The Value of Neonatal Neurological Assessment in ...€¦ · Results of neonatal neurological...

The Value of NeonatalNeurological Assessment

in Predicting NeurodevelopmentalProblems at Preschool Age

Aulikki Lano

Department of Child NeurologyUniversity of Helsinki,

Finland

Academic dissertation

To be publicly discussed by permission of the Medical Faculty of the University of

Helsinki, in Large Lecture Hall at Haartman Institute, Haartmaninkatu 3,

on December 20th, 2002, at 12 noon.

Helsinki 2002

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SUPERVISORS Professor Kalle Österlund, M.D., Ph.D.

and

Elina Liukkonen, M.D., Ph.D.

Department of Child Neurology

Hospital for Children and Adolescents

University of Helsinki

Helsinki, Finland

REVIEWERS Professor Mijna Hadders-Algra, M.D., Ph.D.

Institute of Developmental Neurology

University of Groningen

Groningen, The Netherlands

and

Docent Kirsti Heinonen, M.D., Ph.D.

Department of Pediatrics

University of Kuopio

Kuopio, Finland

OFFICIAL OPPONENT Docent Leena Vainionpää, M.D., Ph.D.

Department of Pediatrics

University of Oulu

Oulu, Finland

ISBN 952-91-5314-7 (nid.)

ISBN 952-10-0786-9 (PDF)

Yliopistopaino

Helsinki 2002

3

To Tapio, Juhana, Henrik and Heidi-Maaria

5

ABSTRACT

The predictive value of neonatal neurological abnormality on outcome at preschool age was in the present

study evaluated by means of a quantitative and qualitative neurological examination.

A representative regional cohort of 2193 neonates consisting of hospitalized infants (N=1535) and control

infants (N=658), born in 1985-1986, was followed prospectively from birth to 56 months of age. Both the

hospitalized infants and control infants were examined neonatally at 40 weeks of postmenstrual age and

again at 56 months of chronological age using the same methods. The two neonatal neurological classifica-

tion methods used were based on the same standardized and modified examination (Prechtl). The first one

was based on the total optimality score (quantitative method) and the second one on the clinical classification

of neurological normality and abnormality in five subsystems of CNS (qualitative method). The allocation of

the neonates into the three study groups by the two methods was based on the results of the neonatal neuro-

logical examination and the need for early neonatal hospitalization. Follow-up assessment at 56 months of

age included neurological (modified Touwen’s test) and neuromotor (motor competence) assessment, tests of

visual-motor integration (VMI), cognitive ability (CMM), verbal competence (AWST) and language com-

prehension (LSVT).

The quantitative and qualitative neurological classification methods selected neonatally neurologically

different abnormal infants in respect to pre-perinatal risk and gestational age. The quantitative method

included more preterm infants, whereas the qualitative method included more sick full-term infants. Gesta-

tional age had a significant effect on the result of neonatal neurological examination.

Different profiles of minor neurological impairments at 56 months of age were found to associate with the

neonatally neurologically abnormal groups defined by the quantitative and qualitative methods. The prob-

lems in the quantitatively abnormal group were mainly related to gross motor function and strabismus,

whereas those in the qualitatively abnormal group to fine motor and facial-oral motor function. The profiles

resembled those described earlier in the literature in preterm and full-term infants with respect to major

motor impairments after ischemic brain injury. It appears that there is a similar but milder spectrum in the

continuum of neurological impairments after ischemic brain injury for preterm and full-term children.

MND (mild neurological dysfunction) as a qualitative measure and DMC (deviant motor competence) as a

quantitative measure of minor neurological abnormality at 56 months of age did not overlap entirely, and

both are thus presumed to describe different aspects of minor neurological morbidity. Both of them were also

significantly associated with deviancy in visual-motor function, cognitive and language skills. Of all subsys-

tems of CNS, fine motor function correlated best with cognitive capacity and language skills.

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Male gender, prematurity- and asphyxia-related obstetrical and neonatal morbidity factors were most impor-

tant risk factors for neonatal and 56 months’ neurological abnormalities. Boys and very preterm children

compared with girls and full-term children had significantly more often minor neurological abnormalities,

especially poor fine motor function. The low education of the father associated with DMC.

Neonatal neurological abnormality, significantly more often than neonatal neurological normality, was

associated with MND, DMC, CP and problems in visual-motor integration, and poorer performance in

cognitive ability and language comprehension tests, and with major and minor impairments at preschool age.

Among the neonatal neurological normal infants, early neonatal morbidity increased the probability of future

developmental problems. However, sensitivity and positive predictive values of an abnormal single neonatal

neurological examination were low by both neonatal neurological classification methods, whereas specificity

and negative predictive values were high.

An abnormal result in a single age-specific neonatal neurological examination at term postmenstrual age did

not predict reliably the future development of an individual child. Children with a severe brain injury as a

consequence of pre-, peri- or neonatal complications will develop neurodevelopmental abnormalities early,

whereas some of the neonatally neurologically abnormal infants will recover and develop normally. Instead,

a normal result in a neonatal neurological examination, without neonatal morbidity risk factors, predicts,

with high certainty, development without major impairments.

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CONTENTS

1. ABBREVIATIONS /11

2. INTRODUCTION /13

3. REVIEW OF THE LITERATURE /15

3.1. Neonatal neurological examination /15

3.1.1. Methods of neonatal neurological examination

3.1.2. Specific features and criteria of abnormality in neonatal neurological assessment

3.1.3. Incidence of neonatal neurological abnormalities in previous studies

3.2. Classification and definition of neurodevelopmental impairments, disabilities and handicaps /21

3.3. Major impairments / disabilities /22

3.3.1. Cerebral palsy

3.3.2. Mental retardation

3.3.3. Hydrocephalus

3.3.4. Epilepsy

3.3.5. Visual impairment

3.3.6. Hearing impairment

3.4. Minor impairments / disabilities /26

3.4.1. Minor neurological/neuromotor dysfunction

3.4.2. Minor neurodevelopmental disorders

3.4.3. Speech/Language disorders

3.5. Effect of gender on morbidity /29

3.6. Effect of environmental factors on developmental disturbances /30

3.7. Mortality / Survival /30

3.7.1. Perinatal, neonatal and postneonatal mortality, and survival rates

3.8. Incidence of prematurity /31

3.9. Follow-up studies /32

3.9.1. Infants with neonatal neurological examination

3.9.2. Premature infants

3.9.3. Infants with hemorrhagic/ischemic brain lesions

3.9.4. Infants with asphyxia

3.9.5. Infants with neonatal seizures

3.9.6. Small-for-gestational-age infants

3.9.7. Infants with multiple risk factors (high-risk infants)

4. AIMS OF THE STUDY /49

5. SUBJECTS AND METHODS /50

5.1. Neonatal study population /50

5.1.1. Hospitalized group

5.1.2. Control group

5.1.3. Neonatal dropouts and exclusions

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5.1.4. Final neonatal study series

5.2. Sociodemographic, pre-, peri- and neonatal data collection /52


5.3.1. Classification methods and study groups

5.3.1.1. Quantitative method (NeoQuan)

5.3.1.2. The study groups by the quantitative method (NeoQuan1, 2 and 3)

5.3.1.3. Qualitative method (NeoQual)

5.3.1.4. The study groups by the qualitative method (NeoQual1, 2 and 3)

5.3.1.5. Interrelationships of NeoQuan and NeoQual groups

5.4. Follow-up study series at the age of 56 months /57

5.4.1. Dropouts and exclusions after neonatal neurological examination

5.4.2. Analysis of predictability of impairments and disabilities at 56 months of age

5.4.3. NeoQuan and NeoQual groups at 56 months of age

5.5. Follow-up evaluations at the age of 56 months /59

5.5.1. Neurological examination

5.5.1.1. Mild neurological dysfunction (MND), qualitative assessment

5.5.1.2. Deviant motor competence (DMC), quantitative assessment

5.5.1.3. Definite neurological abnormality

5.5.2. Vision and hearing

5.5.3. Hand preference

5.5.4. Visual-motor integration

5.5.5. Cognitive development

5.5.6. Speech and language

5.6. Definitions of impairment and disability /63

5.7. Statistical methods /66

6. RESULTS /68

6.1. Results of neonatal neurological examination among the hospitalized and control infant /68

6.1.1. Non-optimal signs

6.1.2. Neurological optimality score

6.1.3. Subsystems of CNS

6.2. Neonatal characteristics within the six study groups defined by results of the quantitative and qualitative as-

sessments /72

6.2.1. Gender

6.2.2. Gestational age and birth-weight

6.2.3. Sociodemographic characteristics

6.3. Antecedents and co-morbidity of neonatal neurological abnormality /75

6.3.1. Variables associated with obstetrics and delivery

6.3.2. Neonatal morbidity during primary hospitalization

6.3.3. Casaer’s intensity score

6.4. Background factors of abnormal neonatal neurology /85

6.4.1. Quantitative method (NeoQuan1)

9

6.4.2. Qualitative method (NeoQual1)

6.5. Neurodevelopmental assessment at the age of 56 months /87

6.5.1. Neurological examination

6.5.1.1. Qualitative assessment /87

6.5.1.1.1. Eight subsystems of CNS, percentage sum scores

6.5.1.1.2. Eight subsystems of CNS, dichotomized variables

6.5.1.1.3. Mild neurological dysfunction (MND)

6.5.1.2. Quantitative assessment /96

6.5.1.2.1. Motor competence, percentage sum score

6.5.1.2.2. Deviant motor competence (DMC), dichotomized variable

6.5.1.3. Hand preference


6.5.3. Cognitive/language tests

6.5.4. Speech problems

6.5.5. The effect of parents’ education on performance in VMI, cognitive and language tests

6.6. Outcome at 56 months of age /109

6.6.1. Major and minor impairments among the study subjects

6.6.1.1. Cerebral palsy

6.6.1.2. Mental retardation

6.6.1.3. Epilepsy

6.6.1.4. Hydrocephalus

6.6.1.5. Visual impairment

6.6.1.6. Hearing impairment

6.7. Impairments and disabilities at the age of 56 months /113

6.8. Association between outcome variables at the age of 56 months /115

6.9. Background factors of abnormal subsystems of CNS, mild neurological dysfunction (MND) and deviant motor

competence (DMC) /116

6.10. Association of neonatal neurological examination with results of neurodevelopmental examination at the age of

56 months /118

6.11. The predictive power of the neonatal neurological examination on the neurodevelopmental assessment at the

age of 56 months /122

7. DISCUSSION /124

7.1. Subjects and methods /124

7.1.1. Study population

7.1.2. Neonatal neurological examination methods

7.1.3. Assessment methods at 56 months of age

7.1.4. Dropouts

7.2. Survival /128


7.4. Background factors of neonatal neurological abnormality /132

7.5. Assessment at 56 months of age /136

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7.5.1. Abnormalities in subsystems of CNS, mild neurological dysfunction (MND) and deviant motor compe-

tence (DMC)

7.5.2. Hand preference

7.5.3. Background factors of subsystems of CNS, MND and DMC


7.5.5. Cognitive and language tests

7.5.6. Major impairments/disabilities

7.6. Interrelationship between the outcome measures and implications of abnormal preschool examination /145

7.7. Predictive validity of the neonatal neurological examination /147

7.8. Usefulness of the two neonatal neurological classification methods /148

8. CONCLUSIONS /152

9. ACKNOWLEDGEMENTS /154

10. REFERENCES /157

11. APPENDICES /178

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1. ABBREVIATIONS

ADHD Attention deficit hyperactivity disorder

AGA Appropriate for gestational age

ANCOVA Analysis of covariance

ANOVA Analysis of variance

ATNR Asymmetric tonic neck reflex

AWST Aktiver Wortschatztest

BW Birth-weight

CMM Columbia Mental Maturity Scale

CNS Central nervous system

CP Cerebral palsy

CTG Cardiotocografia

DAMP Deficits in attention, motor control and perception

DCD Developmental coordination disorder

DMC Deviant motor competence

DQ Developmental quotient

EEG Electroencephalogram

ELBW Extremely low birth-weight, BW 1000g or less

FT Full-term, 37 or more completed weeks of gestation

FU Follow-up

GA Gestational age

GWK Gestational week

HC Hydrocephalus

HIE Hypoxic-ischemic encephalopathy

IQ Intelligence quotient

IVH Intraventricular hemorrhage

LBW Low birth-weight, 2500g or less, 2000g or less in some studies

LGA Large for gestational age, birth-weight above 2SD of the mean standards

LSVT Logopädischer Sprachverständnis Test

MBD Minimal brain dysfunction

MMR Mild mental retardation

MND Mild neurological dysfunction

MPT Moderate preterm, gestational age between 32 and 36 weeks

MR Mental retardation

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MRI Magnetic resonance imaging

NCPP The Collaborative Perinatal Project of the National Institute of Neurological

and Communicative Disorders and Stroke

NE Neonatal encephalopathy

NEOQUA The study groups by the quantitative and qualitative neonatal neurological

classification method

NEOQUAL The study group by the qualitative neonatal neurological classification method

NEOQUAN The study group by the quantitative neonatal neurological classification method

NPV Negative predictive value

PIVH Periventricular-intraventricular hemorrhage

PNM Perinatal mortality

PPV Positive predictive value

PROM Premature rupture of membranes

PT Preterm, 37 or less completed weeks of gestation

PVL Periventricular leucomalacia

ROP Retinopathy of prematurity

SD Standard deviation of the mean

SES Socioeducational status

SGA Small for gestational age, birth-weight below 10th

centile or below -2SD of the mean standards

SMR Severe mental retardation

TOMI Test of Motor Impairment

VLBW Very low birth-weight, 1500g or less

VMI Visual motor integration

VPT Very preterm, less than 32 completed weeks of gestation

WHO World Health Organization

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2. INTRODUCTION

As a result of vast progress in antenatal and neonatal intensive care during the past two decades, an increas-

ing number of extremely preterm and/or seriously ill infants survive. It has been debated whether, at the same

time, the number of children with disabilities has increased. At least there are more and more newborn

infants every year who may have an increased risk for developmental disabilities, and who therefore need

special follow-up (Allen 1993, Lee et al. 1995, Pharoah et al. 1998, Lorenz et al. 1998).

Although the extensive developments in brain imaging techniques have opened new insight into the anatomy

and pathology of the neonatal brain, they still have limitations in predicting future development, especially

concerning mild brain dysfunction (Levine 1990, Whitelaw 1994, Martin and Barkovich 1995, de Vries

1996, Holling and Leviton 1999). Consequently, clinical follow-up programs are still mostly based on a

variety of biologic and environmental risk factors such as prematurity, intracranial hemorrhage or periven-

tricular leucomalacia, perinatal asphyxia, intrauterine growth retardation, congenital malformations and

congenital infections.

Due to limited resources, a growing problem today is, however, which infants should be followed up in

special clinics. The problem is not made easier by the fact that about one quarter of the children with cerebral

palsy has no identifiable risk factor (Eicher and Batshaw 1993). Modern child health care should be able to

pick out and rehabilitate, not only children with major disabilities, but also children who have subtle weak-

nesses in specific developmental areas such as in language, visual-perceptual or motor function. Intervention

services should be offered before school age, because later rehabilitation or therapeutic intervention may not

prevent or repair secondary behavioral problems caused by developmental disorders and lowered self-esteem

(McCormick et al. 1993, Brooks-Gunn et al. 1994).

Follow-up studies with a careful study design can give valuable information on the proportion of children

who will develop impairments (Johnson 1997), the timing when particular impairments can be most accu-

rately and reliably observed (Astbury et al. 1990), on possible causal relationships between perinatal factors

and outcome (Mutch et al. 1989), and about the influence of new methods and treatments for neonatal

intensive units (Davies 1984). These data are important to physicians taking care of families with high-risk

infants, in order to decrease the `wait-and-see attitude´ (Page 1986), and the underestimation of parents’ need

to know the diagnosis and prognosis of their child (Escobar 1992, den Ouden 1993).

Neonatal neurological examination is one of the available tools in predicting the future development of an

infant. An abnormal result of the examination has been shown to associate with an abnormal developmental

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outcome in full-term infants with or without asphyxia, and in preterm infants (Brown 1974, Dubowitz et al.

1984, Robertson and Finer 1985, Hadders-Algra et al. 1986, Ishikawa et al. 1987, Allen and Capute 1989,

den Ouden 1990, Mercuri et al. 1999).

A Finnish-Bavarian prospective multicenter longitudinal study (`Arvo Ylppö study´) was started in order to

evaluate pre-, peri- and postnatal risk factors of the somatic, neurological, cognitive and social development

of children (Riegel et al. 1995). As a part of this project, the present study focuses on the value of neonatal

neurological assessments in predicting motor and cognitive problems of the children at pre-school age.

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3. REVIEW OF THE LITERATURE

3.1. NEONATAL NEUROLOGICAL EXAMINATION

3.1.1. METHODS OF NEONATAL NEUROLOGICAL EXAMINATION

There are several methods of neurological assessment for preterm and/or full-term newborn infants for

various diagnostic purposes. Table 1 lists different assessment methods, which have been used for the

neurological examination of the newborn infant.

Table 1. Neonatal neurological examination methods

AUTHOR(S) YEAR

SUITABLE FOR, BASED ON

CONTENTS

ANDRE-THOMAS, CHESNI SAINT-ANNE DARGASSIES 1960

General activity, muscle tone ( active, passive ) spontaneous movement, reactions, reflexes

SAINT-ANNE DARGASSIES 1977

FT+PT 106 items; posture, activity/ reactivity, motility, reflexes, straightening functions, muscle tone, sensory acquisitions

AMIEL-TISON, GRENIER 1986

FT+PT State of consciousness ( 6 ), muscle tone ( active, passive), reflexes, sensorial abilities ( visual pursuit, hearing, contact, interaction with environment )

PRECHTL, BEINTEMA 1964, 1977

FT+PT at 38 – 42 GA 42 items (optimal / non-optimal); behavioral state ( 6 ), posture, motility, pathological movements, eyes, motor system, responses ( intensity, threshold ), reflexes, cry

16

AUTHOR(S) YEAR


CONTENTS

BRAZELTON 1973,1995

FT+ healthy PT 28 behavioral items ( 9-point score ), 18 elicited responses ( 4-point score ), 7 supplementary items; state (6), habituation, orientation, motor processes, range of state, regulation of state, autonomic stability, reflexes

DUBOWITZ, DUBOWITZ 1981,updated 1999

FT+ PT

Parmelee Brazelton Saint-Anne Dargassies

33 items (5-point score); state ( 6 ), posture and tone ( 10 ), tone patterns ( 5 ), reflexes ( 6 ), movements ( 2 ), abnormal signs ( 3 ), behavior ( 7 )

MILANI-COMPARETTI 1967

Newborn to 24 mo 27 items; spontaneous behavior: postural control ( 7 ), active movement ( 2 ), evoked responses: primary reflexes ( 5 ), righting reactions ( 4 ), parachute reactions ( 4 ), tilting reactions ( 5 )

KURTZBERG et al. 1979

Einstein Neonatal Neurobehavioral Assessment Scale ( ENNAS )

FT+PT

Prechtl Brazelton

20 items (3-4-point score) + 4 summary items; state ( 6 ), orienting ( 2 ), active motility ( 6 ), reflexive responses ( 9 ), passive tone ( 2 ), summary items (spontaneous movements, incidence and quality of tremor, muscle tone, cuddliness)

MORGAN 1988

Neonatal Neurobehavioral Examination ( NNE )

FT+PT

Thomas Dubowitz Brazelton

27 items (3-point score); tone and motor patterns, primitive reflexes, behavioral responses, total score 27-81

17

AUTHOR(S) YEAR


CONTENTS

KORNER, THOM 1990

Neurobehavioral Assessment of the Preterm Infant (NAPI)

PT at 32-40 GA behavioral state, motor development and vigor, passive muscle tone, alertness and orientation, irritability, vigor of crying, percent asleep ratings

SHERIDAN-PEREIRA, ELLISON 1991

Neonatal Neurological Examination ( Neoneuro )

FT

Prechtl Dubowitz

32 items (5-point score); state (Prechtl 3-4), habituation ( 2 ), movement and tone ( 22 ), reflexes ( 11 ), neurobehavioral ( 9 )

PRECHTL 1990

Spontaneous Motor Activity (General Movements )

FT+PT functional assessment by video recording

In clinical practice, neonatal neurological assessment has been mainly based on the methods of Prechtl at

full-term age, that of Dubowitz and Dubowitz at preterm age, and that of Saint-Anne Dargassies and Amiel-

Tison at both ages. The Brazelton method, on the other hand, is a time-consuming tool, and is used mostly by

researchers. All four first-mentioned methods have been reported to be of considerable value in predicting

the neurodevelopmental outcome of an infant (Dubowitz et al. 1984, Hadders-Algra et al. 1986, Stewart et al.

1988, Bozynski et al. 1993)(see also Table 2). A normal result in the Einstein Neonatal Neurobehavioral

Assessment Scale was reported to associate with favorable outcome, but false positive results remained a

problem (Majnemer et al. 1995).

The tradition in the neurological examination technique of the French school (Andre-Thomas, Saint-Anne

Dargassies) was followed by methodology suggested by Prechtl (Prechtl and Beintema 1964, Prechtl 1977).

The method changed the neurological thinking from morphologically oriented to a comprehensive descrip-

tion of functional subsystems of the nervous system. The method was developed for full-term newborn

infants, but it is suitable also for prematurely born infants when they have reached full-term postconceptual

age. Prechtl introduced the concept of behavioral state (vide infra) of the infant to be crucial for the consis-

tency of an assessment. In addition to the qualitative description of pathological signs and consequent

neurological syndromes, the optimal findings in individual test variables as a quantitative measure were

summed up (optimality score). Prechtl introduced the optimality concept instead of normal-abnormal catego-

rizing for scoring, meaning the best possible condition/response in the neonatal neurological area (Prechtl

1980).

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The neurological examination by Dubowitz and Dubowitz (1981) combined both neurological and neurobe-

havioral items of assessment methods by Parmelee, Saint-Anne Dargassies and Brazelton.

Recently a new method of evaluating neonatal neurological integrity has been introduced by Prechtl (Prechtl

1990, Prechtl 1997) based on the quality of spontaneous motor activity. General movements, which are one

type of spontaneous movement pattern in the fetus and newborn infant, are complex, frequent and long-

lasting gross movements involving the head, trunk, arms and legs. Changes in the complexity, variability and

fluency of these movements have been shown to indicate brain dysfunction (Prechtl 1990, 1997, Ferrari et al.

1990).

3.1.2. SPECIFIC FEATURES AND CRITERIA OF ABNORMALITY IN NEONATAL

NEUROLOGICAL ASSESSMENT

The behavioral state of the newborn has to be taken into account for reliable neonatal neurological assess-

ment. The behavioral state of the full-term infant, defined by Prechtl (1977), is a relatively stable condition

characterized by eye movements, respiration, motility and vocalization. The five behavioral states in his

classification are: 1) quiet sleep, 2) REM sleep, 3) quiet wakefulness, 4) active wakefulness and 5) crying,

with quiet wakefulness being the optimal state. The three last-mentioned states describe normal levels of

alertness, which is said to be a sensitive indicator of the integrity of the nervous system of the newborn; most

disorders that affect the central nervous system disturb the level of alertness (Casaer et al. 1986, Volpe

1995).

