known to be at risk for neurodevelopmental problems. Relatively few studies addressed the role of perinatal asphyxia as an additional risk for adverse developmental outcome in preterm 133

135 children. This is probably because perinatal asphyxia in preterm infants is even more difficult to define than in term infants. In this study we analysed the contribution of perinatal asphyxia to neurological outcome. We included 17 preterm children with asphyxia and 34 preterms without asphyxia. The infants were born at a gestational age of less than 35 weeks and the presence of perinatal asphyxia was based on similar criteria as those used in the full-term infants. Neurological condition at early age was assessed by means of the quality of GMs. The presence of CP was determined by clinical follow-up at the age of 2 years corrected age. Outcome in the preterms with asphyxia was similar to that of preterms without asphyxia: DA GMs at fidgety age occurred in 12 to 18% of infants, and 11% of children (in both groups) were diagnosed with CP. DA GMs around 3 months were not related to markers of asphyxia, but to the severity of periventricular leukomalacia (PVL) on the ultrasound scan of the brain. DA GMs at fidgety age were also clearly associated with CP. Study 3: Limitations in the activity of mobility at the age of 6 years after difficult birth at term. Fifty nine (95%) of the surviving infants with DBAT from study 1 were reassessed at the age of 6 years, together with a matched reference cohort of 81 children born without DBAT. Primary outcome was limited mobility defined as performance on the Movement ABC at or below the 15 th percentile ( P15). The three children of the DBAT group who had developed CP were excluded from the analyses as they were unable to perform the Movement ABC. Secondary outcomes were the presence of minor neurological dysfunction, the need of physical therapy and learning and behaviour problems. Children with DBAT who had presented with mild to moderate NE more often had limited mobility than children without NE. The increased risk for limited mobility in children with NE was mainly explained by an increased risk for limited manual abilities. The risk of limited mobility rose with increasing severity of NE. Children without NE were not at risk for 134

136 limited mobility. Complex MND, learning problems and need for physical therapy were more common in children with DBAT than in children without DBAT, behavioural problems were not. The likelihood of complex MND was similar to limited mobility associated with the severity of NE. In contrast, the occurrence of learning problems and physical therapy guidance did not depend of the degree of NE. The study concluded that children with DBAT presenting with mild to moderate NE and diagnosed in a non-academic setting, more often have limitations in the activity of mobility at 6 years than children without DBAT. Therefore, routine monitoring of neuromotor development in these children is warranted. Study 4: Evaluation of the Assessment of General Movements to predict cerebral palsy and milder forms of limited mobility at 6 years. The assessment of the quality of GMs is a non-invasive tool which assists the detection of infants at risk for developmental disorders in early life. GMs are spontaneous movement patterns involving the whole body, that are present up until 3 to 4 months post-term. The quality of GMs - in particular the degree of variation and complexity - is used to evaluate the integrity of the nervous system. Most studies about the predictive value of quality of GMs included only preterms, groups of very high risk full-terms or groups consisting of a mix of full-term and preterm infants. These studies concluded that the value of GM-quality to predict CP is excellent, but little is known about the predictive value in full-term infants with limited risk for developmental disorders. Therefore we evaluated in full-term infants associations between the quality of GMs and developmental outcome at 6 years, in terms of CP and in terms of limited mobility in children without CP. The study was based on the participants of study 3 and included GMassessment at writhing and fidgety GM-age and the outcomes used in study

137 DA GMs at fidgety age were associated with CP with the following predictive values: sensitivity 60%; specificity 91%; positive predictive value 19%, and negative predictive value 98%. In children without CP GM-quality at fidgety age was not associated with limited mobility. GM-quality at writhing age did not predict development at 6. We concluded that DA GMs at fidgety age do predict CP, but with lower accuracy than in preterm infants. GM-quality does not predict limited mobility in children without CP. The study supports suggestions that the predictive value of GM-assessment in full-term infants is lower than that in preterm infants. Main conclusions of the thesis In full-term infants with a difficult birth GM-assessment is a valuable tool to evaluate the integrity of the nervous system during the first three months of life, especially in non-academic settings. Difficult birth in preterm infants was not associated with an increased rate of abnormal GMs nor with the diagnosis CP at the age of 18 months. Abnormal GMs at 3 months were associated with periventricular leucomalacia (PVL). Infants with a difficult birth at term resulting in mild or moderate NE showed an increased prevalence of limited mobility at the age of 6 years. The risk was larger in children who had suffered from moderate NE than in those who had presented with mild NE. Definitely abnormal GMs at fidgety GM-age in full-term infants do predict CP, but with lower accuracy than they do in preterm infants. GM-quality of full-term infants does not predict limited mobility at the age of 6 years in children without CP. It is conceivable that the difference in power of GM-assessment to predict CP between preterm and full-term infants is explained by the difference in the site of the brain lesion between the two groups. 136