The results of the neonatal neurological examination of an infant are significantly influenced by his/her

maturity. The method of assessment must therefore be age-specific, taking into account the gestational age of

the neonate. From preterm to term age the acquisition of muscle tone, motor function and reflexes proceeds

from the lower extremities to the direction of the head (caudocephalic) (Amiel-Tison and Stewart 1989) and

from distal to proximal parts of the body (centripetal) (Allen and Capute 1990).

Although the neurological maturation of a preterm infant has been observed to follow an endogenously

determined sequential pattern unaffected by the time of birth (Saint-Anne Dargassies 1977, Allen and Capute

1990), which is supported by electrophysiological evidence (Majnemer et al. 1990), differences between

premature and full-term infants have been described at term conceptional age. The observed differences are

lower muscle tone and less flexion in preterm infants, especially those of the lowest gestational age at birth

(Howard et al. 1976, Kurtzberg et al. 1979, Palmer et al. 1982, Forslund and Bjerre 1983, Aylward et al.

1984, Martikainen et al. 1988, Majnemer et al. 1992, Molteno et al. 1995), weaker reflexes or responses

19

(Kurtzberg et al. 1979, Forslund and Bjerre 1983, Piper 1985, Majnemer et al. 1992) despite a higher level of

activity (Howard et al. 1976), and greater incidence of tremor (60%/22.5%, PT/FT) (Majnemer et al. 1992).

41% of LBW infants compared with 2% of full-terms displayed deviant muscle tone (Kurtzberg 1979). On

the other hand, full-term infants were observed to have more head lag (94%/68%, PT/FT) than expected in

the traction test (Molteno et al. 1995), and both the tone and responses of full-term infants were much more

like those of premature infants, when they were examined on the fifth day of life, compared to the first day

(Palmer et al. 1982). Preterm infants were observed to have either better (Palmer et al. 1982, Forslund and

Bjerre 1983) or inferior (Kurtzberg et al. 1979, Ferrari et al. 1983, Aylward et al. 1984, Majnemer et al.

1992) performance of visual tracking and auditory orientation, and also better alertness (Howard et al. 1976,

Palmer et al. 1982). 96-100% of full-terms showed normal visual following, compared with 21-31% of LBW

infants (Kurtzberg et al. 1979, Majnemer et al. 1992). The pattern of primitive reflexes in the premature

infant at term was similar to that of full-term newborns (Allen and Capute 1986), but ATNR was more easily

obtained among preterm infants (Majnemer et al. 1992).

Various criteria and definitions for neurological abnormality have been used. Prechtl (1977) classified

deviant neurological signs as syndromes of abnormal reactivity, such as hyperexcitability syndrome and

apathy syndrome, the extreme conditions of which are convulsions and coma, respectively. Syndromes

describing quantity of motility (hyper/hypokinesia) and the sensorimotor apparatus (hyper/hypotonia) can be

observed isolated or as a part of the two afore-mentioned conditions. Hemisyndrome included asymmetries

in posture, motility, muscle tone or responses, and may be peripheral or central in origin.

The neurological abnormality of a preterm infant at 40 weeks postconceptual age was defined by Dubowitz

et al. (1984) as marked trunk hypotonia with head lag, or three of the following deviant signs: arm flexor

tone greater than leg flexor tone, abnormal head control, increased tremors with startles, persistently ad-

ducted thumb, only extension component of Moro reflex, abnormal eye movements, poor orientation,

irritability or asymmetry.

A set of criteria for optimal/nonoptimal responses in neonatal neurological examination at term age was

presented by Amiel-Tison (1996). Her proposal for the requirement of special follow-up of a newborn infant

with normal brain ultrasound was: abnormalities in cranial sutures or in head circumference in relation to

birth-weight, missing fixation/visual tracking or social interaction, absent/weak sucking reflex, deviant active

muscle tone or imbalanced passive axial tone, `cortical thumb´ or signs of autonomic disturbance.

Other criteria used in follow-up studies of definite neonatal neurological abnormality for full-term or preterm

infants have been different combinations of severe lethargy, seizures, marked hypotonia, neck extensor

hypertonia, sustained clonus, sun setting of eyes, absence of habituation (Gross et al. 1978, Allen and Capute

1989) or subnormal/reduced optimality score (Njiokiktjien and Kurver 1980, Forslund and Bjerre 1983,

20

Weisglas-Kuperus et al. 1992). Moreover, the quality of the movements has been shown to be important;

health is described by variability in motility, whereas stereotyped motility indicates disease (Touwen 1976).

3.1.3. INCIDENCE OF NEONATAL NEUROLOGICAL ABNORMALITIES

IN PREVIOUS STUDIES

The incidence of deviant neonatal neurological signs depends on populations from which the neonates are

selected and examination methods used. In a large unselected prenatally defined population from 12 teaching

hospitals in the USA (Collaborative Perinatal Project, NCPP) consisting of about 40,000 singleton infants

born between 1959-1966, Nelson and Ellenberg (1979) found definite neurological abnormality, which was

based on repeated neurological examinations and nursery observations during hospital stay in 0.5% of the

surviving neonates. A similar occurrence of severe neurological signs and symptoms was observed by Amiel-

Tison (1969) among a three-year cohort of 7500 full-term neonates born in the early 1960s at one maternity

hospital. In smaller hospital series from the ´60s, consisting of about 200 full-term (Donovan et al. 1962) or

mainly preterm infants (Parmelee et al. 1970), 18% and 26% of the examined neonates, respectively, were

considered neurologically abnormal.

The Groningen Perinatal Project consisted of two cohorts totaling more than 3000 mostly full-term newborn

infants enrolled in the hospital-based (regional center) follow-up study during a three-year period (1975-78).

All the newborns (preterms at term gestational age) were submitted to a standardized neurological examina-

tion (Prechtl and Beintema, 1964) and the classification in terms of abnormal - normal was based on defined

neonatal neurological syndromes (Prechtl 1977). Of the first cohort of 1507 newborns, 5.3%, (4.7% of the

full-terms and 17% of the preterms), were considered neurologically abnormal (Jurgens van der Zee et al.

1979).

Among hospital-based preterm populations - mostly infants born in the ´80s – the occurrence of definite

neonatal neurological abnormalities varies from 11% to 40% observed at term age (Gross et al. 1978,

Forslund and Bjerre 1983, Dubowitz et al. 1984, Stewart et al. 1988, Allen and Capute 1989, Bozynski et al.

1993) or at preterm age (Weisglas-Kuperus et al. 1992).

In a prospective nationwide survey of 1192 preterm infants, i.e. less than 32 weeks and/or birth-weight less

than 1500g, den Ouden et al. (1990) found the incidence of neurological abnormalities to be 14.1% in the

neonatal period, obvious neurological dysfunction was observed in 8.1% of the infants and suspected

neurological dysfunction in 6.1%. The classification was based on the abnormalities in the subsystems of

CNS according to Prechtl and observed at any time during the neonatal period or at home discharge.

21

3.2. CLASSIFICATION AND DEFINITION OF NEURODEVELOPMENTAL IMPAIRMENTS,

DISABILITIES AND HANDICAPS

Diagnostic criteria should be uniform to be able to adequately compare the neurodevelopmental status of

children in epidemiological and follow-up studies (Davies 1984, Mutch et al. 1989). WHO (1980) presented

a concept of definitions for impairments, disabilities and handicaps.

"An impairment is any loss or abnormality of psychological, physiological, or anatomical structure or

function. It reflects disturbances at the level of the organ."

"Disability is any restriction or lack (resulting from an impairment) of ability to perform an activity in the

manner or within the range considered normal for a human being. It reflects disturbances at the level of the

person."

"Handicap is a disadvantage for a given individual, resulting from an impairment or a disability, that limits or

prevents the fulfillment of a role that is normal (depending on age, sex, and social and cultural factors) for

that individual. Rather is it classification of circumstances that place such individuals at a disadvantage

relative to their peers when viewed from the norms of society."

The WHO classification scheme, originally prepared for adults, is suitable for small children as concerns

impairment and disability, but handicap - the disadvantage in relation to society - is more difficult to define

in pre-school children.

The interpretation of these definitions in follow-up studies is still far from uniform, as is the definition of the

grade of severity of different impairments and disabilities. Authors invariably classify cerebral palsy, mental

retardation or developmental delay with DQ/IQ less than 50 or 70, blindness and deafness as major impair-

ments/disabilities (Kitchen et al. 1986, Marlow et al. 1987, Lefebvre et al. 1988, Saigal et al. 1989, Stewart

et al. 1989, Fawer and Calame 1991, Msall et al. 1991, Teplin et al. 1991, Johnson et al. 1993, Cooke 1994,

Fazzi et al. 1994), but shunted hydrocephalus or epilepsy are considered either as a major or minor impair-

ment/disability (Lloyd et al. 1984, Marlow et al. 1987, Lefebvre et al. 1988, Stewart et al. 1989, Cooke 1994,

Fazzi et al. 1994).

Cerebral palsy entailing inability to walk is graded as severe, whereas the ability to ambulate even with

considerable limitation of movement brings the grading to moderate, while minimal limitation of movement

is considered a mild impairment (Lefebvre et al. 1988, Vekerdy-Lakatos et al. 1989, Victorian Infant Col-

laborative Study Group 1995).

A developmental/intelligence quotient less than/equal to 70 is considered as severe disability (Kitchen et al.

1986, Lefebvre et al. 1988, Vekerdy-Lakatos 1989, Fawer and Calame 1991, Johnson et al. 1993, Teplin et

al. 1991), and a DQ/IQ between 70-85 as moderate, mild or borderline disability (Drillien 1972, Marlow et

22

al. 1987, Lefebvre et al. 1988, Teplin et al. 1991). If psychometric tests are used for the evaluation of

developmental delay, the cut-off value for severe disability is considered to be -3SD or -2SD below the test

mean, for moderate disability -2SD or -1SD, for mild disability -2SD or -1SD, and for borderline disability

-1SD below the test mean (Kitchen et al. 1987b, Gray et al. 1993, Johnson et al. 1993, Victorian Infant

Collaborative Study Group 1995).

Hearing loss requiring a hearing aid (Kitchen et al. 1986, Lefebvre et al. 1988) and visual acuity less than

20/200 (Teplin et al. 1991, Msall et al. 1991) are considered major disabilities.

Strabismus, refractive errors, clumsiness (fine/gross motor), abnormalities of tone and reflexes, balance

disturbances, language and speech problems, as well as visual-motor, visual-perceptual, behavioral and

learning problems are usually interpreted as mild impairments (Fawer et al. 1987, Marlow et al. 1987, Teplin

et al. 1991, Cooke 1994).

Amiel-Tison and Stewart (1989) published instructions based on a structured neurological examination for

reporting neurological impairments during the first five years of life. The presence or absence of particular

signs gives a summary description of a neurodevelopmental condition, which can be described as ùnim-

paired´, ìmpaired, without disability´ (mildly deviant), or ìmpaired with disability´ (severely deviant).

The use of different combinations and scoring methods has been proposed by some authors (Saigal et al.

1989, 1994, Williamson 1990, Herrgård 1993, Rosenbaum 1995, Johnson 1997).

3.3. MAJOR IMPAIRMENTS/DISABILITIES

3.3.1. CEREBRAL PALSY

In an amended form of Bax’s definition of cerebral palsy in 1964, CP was defined as “an umbrella term

covering a group of non-progressive, but often changing, motor impairment syndromes secondary to lesions

or anomalies of the brain arising in the early stages of its development” (Mutch et al. 1992).

Since the 1960s, the overall rate of cerebral palsy has been reported in different Western countries to vary

between 1.4 and 2.5 per 1000 live births (Hagberg et al. 1989, 1996, Riikonen et al. 1989, Pharoah et al.

1990, Stanley and Watson 1992, Bottos et al. 1999). A trend for increasing cerebral palsy rates with decrea-

sing birth-weights has been observed (Pharoah et al. 1990, Mutch et al. 1992, Stanley and Watson 1992,

Hagberg et al. 1996, Pharoah et al. 1998), but heavier infants have been found to display more severe

cognitive and motor disabilities (Pharoah et al. 1998). Birth-weight specific mean CP prevalences among

23

infants born in the 1980’s per 1000 live births/neonatal survivors were 57/78 for ELBW, 68/66 for VLBW,

14/10 for LBW and 1.4/1.1, respectively for term infants (Hagberg et al. 1996, Pharoah et al. 1998). The

median CP prevalence among ELBW/VLBW cohorts was 7.5%/7.7% (CI 5.3-9.0) (Escobar et al. 1991,

Lorenz et al. 1998).

Diplegic and hemiplegic syndromes were found to account for one third to nearly a half of all CP syndromes

(Hagberg et al. 1996, Pharoah et al. 1998). Diplegia was present in 80% of extremely preterm, 66% of very

preterm, 58% in the moderately preterm, and 29% in the term group with CP (Hagberg et al. 1996). Hemi-

plegia was most common among term infants.

Genetic and prenatal factors have recently been shown to be far more important than perinatal adversities in

the etiology of CP (Torfs et al. 1990, Kuban and Leviton 1994, Hagberg 1996, Pharoah and Cooke 1997,

Stanley et al. 2000). The proportion of CP with a prenatal etiology has been reported to increase with

gestational age from none in the extremely preterm group to one third in the term group, while the proportion

of CP with peri/neonatal etiology decreases from 80% to 28%, respectively (Hagberg et al. 1996). Birth

asphyxia is a rare cause of cerebral palsy (Pharoah et al. 1987, Blair and Stanley 1988, Naeye et al. 1989,

Torfs et al. 1990, Bax and Nelson 1993, Gaffney et al. 1994); 10% of CP has been estimated to result from

intrapartum events (Stanley et al. 2000).

3.3.2. MENTAL RETARDATION

Mental retardation, as defined by Aicardi (1992), “is not a disease, disorder, syndrome or specific disability”,

but “it is an administrative blanket term for a wide variety of conditions” with sub average intellectual

functioning. Sub grouping of mental retardation is based on the tested intelligence quotient. Recently a

categorization into the levels of mild and severe mental retardation instead of four levels (mild, moderate,

severe, profound) is more commonly used (Aicardi 1992). Severe mental retardation (SMR) includes tested

IQ scores below 50, and mild mental retardation (MMR) IQs in the range of 50-70. Borderline intellectual

functioning is used for IQs of 71-84.

Roeleveld and coworkers (1997) have reviewed the prevalence rates for severe mental retardation (SMR;

IQ<50) and mild mental retardation (MMR; IQ 50-70) among school-aged children (age range 5-19 years)

since 1960. The prevalence of SMR seemed to be relatively stable, being on the average around 3.8 per 1000

among populations in developed countries. A tentative true average prevalence rate for MMR was calculated

to be 29.8 per 1000 (Roeleveld et al. 1997). Rantakallio and von Wendt (1985) found a cumulative incidence

of SMR (IQ <50) of 8.3/1000 and MMR (IQ 50-70) of 5.5/1000 by the age of 14 years. The incidence was

24

seven to nine times higher in children with a birth-weight less than 1500g than in those with birth-weight

2500g or more (Rantakallio and von Wendt 1985).

The causes of SMR are mostly prenatal (chromosomal, genetic, biochemical, infectious, malformations) and

seldom related to birth events. The definite etiology of MMR is less common and appears to be related to

social and environmental conditions rather than pregnancy or birth events (Paneth and Stark 1983, Aicardi

1992, Roeleveld et al. 1997). Yeargin-Allsop et al. (1997) identified prenatal causes in 25%/12% and

perinatal causes in 11%/4% of children with SMR/MMR, respectively. In one third to a half of the mentally

retarded children, no known cause or associated medical condition was found for the etiology of mental

retardation (Yeargin-Allsop et al. 1997, Cans et al. 1999).

3.3.3. HYDROCEPHALUS

The incidence of hydrocephalus secondary to peri-neonatal intraventricular hemorrhage has been on the rise

with the increased survival of very and extremely premature infants (Fernell et al. 1994, Volpe 1995). 35%

of infants with IVH develop progressive ventricular dilatation, 15% of whom will need a shunt operation

within the first four weeks of life (Volpe 1995).

Fernell et al. (1994) reported the mean crude prevalence of 0.60 per 1000 live births of infantile hydrocepha-

lus in a Swedish population based study consisting of all live-born infants born in 1973-1990. The preva-

lence was 17.4/1000 for infants less than 32 gestational weeks, 2.2/1000 for infants of 32-36 weeks and

0.37/1000 for full-term infants. There was a significant increase in the prevalence from the 1970s to the early

1980s, but it did not continue in late 1980s.

Of the very/moderately preterm hydrocephalic infants, 82%/30% had postpartum intraventricular hemor-

rhage as the etiology, while half of the full-term infants had prenatal origins of HC (Fernell et al. 1994).

3.3.4. EPILEPSY

Epilepsy is defined as a chronic brain disorder of various etiologies characterized by recurrent epileptic

seizures (Gastaut 1973).

The mean incidence rate for epilepsy can be considered to be 40-70/100.000 (Sander 1996). An incidence as

high as 42% has been observed in children with CP (Hadjipanayis et al. 1997). The prevalence of active

epilepsy has been reported to be 3.9-6.8/1000 among children under 16 years of age (Cowan et al. 1989,

25

Sillanpää et al. 1992, Sidenvall et al. 1996, Eriksson et al. 1997). A 35-40% neurological co-morbidity has

been associated with epilepsy (Sillanpää et al. 1992, Murphy et al. 1995).

The etiology of epilepsy was prenatal in 15%, perinatal in 9% and postnatal in 12% of the children in whom

the cause could be identified (Eriksson et al. 1997).

3.3.5. VISUAL IMPAIRMENTS

WHO (1980) has defined vision as normal when visual acuity with the best possible correction is at least 0.8,

and as slight impairment with visual acuity 0.3-0.8. Low vision with moderate impairment means visual

acuity less than 0.3 but more than or equal to 0.12. Blindness means visual acuity less than 0.05.

The prevalence of visual impairment less than 0.3 was 0.80/1000 and that of blindness 0.28/1000 among

children under 9 years of age born in the 1970s and 1980s (Arnaud et al. 1998). Strabismus is a common

condition, occurring in about 4% of children younger than 6 years (Lavrich and Nelson 1993, Kasmann-

Kellner et al. 1998). Cortical visual impairment leading to bilateral visual impairment is a growing visual

problem because of its association with hypoxic-ischemic brain injury (Good et al. 2001).

Retinopathy of prematurity (ROP) is a disorder of developing retinal blood vessels in premature infants; it

may heal completely or leave sequalae from mild myopia to blindness (Phelps 1993). In ELBW/VLBW

infants born in the mid-80s the rate of ROP was reported to be 50%/31% and ROP with blindness 10%/2.9%,

respectively (Fledelius 1990). Tuppurainen et al. (1990) observed severe visual impairment or blindness

because of ROP in 2.9% of preterm infants less than 33 gestational weeks, born in 1975-1989 in eastern

Finland. On the other hand, 5.4% of all visually impaired children born in 1984-1987 were found to have

ROP in a population-based study (Crofts et al. 1998).

The etiology is antenatal in about half of the children with visual impairment, and in one fifth to one fourth

of the cases peri-neonatal causes can be found (Blohme and Tornqvist 1997, Arnaud et al. 1998). From the

middle of ´80s onwards as high as 72% prevalence of visual impairments, and 50% prevalence of strabismus

have been observed in children with ischemic brain lesions neonatally (Gibson et al. 1990, Mercuri et al.

1997, van-Hof-van Duin 1998).

26

3.3.6. HEARING IMPAIRMENTS

The classification of hearing impairment is based on the anatomical site of the injury (conductive, sen-

sorineural, central) and the grade of severity is based on measurements of pure tone audiometry. According

to WHO (1980) the threshold level for normal hearing is 25 db, but social incapacity requiring the need for a

hearing aid is caused by hearing loss of more than 40 db in both ears (DeWeese and Saunders 1973). Severe

hearing impairment/deafness means a hearing loss of more than 60/81 db.

The prevalence of hearing impairment of at least 40 db in childhood has been reported to be 0.7-1.3/1000

live births (Fortnum and Davis 1997, Darin et al 1997, Mäki-Torkko et al. 1998), but greater among children,

who have been in neonatal intensive care (Davis and Wood 1992, Darin et al. 1997).

The etiology of severe childhood hearing impairment is hereditary in 30%-50% (Thiringer et al. 1984,

Parving and Hauch 1994, Darin et al. 1997, Mäki-Torkko et al. 1998,). When perinatal factors (prevalence of

7-8%) (Darin et al. 1997, Mäki-Torkko et al. 1998) are considered, the requirement of mechanical ventila-

tion, low birth-weight, smallness for gestational age and neonatal infections carry the greatest risk (Thiringer

et al. 1984).

3.4. MINOR IMPAIRMENTS/DISABILITIES

3.4.1. MINOR NEUROLOGICAL/NEUROMOTOR DYSFUNCTION

The term neurological `soft signs´ has been defined as deviant motor or sensory performance in children

without a neurological lesion or disorder (Shafer 1986). Minor neurological dysfunction based on a standard-

ized neurological examination of the subsystems of the central nervous system, introduced by Touwen

(1979), offered a more precise definition. Later, Hadders-Algra et al. (1988a) classified minor neurological

dysfunction according to a summarized cluster profile of posture and muscle tone, reflexes, coordination and

balance, fine manipulative ability, choreiform dyskinesia and miscellaneous dysfunctions, and defined

simple and complex MND.

Motor clumsiness, recently named developmental coordination disorder (DCD, American Psychiatric

Association 1994), is a concept used in the literature to describe the heterogenic group of normal intelligent

children whose motor coordination performance is below their chronological age and who nevertheless have

no evidence of neurological disorder. DCD interferes significantly with academic achievement or adaptive

function.

27

Mild neurological dysfunction was found in 5% of neonatally neurologically normal and in 30% of neona-

tally deviant children at 6 years of age (Hadders-Algra et al. 1986). It increased with age until 12 years ( 28%

/ 49%, respectively) (Lunsing et al. 1992a), but decreased with pubertal development (Lunsing et al 1992b).

The incidence of developmental coordination disorder among children aged five to eight years was reported

as 5%-13.5% (Gillberg and Rasmussen 1982, Henderson and Hall 1982, Ahonen 1990, Kadesjö and Gillberg

1999).

Both mild neurological dysfunction and clumsiness may occur isolated, but they have often been associated

with speech/language disorders (Wolff 1985, Michelsson et al. 1984, Dewey et al. 1988, Powell and Bishop

1992), learning problems (Silva and Ross 1980, Herzig 1981, Henderson and Hall 1982, Lindahl et al. 1988a,

Ahonen 1990, Losse et al 1991), behavioral and social/emotional (Herzig 1981, Henderson and Hall 1982,

Szatmari et al. 1990, Losse et al. 1991, Scoemaker 1994) and psychiatric (Shaffer 1985) disturbances.

Clumsiness has been connected as an essential part to DAMP (Gillberg and Rasmussen 1982). Ahonen

(1990) identified six subgroups among 7-year-old clumsy children according to their performances in

cognitive, perceptual, kinesthetic and academic domains.

It is still not clear whether neurological `soft signs´ and clumsiness are signs of developmental lag or neuro-

logical deficit (Blondis 1990, Losse et al. 1991). The latter alternative is supported by the fact that some of

these children do not grow out of their motor problems by their teenage years (Shafer et al. 1986, Gillberg et

al. 1989b, Losse et al. 1991, Soorani-Lunsing et al. 1993). Prenatal factors, obstetric non-optimality, neonatal

neurological symptoms, seizures, intraventricular hemorrhage, hydrocephalus and male gender have been

found to associate with mild neurological dysfunction (Gillberg and Rasmussen 1982, Hadders-Algra et al.

1986, 1988a, Lindahl et al. 1988a, Ellison and Foster 1992). Pre-perinatal factors, neonatal neurological

signs, low birth-weight with associated factors, smallness for gestational age, and social disadvantage have

been shown to be important etiological factors of impairment in motor performance (Lindahl et al. 1988a,

Ahonen 1990, Hadders-Algra 2000).

3.4.2. MINOR NEURODEVELOPMENTAL DISORDERS

The term minimal brain dysfunction (MBD) has been used, since its introduction by Clements in 1966, to

describe a large variety of problems with respect to attention, concentration, activity level and motor control

in children without mental retardation or cerebral palsy. These problems interfere with the child’s school and

home amativeness and cognitive and social development (Kalverboer 1993).

Later, the concept of DAMP (deficits in attention, motor control and perception) was introduced by Gillberg

(1989ab). DAMP can be subdivided into severe cases showing symptoms of all five dysfunctions: attention,

28

gross motor, fine motor, perceptual and speech/language (Gillberg and Rasmussen 2001). Milder forms,

showing part of the deficits, have been defined as MPD (motor perception dysfunction) and ADD (attention

deficit disorder)/ ADHD (attention-deficit/ hyperactivity disorder) (Gillberg et al. 1982, Gillberg 1985).

Among 6-year-olds in Sweden, a population rate of 1.2% for a severe form of DAMP and a further 5.9% for

a milder spectrum of the disorder was observed by Gillberg and Rasmussen (1982). A minimum population

rate of 5.3% for DAMP, 2.4% for ADHD and 1.7% for MPD among children born in 1986-87 was found by

Landgren et al. (1996).

The etiology of DAMP is mainly hereditary in one third of the cases, it is due to pre-, peri- or postnatal brain

damage in another third, and to a combination of the former in one fifth of the cases. The cause is not iden-

tifiable in 10 % of the cases (Gillberg and Rasmussen 2001).

In follow-up studies the concept of minor neurodevelopmental disorders differs and has not achieved any

consensus. However, in the ´90s the definitions became more congruent. Among three- to six-year-old

children, a variety of definitions of mild neurodevelopmental abnormalities/ impairments in different com-

binations have been used, including minor refractive errors, strabismus, minor hearing loss, non-febrile fits,

fine and/or gross motor disorders, mild abnormalities of tone and balance, hyperactive deep tendon reflexes,

a ventriculoperitoneal shunt in an otherwise normal infant, borderline intelligence, language disorders,

speech articulation abnormalities, visual-motor abnormalities and behavior problems (Clayes et al. 1984,

Lloyd 1984, Kitchen et al. 1987a, Stewart et al. 1989, Teplin et al. 1991)

Minor impairments do not cause disability according to Stewart et al. (1989). Mild motor disability was

defined as an impairment that does not interfere with mobility (Stewart et al 1989). Additionally, mild motor

disability may be manifested as mere motor clumsiness (Cooke 1994), or ambulant cerebral palsy, which

limits movement only minimally (Victorian Study Group 1995) with or without mild developmental lag

(Saigal et al, 1989). Mild cognitive disability was classified as language delay (Cooke 1994) or low scores

(-2SD to -1SD, Victorian Infant Collaborative Study Group 1995) or poor performance in one or more areas

of development, causing need for additional help with learning at school (Stewart et al. 1989, Johnson et al.

1993) with or without neurosensory disability (Stewart et al. 1989, Victorian Infant Collaborative Study

Group 1995). Mild neurosensory disability included myopia and mild hearing loss (Cooke 1994).

3.4.3. SPEECH/LANGUAGE DISORDERS

The clinical term `specific speech and language disorder´ is used for preschool or early school-aged children

with deficits in the production and/or comprehension of spoken language (Hall 1988, Klein 1991). The

29

criteria for the developmental language disorder (syndrome of primarily receptive, primarily expressive or

mixed deficits) imply that the deficit is manifested before three years of age without any signs of hearing

defect, mental retardation, motor handicap, psychiatric, emotional or social disturbances (Korkman 1995).

The prevalence of speech problems has been reported to be 14% in 3-year-olds and 5.5% in 4.5-year-olds

(Bax et al 1980). Specific language delay (expressive or receptive) has been found in 4.0-7.4% of 4.5-5-year-

old children (Silva et al. 1983, Weindrich et al. 1998).

Language status was not related to specific perinatal medical variables in a study by Byrne et al. (1993).

Instead, Largo et al. (1986) found that non-optimal perinatal conditions affected language development and

articulation until the age of five. Moreover, the language performances of the children who required inten-

sive care neonatally, were inferior to those of the control children (Jennisce 1999). Birth-weight and gesta-

tional age correlated negatively to the language measures (Largo et al. 1986, Scottish LBW Study Group

1992b).

Delayed or disturbed language development during the first 2-5 years of life has been observed to precede

low intelligence and/or later reading/school difficulties (Silva et al. 1983, Claeys et al. 1984, Lindahl et al.

1988b, Shapiro 1993). Children with language impairment have also been found to display minor motor

deficits (Bishop and Edmundson 1987, Jensen et al. 1988).

3.5. EFFECT OF GENDER ON MORBIDITY

Boys had a significantly higher perinatal mortality and more postnatal complications than girls (Brothwood

et al. 1986, Cartilidge and Stewart 1997, Xu B et al. 1998, Stevenson et al. 2000). They had an 11% higher

risk of being born prematurely (Gissler et al. 1999), and an increased incidence of handicaps (Rantakallio

and von Wendt 1985, Verloove-Vanhorick et al. 1989, Stanley et al. 1993, Roeleveld et al. 1997). The

proportion of boys among children with CP was higher than that of girls (Stanley and English 1986, Largo et

al. 1990a, Cummins et al. 1993).

Boys had also more minor neurological abnormalities (Neligan 1976, Drillien 1980, Hadders-Algra et al.

1988a, Lindahl et al. 1988a, Verloove-Vanhorick 1989, Ahonen 1990, Largo et al. 1990a, Lunsing et al.

1992a). As regards articulation, girls tended to be more advanced and to have fewer problems than boys at

age five, sex differences being similar in preterm and full-term infants (Largo et al. 1986, O’Callaghan et al.

1995). Compared with girls, boys had a two- to three-fold risk to have developmental delay and postponed

school start. They also had more learning difficulties (Drillien et al. 1980, Rantakallio and von Wendt 1985,

Gissler et al. 1999) and hyperactive disorder (Sandberg 1985).

30

3.6. EFFECT OF ENVIRONMENTAL FACTORS ON DEVELOPMENTAL DISTURBANCES

Environmental factors are reported to influence a child’s development, especially after two years of age.

Preterm infants have been observed to be more vulnerable to environmental insufficiencies than full-term in-

fants (Escalona 1982, Fawer and Calame 1991, Bradley and Casey 1992). Sameroff and Chandler (1975)

emphasized the importance of the quality of childcare in their classical concept of `continuum of care taking

casualty´.

Escobar et al. (1991) reported cohorts of high SES to have lower rates of disability than those of low SES

among very low birth-weight infants. The effect of environmental or socioeconomic factors has been ob-

served among full-term, preterm and `at risk´ children on language development (Siegel 1982, Taylor et al.

1985, Lindahl et al. 1988a, Lewis and Bendersky 1989, Vohr et al. 1989, The Scottish LBW Study Group

1992b, Damman et al. 1996), on cognitive function (Drillien et al. 1980, Escalona 1982, Taylor et al. 1985,

Ounsted et al. 1986, Lindahl et al. 1988a, Leonard et al. 1990, Fawer and Calame 1991, Vohr et al. 1992,

Forfar et al. 1994, Damman et al. 1996), on behavioral and emotional health (Taylor et al. 1985, McCormick

et al. 1996), and on mild neurological dysfunction (Hadders-Algra et al. 1988a).

Some authors have not found environmental effects in their studies of premature children (Vekerdy-Lakatos

et al 1989, Abel-Smith and Knight-Jones 1990, Herrgård 1993). Neither have environmental effects been

found to cause disturbances in motor (Lindahl et al. 1988a, Ahonen 1990) or neurologic function (Taylor et

al. 1985, Aylward et al. 1989a, Vohr et al. 1992).

3.7. MORTALITY/SURVIVAL

3.7.1. PERINATAL, NEONATAL AND POSTNEONATAL MORTALITY, AND SURVIVAL

RATES

In Finland, PNM (death of fetuses and infants less than seven completed days from birth) was 7.3/1000 in

1985 and 6.4/1000 in 1986. Neonatal mortality (number of deaths during the first 28 days of life among all

live-born infants) was 4.4/1000 in 1985 and 4.0/1000 in 1986 (Causes of death, Statistics Finland 1999). No

major changes in postneonatal mortality rate among very preterm infants were found in Finland in 1978-1986

(results of 3-year periods: 25.4/25.0/23.4/1000) (Heinonen et al. 1988).

In South Bavaria 96.4% of the whole study population (N=8421) and 71.8% of VLBW infants survived

during primary hospitalization. 95.4% of the whole study population and 70.7% of the VLBW infants were

alive at 56 months of age (Riegel et al. 1995).

31

Also studies in other countries show that postneonatal survival of preterm infants has become longer. It has

been reported that of the infants born in the 1980s, 72.4-77.9% of VLBW infants (Powell et al. 1986, van

Zeben-van der Aa et al. 1989, Veelken et al. 1991) and 25.4% of ELBW infants lived at least for 2 years

(Kitchen et al. 1984). 71% of the infants with birth-weight less than 1750g survived 4.5 years (The Scottish

Low Birthweight Study Group 1992a), and long-term survival of 87% was reported for infants less than

2000g (Sommerfelt et al. 1996).

3.8. INCIDENCE OF PREMATURITY

The proportions of infants with a birth-weight less than 2500 g of all infants born in Finland were 4.1% and

4.2% in the years 1985 and 1986, respectively (Nomesco 1993). The proportions of infants with a birth-

weight less than 1500 g were 0.7% and 0.6%, and those of infants with birth-weight less than 1000 g 0.2%

and 0.1% in the same years, respectively. (Nomesco 1993). In the county of Uusimaa, 3.2% of the infants

born in 1981-1983 were LBW infants, and 0.7% were VLBW infants (Raivio 1987).

The proportion of infants with gestational age less than 37 completed weeks in Finland was 4.7% and that of

infants less than 33 completed weeks 1.4% in 1987 (Nomesco 1993).

32

3.9. FOLLOW-UP STUDIES

3.9.1. INFANTS WITH NEONATAL NEUROLOGIGAL EXAMINATION

The neurological assessment of the newborn infant and its predictive value on later development has been

dealt with in numerous previous studies (Table 2).

Table 2. Follow-up studies of neonatally neurologically abnormal infants

Classification Predictability

Aut

hor

Yea

r of

birt

h

Pop

ulat

ion

N

Incl

usio

n cr

iteria

Fol

low

-up

age

Met

hod

Age

at n

eona

tal

neur

olog

ical

exa

min

atio

n

Neo

neur

o

Out

com

e

Sen

sitiv

ity %

Spe

cific

ity %

Pos

itive

pre

dict

ive

valu

e %

Neg

ativ

e pr

edic

tive

valu

e %

FULL-TERM AND PRETERM INFANTS

26% Abn 26% Abn

42% Susp 32% Norm

45% Susp 7% Abn 52% Norm

Parmelee 1970NICU Paris France

1962 187 FTPT 73%

2-6y Saint-Anne Dargassies

29% Norm 7% Abn 50% Susp

Amiel-Tison 1969NCParis

1962-64 7500 FT

2-5y 0.5% Abn 20% Major 4% Mod 16% Minor

0.5% Abn 16% CP 11% Susp 1% CP

Nelson, Ellenberg 1979NCPP

1959-66 40057 FTPT

7y Paine

18% Subopt

Behav probl Minor neuro

Njiokiktjien, Kurver 1980Amsterdam Netherlands

1972-75 144 Red. Opt. >15%

22-36mo

Prechtl term

82% Opt

GRONINGEN PERINATAL PROJECT Groningen Netherlands

1975-78 3162 FTPT<37gwk

Prechtl term

80 Abn 10% Major 13% MND

Touwen 1982

1975-76 1507 FTPT 5%

4y

80 Norm 0% Major 8% MND

75 55 23 93*

71 Abn 8% Major 30% MND

Hadders-Algra 1986

1977-78 1655 FTPT

6y

75 Norm 0% Major 5% MND

33


Aut

hor

Yea

r of

birt

h

Pop

ulat

ion

N

Incl

usio

n cr

iteria

Fol

low

-up

age

Met

hod

Age

at n

eona

tal

neur

olog

ical

exa

min

atio

n

Neo

neur

o

Out

com

e

Sen

sitiv

ity %

Spe

cific

ity %

Pos

itive

pre

dict

ive

valu

e %

Neg

ativ

e pr

edic

tive

valu

e %

147 Abn 10% Major 18% MND2 17% MND1

300 Mild 2% Major 10% MND2 15% MND1

Hadders-Algra 1988

1975-78 804 FTPT

6y+9y

300 Norm 1% Major 5% MND2 15% MND1

67 82 10 99**

Abn 10% Major 49% MND

Lunsing 1992

1975-78 185 MND 9y 172contr

12y

Norm 1% Major 28% MND

Locomotor (Griffith)

71 83

VMI 100 100 IQ>69 80-89 92-93

Majnemer, Rosenblatt 1995NICU Sidney Australia

1982-841986-88

78High-risk FTPT24FT contr

5-6y ENNAS 40 gwk 57% Abn

Molteno 1995NICU FloridaUSA

1990 100 High-risk FTPT 84%

1y Dubowitz Abn # 25% Major 17% Mod 22% Border 36% Norm

55 97 92 74 ##

57% Abn 43% Norm

Cioni 1997Modena,Pisa Italy

1985-> 58 FT

2y Prechtl +GMs

term 88 59

PRETERM INFANTS

11% Abn 23% Major 77% Norm

Gross 1978NICU Syracuse NY USA

1971 118 <2001g

4;3- 5;6y

Norm 3% Major 7% Minor 90% Norm

PT26% Abn ¤ 22% Minor

Motor 35% School problems

Forslund, Bjerre 1989NICU LundSweden

1983 46 PT<35 gwk 26FTcontr

8y+9y Prechtl 40gwk

FT3.8% Abn ¤ 17% Minor

Motor

40% Abn 38% Major 27% Susp 35% Norm

Allen, Capute 1989NICU Baltimore USA

1981-86 210 High-risk PT23-36 gwk

1-5y Combined Capute Saint-Anne Dargassies Amiel-Tison Dubowitz

m38gwk

60% Norm 6% Major 13% Susp 35% Norm

63-80 69-78 38-69 73-94

34


Aut

hor

Yea

r of

birt

h

Pop

ulat

ion

N

Incl

usio

n cr

iteria

Fol

low

-up

age

Met

hod

Age

at n

eona

tal

neur

olog

ical

exa

min

atio

n

Neo

neur

o

Out

com

e

Sen

sitiv

ity %

Spe

cific

ity %

Pos

itive

pre

dict

ive

valu

e %

Neg

ativ

e pr

edic

tive

valu

e %

8% Abn 50% Major

17% Minor 33% Norm

6% Susp 15% Major 24% Minor 52% Norm

POPS (Nationwide Netherlands)

den Ouden 1990

1983 1192 PT<1500g/ <32 gwk

2y Prechtl preterm

86% Norm 4% Major 10% Minor 84% Norm

21 96

20% Abn 50% Abn

25% MND 25% Norm

33% Mild 0% Abn 42% MND 58% Norm

Weisglas- Kuperus 1992RTNC Rotterdam Netherlands

1985-86 79 <1500g/ <36 gwk/

3.6y CA Prechtl preterm

47% Norm 3% Abn 13% MND 84% Norm

52% Abn 48% Norm

Cioni 1997Multicenter Netherlands Italy

1985 -> 66 PTHigh-risk

2y CA Prechtl +GMs

38-42gwk 79 71 72 78

7% Abn 63% Major

19% Minor 17% Trans 12% Major

23% Minor

Lacey, Henderson- Smart 1998NICU Sydney Australia

1982-84 153 <35 gwk/ <2000g/ <10th

centile

6y Lacey preterm

76% Norm 8% Major 30% Minor

- Neoneuro=neonatal neurological examination - NC=Neonatal center, RTNC=Regional tertiary neonatal center, NICU=Neonatal intensive care unit - CA=corrected age - FT=full-term, PT=preterm - GMs= General movements - ENNAS=Einstein Neonatal Neurobehavioral Assessment - * calculated by the author - ** calculated by the author, suspect and normal neonatal neurological findings joined, congenital malformations included - # >2 deviant signs of 33 items, ## 4 deviant signs - ¤ Reduced optimality > 25%

It is difficult to compare the results of the follow-up studies because of different examination methods, clas-

sification criteria of neurological abnormalities, and inclusion and exclusion criteria of populations (Table 2).

Only few studies have followed neonatally neurologically examined infants up to preschool or school age

(Gross et al. 1978, Nelson and Ellenberg 1979, Touwen et al. 1982, Hadders-Algra et al. 1988a, Forslund and

Bjerre 1989, Soorani-Lunsing et al. 1993, Majnemer et Rosenblatt 1995, Lacey and Hendersson-Smart

35

1998). Most studies report the follow-up until only 1-2 years (Donovan et al. 1962, Dubowitz et al. 1984,

Allen and Capute 1989, Bozynski et al. 1993, Molteno et al. 1995, Cioni et al. 1997, Amess et al. 1999).

The common opinion of the referred authors is that the predictive value of neonatal neurological examination

is high for later normality, but poorer for abnormality. 80-90% of the neonatally neurologically normal in-

fants have been considered as normal (Gross et al. 1978, Dubowitz et al. 1984, Allen and Capute 1989,

Majnemer and Rosenblatt 1995) and 0-7% as severely abnormal (Donovan et al. 1962, Parmelee et al. 1970,

Gross et al. 1978, Touwen et al. 1980, Allen and Capute 1989, den Ouden et al. 1990) in follow-up (Table 2).

On the other hand, of the neonatally neurologically abnormal neonates, 4.3-50% have been observed to have

major impairments (Donovan et al. 1962, Amiel-Tison 1969, Parmalee et al. 1970, Gross et al. 1978, Nelson

and Ellenberg 1979, Dubowitz et al. 1984, Hadders-Algra et al. 1986, Stewart et al. 1988, Allen and Capute

1989, den Ouden et al. 1990), whereas 35-77% have been considered normal. Premature populations have

showed the greatest proportions of abnormalities. Cioni et al. (1997a) found a sensitivity of 79% and a

specificity of 71% for abnormal neonatal neurological examination (Precthl 1977) at term age related to

neurological outcome at two years of age among 66 at-risk preterm infants, nearly half of which had severe

brain lesions revealed by ultrasound. However, when they used the Prechtl method of qualitative assessment

of general movements (GMs), none of the infants with later major impairment was missed.

CP has been found later in 6-38% (Nelson and Ellenberg 1979, Dubowitz et al. 1984, Allen and Capute

1989) and minor neuromotor dysfunction in one fourth to one third (Hadders-Algra et al. 1988a, Allen and

Capute 1989) of neonatally neurologically abnormal preterm and full-term infants. On the contrary, 57-80%

of the children with moderate to severe CP were abnormal in neonatal neurological examination, whereas

43% had been regarded as normal (Nelson and Ellenberg 1979, Allen and Capute 1989). A significant

relationship has been found between neonatal neurological abnormality and minor neurological dysfunction

at 4 years (Touwen et al. 1980), at 6 and 9 years (Hadders-Algra et al. 1986, 1988b, Lacey and Henderson-

Smart 1998), at 12 years (Lunsing et al. 1992a), and signs of MND and especially fine manipulative disabil-

ity at 14 years (Soorani-Lunsing et al. 1993). An association between neonatal neurological deviancy and

poor neurological outcome has also been observed among premature infants examined at term age, at 1 year

(Dubowitz et al. 1984) and at 5 years (Gross et al. 1978), as well as among at-risk (NICU) infants at one year

of age (Molteno et al. 1995). Neonatally neurologically abnormal children showed more speech and language

problems and undesirable behavior at 6 years compared with neonatally neurologically normal controls

(Hadders-Algra et al. 1986). No significant relationship, however, was found between cognitive assessment

at 3-5 years and the results of neonatal neurological examinations (Gross et al. 1978, Weisglas-Kuperus et al.

1992a).

Abnormal neonatal neurological signs, even if transient, have been observed to be associated with develop-

mental abnormalities or learning difficulties (Drillien 1980, Rubin and Barlow 1980, Amiel-Tison et al.

36

1983). 27% of children with transient neurological signs or symptoms during the first week of life performed

abnormally (dyspraxia, fine motor problems, behavioral disturbances and developmental subnormality) at 5.5

years of age compared to 7% of controls (Amiel-Tison et al. 1983).

Those individual neonatal neurological signs which described active and passive muscle tone, spontaneous

motility, tremors, grasp reflexes, Moro responses and eye appearances were found to be significant predic-

tors for neurodevelopmental outcome at 1 year of age (Donovan et al. 1962, Molteno et al. 1995). Neurologi-

cal findings that were observed to be associated with risk of CP, were nystagmus (39-fold), jerky and

myoclonic movements (26-fold), weakness or absence of suck or cry for more than one day (14-15-fold) and

abnormalities of tone or palmar and plantar grasp reflexes (12 to 15-fold) (Nelson and Ellenberg 1979). Of

the neonatal neurological syndromes, hypertonia and hyperexcitability showed the worst prognosis (Hadders-

Algra et al. 1986). Dubowitz et al. (1984) found no individual abnormal signs that were predictive in isola-

tion, but clusters of abnormal signs correlated directly with poor outcome.

Complicated birth was found to increase risk of CP at the age of seven years, only if the infant had also

abnormal neonatal neurological signs, and the number and duration of abnormal neurological signs were

important (Nelson and Ellenberg 1987). A positive correlation between abnormal neonatal neurological

examination and later CP or developmental disability remained significant after adjusting for different

perinatal, demographic and social variables such as gestational age, inborn/outborn status, five-minute Apgar

scores, severe chronic lung disease, periventricular/ intraventricular hemorrhage, gender and parental

education (Allen and Capute 1989).