138 Nederlandse samenvatting In 2014 werden in Nederland ongeveer kinderen geboren; wereldwijd waren het er ongeveer Bij een deel van deze geboortes traden perinatale complicaties op, zoals prematuriteit, perinatale asfyxie en dysmaturiteit. Perinatale asfyxie komt nogal eens voor; de term verwijst naar moeilijkheden rond en tijdens de geboorte. Asfyxie wordt echter nogal verschillend gedefinieerd. In het huidige onderzoek zijn met name de gevolgen van asfyxie voor de neuromotorische ontwikkeling van het à terme geboren kind bestudeerd. A terme geboren kinderen met asfyxie worden in dit proefschrift kinderen met een moeilijke start genoemd (Difficult Birth At Term, DBAT). In de loop van de jaren werd steeds duidelijker dat het risico voor ontwikkelingsproblemen bij kinderen met DBAT vooral werd bepaald door de ernst van de resulterende neonatale encephalopathie (NE). Dit werd ontdekt doordat in de laatste decennia met name westerse academische centra steeds modernere beeldvormende technieken gebruikten om de ernst van de NE te bepalen. Het voor handen zijn van deze beeldvormende technieken en de introductie van koeltechnieken na asfyxie om hersenschade te beperken hebben de therapeutische benadering van kinderen met DBAT aanzienlijk beinvloed. Niettemin zijn deze techieken meestal niet beschikbaar in nietgeindustrialiseerde landen; evenmin zijn zij beschikbaar in nietacademische centra in geindustrialiseerde, westerse landen. Echter, ook in deze settings is het belangrijk om het risico op negatieve gevolgen zo vroeg mogelijk te kunnen bepalen. Vroege diagnostiek biedt de mogelijkheid tot vroegtijdige behandeling in een periode dat de plasticiteit van het brein op zijn grootst is. Het beoordelen van de General Movements (GMs) is een goedkoop diagnostisch instrument dat in alle klinische situaties kan worden gebruikt. De GM-methode heeft een hoge voorspellende waarde voor de verdere neuromotorische ontwikkeling, inclusief de ontwikkeling van cerebrale parese (CP) - vooral bij kinderen met een hoog risico op 137

139 ontwikkelingsstoornissen. Deze kinderen worden meestal opgenomen in academische centra. Vooral duidelijk afwijkende (DA) GMs rond de leeftijd van 3 maanden (de fidgety GM-fase) zijn geassocieerd met het ontstaan van CP. In de studies van dit proefschrift (studies 1-4) is de neuromotorische ontwikkeling bestudeerd van premature, maar in het bijzonder van à terme geboren kinderen na een lichte tot matige asfyxie. De kinderen werden zowel kort na de geboorte als op de leeftijd van 3 maanden (gecorrigeerde leeftijd) onderzocht met behulp van de GM-methode (studies 1 en 2). De mogelijk latere gevolgen van DBAT zijn bij de à terme kinderen op de leeftijd van 6 jaar onderzocht. In deze follow-up werd speciale aandacht besteed aan de activiteiten binnen het domein mobiliteit van de International Classification of Functioning, Disability and Health: Children and Youth version (studie 3). Door de vervolgstudie was het ook mogelijk om de voorspellende waarde van de GMs te evalueren zowel voor CP, als voor lichtere vormen van beperkte mobiliteit bij à terme kinderen op de leeftijd van 6 jaar (studie 4). Studie 1: Kwaliteit van General Movements van à terme geboren kinderen met een moeilijke start. In dit onderzoek hebben wij onderzocht welke risicofactoren rond de geboorte invloed hebben op de neurologische conditie van baby s met DBAT, zowel kort na de geboorte ( writhing GM fase) als rond de leeftijd van 3 maanden ( fidgety GM fase). Wij onderzochten daartoe 64 à terme kinderen geboren na DBAT in een regionaal ziekenhuis in Nederland. De kinderen behoorden tot de studiegroep wanneer ze voldeden aan twee van de vier volgende voorwaarden: een abnormaal cardiotocogram, een Apgar score < 7 na 5 minuten, een navelstreng ph < 7.20 en een navelstreng base excess <-10 mmol/liter. 138