3.9.2. PREMATURE INFANTS

Although a vast number follow-up studies on the outcome of premature infants has been published, popula-

tion-based studies, especially ones including full-term control infants, are scarce. Due to the advances in

obstetrical and neonatal care, including antenatal corticosteroids, postnatal surfactants and high-frequency

respirators, neonatal mortality has dramatically decreased even among the most tiny preterm infants (Crow-

ley et al. 1990, Kari et al. 1994, Soll et al. 1994, Cooke 1999). This has shifted the interest of follow-up

studies towards extremely low birth-weight subgroups. At the same time, the scope of evaluated outcome has

broadened from major disabilities to more subtle long-term morbidities (Ornstein et al. 1991). Methodologi-

cal problems, referred by Aylward et al. (1989b) and Ornstein et al. (1991), make comparison between

different studies difficult, although they have been better taken into account in most recent studies.

Table 3 gives a summary of regional follow-up studies of LBW, VLBW and ELBW infants, born in the ´80s,

showing the proportions of children with major and minor impairments/disabilities.

37

Table 3. Regionally representative follow-up studies of premature infants

Outcome

Major % Minor %

Aut

hor

Yea

r of

birt

h

Pop

ulat

ion

N

Incl

usio

n cr

iteria

Sur

viva

l %

Fol

low

-up

age

%

of e

ligib

le

Con

trol

gro

up N

Impa

irmen

t to

tal

Dis

abili

ty

tota

l

Cer

ebra

l pa

lsy

Men

tal

reta

rdat

ion

Vis

ual d

efec

t

Hea

ring

defe

ct

Hyd

ro-

ceph

alus

Epi

leps

y

Impa

irmen

t to

tal

Mot

or

Str

abis

mus

Spe

ech

1) <2500 g

Powell 1986Mersey UK

1979-1981

1420<2001g

75.5 2ys

3-5y98

6.8 4.0 2.4 3)

0.9 0.9 0.9 1.8

Scottish LBW Study Group 1992Scotland

1984 896 <1750g

714.5ys

4.5y 96

28.5 5.9 sev

11.0 mod

7.7 5.3 1)

20.3

Sommerfelt 1996Hordaland Norway

1986-1988

217<2000g

875ys

5y83

16396% FT

6.0 0 0.5 Lbw =2x FT

2) < 1500 g

Veen 1991Netherlands

1983 1338 <1500gand/or <32gwk

74.6 disch

5y CA 96

49.7 27.7 20.4

Veelken 1991Hamburg

1983-1986

591<1501g

71disch

2y91

18.9 14.8 1.9 1)

1.5 23.5 11.1 2.2

Damman 1996Hamburg Germany

1983-1986

591<1501g

69lts

6y81

11.1 18.8

Robertson 1992Alberta Canada

1988-1989

291500-1250g

671ys

1.5-3y CA

15 10 7 5 4 2

3) < 1000 g

Saigal 1989TCC Ontario Canada

1977-1980

1981-1984

255

266501-1000g

46

48

3y CA 94

94

24

17

24

12

15

12

8

6

0

1.6

3.6

6.6

Victorian Study Group1995,1997 Australia

1979-1980

1985-1987

351

560

25.4

37.9

5.5y 96

5y98.6

12.4

6.6

9.0

9.6

9.0

4.3

2)

6.7

2.9

5.6

0.5 22.5

38

Outcome

Major % Minor % A

utho

r

Yea

r of

birt

h

Pop

ulat

ion

N

Incl

usio

n cr

iteria

Sur

viva

l %

Fol

low

-up

age

%

of e

ligib

le

Con

trol

gro

up N

Impa

irmen

t to

tal

Dis

abili

ty

tota

l

Cer

ebra

l pa

lsy

Men

tal

reta

rdat

ion

Vis

ual d

efec

t

Hea

ring

defe

ct

Hyd

ro-

ceph

alus

Epi

leps

y

Impa

irmen

t to

tal

Mot

or

Str

abis

mus

Spe

ech

Astbury 1990NICU Melbourne Australia

1979-1981

110<1001g

51.8 disch

5y CA 93

24.5 9.4 9.4 5.7 1.9 7.5 26

Piecuch 1997NICU California USA

1979-1991

518disch

500-999g

55mo 88

11.0 neu14.0 cog sev+mod

9.3 14.0 3)

1.1 0.2

Teplin 1991NICU North- Carolina USA

1980 56<1001g

51.8 1ys

6y96.5

26FTmd

18.0

FT:4.0 sev+mod

10.7

FT:0

7.0

FT:4.0

12

FT:0

7.0

FT:4.0

0

FT:0

0

FT:0

36.0

FT:21.0 dis

50.0

FT:23.0

39.0

FT:15.0

Cooke 1994RCMersey UK

1980-1989

823<29gwk

56.5 disch

3y99.5

19

9sev

12.8 9.9 1)

3.6 1.6 2.5 9

Johnson 1993Oxford UK

1984-1986

342<29gwk

49.7 disch

4y93

23.0 sev 13.0 mod

5.9 4.6 1)

3.9 2.0 29.0

Emsley 1998RCManchester UK

1984-1989

9623-25gwk

27 3.3-10.6y

38 3)

21 13 4 8 4 13 8 21

- Sev=severe, mod=moderate, cog=cognitive, neu=neurological, md=matched - 1) IQ<70, 2) IQ< -3SD, 3) IQ< -2SD - Lts=long-term survival - 1,2,5ys=1,2,5-year survival - disch=discharged - CA=corrected age

The classification of impairments, disabilities and handicaps suggested by WHO has been used in some

population-based studies (Veen et al. 1991, Scottish LBW Study Group 1992a, Johnson 1993, de Vonder-

weid et al. 1994). In the studies published earlier, only major handicapping conditions were presented, while

in the most recent ones an overall measure of normality/functional disability is reported to be related to the

quality of pre-neonatal care.

Lee and coworkers (1995) reported that between 1947-1987 both major and nonmajor handicaps among

39

VLBW survivors showed a decreasing trend, with no increase among ELBW survivors, either. However, an

increasing prevalence and multiplicity of neurodevelopmental impairments and disabilities has been reported

to relate to decreasing birth-weight and gestation (Marlow et al. 1989, Scottish LBW Study Group 1992a).

Functionally complete performance at four years of age was observed in 73% of NBW, 62% of LBW and

26% of ELBW children born in the mid 1980s (Halsey et al. 1993).

An incidence of major handicap/neurosensory impairment with severe disability was observed in 3.6-9.0% of

children with a birth-weight of less than 1500-2000 g (Powell et al. 1986, Marlow et al. 1987, Scottish LBW

Study Group 1992a, Forfar et al. 1994), in 3.9-15% of VLBW children (Marlow et al. 1987, Robertson et al.

1992, Scottish LBW Study Group 1992a) and in 5.8-23% of ELBW children (Saigal et al. 1989, Astbury et

al. 1990, Msall et al. 1991, Johnsson et al. 1993, Cooke et al. 1994, Doyle et al. 1995, Stjernqvist et al. 1995,

Victorian Infant Collaborative Study Group 1995) compared with less than 1% of the control population

(Aylward et al. 1989b, Saigal et al. 1991). Moreover, the median incidence of neurodevelopmental disability

among VLBW cohorts was 25% (Escobar et al. 1991). The incidences were lower in larger and more recent

cohorts, and higher in studies that followed up children for longer time periods. Among ELBW cohorts, the

prevalence of major disabilities was 22% for extremely immature and 24% for extremely small survivors

(Lorenz et al. 1998).

Of single major impairments, CP was found in 3.3-5.1% of children with birth-weight of less than 1500-2000

g (Marlow et al. 1989, Scottish LBW Study Group 1992a, Sommerfelt et al. 1996), in 10-11% of VLBW

(Robertson et al. 1992, de Vonderweid et al. 1994, Damman et al. 1996) and in 5-13% of ELBW children

(Saigal et al. 1989, Teplin et al. 1991, Johnson et al. 1993, Msall et al. 1993, Cooke et al. 1994, Hack et al.

1994, Doyle et al. 1995, Victorian Infant Collaborative Study Group 1995) among those born in the ´80s and

assessed at the age of at least three years. In another Finnish population-based study, 10% of the infants with

a birth-weight of less than 1750 g had CP (Olsen et al. 1998).

MR as defined by DQ/IQ less than 68-71 was observed in 3.6-21% of the infants in all birth-weight groups

(Veen et al. 1991, Scottish Low Birthweight Study Group 1992b, Herrgård 1993, Johnson et al. 1993, Msall

et al. 1993, Pharoah et al. 1994), but in preterms (8%) higher proportions were noted than in full-term

controls (1%) (Ross et al. 1985). Low/borderline intelligence (DQ/IQ 71-85) was observed in 7-14% of

preterms (Ross et al. 1985, Kitchen et al. 1987b).

The proportion of children with blindness has been reported to have decreased from the late ´70s to the ´80s

in successive study cohorts from 6.7 to 2.9% (Victorian Infant Collaborative Study Group 1995). In other

studies, the rate of blindness varied from 0 to 5%, the highest proportions occurring among children with the

lowest birth-weights (Alberman et al. 1982, Powell et al. 1986, Saigal et al. 1989, Teplin et al. 1991, Veen

40

et al. 1991, Johnsson et al. 1993, Sommerfelt et al. 1996, Scottish LBW Study Group 1992a, Robertson et al.

1992). Retinopathy was reported in 1.1-13% of preterms (Saigal et al. 1989, Veelken et al. 1991, Stjernqvist

et al. 1993, Victorian Infant Collaborative Study Group 1995).

The incidence of deafness varied from 0 to 2% in the different birth-weight groups (Scottish LBW Study

Group 1992a, Johnsson et al. 1993, Msall et al. 1993, Victorian Collaborative Study Group 1995, Sommefelt

et al. 1996) and unilateral hearing loss or hearing impairment from 4 to 16% in ELBW or VLBW children

(Marlow et al. 1987, Saigal et al. 1989, Teplin et al. 1991, Scottish LBW Study Group 1992a, Johnsson et al.

1993, Herrgård et al. 1995, Victorian Study Group 1995) compared with 3-4% of the controls.

Shunted hydrocephalus was found in 0.9-1.4% of children with a birthweight of less than 2001 g (Powell

et al. 1986, Marlow et al. 1987) and in 8.7% of the ELBW population (Stjernqvist et al. 1993). The rate of

epilepsy was found to increase from 1.2% for BW groups more than 1500 g to 2.5% for VLBW children and

to 6.5% for ELBW children (Powell et al. 1986). In other studies, an epilepsy rate of 2-7.1% has been

reported for different preterm groups (Kitchen et al. 1986, Victorian Infant Collaborative Study Group 1991,

Robertson et al. 1992, Herrgård 1993, Ishikawa et al. 1995).

Minor impairments are reported more seldom than major ones in follow-up studies. Therefore also studies

concerning children born before the ´80s, are included. Minor visual impairments were observed in 8.7% and

visual acuity less than 0.3 in 4.6% of LBW children examined at 3-4.5 years of age (Marlow et al. 1987,

Scottish LBW Study Group 1992a). Strabismus was observed in 2.7-26% in different low birth-weight

groups (Kitchen et al. 1986, Astbury et al. 1990, Teplin et al. 1991, Järvenpää et al. 1991, Stjernqvist et al.

1993, Weisglas-Kuperus et al. 1993, Powls et al. 1997), and 11.6-24% when examined at 4.5-5 years of age

(Scottish LBW Study Group 1992a, Herrgård 1993).

Preterm children were reported to have more difficulties, with the smallest children performing worst, in

balance, co-ordination, fine manipulative ability, quality of gross motor movements, and more asymmetry

and associated movements compared with full-term/normal birth-weight controls at 4-10 years of age

(Drillien et al. 1980, Nickel et al. 1982, Michelsson et al. 1983, Crowe et al. 1988, Forslund and Bjerre 1989,

Largo et al. 1990a, Elliman et al. 1991, Herrgård 1993, Pharoah et al. 1994, Goyen et al. 1998, Olsen et al.

1998) despite similar intelligence quotient scores (Hack et al. 1992). Minor motor abnormalities were found

in 20% of VLBW children compared with 2.6% of full-term controls at 9 years (Michelsson et al 1983). 13%

of the VLBW children had fine motor impairments, and 71% of them had below average fine motor scores at

five years (Goyen et al. 1998). Fine and/or gross motor problems were observed in ELBW children twice as

often as in the heavier peer groups (Halsey et al. 1993), and 28% had motor performance below -2SD of the

test mean (Saigal et al 1990) at four to five years of age.

Motor competence was impaired in 16% of LBW, 20% of VLBW and 40% of ELBW children (Scottish

41

LBW Study Group 1992a), and the total impairment score of ELBW/VLBW children was significantly

higher than that of controls (Marlow et al. 1989, Levene et al. 1992) as assessed by the test of motor impair-

ment (TOMI) at 4-6 years of age.

Visual-motor or visual-spatial problems are frequently observed in preterm children, especially in ELBW

children, even those with normal intelligence and no overt neurologic abnormality (Hunt et al. 1982, Klein et

al. 1985, Calame et al. 1986, Robertson et al. 1990, Saigal et al. 1990, 1991, Ornstein et al. 1991, Teplin et

al. 1991, Halsey et al. 1993, Herrgård 1993, Goyen et al. 1998, Luoma et al. 1998, Olsen et al. 1998). These

problems occur in 17-41% of VLBW/ELBW children at 5-11 years of age (Hunt et al. 1982, Saigal et al.

1990, Goyen et al. 1998, Luoma et al. 1998).

The mean IQ/DQ scores of LBW infants have been reported to fall within the average range, but to be

significantly lower (Drillien et al. 1980, Noble-Jamieson et al. 1982, Hirata et al. 1983, Lloyd et al. 1984,

Michelsson et al. 1984, Aylward et al. 1989b, Marlow et al. 1989, Abel-Smith and Knight-Jones 1990,

Astbury et al. 1990, Ornstein et al. 1991, Luoma et al. 1998, Olsen et al. 1998) than of the matched full-term

controls.

The speech and language development of unimpaired (without sensory or mental deficit) LBW/VLBW or

premature children was mildly to moderately delayed compared to that of full-term children within the first

two years (Byrne et al. 1993), at 5 years (Michelson et al. 1983, Largo et al. 1986, Abel-Smith and Knight-

Jones 1990, Levene et al. 1992) and at 9 years (Michelson et al. 1984). On the other hand, intellectually

normal very preterm infants without major neurological disability did not differ from full-term controls on

global verbal measures at 5 years of age (Luoma et al 1998). Speech/language impairment was found in 11.9-

20.4% of VLBW children at 3-5 years of age (Marlow et al. 1987, Veen et al. 1991). Preterm children

tended to have more articulation defects than term children, and boys more than girls (Michelsson et al.

1983, Largo et al. 1990b). Articulation defects at 5-6 years of age were found in 16-20% of LBW children

(Michelsson et al. 1983, Scottish LBW Study Group 1992b) and 39% of ELBW children (Teplin et al. 1991).

3.9.3. INFANTS WITH HEMORRHAGIC/ISCHEMIC BRAIN LESIONS

Periventricular-intraventricular hemorrhage (PIVH) is the most common type of intracranial hemorrhage in

the neonatal period. It is mainly a condition of premature infants because of the vulnerability of the immature

periventricular vessels to rupture as a consequence of hemodynamic instability (Volpe 1995). Among VLBW

infants, the rate of PIVH in the ´80s ranged from 25-49% (Levene et al. 1983, Perlman et al. 1986, Graham et

al. 1987, van de Bor et al. 1988, Eken et al. 1995) and showed a decreasing trend (Philip et al. 1989). ELBW

42

infants had a higher incidence of PIVH, more severe appearance, and earlier onset compared with VLBW

infants (Perlman et al. 1986). PIVH is frequently associated with periventricular hemorrhagic venous

infarction, and may coexist with periventricular leucomalacia, another ischemic injury of the periventricular

white matter (Banker and Larroche 1962, Takashima et al. 1986, Volpe 1997).

However, PIVH occurs occasionally in full-term neonates (Roland et al. 1990, Jocelyn et al. 1992). 5% of

healthy full-term neonates had mild PIVH in early ultrascan (Hayden et al. 1985). In addition, in the ´80s a

prevalence of 0.36/1000 live births of symptomatic IVH was reported among full-term infants (Jocelyn et al.

1992).

The classification of PIVH into four grades of severity has been widely used (Papile et al. 1978). According

to follow-up studies, an isolated hemorrhage of the germinal matrix (Grade I) or a minor one confined to the

lateral ventricles (Grade II) did not increase the infant’s risk of adverse outcome (Papile et al. 1983, Fawer et

al. 1987, Graham et al. 1987, Stewart et al. 1987, Roth et al. 1994). Instead, IVH with ventricular dilatation

(Grade III), parenchymal hemorrhage (Grade IV) or posthemorrhagic hydrocephalus carry a significant risk

(30-100% risk) of severe motor and multisensory impairment both in preterm (Papile et al. 1983, Guzzetta et

al. 1986, Ford et al. 1989, Vohr et al. 1992, Fazzi et al. 1994, Fernell et al. 1994, Roth et al. 1994) and full-

term (Jocelyn et al. 1992) infants.

Ischemic lesions have been reported to be a more potent cause of severe disability than hemorrhagic ones (de

Vries et al. 1985, 1996). 15-25% incidence of PVL has been noted among VLBW infants; in 3-8% it was

observed to lead to cystic evolution (Weindling et al. 1985, Graham et al. 1987, de Vries et al. 1993, Eken et

al. 1995). Periventricular echodensities (flares) also without cystic evolution, observed in cranial ultrasound,

are reported to be a risk for developing abnormal neuromotor signs (de Vries et al. 1988, Appleton et al.

1990, Levene et al. 1992, Jongmans et al. 1993, Fazzi et al. 1994), visual deficits (Gibson et al. 1990, Cioni

et al. 2000) or lower cognitive abilities and attention deficits (Fawer and Calame 1991). Cystic PVL carries a

60-100% risk for major impairments, especially CP (de Vries et al. 1985, Weindling et al. 1985, Cooke et al.

1987, Fawer et al. 1987, Graham et al. 1987, Fazzi et al. 1994). The size and site of a lesion is important: the

majority of infants with large lesions located in the parieto-occipital region will most probably develop

cerebral palsy, but if the lesion is limited to the frontal lobe, only a few will develop CP (Holling and

Leviton 1999). Intrauterine infection (maternal chorioamnionitis) is considered an important risk factor for

PVL (Zupan et al. 1996, Yoon et al. 1997, Badawi et al. 1998, Hallman 1999).

43

3.9.4. INFANTS WITH ASPHYXIA

Perinatal or birth asphyxia is associated with acute or later neurologic dysfunction and developmental

disorders in both full-term and preterm infants, in whom it is often accompanied by PIVH. The question

whether birth asphyxia is the consequence of earlier lesions or risk factors, or whether it is an acute event,

remains to be answered (Bax and Nelson 1993).

The incidence of asphyxia among full-term infants, defined by the presence of immediate neonatal distress

and/or signs of neonatal encephalopathy, born in the ´70s or ´80s was reported to vary between 2.9-7.7/1000

live-born infants (Brown et al. 1974, Finer et al. 1981, Ergander et al. 1983, Levene et al. 1985, Amiel-Tison

1988, Hull and Dodd 1992, Thornberg et al. 1995). The incidence was indirectly related to gestational age

and birth-weight, and was 9% for preterm infants and 0.5% for full-term infants (MacDonald et al. 1980).

No single clinical marker suggesting asphyxia, such as low Apgar scores, metabolic acidemia, meconium-

stained amniotic fluid or abnormal patterns of fetal heart rate, has proved to be a significant prognostic

indicator (Naeye and Peters 1987, Lumley 1988, Ruth and Raivio 1988). The criteria for perinatal asphyxia

potentially causing neurologic sequalae, including profound umbilical artery acidemia, 5-minute Apgar

scores, neonatal neurological symptoms and multiorgan system dysfunction, have been suggested (Carter et

al. 1993).

During the past two decades, improvement has been reported both in survival and long-term outcome for

infants with asphyxia, although there are only few follow-up studies of children up to school-age (Naeye and

Peters 1987, Robertson and Finer 1989, Handley-Derry et al 1997). The survival of full-term infants has risen

from 50% to above 90% (Brown et al. 1974, Scott 1976, Robertson and Finer 1985, 1989, Ishikawa et al.

1987) and normal long-term outcome from 36% to 80% (Brown et al. 1974, Scott 1976, de Souza and

Richards 1978, Mulligan et al. 1980, Finer and Robertson 1983, Ishikawa et al. 1987). Term and preterm

infants with asphyxia did not differ from each other either as to incidence of sequalae or severity of impair-

ment, but survival was directly related to gestational age (Mulligan et al. 1980). Severe neurological impair-

ments were observed in about 10-28% of asphyxiated surviving infants at 1-5 years of age (Brown et al.

1974, deSouza and Richards 1978, Mulligan et al. 1980, Ergander et al. 1983, Finer and Robertson 1983,

Robertson and Finer 1993) and minor impairments in 14-36% of survivors (Brown et al. 1974, deSouza and

Richards 1978, Finer and Robertson 1983).

The term hypoxic-ischemic or postasphyxial encephalopathy (HIE), or the recently recommended term

neonatal encephalopathy (NE), has been used to describe the neonatal neurological syndrome, which is

thought to originate from asphyxia (Sarnat and Sarnat 1976, Finer et al. 1981, Amiel-Tison and Ellison 1986,

Nelson and Leviton 1991, Bax and Nelson 1993). Sarnat and Sarnat (1976) defined three clinical stages of

44

asphyxiated term infants with HIE. Stage I included hyperalertness, hyperexcitability, Stage II lethargy,

hypotonia, hyperreflexia, seizures, weak Moro and sucking responses, and Stage III stupor, flaccidity,

decreased or absent tendon reflexes, absent Moro and sucking reflexes, and apneic spells. Other classifica-

tions of NE, emphasizing the duration of symptoms, have been reported by Levene (1985) and Amiel-Tison

and Ellison (1986).

The incidence of severe hypoxic-ischemic encephalopathy among full-term infants has fallen from the ´70s

to the ´80s according to hospital-based or population-based samples from 1.1-2.6/1000 to 0.5-2.1/1000 live-

born infants (Levene et al. 1985, Amiel-Tison 1988, Hull and Dodd 1992, Thornberg et al. 1995). According

to different classifications, mild neurological abnormalities have been observed in 14-67%, moderate

abnormalities in 21-84% and severe abnormalities in 2-32% of infants with neonatal encephalopathy (Finer

and Robertson 1981, 1983, Lipp-Zwahlen et al. 1985, Hull and Dodd 1992).

The duration of neurological abnormalities - especially disturbance of consciousness, poor sucking and

absent Moro reflex (Brown et al. 1974, Sarnat and Sarnat 1976, deSouza and Richards 1978, Finer and

Robertson 1983, Lipp-Zwahlen et al. 1985, Amiel-Tison and Ellison 1986, Levene et al. 1986, Ishikawa et al.

1987), the time of appearance and quality of the seizures (Sarnat and Sarnat 1976, Mulligan et al. 1980,

Robertson and Finer 1985, Naeye and Peters 1987, Ellenberg and Nelson 1988), the neurological condition

of the newborn after the second week of life or at discharge (Robertson and Finer 1985, Mercuri et al.

1999b), EEG abnormalities (Taceuchi and Watanabe 1989, Eken et al. 1995, Selton and Andre 1997) as well

as neuro-imaging abnormalities (Martin and Barkovich 1995, Rutherford et al. 1996, Amess et al. 1999,

Hanharan et al. 1999, Mercuri et al. 1999b), and delayed potentials in evoked potentials (Muttitt et al. 1991,

Whyte 1993) have been associated with adverse outcome.

Neonatal encephalopathy has been reported to be a valuable marker of a central nervous system injury, and

also an important predictor of subsequent neurological deficits (Low et al. 1985, Volpe 1995). A relationship

between the grade of neonatal encephalopathy and the outcome of the infants has been observed by many

authors. No child with mild neonatal neurological disturbance (Robertson and Finer 1985) and recovery

within one to five days (Sarnat and Sarnat 1976, Levene et al. 1986) had an adverse outcome or even minor

motor or cognitive deficits (Handley-Derry 1997) at 3-8 years of age. Their later motor coordination and

school performance were similar to those of their peers (Robertson and Finer 1989, Handley-Derry et al.

1997). However, infants with severe HIE either died or had significant neurological impairments (Sarnat and

Sarnat 1976, Lipp-Zwahlen et al. 1985, Robertson and Finer 1985, Mercuri et al. 1999b). The outcome of

infants with moderate HIE was more difficult to predict. Those whose neurological examination and EEG

remained abnormal for more than a week, had a significant risk for an adverse outcome (Sarnat and Sarnat

1976, Lipp-Zwahlen et al. 1985, Robertson and Finer 1985, 1993). At 8 years of age, intellectual, visual-

motor integration and receptive vocabulary scores for those with moderate encephalopathy were significantly

45

below those in the group of mild encephalopathy or in the peer comparison group (Robertson and Finer

1989).

The prediction of abnormal outcome for a full-term asphyxiated infant was proposed by Amiel-Tison and

Ellison (1986) to be based on the persistence of abnormal neurological function after seven days of life, par-

ticularly in association with brainstem abnormalities, repetitive seizures which are difficult to control,

markedly abnormal EEG, abnormal brain ultrasound within the first two weeks, and abnormal BAEP. Later

on, VEP, SEP and neuro-imaging techniques, especially MRI and newer magnetic spectroscopy and near

infrared spectroscopy, which are under active research, have been proven good prognostic tools, too (Gibson

et al. 1992, Amess et al. 1999, Hanharan et al. 1999, Mercuri et al. 1999b).

3.9.5. INFANTS WITH NEONATAL SEIZURES

Volpe (1995) classified neonatal seizures as subtle, focal/multifocal clonic, focal/generalized tonic, and

myoclonic seizure types. The distribution of different seizure types was similar in full-term and preterm in-

fants (Scher et al. 1993). Tonic and myoclonic seizures related to adverse outcome (Holden et al. 1982), and

focal clonic seizures had the best prognosis (Mizrahi and Kellaway 1987, Watkins et al. 1988).

The incidence of neonatal seizures varies according to the classification criteria, EEG documentation and to

populations, and has been reported to be 1.3-2.0/1000 for full-terms (Eriksson and Zetterström 1979,

Minchom et al. 1987, Ronen et al. 1999), 4-26/1000 for both full-term and preterm population (Brown et al.

1972, Dennis 1978, Holden et al. 1982, Scher et al. 1993, Ronen et al. 1999) and 3.9-13% for preterm

neonates (Watkins et al. 1988, van Zeben-van der Aa et al. 1990, Scher et al. 1993). Scher reported a 0.2%

incidence of electrographically confirmed neonatal seizures among all live-births.

Hypoxic-ischemic encephalopathy, manifesting mostly as a subtle seizure, is the cause of neonatal seizures in

40-65% of both full-term and preterm infants (Eriksson and Zetterström 1979, Mizrahi and Kellaway 1987,

Watkins et al. 1988, Volpe 1995, Ronen et al. 1999). Other important underlying conditions associated with

neonatal seizures are intracranial hemorrhages, cerebral infarcts, metabolic abnormalities, infections and

cerebral dysgenesis (Mizrahi and Kellaway 1987, Scher et al. 1993, Mercuri et al 1995, Leth et al. 1997,

Ronen et al. 1999).

Neonatal seizures have been connected with high mortality, 9-30% among full-term infants and 54-64%

among preterm or very low birth-weight infants (Rose and Lombroso 1970, Eriksson and Zetterström 1979,

Minchom et al. 1987, Watkins et al. 1988, van Zeben et al. 1990, Scher et al. 1993).

46

An increased rate of adverse outcome is more common among preterm survivors compared with full-term

infants with neonatal seizures (Scher et al. 1993). The incidence of handicaps/disabilities after neonatal sei-

zures was reported to be 28-53% (Dennis 1978, Eriksson and Zetterström 1979, Bergman et al. 1983).

Among VLBW survivors, the impairment rate was 65% at 5 years, and almost a half of these children were

functionally disabled (Watkins et al. 1988). CP has been reported to occur in 13-41% of mainly full-term

populations, and in 40-59% of preterm infants at 2-7 years of age. The rate of MR or developmental delay,

respectively, has been 19-25% and 35-40%, and that of epilepsy 22-30% and 17% (Holden et al. 1982, Scher

et al. 1993). 44-70% of full-terms and 25-57% of preterm infants had a normal outcome after neonatal

seizures.

Recurrent seizures with early onset, duration over 48 hours, poorly controlled and requiring additional

anticonvulsants, were associated with poor outcome (Scott 1976, Mulligan et al. 1980, Finer et al. 1981,

Holden et al. 1982, Minchom et al. 1987, Watkins et al. 1988, Volpe 1995).

3.9.6. SMALL FOR GESTATIONAL AGE INFANTS

Infants small for gestational age, or infants with intrauterine growth retardation are defined as those with a

birth-weight below the 10th percentile (Parkinson et al. 1981, Harvey et al. 1982, Hadders-Algra et al. 1988c,

Tenovuo et al. 1988, Veelken et al. 1992) or below 2SD (Ounsted et al. 1986, Matilainen et al. 1987, Cnat-

tingius et al. 1987, Hawdon et al. 1990, Smedler et al. 1992) of the expected mean for gestational age and

sex. Among preterm infants, the use of the birth-weight ratio has been suggested (Morley et al. 1990, Hutton

et al. 1997).

The incidence of intrauterine growth retardation was reported to be 0.9% ( -2SD) (Cnattingius et al. 1987)

or 10% (<10th percentile) (Tenovuo et al. 1988) in liveborn infants. 26% of the infants in a population-based

VLBW cohort born in the mid 1980s were growth-retarded (Veelken et al. 1991).

The developmental outcome is influenced by the multiplicity of etiology, and especially among full-term

SGA children the onset of growth retardation is important (Harvey et al. 1982, Allen 1993). The vulnerabil-

ity of SGA children to peri-neonatal complications such as asphyxia and metabolic disturbances (Stanley et

al. 2000) may increase the risk for adverse development later.

Major neurological defects such as cerebral palsy and mental retardation are uncommon among full-term

SGA children, although they are more frequent than in full-term AGA controls (Fitzhardinge and Stewen

1972, Hadders-Algra et al. 1988c). The differences are clearly to the disadvantage of SGA children as

regards minor neurological dysfunction at 3-7 years (Neligan 1976, Harvey et al. 1982, Ounsted et al. 1986,

47

Hadders-Algra et al. 1988c), language delay and perceptual dysfunction (Fitzhardinge and Steven 1972,

Harvey et al. 1982, Walther and Ramaekers 1982), as well as behavior problems at school-age (Parkinson et

al. 1986) compared with normal birth-weight peers. However, contradictory observations in neurologic

outcome at 3 years have also been reported (Sung et al. 1993). In spite of later normal average intelligence,

school difficulties (Parkinson et al. 1981) were found among half of the full-term SGA boys and one third of

the girls (Fitzhardinge and Stewen 1972). On the other hand, no differences in intelligence or school

achievement were found between 10-11-year-old SGA boys and control boys when social class and family

background factors were controlled for (Hawdon et al. 1990).

The importance of intrauterine growth retardation among preterm infants has been debated. Neonatal

complications may have a greater adverse effect than intrauterine growth retardation (Gutbrod et al. 2000).

The results of studies are essentially influenced by whether the different groups are compared within similar

birth-weights or similar gestational ages. Preterm SGA infants were observed to be more vulnerable to

developmental disorders than preterm AGA infants of similar gestational age (Vohr and Oh 1983, Matilainen

et al. 1987, Hadders-Algra et al. 1988c, Tenovuo et al. 1988, McCarton et al. 1996), especially if the growth

retardation was symmetric (Martikainen et al. 1992). On the other hand, intrauterine growth retardation in

preterm or VLBW infants was a less serious risk factor than severe prematurity, if the birth-weight was

similar (Calame et al. 1983, Veelken et al. 1991). In addition, gestational age was found to be a more impor-

tant risk factor for major impairments (Calame et al. 1983, Vohr and Oh 1983, Veelken 1992, Korkman et al.

1996, Kok et al. 1998), while intrauterine growth retardation was associated more with minor impairments

among VLBW children (Veelken 1992, Korkman et al. 1996, Kok et al. 1998). Furthermore, growth retarda-

tion affected cognitive ability more clearly than motor ability, whereas motor problems were associated with

low gestational age among very preterm children (Calame et al. 1983, Hutton et al. 1997).

3.9.7. INFANTS WITH MULTIPLE RISK FACTORS (HIGH-RISK INFANTS)

The term `high-risk´ is used in neonatology for biologic and environmental factors, which carry an increased

risk for neurodevelopmental disorders. Most of these high-risk infants, comprising 4-6% of all neonates, are

at present treated in neonatal intensive care units (Blackman 1991). There are some studies on children -

most of whom were born in the ´70s - with several risk factors (Calame et al. 1976, Sell et al. 1985, Black-

man et al. 1987, Lindahl et al. 1988a, Vähä-Eskeli 1992).

Multiple handicaps were observed in 6-12% of children with several serious peri-neonatal risk factors

(Calame et al. 1976, Clayes et al. 1984, Lindahl et al. 1988a). The incidence of minor neurodevelopmental

abnormalities, such as gross and/or fine motor disorders, visual-motor abnormalities, language problems and

borderline intelligence, was 20% (Clayes et al. 1984) and that of behavioral problems 14.5% (Calame et al.

48

1976) at preschool age. 16% of the children in a high-risk group showed definitely abnormal performance,

and 25% moderately to markedly impaired performance according to neurodevelopmental screening tests

(Lindahl et al. 1988b). High-risk children performed significantly below the comparison group in verbal,

perceptual-motor and preacademic tests (Zarin-Ackerman et al. 1977, Blackman et al. 1987, Jensen et al.

1988) at 2-6 years of age. 17-85% of high-risk children had minor neurodevelopmental abnormalities and

19.5-46% had school problems compared with 13-37% and 10.5-12% of matched controls, respectively, at

school age (Clayes et al. 1984, Sell et al. 1985, Lindahl et al. 1988b). Minor neurological dysfunction and

impaired motor skills were observed among 29% and 17% of high-risk children and 13% of controls,

respectively (Lindahl et al. 1987, 1988b).

Abnormal neonatal neurological signs and symptoms were significant predisposers to later developmental

problems (Calame et al. 1976, Low et al. 1985, Lindahl et al. 1988a, Vähä-Eskeli 1992). 40-74% of children

with neonatal neurological symptoms had an abnormal outcome at 3 years (Calame et al. 1976) or at 9 years

(Lindahl et al. 1988a), and 44% of the children with major handicaps had had neurological symptoms

neonatally (Lindahl et al. 1988a).

The duration of neonatal hospitalization, preterm birth, low birth-weight, respiratory difficulties, infection,

fetal hypoxia, male gender and low social class (Calame et al. 1976, Low et al. 1985, Sell et al. 1985,

Lindahl et al. 1988a, Hadders-Algra et al. 1988b) were observed among the most significant predictors of

later developmental outcome.

49

4. THE AIMS OF THE STUDY

The aims of the present study were

1. to describe and analyze neonatal neurological findings at 40 weeks of postmenstrual age by means

of a standardized age-specific quantitative and qualitative neurological examination

2. to evaluate neurological/neuromotor abnormalities observed at 56 months using a standardized age-

specific neurological examination

3. to assess the impact of pre-, peri- and neonatal risk factors and socioeducational factors on the ab-

normal neonatal neurological findings, and mild neurological dysfunction (MND) and deviant motor

competence (DMC) at the age of 56 months.

4. to examine the relationships between MND and DMC and visual-motor integration/ cognitive/ lan-

guage abnormalities at the age of 56 months

5. to study the predictive value of the abnormal neonatal neurological examination on the occurrence

of

a) MND/DMC

b) Cerebral palsy

c) Problems in visual-motor integration

d) Developmental delay

e) Speech/language problems

f) Major/minor impairments

at the age of 56 months, comparing the feasibility of the quantitative and qualitative methods.

50

5. SUBJECTS AND METHODS

5.1. NEONATAL STUDY POPULATION

The present study is a part of an extensive bi-national multicenter follow-up study conducted in Bavaria,

Germany, and Uusimaa, Finland (Riegel et al. 1995). The subjects of this Finnish study were recruited from

a total of 15311 deliveries, including 49 stillbirths, born in the seven maternity hospitals in the county of

Uusimaa (the study region) between March 15, 1985 and March 14, 1986.

The study population originally consisted of a representative regional cohort of 2193 neonates, including the

hospitalized group and the control group (vide infra), who were followed prospectively from birth to 56

months of age. Both the hospitalized infants and control infants were examined neonatally at 40 weeks of

postmenstrual age and again at 56 months of chronological age using the same methods. The infants who

underwent the neonatal neurological examination were included in the present study.

Written parental consent was obtained prior to participation. The study protocol was approved by the Ethical

Committees of all participating hospitals.

5.1.1. HOSPITALIZED GROUP

The hospitalized group comprised all liveborn infants born to mothers residing in the county of Uusimaa and

who, within ten days from birth, were due to any medical concern admitted to the neonatal wards of the

obstetric units, or transferred to the Neonatal Intensive Care Unit (NICU) of the Children’s Hospital (pres-

ently the Hospital for Children and Adolescents), Helsinki University Central Hospital, which serves as the

tertiary center of the region for neonatal care.

Altogether 1535 neonates - 10% of the total number of deliveries - were enrolled (Table 4). There were 867

(56.5%) boys and 667 (43.5%) girls. 1069 (69.7%) of the infants were full-term (more than 36 completed

gestational weeks) and 466 (30.3%) were preterm (24-36 weeks of gestational age) (Table 5). 96 infants

(4.4% of all) were preterm, less than 32 gwks, and 44 (2.0% of all) were less than 29 gwks. 366 (24.1% of

data known) infants had a birth-weight less than 2500 g, 81 (3.7% of all) less than 1500 g and 24 (1.1% of

all) less than 1000 g. 391 (25.5%) of all hospitalized infants were treated in the neonatal intensive care unit

and 171 (43.7%) of them were preterm. Due to the centralization of at-risk deliveries to the University

Central Hospital, only 126/1535 (8.2%) neonates referred to NICU were born outside the University Obstet-

51

ric Unit (called here outborn infants). During the same period, a study of diabetic mothers was going on at

the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, leading to hospitaliza-

tion of all newborn infants of diabetic mothers (N=30).

58 infants died neonatally during the primary hospitalization and 9 infants after being discharged but before

56 months of age (Appendix 1). The survival rate was 96.9% for the whole study population, 91.3% for

preterm and 67.7% for VPT infants up to 56 months of age. The survival rates for the three low birth-weight

groups (<2500g,<1500g,<1000g) were 87.7%, 65.4% and 54.2%.

Table 4. The study population

HOSPITALIZED

INFANTS

CONTROL

INFANTS

TOTAL

N N N

Liveborn infants 1535 658 2193

Died neonatally before neonatal examination 53 0 53

Dropout before neonatal examination due to refusal or early discharge 48 26 74

Excluded due to congenital anomalies or brachial plexus injury 25 2 27

Included in the neonatal analysis 1409 630 2039

Died after neonatal examination 14 1 15

Dropout after neonatal examination 354 140 494

Examined at 56 months of age 1041 489 1530

Excluded due to a congenital disorder or progressive disease 5 0 5

Final study population 1036 489 1525

5.1.2. CONTROL GROUP

658 infants without evidence of neonatal illness born during the same period were recruited at the three

largest maternity hospitals of the study area (Table 4). The neonate born after every second hospitalized

infant was selected. 328 (49.8%) of the infants were boys and 330 (50.2%) were girls. The group consisted

of 642 (97.6%) full-term infants and 16 (2.4%) preterm infants (Table 5). Seven infants (0.3%) had a birth-

weight less than 2500 g, no one less than 1500 g.

One infant died after primary hospitalization but before 56 months of age (Appendix 1).

52

Table 5. Gestational age of the hospitalized and control infants

HOSPITALIZED INFANTS CONTROL INFANTS

GA wks Total In analysis Total In analysis

N % N % N % N %

=<28 44 2.9 28 2.0 -

29-31 52 3.4 36 2.6 -

32-36 370 24.1 348 24.7 16 2.4 16 2.5

37-41 1002 64.3 933 66.2 617 93.8 590 93.7

>41 67 4.4 65 4.5 25 3.8 24 3.8

Total 1535 100 1409 100 658 100 630 100

5.1.3. NEONATAL DROPOUTS AND EXCLUSIONS

Neonatal dropouts and exclusions are given in Table 4. Of the 74 infants who were not examined neonatally,

three were preterms less than 32 completed weeks, 12 had a gestational age more than 31 weeks, but less

than 37 weeks and 59 were full-terms.

18 infants in the hospitalized group were excluded due to obvious congenital anomalies or chromosomal

abnormalities (5 spina bifida cystica, 1 encephalocele, 1 congenital hydrocephaly, 10 Down’s syndrome, 1

46XY8p+) as well as 7 infants with brachial plexus injury (Table 4). Two infants were excluded from the

control group, one with Down’s syndrome and the other because of mild brachial plexus injury (Table 4).

5.1.4 FINAL NEONATAL STUDY SERIES

Altogether 1409 hospitalized and 630 control infants (N=2039) were included in the neonatal data analysis

and follow-up (Table 4).

5.2. SOCIODEMOGRAPHIC, PRE-, PERI- AND NEONATAL DATA COLLECTION

Detailed pre- and perinatal data on maternal history, present pregnancy, delivery, and data about the neonatal

period were collected on precoded forms from the hospital charts by trained nurses belonging to the research

group. The data concerning educational and socioeconomic status of the parents, and the family status, were

collected by interviewing the mothers.

Background factors were dichotomized as optimal or nonoptimal, using the concept described by Prechtl

53

(1968) and modified by Michaelis (1979). Obstetrical and neonatal optimality sum scores consisting of

the number of items within the optimal range were calculated for each infant. Missing data were presumed

optimal. The obstetric optimality sum score was calculated by using 9 items for risk factors before preg-

nancy, 13 items during pregnancy, 12 items during delivery, and 5 items for immediate neonatal condition,

and by giving one point for every optimal condition. The maximum obstetric optimality sum score was 39.

The neonatal optimality sum score was calculated by the same principle using 13 items, which described

neonatal morbidity and treatment needed in the neonatal ward (Appendix 2).

Apnea and/or bradycardia, metabolic disturbances, circulatory/septic shock, intracerebral hemorrhage,

pneumothorax, clinical seizures, as well as operations and drugs administered were also recorded. Cranial

ultrasound examination was done when clinically pertinent. Periventricular-intraventricular hemorrhages in

the cranial ultrasound were graded according to Papile et al. (1978). Periventricular leucomalacia was

combined with Grade IV IVH. Smallness for gestational age was defined as birth-weight below -2SD of

Finnish standards (Pihkala et al. 1989) and largeness for gestational age above 2SD of the same standards.

During the hospital stay, the intensity of the care level (Casaer et al. 1982) of every infant was evaluated

daily by one of the four pediatricians recruited to the study and not personally responsible for the clinical

treatment of the infants studied. The intensity of the care level consisted of six items describing the level of

treatment needed to support respiration, nutritional status and overall condition of the neonate (clinical

intensity) as well as observed neurological behavior - quantity of spontaneous motility, muscle tone, ir-

ritability of the central nervous system - (neurological intensity). Four-grade scoring (0-3) for each item was

used. The most favorable sum score was 0 and the maximal adverse sum score was 18. The infant’s condition

was considered unstable until the daily assessment gave a sum score of less than 3 on three consecutive days.

The number of days needed until the child’s clinical condition stabilized, was counted. The intensity of

neonatal care was defined as the mean of the daily sum scores of the first ten days at hospital, or if stabilized

earlier, until a stable clinical condition was reached. The total score was subdivided into clinical (3 items)

and neurological (3 items) intensity scores.


The concept of neonatal neurological examination was based on the method presented by Prechtl (1977) and

modified for the use of the present study project by the Bavarian Study Group (Riegel and Ohrt 1988, Riegel

et al. 1995). Visual fixation and horizontal tracking of items, not included in the original examination

scheme, were included in the assessment. Abnormal head size at birth was defined as head size below -2SD

or above 2SD of the mean for gestational age and sex of the Finnish standards (Pihkala et al. 1989). The

results of the neurological examination were recorded in the forms (Appendix 4) in which the expected

54

optimal (i.e. best possible) neurological response and possible deviant signs for each of the 28 assessed

neurological items were predefined. The number of optimal responses was used as the quantitative measure

of the neonatal neurological examination. As a conclusion of the examination, a clinical evaluation of six

subsystems of CNS (CNS irritability, quantity and quality of spontaneous motility, muscle tone, cranial nerve

function and symmetry of posture and/or motility and/or responses) (Appendix 4) was recorded for each

infant (Prechtl 1977) to be used as the qualitative assessment scores.

During the neurological examination, the environmental conditions (temperature, light) were kept as stable

as possible. The examination was performed, whenever possible, exactly between two meals and in behav-

ioral state 3 (eyes open, some isolated spontaneous movements, no crying) defined by Prechtl (1977). The

level of alertness of the infants was recorded during the examination.

All infants were scheduled to be examined between the 5th and 7th days of life by one of the four pediatrici-

ans of the Finnish research group. The preterm infants were re-examined as near their 40-week postmenstrual

age as possible during the hospital stay, and very sick infants after stabilization of their condition (vide

supra). The results of the latest neurological examination were used in defining the neurological normality or

abnormality in the neonatal period to be used in later analyses.

An assessment of clinical maturity of the infant was done using the scoring technique published by Dubowitz

et al. (1970). Gestational age was corrected according to the assessment results, if there was a discrepancy of

more than two weeks between the maternal history of the last menstrual period and/or early ultrasound and

Dubowitz assessment results, except for preterms under 32 weeks gestational age (Sanders et al. 1991).

5.3.1. CLASSIFICATION METHODS AND STUDY GROUPS

The neonatal neurological examination was used to define quantitative and qualitative neurological normal-

ity or abnormality.