140 Uit het onderzoek bleek dat baby s met DBAT vaker afwijkende GMs lieten zien rond de leeftijd van 3 maanden dan 3 maanden oude baby s uit de algemene populatie (licht afwijkende (MA) GMs: 38% vs 25%, DA GMs: 14% vs. 4%). DA GMs rond de geboorte hielden vooral verband met het algemeen ziek zijn van het kind door de moeilijke geboorte. DA GMs op 3 maanden hielden vooral verband met afwijkingen op de schedelecho, maar niet met de mate van ernst hiervan. Wij concludeerden hieruit dat het GMonderzoek, in het bijzonder rond de 3 maanden, een waardevol instrument is om de conditie van het zenuwstelsel te beoordelen van baby s met DBAT. Studie 2: Draagt asfyxie rond de geboorte bij tot slechter neurologisch functioneren van prematuur geboren kinderen? Van prematuur geboren kinderen is in het algemeen bekend dat ze een groter risico lopen op neurologische ontwikkelingsproblemen dan à terme geboren kinderen. Er bestaan echter relatief weinig studies over het extra risico van asfyxie op neuromotorische afwijkingen bij premature kinderen. De oorzaak hiervan is waarschijnlijk dat asfyxie bij prematuur geboren kinderen nog moeilijker te definiëren is dan bij à terme geboren kinderen. In deze studie hebben we de invloed van asfyxie op de neurologische ontwikkeling geanalyseerd. Zeventien premature kinderen met asfyxie namen deel aan het onderzoek samen met 34 premature kinderen zonder asfyxie. De leeftijd van alle kinderen lag onder de 35 weken zwangerschapsduur en de kinderen met asfyxie namen op dezelfde voorwaarden deel, als die van à terme kinderen in studie 1. De beoordeling van de neurologische conditie werd gedaan op basis van de GM-methode. De diagnose CP werd gesteld op basis van klinisch onderzoek op de (gecorrigeerde) leeftijd van 2 jaar. De uitkomsten van het onderzoek waren gelijk voor de premature kinderen met en zonder asfyxie: 12-18% van de kinderen lieten DA GMs zien rond de 3 maanden in beide groepen en 11% van de kinderen in beide groepen ontwikkelden CP. 139

141 DA GMs in de fidgety GM fase hielden geen verband met de criteria van asfyxie, maar wel met de ernst van de periventriculaire leucomalacie (PVL) op de schedelecho. Ook was er een duidelijk verband tussen DA GMs en CP. Studie 3: Beperkingen in activiteiten binnen het domein mobiliteit op 6- jarige leeftijd bij à terme geboren kinderen met een moeilijke start (DBAT). Negenenvijftig kinderen (95%) uit studie 1 werden op 6-jarige leeftijd opnieuw onderzocht, samen met een - in samenstelling qua gestatieleeftijd bij geboorte, geboortegewicht, geboorte via keizersnede en geslacht overeenkomende - contrôle groep van 81 kinderen met een goede start bij geboorte. Als belangrijkste uitkomst namen wij beperkte mobiliteit die wij definieerden als een percentielscore P15 van de Movement ABC. De drie kinderen die CP ontwikkelden werden van detailonderzoek uitgesloten, omdat zij de Movement ABC niet konden uitvoeren. Andere uitkomsten waren: het aanwezig zijn van minor neurological dysfunction (MND), leeren gedragsstoornissen en de behoefte aan fysiotherapeutische behandeling. Kinderen met DBAT, die een lichte tot matige neonatale encefalopathie (NE) hadden, lieten vaker een beperkte mobiliteit zien op 6-jarige leeftijd dan kinderen zonder NE. Het verhoogde risico op beperkte mobiliteit kwam voornamelijk op het conto van het verhoogde risico op beperkingen in de fijne handmotoriek. Het risico op beperkte mobiliteit steeg met de ernst van de NE. Kinderen met DBAT zonder NE hadden geen verhoogd risico. De klinisch relevante vorm van MND (complexe MND), leerproblemen en behoefte aan kinderfysiotherapie kwamen vaker voor bij kinderen met DBAT dan bij kinderen zonder DBAT. Er was geen verschil in het voorkomen van gedragsproblemen tussen beide groepen. De aanwezigheid van complexe MND hing, net als beperkte mobiliteit, samen met de ernst van de NE. Dat gold echter niet voor leerproblemen en de behoefte aan kinderfysiotherapie. 140