5.3.1.1. QUANTITATIVE METHOD (NEOQUAN)

As a quantitative measure, a neonatal neurological optimality score was calculated from the 28 items of the

examination (Appendix 4). One point was given for every optimal response with a maximal sum of 28. The

lower the scores, the more reduced optimality. The infant was defined as definitely abnormal, if the optimal-

ity sum score was reduced more than 25% of the maximum (score <21) (Stave and Ruvalo 1980). Missing

data was considered as optimal (Touwen et al. 1980).

55

5.3.1.2. THE STUDY GROUPS BY THE QUANTITATIVE METHOD (NeoQuan1, 2 and 3)

The infants classified as neurologically definitely abnormal by the quantitative assessment (NeoQuan1),

comprised 113 (8.0%) hospitalized infants and 4 (0.6%) control infants (Table 6). 47.9% of the infants in the

quantitatively abnormal group were preterm, 15.4% were less than 32 weeks of gestational age. The infants

with an optimality score 75% or more, regarded as neurologically normal, were allocated to two separate

comparison groups; one (NeoQuan2) (N=1296) from the original hospitalized group, and the other (Neo-

Quan3) (N=626) from the original control group.

5.3.1.3. QUALITATIVE METHOD (NEOQUAL)

The qualitative method was based on normality or abnormality in the six subsystems of CNS defined by the

neonatal neurological examination. The infant was classified as qualitatively normal, if the subsystems of

CNS (CNS irritability, the quality and quantity of spontaneous motility, muscle tone and cranial nerve func-

tion, symmetry of posture and/or motility and/or responses), by the clinical evaluation, were intact. The

infant was considered definitely abnormal, if at least one of the following signs was observed: apathy/coma

or hyperexcitability, definite/marked hypo/hyperkinesia, definite/marked hypo/hypertonia, hemisyndrome

(asymmetric posture or movements), abnormalities of cranial nerve function (e.g. facial nerve palsy, asym-

metric pupils, nystagmus, constant strabismus, sun setting of eyes, sucking/swallowing difficulties, missing

visual fixation/tracking or acoustical response), convulsions or abnormal cry. Infants with mild abnormalities

were classified as normal.

5.3.1.4. THE STUDY GROUPS BY THE QUALITATIVE METHOD (NeoQual1, 2 and 3)

Definite abnormality by the qualitative method was observed in 242 (17.2%) hospitalized infants and in 40

(6.3%) control infants (NeoQual1) (Table 6). 41.5% of the infants were preterm, 10.3% of them less than 32

completed weeks. Neurologically normal hospitalized infants formed a second group (NeoQual2)(N=1167)

and neurologically normal control infants a third group (NeoQual3)(N=590).

Allocation of the infants into the six study groups is presented in Table 6.

56

Table 6. The study groups by the quantitative and qualitative method

HOSPITALIZED

INFANTS

N

CONTROL

INFANTS

N

Total

N

NeoQuan1 113 4 117

NeoQuan2 1296 1296

NeoQuan3 626 626

Total 1409 630 2039

NeoQual1 242 40 282

NeoQual2 1167 1167

NeoQual3 590 590

5.3.1.5. INTERRELATIONSHIPS OF NEOQUAN AND NEOQUAL GROUPS

The number of infants belonging to the three study groups according to quantitative and qualitative methods

in relation to each other is shown in Table 7. When the qualitative method was used, 282 (13.8%) infants of

all the examined neonates were estimated as definitely abnormal. With the quantitative method, reduced op-

timality of more than 25% of the maximum was observed in 117 (5.7%) of the examined neonates. There

were 77 (3.8% of all examined) neonates who were neurologically abnormal according to both quantitative

and qualitative methods.

Table 7. Interrelation of the groups defined by quantitative and qualitative neonatal neurological assessment. Percent-

ages calculated from the total study population.

QUALITATIVE METHOD

NEOQUAL1 NEOQUAL2 NEOQUAL3 Total

QUANTITATIVE METHOD

N % N % N % N

NEOQUAN1 77 3.8 38 1.9 2 0.1 117

NEOQUAN2 167 8.2 1129 55.4 0 1296

NEOQUAN3 38 1.9 0 588 28.8 629

Total 282 1167 590 2039

57

5.4. FOLLOW-UP STUDY SERIES AT THE AGE OF 56 MONTHS

In all, 1530 out of 2039 (75%) children (1409 hospitalized and 630 controls) included in the neonatal

analysis were examined at 56 months of age. 833 (54.4%) were boys and 697 (45.6%) girls. Altogether 1525

of the children were included in the analysis at 56 months of age (Table 8).

5.4.1. DROPOUTS AND EXCLUSIONS AFTER NEONATAL NEUROLOGICAL

EXAMINATION

Five of the examined 1530 children were excluded from the analysis due to congenital disorders diagnosed

after the neonatal period (one Salla disease, one Williams’ syndrome, one Moebius’ syndrome, one

Albright’s syndrome and one child with multiple anomalies) probably affecting their examination result.

The causes of death are given in Appendix 1.

Neo-postneonatal mortality was 68/2193=3.1% for the whole study cohort. It was 67/1535=4.4% for the

hospitalized group and 1/658=0.15% for the control group. The mortality was 8.7% for preterms less than 37

gwks and 32.3% for very preterm infants.

494 (24.4%) children did not participate in the examination at the age of 56 months (Table 8). 264 (13.0%)

of the families could not be traced.

5.4.2. ANALYSIS OF PREDICTABILITY OF IMPAIRMENTS AND DISABILITIES AT 56

MONTHS OF AGE

In order to extend the analysis of predictability of impairments and disabilities at the age of 56 months to as

large a proportion of the original population as possible, also the children with indirect data were included, in

addition to those who were examined at 56 months. Data on the health and development of 230 children after

the neonatal period were available either from the parents, hospital records, or earlier assessments (Appendix

3). Five of these children were diagnosed to have a congenital disorder or progressive disease. In all, 1750

(1525 examined and 225 with indirect data) children were included in the analysis of the predictability of

impairments and disabilities (Table 8).

58

Table 8. The follow-up of infants in the six study groups

QUANTITATIVE QUALITATIVE TOTAL

NEOQUAN1 NEOQUAN2 NEOQUAN3 NEOQUAL1 NEOQUAL2 NEOQUAL3

Neonatal neurological examination

N 117 1296 626 282 1167 590 2039

Died

N%

86.8

60.5

10.2

103.5

40.3

10.2

150.7

Not traced a)N%

1412.8

17813.8

7211.5

3914.3

15613.4

6911.7

26413.0

Indirect data a) b)

N%

1816.5

14611.3

6610.6

3412.5

13311.4

6310.7

23011.4

Examined at age 56 months a)

N%

7770.6

96674.9

48777.9

19973.2

87475.2

4577.6

153075.6

Excluded at age 56 months

N%

10.9

40.3

00

20.7

30.3

00

50.2

Included in analysis of 56- month examination a)

N%

7670.0

96274.6

48777.9

19772.4

87174.9

45777.6

152575.3

Included in analysis of predictability a) c)

N%

9183.5

110685.7

55388.5

22883.8

100286.2

52088.3

175086.5

a) percentages of surviving children b) 5 children with congenital disorders excluded from analysis of predictability

c) those, who were examined and those with indirect data included

5.4.3. NEOQUAN AND NEOQUAL GROUPS AT 56 MONTHS OF AGE

Of the three study groups defined by neonatal quantitative assessment, 70.6%/74.9%/77.9% (NeoQuan 1, 2

and 3, respectively) of the surviving children were examined at the age of 56 months. The proportions of the

qualitatively defined neonatal groups were 73.2%/75.2%/77.6% groups (NeoQual1, 2 and 3, respectively).

Of the 15 children who died after neonatal neurological examination, 8/15 (53.3%) and 10/15 (66.7%) had

been definitely abnormal neonatally by quantitative and qualitative methods, respectively. The overall

mortality among the neonatally neurologically abnormal quantitative and qualitative groups was 6.8%/3.5%

(NeoQuan1,NeoQual1), respectively, whereas it varied from 0.2-0.5% in neurologically normal groups

(NeoQuan2-3, NeoQual2-3).

59

The distribution of the gestational age of children examined at the age of 56 months is shown in Table 9.

Table 9. Gestational age of the examined children


GA wks NEOQUAN1 NEOQUAN2 NEOQUAN3 NEOQUAL1 NEOQUAL2 NEOQUAL3

< 32 N%

1013.2

363.7

00.0

2110.7

252.9

00.0

463.0

32-36N%

2634.2

23424.3

122.5

5728.9

20323.3

122.6

27217.8

37-41N%

3951.3

64867.4

45793.8

11558.4

60169.0

42893.7

114475.0

>41N%

11.3

444.6

183.7

42.0

424.8

173.7

634.1

TOTALN%

76100

962100

487100

197100

871100

457100

1525100

5.5. FOLLOW-UP EVALUATIONS AT THE AGE OF 56 MONTHS

The neurodevelopmental follow-up assessment was performed at the chronological age of 56 months (+-

1mo) by the four pediatricians involved also in the neonatal examinations. The examiners were blinded as to

the perinatal history of the children.

5.5.1. NEUROLOGICAL EXAMINATION

The concept for qualitative neurological assessment was based on the examination described by Touwen

(1979) and modified by the Bavarian Study Group (Riegel and Ohrt 1988, Riegel et al. 1995) (Appendix 5).

Some items measuring gross motor function and balance (walking up and down stairs), fine manipulative

ability (drawing, peg-board) and facial-oral motor function (drooling) were added to the examination scheme

by the Bavarian Study Group. The maturity and integrity of eight subsystems of the CNS (gross motor

function, trunk balance, fine motor function, coordination of the upper extremities, muscle tone, tendon

reflexes, facial-oral motor function and visual system/conjugated eye movements/strabismus) were evaluated

in a comprehensive age-appropriate manner. The expected optimal neurological expression of each item and

possible deviant signs were defined in advance. The child’s behavioral state and ability to cooperate during

the examination were also recorded.

60

Items for quantitative neurological assessment were selected from the examination protocol of Touwen, with

an additional eight items (such as running, sideways hopping, finger tapping, hand clapping) included

(Appendix 6).

Some children refused to attempt every test item. For these children a reliable estimation of normali-

ty/abnormality was not possible. In order not to exclude all children with incomplete performance or not to

label them too hastily as impaired, a percentage sum score of successful tasks (Aylward et al. 1989) (i.e. the

number of successfully performed tasks / the number of attempted tasks x 100) was calculated for each child

in each of the eight subsystems of CNS, and the tasks of motor competence with a predefined acceptable

minimum number of attempts. The number of attempts of the individual tasks demanded for an approved per-

formance are shown in Tables 10 and 11. If a child made fewer attempts than required within a subsystem

and was unsuccessful even in them, he/she was classified as abnormal in that area. If a percentage score was

within normal range with insufficient attempts, reliable estimation was not possible and the child was exclu-

ded from the analysis. Dichotomized variables were constructed to define mild neurological abnormality.

All distributions of percentage scores were skewed to the left, consequently the cut-off points for defining

abnormality in the eight subsystems of CNS and motor competence were defined as the point at which

approximately 10% of the control subjects in the original study population failed.

5.5.1.1. MILD NEUROLOGICAL DYSFUNCTION (MND), QUALITATIVE ASSESSMENT

A qualitative measure of the neurological examination, used to define mild neurological dysfunction, was

based on 23 variables (of which five were bilateral) of the eight subsystems of CNS (Appendix 5). Table 10

shows the cut-off points of percentage scores for the dichotomized variables to define abnormal performance

in the eight subsystems of CNS.

Mild neurological dysfunction (MND) at the age of 56 months was defined as an abnormality in the

subsystems of gross motor or balance or fine motor function, or at least three of the other subsystems (hand

coordination, muscle tone, tendon reflexes, facial-oral motor, strabismus) after exclusion of children with

cerebral palsy grade 2-4 (Hagberg 1975). Children with cerebral palsy grade 1 (N=2) were considered as

having mild neurological dysfunction.

5.5.1.2. DEVIANT MOTOR COMPETENCE (DMC), QUANTITATIVE ASSESSMENT

As a quantitative measure of the neurological examination, defined as the motor competence of the child, 14

items from the neurological examination assessing the child’s motor skills or clumsiness were used (Appen-

dix 6 ). Table 11 shows the cut-off points of percentage scores for the abnormal performances for motor

61

competence. Abnormal performance according to the dichotomized variable was defined as deviant motor

competence (DMC).

5.5.1.3. DEFINITE NEUROLOGICAL ABNORMALITY

At the age of 56 months, definite neurological abnormality was defined as an evident impairment/disability,

such as CP. The grade of functional severity of cerebral palsy was based on Hagberg’s recommendation

(Hagberg 1975). Definite neurological abnormality included CP grades 2-4.

Table 10. Qualitative assessment

NO. OF VARIABLES

MIN. NO. OF ATTEMPTS FOR

APPROVAL

CUT-OFF PERCENTAGE

SCORE

% OF ABNORMAL IN

CONTROL GROUP

INCOMPLETE OR MISSING

PERFORMANCE

N N % % N

Gross motor 6 4 <83 5.5 38

Balance 3 2 <67 5.7 18

Fine motor 3 2 <67 7.7 20

Hand coordination 5

( 2 right and left ) 3 <100 0.4 106

Muscle tone 1 1 <100 0.4 83

Tendon reflexes 6

( 3 right and left ) 4 <100 0.8 48

Facial-oral motor 3 2 <67 2.0 18

Eye movements 1 1 <100 3.2 5

Table 11. Quantitative assessment

NO. OF VARIABLES

MIN. NO. OF ATTEMPS FOR

APPROVAL

CUT-OFF PERCENTAGE

SCORE

% OF ABNORMAL IN

CONTROL GROUP

INCOMPLETE OR MISSING

PERFORMANCE

N N % % N

20(6 right and left )

7 <75 8.9 33

62

5.5.2. VISION AND HEARING

At 56 months of age, the children’s monocular visual acuity of each eye was tested by Snellen E-chart at a

distance of 5 m. Visual acuity less than 0.3 in the better eye was considered as moderately lowered vision,

and visual acuity from 0.3 to 0.6 as mildly lowered vision. Hearing was screened by whispering at a distance

of 5 m the names of 4/10 objects, placed in front of the child, which the child could see and point out as a

positive response. Both ears were tested separately.

5.5.3. HAND PREFERENCE

Five test items were used to define hand preference. The items were drawing, cutting out a circle from a

piece of paper with scissors, throwing a ball, brushing one’s teeth, and grasping a kaleidoscope handed to the

child.

If the child used the same hand in at least 4/5 test items, handedness was defined to the preferred side. If the

child refused more than two tasks, the hand dominance could not be determined. If the child performed three

successful tasks with the same hand, one of which was drawing, handedness could be defined; otherwise the

child was considered ambidextrous (Riegel et al. 1995).

5.5.4. VISUAL-MOTOR INTEGRATION

The Developmental Test of Visual-Motor-Integration (VMI, Beery and Buktenica 1967, Beery 1982) was

used to assess visual-motor integration and function. The higher the scores by the predefined criteria, the

more competent the performance. The test has been revised in 1982 for children aged 3-15 years (Beery

1982). We used the first 12 figures of the test.

Moderate visual-motor delay was defined as VMI test scores lower than 2SD below the mean scores of the

original control group of the present study (N=493), and mild visual-motor delay as test scores between -2SD

and -1SD of the mean scores.

5.5.5. COGNITIVE DEVELOPMENT

Non-verbal cognitive ability was assessed using the Columbia Mental Maturity Scale (Burgemeister et al.

1954), a nonverbal screening measure of general reasoning ability. The test material consists of 100 cards, in

each of which the subject has to select from a set of 3-5 drawings the one, which is different from, or unre-

63

lated to, the others. The test has been designed for children aged 3-12 years. The test result is not dependent

on verbal ability or fine motor skills. The number of correct responses gives the total score. The test had been

standardized for normally developed German children (Schuck et al. 1975). Test reliability had been reported

as .93 (Kuder-Richardson Formel 20).

Severe developmental delay was defined as a test score more than 3SD below the mean score of the original

control group (N=498), moderate developmental delay as a test score between -3SD and -2SD of the mean

score, and mild developmental delay between -2SD and -1SD of the mean score.

5.5.6. SPEECH AND LANGUAGE

Verbal competence was assessed using a Verbal Ability Test (Aktiver Wortschatztest für drei-bis

sechsjährige Kinder, AWST 3-6, Kiese und Kozielski,1979) consisting of 82 tasks of picture naming. One

point was given for every correct response, and the number of correct responses gave the total score.

Language comprehension was assessed using the LSVT-Test (Logopädisher Sprachverständnis Test, -

Wettstein, 1983). This test has been developed for children aged 4 to 8 years. We used two of the three parts

included in the original test, both of which consisted of 17 test items. In part A the child was asked by the

examiner to perform sequences of actions with eight standardized test objects, according to verbal directions

with predefined expressions. In part C the examiner repeated the same scenes/actions, which the child had to

describe verbally. One point was given for each correctly executed task. During the test it was possible to

assess also the child’s errors in articulation or grammar.

Moderate language delay was defined by a test score lower than 2SD below the mean score of the original

control group (N=489/AWST, N=491/LSVT-A, N=473/LSVT-C), and mild language delay by test scores

between -2SD and -1SD of the mean scores.

5.6. DEFINITIONS OF IMPAIRMENT AND DISABILITY

According to the assessment at the age of 56 months, the children were categorized according to the WHO

recommendation of classification as having major/minor impairment and major/moderate/minor disability.

In the present study the criteria were as follows (see also Table 12):

64

MAJOR IMPAIRMENT

• CP grade 2-4 (5.5.1.3.) • Blindness/moderately lowered vision (visual acuity <0.3 with better

eye) • Deafness/hearing defect requiring hearing aid • Epilepsy • Hydrocephalus with ventriculoperitoneal shunt • Moderate-severe developmental delay defined by CMM <-2SD • Severe mental retardation*.

MINOR IMPAIRMENT

• CP grade 1 • Mild neurological dysfunction • Deviant motor competence • Mildly lowered vision (visual acuity 0.3-0.6 with better eye) • Mild developmental delay defined by CMM -2SD - (-1SD) • Mild-moderate speech/language delay defined by AWST/LSVT <-1SD • Mild-moderate visual-motor delay defined by VMI <-1SD • Mild mental retardation* • Speech/language problems requiring speech therapy*

MAJOR DISABILITY

• CP grade 3-4 • Epilepsy • Blindness• Deafness/hearing defect requiring hearing aid • Hydrocephalus with ventriculoperitoneal shunt • Severe developmental delay defined by CMM <-3SD.

MODERATE DISABILITY

• CP grade 2 • Moderate visual defect (visual acuity <0.3 with better eye) • Moderate developmental delay defined by CMM -3SD - (-2SD) • Moderate speech/language delay defined by AWST/LSVT <-2SD • Moderate visual-motor delay defined by VMI <-2SD.

MINOR DISABILITY

• CP grade 1 • Mild neurological dysfunction • Deviant motor competence • Mild developmental delay defined by CMM -2SD - (-1SD) • Mild speech/language delay defined by AWST/LSVT -2SD -(-1SD) • Mild visual-motor delay defined by VMI -2SD - (-1SD).

* the children, who were not seen at 56 months of age, but were included in the prevalences of impairments and disabili-

ties and in the analysis of predictability:

• the exact diagnosis of MR, CP, hearing defect, epilepsy and HC from hospital records was available • need for speech therapy according to parents

65

Table 12. The criteria of impairment and disability in the present study

IMPAIRMENT DISABILITY

Major Minor Major Moderate Minor

CP grades 4

3

2

1

MND

DMC

Visual

Blind

<0.3

0.3-0.6

Hearing

Deaf / Hearing aid

Epilepsy

Hydrocephalus with shunt

Developmental Delay

Severe

Moderate

Mild

Language Delay

Moderate

Mild

VMI

Moderate

Mild

66

5.7. STATISTICAL METHODS

In the statistical analyses, BMDP Statistical Software (Dixon, 1992), was used.

As descriptive statistics, means, standard deviations and ranges are presented for continuous data, and

frequencies and/or percentages for categorical data.

For the analysis of statistical relationships between discrete variables, the Chi-square test with Yates’

correction or Fisher’s exact test were used. The test of linear trend was used in the analysis of 2x3 tables.

Gestational age was stratified as infants less than 32 gwks = very preterm, between 32 and 36 gwks =

moderately preterm, and more than 36 gwks = full-term. Birth-weight was stratified as follows: infants with

BW<1500g = VLBW, 1500g-2499g = LBW and >2499g = NBW infants.

Differences between means of continuous variables of two groups were analyzed with Student’s t-test, and

those of three groups with analysis of variance (one- or two-way ANOVA). Parametric statistics were used

also in the analysis of not normally distributed sum scores/percentage scores of neurological/neuromotor

variables. This was regarded appropriate due to the great number of subjects in the present study series. The

Welch or Brown-Forsythias procedures were used when group variances according to the Levene test were

not equal. Post hoc analyses by Tukey’s method were used for pairwise multiple comparisons in the case of

statistically significant ANOVA results.

Analysis of covariance (ANCOVA) was used to adjust for effects of sex, gestational age, birth-weight and

age at neonatal neurological examination.

Interrelationships between outcome variables were analyzed using Pearson’s correlation coefficient.

Multivariate statistics were used to find out which pre-perinatal, neonatal morbidity or socioeducational

background factors predict an abnormal neonatal neurological examination result, on the one hand, and

minor neurological dysfunction or deviant motor competence at the age of 56 months, on the other hand.

These techniques were also applied to identify single neonatal neurological variables associated with neuro-

logical/neuromotor outcome measures at 56 months of age.

The logistic regression model allows one to examine the individual and joint effects of various background

factors, and to predict the risk of abnormality in individual cases. Dichotomized dependent (outcome)

variables were analyzed in multiple stepwise logistic regression with the independent variables, which were

proved to be significant at p level <0.05 in univariate analysis. The variables with the similar risk category

were analyzed separately, firstly. Goodness of fit of the model was determined by Hosmer-Lemeshow

67

statistics, in which a high p value indicates an adequate fit of the data to the model. Relative risk was ex-

pressed as an odds ratio with 95% confidence limits.

Stepwise linear multiple regression was chosen when the dependent outcome variable was continuous. The

regression equation gives the multiple correlation coefficient (R) and multiple R2, which is the proportion of

the total variance in the dependent variable accounted for (explained) by the independent background

variable in the model.

Gender, gestational age, birth-weight and the education level of both parents were included into the models,

which implies that in all multivariate analyses the effect of these factors was controlled for.

The criterion for statistical significance was p-values <0.05.

Predictability was calculated as follows (Armitage 1987):

Screening Test Disorder

Present Absent

Positive (Abnormal) a b

Negative (Normal) c d

a=true positives, b=false positives, c=false negatives, d=true negatives

Sensitivity=a/a+c

Specificity=d/b+d

Predictive value of a positive test (PPV)=a/a+b

Predictive value of a negative test (NPV)=d/c+d

68

6. RESULTS

6.1. RESULTS OF NEONATAL NEUROLOGICAL EXAMINATION AMONG THE

HOSPITALIZED AND CONTROL INFANTS

6.1.1. NON-OPTIMAL SIGNS

Neurological non-optimality profiles are given in Figure 1. Non-optimal signs in passive (30%/15%) and

active (8-39%/1.5-27%) muscle tone, mostly diminished, second stage of Moro response (21%/8%), visual

fixation/tracking (18%/10%), tendon reflexes of the legs (14.5%/6-8%), quantity of spontaneous motility

(hypokinesia more commonly than hyperkinesia)(14%/6%) and involuntary movements (13%/4%) were the

greatest sources of differences in the individual non-optimal neurological responses observed among the

hospitalized and control infants in the neonatal neurological examination at term age (Figure 1).

Non-optimal performance in sucking, swallowing, grasping, crying or mimic, on the other hand, were seldom

observed, and no control infant was observed to have abnormal swallowing or foot grasping.

On the other hand, non-optimal performance in resistance to passive movements (15% controls vs. 30%

hospitalized) and head traction (27% vs. 39% resp.) were common also among control infants, 97.5% of

whom were full-terms.

The differences in frequencies between the hospitalized and control infants were statistically significant in

all items except Moro1. The greatest differences were found in Moro2 (χ2=54.267, p<0.0001), resistance to

passive movements (χ2=46.551, p<0.0001), involuntary movements (χ2= 37.090, p<0.0001), muscle tone at

rest (χ2=30.843, p<0.0001) and traction head (χ2=29.373, p<0.0001).

Effect of gender

Boys had significantly greater incidences of non-optimal performance than girls in involuntary movements

(χ2=13.469, p=0.0002), visual fixation/tracking (χ2=9.165, p=0.0025), quality of spontaneous motility (type

χ2=8.847, p=0.0029, progress χ2=4.458, p=0.047), resistance to passive movements (χ2=8.632, p=0.0033),

first stage of Moro response (χ2=5.207, p=0.0225) and glabella reflex (χ2 =4.272, p=0.0387).

Effect of gestational age and birth-weight

Very preterm infants had the greatest, and full-term infants the smallest incidences of non-optimal responses

in all items except swallowing, quality type of spontaneous motility and hand grasp, in which moderately

preterm infants had the smallest frequencies.

70

Very preterm infants had 2-7 times greater frequencies of non-optimal responses compared with full-term in-

fants, increasing with decreasing gestational age. The differences were statistically significant in all items

except mimic and swallowing, and most pronounced in the second stage of Moro response (χ2 =219.462,

p<0.0001), visual fixation/tracking (χ2 =98.455, p<0.0001), posture and muscle tone at rest (χ2 =66.391,

p<0.0001, χ2 =43.500, p<0.0001), resistance to passive movements (χ2 =56.513, p<0.0001), involuntary

movements (χ2 =44.016, p<0.0001) and quality of spontaneous motility (χ2 =37.900, p<0.0001).

Very preterm infants had both hypotonia and hypertonia of the lower extremities more often than infants

with longer gestation. Hyperkinesia was not observed among them at all. Their knee and ankle reflexes were

more often exaggerated than weakened, and more often exaggerated than those of moderately preterms and

full-terms. The first stage of Moro was equally often exaggerated as depressed among very preterm infants.

In older preterms and full-terms it was more often weakened. The second stage of Moro was missing in one

third of very preterm infants, in about one fifth of moderately preterm infants, and in about 6% of full-terms.

The effect of birth-weight, examined in the stratified birth-weight groups, (BW <1500g, 1500g-2499g,

>2499g) paralleled that of gestational age; infants with lowest birth-weights had the highest incidences of

non-optimal neurological responses.

6.1.2. NEUROLOGICAL OPTIMALITY SCORE

The mean, median, SD and range of neonatal neurological optimality score in the hospitalized, control

infants and the whole study population are shown in Table 13, and the corresponding distributions of the

scores of the hospitalized and control groups in Figure 2.

Table 13. Neurological optimality score in hospitalized, control infants and the whole

study population

NEUROLOGIGAL OPTIMALITY SCORE

HOSPITALIZED INFANTS

CONTROL INFANTS

ALL INFANTS

N 1409 630 2039

Mean 25.2 26.7 25.7

Median 26.0 27.0 27.0

SD 3.3 1.8 3.0

Range 3 - 28 18 - 28 3 – 28

71

6.8% of the entire study population, 8.0% of the hospitalized, and 0.6% of the control infants scored 20 or

less, and were consequently defined as neurologically abnormal. 35% of all neonates (29% of hospitalized,

49% of controls) had the highest possible optimality score (score=28) resulting in considerable skewness of

the neurological optimality score. The statistical difference in the means of the neurological optimality score

between the hospitalized and control infants was highly significant (t-test p<0.0001).

Figure 2. The distributions of the neonatal neurological optimality scores of the hospitalized and control infants.

Effect of gender

The mean value of the neurological optimality score of the boys was statistically significantly lower than that

of girls (t-test, p=0.0033).


The means of the optimality score of the three gestational age groups (22.3/24.7/26.0 in <32/32-36/>36 gwk)

and those of the three birth-weight groups (22.6/24.8/25.9 in <1500/1500-2499/>2499 g) differed highly

significantly (p<0.0001) for both GA and BW groups in ANOVA from each other in pairwise comparison

(Tukey, p<0.01). The means increased with increasing GA or BW.

0

10

20

30

40

50

60

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

NEUROLOGICAL OPTIMALITY SCORE

PR

OP

OR

TIO

N (

%)

OF

INF

AN

TS

Hospitalized group

Control group

72

6.1.3. SUBSYSTEMS OF CNS

The frequencies of normal, mildly and definitely abnormal performances within the six neonatal subsystems

of CNS among hospitalized and control groups are presented in Table 14.

The proportions of definite abnormalities were small and seldom observed in control infants. Statistically

significant differences between the hospitalized and control groups were observed in the quantity of sponta-

neous motility, muscle tone and cranial nerve function (Table 14).

Effect of gender, gestational age and birth-weight

No statistical gender differences were found in the occurrence of abnormalities in the subsystems of CNS.

The very preterm and very low birth-weight infants showed the greatest incidences of abnormalities in the

subsystems of CNS compared with moderately preterm and full-term, as well as infants with a greater birth-

weight.

6.2. NEONATAL CHARACTERISTICS WITHIN THE SIX STUDY GROUPS DEFINED BY

RESULTS OF THE QUANTITATIVE AND QUALITATIVE ASSESSMENTS

In the following sections, the stratification of the infants into the six groups, three within NeoQuan and

NeoQual each, as described in 5.3.1., is used in the analysis of the results.

6.2.1. GENDER

The gender distribution in the six study groups is shown in Table 15. There were more boys than girls (65%

vs. 35%) in the neurologically abnormal groups defined by the two assessment methods, compared with the

neurologically normal groups. The proportion of boys and girls was similar in pairwise comparison of the

three groups defined by the quantitative and qualitative method.

6.2.2. GESTATIONAL AGE AND BIRTH-WEIGHT

The distribution of gestational age and birth-weight among the infants in the six study groups is shown in

Table 15.

Infants with short gestational age and low birth-weight were significantly over-represented in both neurologi-

cally abnormal groups (NeoQuan1, NeoQual1). The quantitative assessment method selected proportionally

more very preterm (<32 weeks of GA) and very low birth-weight (BW <1500 g) infants into the abnormal

group (15.4%/11.4%) than did the qualitative method (10.3%/7.6%). See Table 15.

73

Table 14. The frequencies of normal, mildly and definitely abnormal performances within

the six subsystems of CNS in hospitalized and control groups

CLASSIFICATION

HOSPITALIZED GROUP N= 1409

%

CONTROL GROUP N= 630

%

χ2 p

CNS irritability ns

Normal 92.0 99.4

Mildly diminished/ strengthened reactions 7.7 0.7

Apathy/ coma, hyperexcitability/ convulsions 0.2 0

Quantity of spontaneous motility 5.397 0.0202

Normal 86.6 93.7

Mildly diminished/ increased 12.6 6.3

Definitely diminished/ increased 0.9 0

Quality of spontaneous motility ns

Normal 94.5 98.1

Mildly abnormal 4.5 1.9

Definitely abnormal 0.4 0

Not examined / Missing 0.5 0

Muscle tone 10.439 0.0012

Normal, symmetric 71.0 84.8

Mildly abnormal 25.8 14.3

Definitely abnormal 2.9 0

Not examined / Missing 0.3 0.3

Cranial nerves 41.846 <0.0001

Normal 69.7 83.3

Abnormal 29.9 16.3

Not examined / Missing 0.4 0.3

Asymmetry ns

No 97.3 97.5

Yes 2.7 2.5

74

6.2.3. SOCIODEMOGRAPHIC CHARACTERISTICS

The mean age of the mothers in the whole study population was 29.4 years. The neurologically abnormal

infants were observed to have parents with a lower education level. The difference between the three study

groups was statistically significant as to the education of the father (Table 16). The study groups did not

differ in regard to the marital status of the mother.

Table 15. Neonatal characteristics of infants in the six study groups

QUANTITATIVE QUALITATIVE

NEO- QUAN1

NEO-QUAN2

NEO- QUAN3

p NEO- QUAL1

NEO- QUAL2

NEO- QUAL3

p TOTAL

Gender

Boy N 76 723 316 183 637 295 1115 % 65,0 55,8 50,5 64,9 54,6 50,0 54.7

Girl N 41 573 310 99 530 295 924 % 35,0 44,2 49,5 35,1 45,4 50,0 45.3

χ2 0.0065 0.0002

Gestational age (wk)

Mean 36.0 37.9 39.5 36.7 38.0 39.5 SD 4.4 3.0 1.4 4.0 2.9 1.4

Range 24-42 24-43 35-42 24-42 25-43 35-42

ANOVA <0.0001 <0.0001

GA <37 wk N 56 356 16 117 295 16 428 % 47.9 27.5 2.6 41.5 25.3 2.7 21.0

GA <32 wk N 18 48 0 29 37 0 66 % 15.4 3.7 0 10.3 3.2 0 3.2

Birth-weight (g)

Mean 2861 3173 3571 2983 3196 3579 SD 1063 824 475 957 809 472

Range 695-5030 660-5400 2050-4950

660-5030 800-5400 2050-4950

ANOVA <0.0001 <0.0001

BW <2500 g N 42 275 7 82 235 7 324 % 36.8 21.4 1.1 29.7 20.3 1.2 15.9

BW <1500 g N 13 43 0 21 35 0 56 % 11.4 3.3 0 7.6 3.0 0 2.7

BW <1000 g N 5 8 0 7 6 0 13 % 4.4 0.6 0 2.5 0.5 0 0.6

75

Table 16. Education of the father of the infants in the six study groups

6.3. ANTECEDENTS AND CO-MORBIDITY OF NEONATAL NEUROLOGICAL

ABNORMALITY

6.3.1. VARIABLES ASSOCIATED WITH OBSTETRICS AND DELIVERY

Obstetric characteristics of the six study groups (NeoQuan1-3, NeoQual1-3) and statistical comparisons

within the NeoQuan and NeoQual groups are presented in Table 17.

As to maternal, pre- and perinatal risk factors in the study groups, the greatest proportions of risk factors

were observed in neonatally neurologically abnormal groups (NeoQuan1, NeoQual1) and the smallest

proportions in neurologically normal non-hospitalized groups (NeoQuan3, NeoQual3). The increase in

obstetric and perinatal risk factors between the three study groups was often significant also in the linear

trend test.

When the obstetric background data on maternal history were examined, only the occurrence of a previous

preterm birth and severe chronic disease of the mother were factors that differed significantly between the

three study groups both by quantitative/qualitative methods.

Most of the statistically significant differences in pairwise comparison of obstetric risk factors were found

between the hospitalized (NeoQual1-2, NeoQuan1-2) and non-hospitalized (NeoQuan3, NeoQual3) groups.

The most notable factors that were associated with early hospitalization, but not necessarily with neonatal

neurological abnormality (NeoQuan2, NeoQual2), were irregular prenatal care, smoking, psychosocial stress,

toxemia, urinary infection, PROM and fetal distress manifesting as growth retardation, pathologic CTG or

placental insufficiency. Significant delivery-related factors were meconium-stained amniotic fluid, fever

during delivery, placental ablation, and need for instrumental delivery.


FATHER’S EDUCATION NEO- QUAN1

NEO- QUAN2

NEO- QUAN3

NEO- QUAL1

NEO- QUAL2

NEO- QUAL3

N 112 1235 608 267 1112 576

School unfinished or comprehensive school

% 23.2 29.3 24.7 24.3 29.9 24.5

Vocational school % 34.8 30.4 26.8 31.8 30.2 27.3

Intermediate school % 28.6 22.9 25.8 27.0 22.7 25.7

University % 13.4 17.3 22.7 16.9 17.3 25.7

χ2 p 0.0079 0.0165

76

Table 17. Pre-, peri- and postnatal non-optimal background factors in different groups defined by the neonatal neuro-

logical examination


NEO- QUAN1

NEO- QUAN2

NEO- QUAN3

p p

1/2

p

2/3

NEO- QUAL1

NEO- QUAL2

NEO- QUAL3

p p

1/2

p

2/3

N 117 1296 626 282 1167 590

% % % % % %

BEFORE PREGNANCY

Previous preterm birth

8.5 4.5 2.1 ** +++

* ** 6.4 4.3 2.2 ** ++

Severe chronic disease (DM,kidney disease)

9.4 8.6 2.6 ***+++

*** 8.9 8.6 2.2 ***+++

***

Smoking before pregnancy

30.8 30.5 25.1 * +

* 27.7 31.0 25.1 * **

Parity 1 or >2

67.5 66.7 58.6 **++ 64.9 67.2 58.1 ***

DURING PRESENT PREGNANCY

First visit to maternity center >12 gwk 16.2 15.7 12.3 ns 16.3 15.9 11.4

* + **

Irregular prenatal care

5.1 4.4 0.6 ***+++

*** 5.3 4.2 0.5 ***+++

***

Smoking during pregnancy

23.0 23.4 17.7 * +

19.0 24.1 18.0 **

Psychosocial stress

3.4 4.0 1.8 * ** 3.2 4.2 1.5 * **

Toxemia (edema, RR>140/90, proteinuria 1g/l)

12.8 15.7 8.8 ***

*** 14.5 15.6 8.5 ***

***

Urinary infection

10.3 6.6 4.2 * ++

* 7.1 6.8 4.2 +

*

Severe illness, hyperemesis, trauma, anesthesia

6.0 3.9 2.4 + 5.0 3.9 2.4 +

Vaginal bleeding

< 28gwk

> 28gwk

21.4

16.2

8.5

15.2

10.6

5.9

10.7

7.5

2.9

** +++

**++

**+++

**

*

**

20.2

14.5

7.8

14.6

10.2

5.7

10.5

7.5

2.9

***+++

**++

**++

*

*

**

**

Multiple pregnancy

6.0 6.4 2.4 ***

*** 9.2 5.7 2.0 ***+++

* ***

Preterm contractions <37gwk

39.3 29.5 20.4 ***+++

* *** 34.8 28.7 20.8 ***+++

**

77


NEO- QUAN1

NEO- QUAN2

NEO- QUAN3

p p

1/2

p

2/3

NEO- QUAL1

NEO- QUAL2

NEO- QUAL3

p p

1/2

p

2/3 Poly/Oligo-

hydramnion 4.3 4.4 1.1 ***

*** 5.0 4.1 1.2 ** +++ * **

Fetaldistress

-Fetal growth retardation

-Pathologic CTG before birth

-Placental insufficiency (pathological estriol excr.)

13.7

8.5

9.4

4.3

9.7

5.2

6.3

4.0

3.8

2.4

2.1

0.6

***+++

**+++

***+++

***+++

***

**

***

***

9.9

5.3

6.7

3.2

9.9

5.3

6.4

4.1

3.9

2.5

2.0

0.7

***+++

* +

***+++

*** ++

***

**

***

***

Tokolyse 23.1 16.7 12.6

***+++ * 22.3 15.8 12.7

** +++ **

Premature rupture of membranes (before regular contractions) >24h

>12h

23.9

12.8

29.1

19.8

9.6

27.1

10.9

2.7

19.5

***+++

***+++

***+++

*** 21.6

11.7

28.4

19.5

9.3

27.1

10.8

2.7

18.8

***+++

***+++

***+++

***

DELIVERY

Gestational age <37gwk or >41gwk

50.4 32.2 6.4 ***+++ *** *** 44.7 30.2 6.4 ***+++*** ***

Amniotic fluid meconium- stained

12.0 18.1 8.9 ***

*** 16.7 17.8 8.5 ***

***

Fever during delivery

7.0 3.6 0.6 ***+++

*** 5.1 3.5 0.7 ***+++

***

Placental ablation

4.3 3.1 0.5 ***+++

*** 4.3 2.8 0.5 ***+++

**

Fetaldistress

-Pathological CTG

-Acidosis(micro blood sample)

34.2

32.5

0.0

23.5

24.5

2.3

8.1

10.1

0.6

***+++

***+++

**

**

*

***

***

22.0

22.6

1.8

24.4

25.4

2.1

8.1

10.3

0.7

***

***

ns

***

***

Transverse, oblique or breech presenta-tion

7.0 7.0 4.2 + * 8.6 6.6 3.9 * ++

*

Intrapartum medication (oxytocin, opiate, anesthetics)

82.1 80.2 76.0 +

* 82.3 80.1 75.3 * ++

*

78


NEO- QUAN1

NEO- QUAN2

NEO- QUAN3

p p

1/2

p

2/3

NEO- QUAL1

NEO- QUAL2

NEO- QUAL3

p p

1/2

p

2/3

Instrumental delivery

-sectio prim -emergency -vacuum -forceps -breech

47.0

5.1 32.5 7.7 0.0 0.0

41.4

11.3 23.7 5.8 0.2 0.8

21.1

8.1 7.7 4.6 0.0 0.3

***+++ *** 41.5

9.2 24.8

4.6 0.4 0.4

41.3

11.0 23.8 6.2 0.2 0.3

21.2

8.3 7.6 4.4 0.0 0.3

***+++ ***

Duration of stage 2 <10min/>60min

31.6 30.9 38.8 ** ++ 31.2 31.2 38.6 ns

SGA <-2SD

LGA > 2SD

11.1

7.7

10.6

5.2

1.0

2.6

***+++

**++

***

***

10.6

6.4

10.4

5.1

1.0

2.5

***+++

*++

***

***

NEONATAL FACTORS IMMEDIATELY POSTPARTAL

Ventilatory assistance (mask/ intubation)

28.2 14.0 0.8 ***+++ *** *** 20.2 13.6 0.5 ***+++** ***

Medical correction of acidosis or volume substitu-tion

6.8 3.5 0.0 ***+++ 3.9 3.6 0.0 ***+++

Cord blood ph <7.3

ph <7.15

ph Mean z) SD

10.3

3.4

7.23 0.20

10.6

2.9

7.23 0.11

3.4

0.8

7.25 0.10

*** *** 10.0

2.5

7.24 0.18

10.3

3.0

7.23 0.11

3.5

0.8

7.24 0.10

*** ***

Apgar 1 min <9/ 5 min <10

1 min <8/ 5 min <9

63.2

41.9

54.5

26.5

21.9

4.8

***+++

***+++ ***

***

***

56.7

33.7

54.1

25.8

21.4

4.4

***+++

***+++ *

***

***

Body temperature

36.00 C Mean SD

25.6

36.3 1.0

21.1

36.5 0.7

0.5

36.9 0.3

***+++ *** 20.2

36.4 0.9

21.2

36.5 0.7

0.5

36.9 0.3

***+++ ***

OBSTETRIC OPTIMALITY SCORE Mean Median SD Range

30.4 31.0 3.3 21-37

31.6 32.0 3.2 20-38

34.1 35.0 2.2 26-39

***c)

31.1 32.0 3.3 21-38

31.6 32.0 3.1 20-38

34.1 35.0 2.2 26-39

***c)

79


NEO- QUAN1

NEO- QUAN2

NEO- QUAN3

p p

1/2

p

2/3

NEO- QUAL1

NEO- QUAL2

NEO- QUAL3

p p

1/2

p

2/3

N=2017Apgar 1 min <4 4-6 >6

N=1969Apgar 5 min <4 4-6 >6

N=1947Apgar 10 min <4 4-6 >6

115

11.3 13.0 75.7

107

9.3 5.6 85.0

96

2.1 7.3 90.6

1277

6.2 8.0 85.8

1242

1.1 4.8 94.0

1231

0.2 1.1 98.8

625

0.2 1.3 98.6

620

0.0 0.3 99.7

620

0.0 0.0 100

***277

9.0 8.7

82.3

261

5.4 6.1

88.5

249

0.8 3.6

95.6

1151

5.9 8.3

85.8

1124

0.9 4.4

94.7

1114

0.2 1.0

98.8

589

0.0 0.8

99.2

584

0.0 0.3

99.7

584

0.0 0.0 100

***

* χ2- test + linear trend test c) one-way ANOVA Significance levels */+ p<0.05, **/++ p<0.01, ***/+++ p<0.001 p: p-values between all three groups p 1/2: p-values between NeoQua1 and NeoQua2 p 2/3: p-values between NeoQua2 and NeoQua3 z) information with N=20/186/33 in the quantitative groups and N=41/166/32 in the qualitative groups

Additional risk factors which significantly associated with neonatal neurological abnormality were previous

preterm birth and preterm contractions (NeoQuan1), as well as multiple pregnancy, vaginal bleeding, the

need for tokolyse and poly/oligohydramnion (NeoQual1). Furthermore, intrapartum and immediate postpar-

tum factors often associated with an emergency situation, such as fetal distress (NeoQuan1), and pre- or

postmaturity, low Apgar scores and the need for immediate ventilatory assistance (NeoQuan1, NeoQual1)

were highly significantly associated with neonatal neurological abnormality.

When NeoQuan1 and NeoQual1 were compared with each other (after the exclusion of 77 infants abnormal

with both methods), NeoQuan1 was associated significantly more often with fetal distress (χ2 8.973,

p=0.0027) and abnormal heart rate pattern (χ2 8.645, p=0.0033) during labor, and also with instrumental

delivery (χ2 4.407, p=0.0358). NeoQual1, on the other hand, was associated with 5-min Apgar scores under 7

(7.8%/2.6%), meconium-stained amniotic fluid (18.1%/16.7%), toxemia (14.5%/12.8%) and multiple

pregnancy (9.2%/6.0%).

Obstetric optimality sum score

The distribution of the obstetric optimality sum score in the six study groups is presented in Table 17 and

Figures 3A and 3B.

A post hoc pairwise comparison showed a significant difference between all the three study groups by the

80

Figure 3A. The distribution of the obstetric optimality sum score in the three study groups by the quantitative neonatal classification method

Figure 3B. The distribution of the obstetric optimality sum score in the three study groups by the qualitative neonatal classification method

0

5

10

15

20

25

18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

OBSTETRIC OPTIMALITY SUM SCORE

PR

OP

OR

TIO

N (

%)

OF

INF

AN

TS

NEOQUAL1

NEOQUAL2

NEOQUAL3

0

5

10

15

20

25

18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

OBSTETRIC OPTIMALITY SUM SCORE

PR

OP

OR

TIO

N (

%)

OF

INF

AN

TS

NEOQUAN1NEOQUAN2NEOQUAN3

81

quantitative method (p<0.01). With the qualitative method, the difference between the two hospitalized

groups was significant at the 5% level; between the other groups highly significant difference was reached

(p<0.01).