142 Wij concludeerden hieruit, dat kinderen met DBAT resulterend in een lichte tot matige NE, gediagnostiseerd in een niet-academisch ziekenhuis, vaker beperkingen in mobiliteit hebben op 6-jarige leeftijd dan kinderen zonder DBAT. Daarom is het aan te raden om zowel de mobiliteit als de neurologische ontwikkeling van deze kinderen de eerste 6 jaar regelmatig te evalueren. Studie 4: Onderzoek naar de voorspellende waarde van General Movements voor cerebrale parese en voor minder ernstige vormen van beperkte mobiliteit bij kinderen van 6 jaar. Het GM-onderzoek is een niet-invasieve methode, die kan helpen om vroegtijdig te constateren of kinderen risico lopen op ontwikkelingsstoornissen. GMs zijn spontane, niet doelgerichte bewegingen waar het hele lichaam aan deelneemt en die tot ongeveer 3 à 4 maanden te zien zijn. De kwaliteit van deze bewegingen, met name de variatie en de complexiteit, zegt iets over de conditie van het zenuwstelsel. De meeste onderzoeken over GMs gaan over premature kinderen, of gemengde groepen van premature en à terme kinderen met een zeer hoog risico op ontwikkelingsproblemen. In deze onderzoeken werd geconcludeerd dat de voorspellende waarde van de GMs voor latere ontwikkelingsstoornissen zeer hoog was. Maar er is tot nu toe zeer weinig bekend over de voorspellende waarde van GMs bij kinderen met een lager risico op ontwikkelingsstoornissen. Zodoende onderzochten wij verbanden tussen de kwaliteit van GMs en ontwikkelingsproblemen bij à terme kinderen op de leeftijd van 6 jaar. We waren daarbij geïnteresseerd in het voorspellen van CP als ook in het voorspellen van beperkte mobiliteit bij kinderen zonder CP. We gebruikten daartoe de gegevens van alle deelnemers van studie 3. DA GMs omstreeks 3 maanden bleken redelijk goed CP te voorspellen nl. met een sensitiviteit van 60%, een specificiteit van 91%, een positief voorspellende waarde van 19% en een negatief voorspellende waarde van 141

143 98%. Bij kinderen zonder CP was er geen verband tussen de kwaliteit van GMs en beperkte mobiliteit. GM-kwaliteit rond de geboorte voorspelde niet de aanwezigheid van ontwikkelingsproblemen op de leeftijd van 6 jaar. Onze conclusie was dat DA GMs rond de 3 maanden bij à terme kinderen wel degelijk CP voorspellen, maar minder overtuigend dan bij premature kinderen. De kwaliteit van GMs heeft bij à terme kinderen zonder ernstige hersenpathologie en zonder CP geen voorspellende waarde voor beperkte mobiliteit. Deze studie ondersteunt de suggestie uit de literatuur dat de kwaliteit van GMs CP en beperkingen in mobiliteit bij premature kinderen beter voorspelt dan bij à terme geboren kinderen. Belangrijkste conclusies uit dit proefschrift: In een niet-academische setting is het GM-onderzoek bij à terme baby s geboren met een moeilijke start een goede methode om de gezondheid van het zenuwstelsel in de eerste 3 levensmaanden te evalueren. Prematuren met een moeilijke start hadden niet vaker afwijkende GMs dan prematuren zonder een moeilijke start. Zij hadden ook niet vaker CP op de leeftijd van 18 maanden. De afwijkende GMs bij premature baby s rond de (gecorrigeerde) leeftijd van 3 maanden hielden wel verband met PVL op de schedelecho en met de ontwikkeling van CP. Kinderen met DBAT die een lichte tot matige NE ontwikkelen hebben een verhoogde kans op beperkingen in mobiliteit op de leeftijd van 6 jaar. Het risico voor kinderen met matige NE is groter dan voor kinderen met lichte NE. DA GMs op de leeftijd van 3 maanden voorspellen inderdaad CP bij à terme geboren kinderen, maar minder secuur dan bij premature kinderen. De kwaliteit van GMs voorspelt niet de aanwezigheid van beperkingen in mobiliteit op 6-jarige leeftijd bij kinderen zonder CP. 142

144 Mogelijk heeft het verschil in voorspellingskracht van de GMs tussen à terme en preterme kinderen te maken heeft met het verschil in lokalisatie van de hersenbeschadiging van premature - en à terme kinderen. 143

145 144

146 References 145

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156 motor behavior caused by a lesion of the brain at early age? Neural Plast 2003;10: Hadders-Algra M. Two distinct forms of minor neurological dysfunction: perspectives emerging from a review of data of the Groningen Perinatal Project. Dev Med Child Neurol 2002;44: van Hoorn JF, Maathuis CG, Peters LH, Hadders-Algra M. Handwriting, visuomotor integration, and neurological condition at school age. Dev Med Child Neurol 2010;52: Punt M, DE Jong M, DE Groot E, Hadders-Algra M. Minor neurological dysfunction in children with dyslexia. Dev Med Child Neurol 2010;52 : Peters LHJ, Maathuis KGB, Kouw E, Hamming M, Hadders-Algra M. Test-retest, interassessor and intra-assessor reliability of the modified Touwen examination. Eur J Paediatr Neurol 2008;12: Hadders-Algra M, Heineman KR, Bos AF, Middelburg KJ. The assessment of minor neurological dysfunction in infancy using the Touwen Infant Neurological Examination: strengths and limitations. Dev Med Child Neurol 2010;52: Barnett A, Mercuri E, Rutherford M, Haataja L, Frisone MF, Henderson S, Cowan F, Dubowitz L. Neurological and perceptualmotor outcome at 5-6 years of age in children with neonatal encephalopathy: relationship with neonatal brain MRI. Neuropediatrics 2002;33: Arnaud C, Daubisse-Marliac L, White-Koning M, Pierrat V, Larroque B, Grandjean H, Alberge C, Marret S, Burguet A, Ancel PY, Supernant K, Kaminski M. Prevalence and associated factors of minor neuromotor dysfunction at age 5 years in prematurely born children. Arch Pediatr Adolesc 2007;161: Soorani-Lunsing RJ, Hadders-Algra M, Huisjes HJ, Touwen BC. Minor neurological dysfunction after the onset of puberty: association with perinatal events. Early Hum Dev 1993;33:

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158 outcome of asphyxiated term neonates. J Child Neurol 2001;16: Alderliesten T,de Vries LS, Khalil Y, van Haastert IC, Benders MJNL, Koopman-Esseboom C, Groenendaal F. Therapeutic hypothermia modifies perinatal asphyxia-induced changes of the corpus callosum and outcome in neonates. PLoS One2015;10:e Logitharajah P, Rutherford MA, Cowan FM. Hypoxic-ischemic encephalopathy in preterm infants: antecedent factors, brain imaging, and outcome. Pediatr Res 2009;66: Goldenberg RL, Huddlestone JF, Nelson KG. Apgar scores and umbilical arterial ph in preterm newborn infants. Am J Obstet Gynecol 1984;149: Hüseman D, Metze B, Walch E, Bührer C. Laboratory markers of perinatal acidosis are poor predictors of neurodevelopmental impairment in very low birth weight infants. Early Hum Dev 2011;87: Volpe JJ. Neurobiology of periventricular leukomalacia in the premature infant. Pediatric Research 2001;50: Perlman JM. White matter injury in the preterm infant: an important Determination of abnormal neurodevelopmental outcome. Early Hum Dev 1998;53: Serdaroglu G, Tekgul H, Kitis O, Serdaroglu E, Gökben S. Correlative value of magnetic resonance imaging for neurodevelopmental outcome in periventricular leucomalacia. Dev Med Child Neurol 2004;46: Spittle AJ, Cheong J, Doyle LW, Roberts G, Lee KJ, Lim J, Hunt RW, Inder TE, Anderson PJ. Neonatal white matter abnormality predicts childhood motor impairment in very preterm children. Dev Med Child Neurol 2011;53: Shang Q, MA C, LV N, LV ZL, Yan YB, WU ZR, LI JJ, Duan JL, Zhu CL. Clinical study of cerebral palsy in 408 children with periventricular leucomalacia. Exp Ther Med 2015;9:

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161 160

162 Co-authors affiliations 161

163 List of co-authors affiliations Annechien M. Algra, MD University Medical Centre Groningen, Beatrix Children s Hospital, Department of Developmental Neurology, Groningen, the Netherlands. Saskia C.M. Bakker, MD Paediatric Department, Gelre Hospital, Apeldoorn, the Netherlands. Arnold H.J. Jonker, PT Physical Therapy Department and Medical Photography Department, Gelre Hospital, Apeldoorn, the Netherlands. Mijna Hadders-Algra, MD, PhD University Medical Centre Groningen, Beatrix Children s Hospital, Department of Developmental Neurology, Groningen, the Netherlands. 162

164 Dankwoord 163

165 Dankwoord Aan het einde van deze lange, interessante en intensieve rit wil ik iedereen, die uitvoerig of in het heel klein een bijdrage heeft geleverd aan dit onderzoek, bedanken. Ik had het nooit alleen kunnen volbrengen en wil een groot aantal mensen met name noemen, Allereerst Prof. Dr. Mijna Hadders-Algra: Mijna, jij hebt mij enthousiast gemaakt voor ontwikkelings-neurologie en je hebt van een hyperactief praktijkmens toch een nieuwsgierige wetenschapper weten te maken. Je liet me drie keer terugkomen naar Groningen met mijn plannen, maar toen je erin begon te geloven heb je me het hele periode voor 100% gesteund, ook op de minder gemakkelijke momenten in het promotietraject. Ik vind het een eer om met je te mogen samenwerken en fantastisch om je zoveel beter te leren kennen. Bedankt voor het vertrouwen dat je in me hebt gehad en alle hulp die ik van je mocht krijgen. Ik bedank de leden van de leescommissie: Prof. Dr. A. Bos, Prof. Dr. P. Helders en Prof Dr. R. Nijhuis-van der Sanden zeer hartelijk voor het zorgvuldig lezen van het proefschrift Arnold Jonker, mijn studiegenoot, collega en goede vriend vanaf 1969: Je hebt bijna al het filmwerk gedaan, veel vrije tijd aan het uitzoeken en monteren besteed, films mee beoordeeld en de te testen kinderen ( en mij) gekalmeerd als ik bijna mijn geduld verloor. Vanaf de eerste plannen in 1998 zei je tegen me: ik maak hoe dan ook het hele traject met je af! Ik kan me geen betrouwbaarder maatje voorstellen. Saskia Bakker, je bent van het begin af aan altijd enthousiast is geweest voor mijn ideeën, mijn manier van werken en mijn onderzoek. Jij hebt mogelijk gemaakt, dat ik de General Movements onderzoek in 1998 structureel kon implementeren in het Gelre ziekenhuis, zoals het nu nog steeds gedaan wordt. Je stond open voor de nieuwe inzichten uit Groningen en gaf me de benodigde medische achtergrond voor mijn proefschrift. Dank 164

166 voor je steun en het blijmoedig tolereren van mijn opjagende telefoontjes en mailtjes. Maarten Haazebroek, als collega fotograaf van Arnold rolde je in mijn onderzoek. Je was gelijk enthousiast en ook als niet-medicus reuze geïnteresseerd. Dank voor je hulp met filmen en je artistieke input o.a. in de vorm van de cover van mijn proefschrift. Prof. Dr. Ale Algra en Drs. Annemijn Algra, jullie hebben ons geholpen, toen het spelen met cijfers en statistiek zeker voor mij een brug te ver bleek. Annemijn, dank voor je jonge, frisse kijk op tekst en inhoud van m.n. mijn derde artikel. Het was een lange bevalling, gelukkig was het kind niet asfyctisch, maar kerngezond. Kinderartsen en gynaecologen van het Gelre Ziekenhuis: Dank voor jullie ondersteuning bij het signaleren en aanmelden voor de intake van de studie-kinderen. Verloskundigenpraktijk Doevedans: Bedankt voor jullie enthousiaste medewerking met het vinden van een referentie groep van 84 kinderen met de juiste achtergrond. Dan wil ik, als absoluut onmisbaar onderdeel van dit onderzoek de ouders en kinderen bedanken, die hebben deelgenomen aan het onderzoek gedurende dit hele lange traject. Door jaarlijks naar jullie te mailen, heb ik met de meesten van jullie nog contact, waardoor dit onderzoek een onwaarschijnlijk lage uitval van proefpersonen heeft (3 kinderen). Veel dank voor het geduld en enthousiasme. Ook jullie kunnen trots zijn op het resultaat en het gevoel hebben dat jullie aan iets moois hebben bijgedragen. Ook veel dank aan de onderwijskrachten van de kinderen, die ondanks de vele lijsten die ze vaak al moeten invullen, toch trouw mijn vragenlijsten hebben beantwoord. Ik weet hoeveel ik jullie ermee belast heb en waardeer jullie medewerking enorm. Ik noem ook al die praktische hulp van mensen binnen het ziekenhuis, die altijd weer wat voor me wilden opzoeken of navragen, iemand wilden bellen, 165

167 iets voor me wilden regelen: Secretaresses van de kinderafdeling, Marianne Schut van de medische administratie, Fenny, Daphne en Simone van de medische bibliotheek, verpleging van de afdeling neonatologie en gynaecologie. Frank Eggelmeijer bedankt voor het geven van de eerste duw in de richting van wetenschappelijk onderzoek (in de trein naar Amersfoort) en het meelezen en stellen van kritische vragen. Nienke Devlin, ongelooflijke doorzetster, je haalde iedere keer nog kleine foutjes uit alle engelse teksten, waar wij volledig overheen lazen, dank voor je perfectionisme. Joris Hoyng: veel dank voor het kritisch bekijken van het proefschrift met name op leesbaarheid. En: last but not least mijn collegae Bart Coenraads en Ger Derks, voor jullie onconventionele manier van denken over ons vak en vaak geslaagde pogingen om mij uit het Juliana-structuur-denken los te wrikken en in groter verband te leren kijken en denken. Hopelijk heb ik jullie op mijn beurt ook kunnen enthousiasmeren voor de wetenschap. Al mijn collegae bedank ik voor het enthousiasme voor mijn werk en geduld bij het aanhoren van mijn onderzoeks-verhalen en frustraties en bij het jarenlang bezet houden van oefenruimte voor mijn testen. Mijn familie (alle 68): dank dat jullie er altijd voor me zijn en me door dik en dun steunen. Patricia van Iersel 166

168 Curriculum vitae 167

169 Curriculum Vitae van Patricia Anna Maria van Iersel Patricia van Iersel werd geboren op 25 augustus 1949 te Breda. In juni 1967 haalde zij het eindexamen Gymnasium β op het Mencia de Mendoza Lyceum te Breda. Zij werkte een jaar in de verpleging in Leysin, Zwitserland en volgde daarna de opleiding voor Fysiotherapie in Utrecht. Op 26 juni 1972 behaalde zij het staatsexamen voor de bevoegdheid van algemeen fysiotherapeut. Van september 1972 tot augustus 1973 was zij werkzaam als fysiotherapeut op afdeling Kinderneurologie, UMC (destijds AZU) Utrecht, bij Prof. Dr. J. Willemse. Daarna werd zij uitgezonden door de Stichting Nederlandse Vrijwilligers en werkte tot februari 1976 in Kisumu, Kenya, als fysiotherapeut voor de Association for the Physically Disabled in Kenya (APDK). Zij bereisde daar 2 provincies naar poliklinieken voor de hoofdzakelijk orthopedische begeleiding van gehandicapte kinderen, meestal met poliomyelitis, klompvoetjes en soms lijdend aan cerebrale parese. In Kisumu had ze de leiding over een kleine orthopedische werkplaats. Na terugkeer uit Kenya werkte zij van 1 maart 1976 tot 1 november 2013 als geregistreerd algemeen fysiotherapeut en vanaf 1998 tevens als geregistreerd kinderfysiotherapeut in het Gelre Ziekenhuis te Apeldoorn (vroeger Julianaen Lukas Ziekenhuis). Gedurende die periode behaalde zij op 3 november 1979 het diploma docent Fysiotherapie op het Gymnologisch Instituut Universiteit Utrecht bij Prof. Rijsdorp. Daarna volgde een lange periode van voortdurende na- en bijscholing om de bevoegdheid van algemeen- en kinderfysiotherapeut te verkrijgen en te behouden (o.a. N.D.T, prélogopedie, sensomotoriek, F.O.K cursus, aanvullingscursus N.V.F.K, wetenschappelijk onderzoek, Beoordeling General Movements, neuromotorisch leren, Infant Motor Profile, Minor Neurological Dysfunction). 168