No statistical difference between boys and girls was found in obstetric optimality sum scores. Very preterm

infants had the lowest obstetric optimality sum scores compared with moderate preterm and full-term infants

(mean 27.2/30.1/33.3, p<0.0001).

6.3.2. NEONATAL MORBIDITY DURING PRIMARY HOSPITALIZATION

Neonatal morbidity factors in the six study groups are presented in Table 18. Highly significant differences

were found between the neurologically abnormal and normal hospitalized groups (NeoQuan1-2, NeoQual1-

2) in the occurrence of neonatal morbidity, such as need of ventilatory assistance or antibiotic therapy,

apnea/ bradycardia, pneumothorax, severe anemia, and convulsions. Neurologically abnormal neonates

(NeoQuan1, NeoQual1) had most medical problems. `Born outside´ status was a risk factor, too.

After initial neonatal care, hyperbilirubinemia necessitating phototherapy was the only neonatal morbidity

risk factor observed in non-hospitalized infants.

Table 18. Neonatal morbidity in the six study groups after initial care

NEO- QUAN1

NEO- QUAN2

NEO- QUAN3

pp

1/2

NEO- QUAL1

NEO- QUAL2

NEO- QUAL3

pp

1/2

N 117 1296 626 282 1167 590

% % % % % %

Ventilatory treatment

32.5 8.8 - *** 20.9 8.0 - ***

Apnea/ Bradycardia

23.9 4.5 - *** 13.1 4.2 - ***

Cardiopulmonary shock

3.4 1.1 - ns 2.1 0.9 - ns

Pneumothorax indicating suction

10.3 1.9 - *** 5.3 1.8 - ***

Catheterization 12.8 3.2 - *** 7.4 3.1 - ***

Hypoglycemia 6.8 3.8 - ns 4.6 3.8 - ns

Hyper-

bilirubinemia 43.6 30.2 4.0

*** 34.8 29.6 4.1

***

Severe anemia

23.9 6.8 - *** 15.2 6.3 - ***

82

NEO- QUAN1

NEO- QUAN2

NEO- QUAN3

pp

1/2

NEO- QUAL1

NEO- QUAL2

NEO- QUAL3

pp

1/2

Septic infection

12.0 8.0 - ns 9.9 7.7 - Ns

Antibiotic therapy

53.0 33.2 - *** 44.3 31.4 - ***

Surgical measure

6.8 2.5 - ns 4.3 2.4 - Ns

Peri-

intraventricular hemorrhage gr I-IV gr III-IV

10.3 4.3

1.5 0.2

--

***

***

5.7 2.5

1.3 0.1

-- ***

Convulsions 16.2 2.8 - *** 9.3 2.5 - ***

Outborn 14.7 5.6 - *** 11.0 5.1 - ***

NEONATAL OPTIMALITY SCORE Mean Median SD Range

10.8 12.0 2.5

3-13

12.2 13.0 1.3

4-13

12.96 13.0 0.2

12-13

***c) 11.6

12.0 1.9

3-13

12.2 13.0 1.2

4-13

12.96 13.0 0.2

12-13

***c)

02 >21% Mean (days) SD Range

02 >30% Mean (days) SD

Range

17.1 26.5 0-99

14.3 22.0

0-99

3.6 8.8

0-99

3.2 7.5

0-95

***

d)

***

d)

10.5 20.4 0-99

8.4 15.6

0-99

3.5 8.5

0-99

3.2 8.5

0-95

***

d)

***

d)

Ventilatory treatment Mean (days) SD

Range

15.8 23.7

0-97

4.8 8.7

0-49

**

d)

11.8 18.8

0-97

4.8 10.7

0-88

*

d)

Phototherapy Mean (days) SD

Range

2.6 1.7

1-8

1.8 1.5

0-17

1.8 1.1 0-4

**

c)

2.4 1.8

0-8

1.8 1.5

0-17

1.8 1.1

0-4

**

c)

Antibiotic therapy Mean (days) SD

Range

16.7 20.3

1-99

7.2 4.7

0-53

***

d)11.8 15.3

1-99

7.3 4.8

0-53

**

d)

* χ2- test c) one-way ANOVA d) t-test Significance levels * p<0.05, ** p<0.01, *** p<0.001 p:p-values between all three groups p1/2: p-values between NeoQua1 and NeoQua2

Neonatal optimality sum score

The distribution of the neonatal optimality sum score in the six study groups is presented in Table 18 and in

Figures 4A and 4B.

83

Figure 4A. The distribution of the neonatal optimality sum score in the three study groups by the quantitative neonatal classification method

Figure 4B. The distribution of the neonatal optimality sum score in the three study groups by the qualitative neonatal classification method

0

20

40

60

80

100

120

1 2 3 4 5 6 7 8 9 10 11 12 13

NEONATAL OPTIMALITY SUM SCORE

PR

OP

OR

TIO

N (

%)

OF

INF

AN

TS

NEOQUAN1NEOQUAN2NEOQUAN3

0

20

40

60

80

100

120

1 2 3 4 5 6 7 8 9 10 11 12 13

NEONATAL OPTIMALITY SUM SCORE

PR

OP

OR

TIO

N (

%)

OF

INF

AN

TS

NEOQUAL1

NEOQUAL2

NEOQUAL3

84

Pairwise comparison showed a significant difference between all the three study groups by both methods

(p<0.01).

There was no significant gender difference in the neonatal optimality sum score. All gestational age sub-

groups differed significantly from each other in pairwise comparison, VPT infants having the lowest mean

scores (8.8/12.0/12.6, p<0.0001).

6.3.3. CASAER’S INTENSITY SCORE

The quantified intensity of the care level required to maintain vital functions, and the evolution of neurologi-

cal behavior during hospital care, were compared between the two hospitalized groups (Table 19). Neuro-

logically abnormal neonates, as a group, needed significantly more intensive care during their longer hospital

stay, and the severity of their illness was detectable in their neurological condition more clearly and for a

longer period.

The mean durations of hospital stay among the neurologically abnormal groups (NeoQuan1, NeoQual1),

were 24 and 15 days, respectively, compared with four days among the neurologically normal hospitalized

groups (NeoQuan2, NeoQual2).

No gender difference in Casaer’s intensity scores or hospital stay was observed. VPT infants had the highest

intensity mean scores (p<0.0001) and the longest hospitalization times (mean 47.7/7.1/3.2 days, p<0.0001)

compared with the moderately preterm and full-term groups.

Table 19. Clinical and neurological intensity scores (Casaer)


NEOQUAN1 NEOQUAN2 NEOQUAL1 NEOQUAL2

Clinical intensity score

Mean 369 244 343 235

SD 248 189 221 187

ANOVA F 27.19 df 1.124 F 62.10 df 1

p < 0.0001 p < 0.0001

Neurological intensity score

Mean 329 171 274 165

SD 211 163 204 158

ANOVA F 60.74 df 1.124 F 86.38 df 1.305

p < 0.0001 p < 0.0001

85

6.4. BACKGROUND FACTORS OF ABNORMAL NEONATAL NEUROLOGY

6.4.1. QUANTITATIVE METHOD (NeoQuan1)

All significant maternal-, pre-, peri-, and neonatal morbidity background variables were entered into a

multiple logistic stepwise regression analysis to identify predictors of quantitative neonatal neurological

abnormality (optimality score <21).

Head size more than 2SD of gestational age (OR 3.7), clinical seizures in the neonatal period (OR 3.6) and

ventilatory treatment (OR 3.3) had the greatest odds ratio for risk of quantitative neurological abnormality

(Table 20). Male gender carried a slightly increased risk. Of the obstetrical variables, fetal distress during

delivery was the only significant risk factor of quantitative neonatal neurological abnormality in a multiple

stepwise logistic regression model (2-fold risk).

Background factors of the neonatal neurological abnormality by the quantitative method was also analyzed

by means of a linear regression model (Table 21). The variables that were significant in stepwise linear

regression analysis were mostly the same as in the logistic regression. Besides the neonatal factors found to

be significant in logistic regression, low 5-min Apgar scores, antibiotic therapy, apnea/bradycardia and

hypoglycemia were background factors which explained the variance of the optimality score. Maternal

chronic disease, fetal distress during pregnancy, instrumental delivery and fever during delivery were risk

factors, too. In all, 18% of the variance of the optimality score could be explained by obstetrical and neonatal

morbidity factors. Birth-weight or the parents’ education were included into the model, but they were not

significant.

6.4.2. QUALITATIVE METHOD (NeoQual1)

Predictive background factors of neonatal qualitative neurological abnormality (NeoQual1) were also

searched, using the multiple logistic stepwise regression analysis (Table 20).

The risk of qualitative neonatal neurological abnormality was increased among infants with seizures (OR

2.3), with head size 2SD above gestational age standards (2.2) or being born outside the tertiary center (2.2).

Other factors with increased risk for qualitative neurological abnormality neonatally included antibiotic

therapy (OR 1.8), male gender (OR 1.7), low gestational age (OR 1.2) and low 5-min Apgar scores (OR 1.2).

86

Table 20. Background factors in relation to neonatal neurological abnormality by the quantitative

and qualitative method (logistic regression)

BACKGROUND VARIABLE NEOQUAN1 NEOQUAL1

ODDS RATIO CI 95 ODDS RATIO CI 95

Male gender 1.6 1.0 – 2.6 1.7 1.3 – 2.3

Low gestational age 1.1 1.0 – 1.2 1.2 1.1 – 1.2

Fetal distress during delivery 1.8 1.1 – 2.9 -

Low 5-min Apgar scores - 1.2 1.1 – 1-3

Head size > 2 SD 3.7 1.9 – 7.5 2.2 1.3 – 3.9

Ventilatory treatment 3.3 1.8 – 6.3 -

Seizures 3.6 1.6 – 8.1 2.3 1.2 – 4.5

Antibiotic therapy - 1.8 1.3 – 2.5

Outborn - 2.2 1.2 – 3.8

Hosmer- Lemeshow goodness of fit p ( last step ) 0.337 0.551

Table 21. Background factors in relation to neonatal neurological abnormality

by the quantitative method (stepwise linear regression).

BACKGROUND VARIABLE

OPTIMALITY SCORE

b p R2

Ventilatory treatment 0.666 0.03 0.070

Seizures 2.986 <0.01 0.104

Low gestational age 0.121 <0.01 0.131

Head size >2SD 1.622 <0.01 0.144

Antibiotic treatment 0.544 <0.01 0.154

Instrumental delivery 0.301 0.02 0.161

Male gender 0.394 <0.01 0.166

Low 5-min Apgar scores 0.146 <0.01 0.170

Maternal chronic disease 0.719 <0.01 0.174

Fetal distress (pregnancy) 0.594 0.01 0.177

Apnea/bradycardia 0.961 0.01 0.180

Fever during delivery 0.879 0.02 0.182

Hypoglycemia 0.804 0.03 0.184 b=regression coefficient at the last step

Adjusted R2 = 0.179

87

6.5. NEURODEVELOPMENTAL ASSESSMENT AT THE AGE OF 56 MONTHS

1525 (75.5%) of 2019 surviving children - 830 (54.4%) boys and 695 (45.6%) girls - seen at the age of 56

months were included in the analysis of the assessments (Table 8).

The mean age at examination (4.71y, SD=0.04) was almost exactly the same in all three groups defined by

each of the two neonatal neurological examination methods (4.71y-4.72y).

6.5.1. NEUROLOGICAL EXAMINATION

6.5.1.1. QUALITATIVE ASSESSMENT

The occurrence of statistically significant non-optimal/abnormal neurological performances in the individual

test items of the neurological examination at 56 months (Appendix 5) within the six neonatally defined study

groups are presented in Table 22. Children with cerebral palsy grades 2-4 were excluded.

The performance of neonatally neurologically normal non-hospitalized groups (NeoQuan3, NeoQual3) was

better in nearly all individual test items compared with the other groups, whereas deviant performances

were most often observed in the abnormal groups (NeoQuan1, NeoQual1).

The quantitatively defined neonatally neurologically abnormal group (NeoQuan1) had the most significant

failures compared with the two other groups in tasks of gross motor, fine motor and hand coordination. The

neonatally deviant children by the qualitative method (NeoQual1) had most failures in gross motor, fine

motor and facial-oral motor tasks. Strabismus was more common in NeoQuan1 compared with NeoQual1.

Effect of gender

Statistically highly significant differences between boys and girls were observed in items of smoothness of

running (χ2 p<0.001), quality of climbing stairs (χ2 p=0.0069), walking on tiptoe (χ2 p=0.0037) and walking

on heels (χ2 p<0.001); gross motor function favored the girls. The girls were more skillful also in walking

along a straight line (χ2 p=0.0099). Smoothness of movements was not as good in fine motor function among

the boys as among the girls (peg-board χ2 p<0.0001, drawing χ2 p<0.0001). Mouth and tongue movements

were more clumsy among the boys than girls (χ2 p<0.0001). In strabismus, no significant difference between

the boys and girls was observed.

88

Table 22. Non-optimal/abnormal qualitative neurological findings in 56-months examination in the six study groups

χ2 - test , significance levels * p<0.05, ** p<0.01, *** p<0.001

Children with cerebral palsy, grades 2-4 excluded

Effect of gestational age

When the groups of very preterm, moderately preterm and full-term infants were compared with each other,

very preterm infants had the greatest proportion of non-optimal/abnormal performances in most of the

individual test items. The trend of abnormalities increased with decreasing gestational age. After excluding

children with cerebral palsy, statistical significance was maintained in smoothness of running (lin trend

p=0.0003), in climbing stairs (lin trend p=0.0344) and in smoothness of fine motor functions on the peg-

board (lin trend p=0.0003).

6.5.1.1.1. EIGHT SUBSYSTEMS OF CNS, PERCENTAGE SUM SCORES

The distribution of the mean percentage sum scores (see Methods, 5.5.1.) of the eight subsystems of CNS in

the six study groups is shown in Figures 5A and 5B.


NEOQUAN1 NEOQUAN2 NEOQUAN3 p NEOQUAL1 NEOQUAL2 NEOQUAL3 p

N 76 962 487 197 871 457

Gross motor function

Walking % 9.9 3.3 1.0 *** 6.4 3.0 1.1 **

Running % 17.6 8.5 4.6 *** 12.6 8.4 4.2 ***

Walking stairs % 21.7 13.5 9.1 ** 16.7 13.4 9.0 *

Walking on heels % 21.4 7.1 6.6 *** 10.9 7.5 6.6

Balance

Walking on a line % 14.7 13.8 8.4 * 15.7 13.2 8.5 *

Fine motor function

Smoothness of movements % 33.8 28.3 24.3 38.7 26.5 24.1 ***

Smoothness of drawing % 22.9 13.2 11.1 * 16.6 13.0 11.4

Hand coordination

Slight tremor/ intentiotremor % 12.3 13.2 4.2 * 7.3 6.0 4.3

Facial-oral motor function

Mouth/ tongue movement % 5.7 4.1 2.1 7.0 3.5 2.0 **

Strabismus % 11.1 4.7 3.1 ** 9.0 4.4 2.9 **

89

Figure 5A. The distribution of the mean percentage sum scores of the eight subsystems of CNS in the three study groups by the quantitative neonatal classification method.

Figure 5B. The distribution of the mean percentage sum scores of the eight subsystems of CNS in the three study groups by the qualitative neonatal classification method.

GROSS MOTOR

BALANCE

FINE M

OTOR

HAND COORDIN

ATION

MUSCLE

TONE

TENDON REFLE

XES

FACIAL-

ORAL M

OTOR

STRABISM

US

ME

AN

S O

F P

ER

CE

NT

AG

E S

UM

SC

OR

ES

NEOQUAN1

NEOQUAN2

NEOQUAN3

p=0,0001

p=0,0083

p=0,0283

ns ns p=0,0004 p=0,0297

p=0,0243

80

85

90

95

100

GROSS MOTOR

BALANCE

FINE M

OTOR

HAND COORDIN

ATION

MUSCLE

TONE

TENDON REFLE

XES

FACIAL-

ORAL M

OTOR

STRABISM

US

ME

AN

S O

F P

ER

CE

NT

AG

E S

UM

SC

OR

ES

NEOQUAL1

NEOQUAL2

NEOQUAL3

p=0,0003

p=0,0138

p=0,0015

ns ns p=0,0007 p=0,0079

p=0,0143

80

85

90

95

100

90

The neonatally neurologically abnormal children (NeoQuan1, NeoQual1) failed significantly more often than

the two other groups (NeoQuan2-3, NeoQual 2-3) in the area of gross motor, balance, fine motor, tendon

reflexes, facial-oral motor function and conjugated eye movements by both classification methods.

Pairwise comparison of the groups defined by each of the two neonatal classification methods revealed

differences in the subsystem profiles (even after exclusion of children with cerebral palsy grades 2-4 and

mental retardation) (Table 23). The neonatally neurologically abnormal group by the quantitative method

(NeoQuan1) had significantly lower percentage sum scores than the two neonatally neurologically normal

groups (NeoQuan2-3) in gross motor function and strabismus (p<0.01). By the qualitative method, however,

the neonatally neurologically abnormal group (NeoQual1) differed significantly from the two neonatally

neurologically normal groups (NeoQual2-3) in fine motor and facial-oral motor function

(p<0.01).

Table 23. Pairwise comparisons of the three study groups by the quantitative

and qualitative methods

NEOQUAN NEOQUAL

1 vs. 2 1 vs. 3 2 vs. 3 1 vs. 2 1 vs. 3 2 vs. 3

Gross motor ** ** * ** *

Fine motor ** ** **

Facial-oral motor * ** **

Strabismus ** ** * **

Motor competence ** ** ** **

VMI ** ** ** **

CMM ** ** * * **

LSVTa ** * **

Tukey-test, significance levels * p<0.05, ** p<0.01

Effect of gender

The mean percentage sum scores of the girls were higher, i.e. their performances were better than those of

the boys in all subsystem areas, most remarkably so in the fine motor area (Figure 6). The superiority of the

girls to the boys in fine motor function is illustrated by the finding that the means of the percentage sum

scores of neonatally neurologically abnormal girls (NeoQuan1, NeoQual1) were higher than those of neona-

tally neurologically normal non-hospitalized boys (NeoQuan3, NeoQual3).

91

Figure 6. The distribution of the mean percentage sum scores of the eight subsystems of CNS in boys and girls.

Figure 7. The distribution of the mean percentage sum scores of the eight subsystems of CNS in very preterm, moder-ately preterm and full-term children.

GROSS MOTOR

BALANCE

FINE M

OTOR

HAND COORDIN

ATION

MUSCLE

TONUS

TENDON REFLE

XES

FACIAL-

ORAL

STRABISM

US

ME

AN

S O

F P

ER

CE

NT

AG

E S

UM

SC

OR

ES

BOYS

GIRLS

p<0,0001

p=0,0045

p<0,0001

ns ns p=0,0237 p<0,0001

ns

80

85

90

95

100

GROSS MOTOR

BALANCE

FINE M

OTOR

HAND COORDIN

ATION

MUSCLE

TONUS

TENDON REFLE

XES

FACIAL-

ORAL

STRABISM

US

ME

AN

S O

F P

ER

CE

NT

AG

E S

UM

SC

OR

ES

VPT

PT

FT

p=0,0363

ns p=0,0066

ns ns ns ns

p=0,02

80

85

90

95

100

92


Very preterm children had the lowest means of percentage sum scores in all areas, except in hand coordina-

tion and tendon reflexes. The difference in means between the three gestational age groups in ANOVA was

statistically significant in the subsystems of gross motor, fine motor, and strabismus (Figure 7).

In pairwise comparison, VPT children differed from moderately preterm children in fine motor function

(p<0.05), and from full-terms in fine motor (p<0.01), gross motor function, and strabismus (p<0.05).

After adjusting for the effect of gestational age, the significant differences in the means of percentage sum

scores of gross motor function were maintained by both methods, but lost in fine motor and facial-oral motor

function by the quantitative, and in strabismus by the qualitative method (Table 24). Gestational age was

significant except in facial-oral motor function by the qualitative method. The effect of birth-weight on

subsystems of CNS was smaller than that of gestational age. The effect of adjusting for BW was observable

with disappearing group differences in facial-oral motor function by the quantitative method (Table 24).

6.5.1.1.2. EIGHT SUBSYSTEMS OF CNS, DICHOTOMIZED VARIABLES

The 10% cut-off limits (see Methods, 5.5.1.) are shown in Table 10. The proportions of children with poor

performance in the eight subsystems of CNS in the six study groups are presented in Figures 8A and 8B.

19.7%/14.1% of the quantitatively and qualitatively defined neonatally neurologically abnormal groups

(NeoQuan1/NeoQual1) had problems in gross motor function, and 19.7%/14.5% in fine motor function. The

corresponding proportions of poor performance in the neonatally neurologically normal non-hospitalized

groups (NeoQuan3/NeoQual3) were 5.6%/5.6% for gross motor and 7.7%/7.5% for fine motor function.

Thus, neonatally neurologically abnormal children had three to four times more often difficulties in gross

motor function, and two to three times more in fine motor function compared with neonatally neurologically

normal non-hospitalized children. Poor performance in facial-oral motor function was observed in

7.1%/4.4% /2.1% and in 8.6%/3.7%/2.0% of the three study groups by the quantitative and qualitative

classification methods, respectively.

The incidence of strabismus was 13.5%/4.9%/3.3% and 9.5%/4.7%/3.1%, respectively. Most of the inci-

dences were (non-significantly) greater in the quantitatively defined than in the qualitatively defined abnor-

mal group, whereas the numbers were almost equal in the hospitalized and non-hospitalized groups.

93

Table 24. Statistical significances of the differences between group means of percentage sum scores of the eight

subsystems in the six study groups after adjusting for the effect of gestational age or birth-weight (ANCOVA)


df F p df F p

Gestational age as covariate

Gross motor

Group 2 10.70 <0.0001 2 3.92 0.021

GA 1 8.53 0.0035 1 9.52 0.0020

Fine motor

Group 2 1.97 ns 2 4.42 0.0122

GA 1 12.86 0.0003 1 11.25 0.0008

Facial-oral

Group 2 2.02 ns 2 6.11 0.0023

GA 1 4.11 0.0357 1 3.17 ns

Strabismus

Group 2 4.17 0.0156 2 2.52 ns

GA 1 17.05 <0.0001 1 16.42 0.0001

Birth-weight as covariate

Gross motor

Group 2 12.15 <0.0001 2 5.04 0.0066

BW 1 8.37 0.0038 1 8.71 0.0032

Fine motor

Group 2 3.25 0.0391 2 5.95 0.0027

BW 1 4.79 0.0286 1 4.17 0.0411

Facial-oral

Group 2 2.36 ns 2 6.82 0.0011

BW 1 4.98 0.0256 1 4.12 0.0423

Strabismus

Group 2 5.17 0.0058 2 3.58 0.0281

BW 1 15.62 0.0001 1 14.87 0.0001

Children with CP grades 2-4 excluded

94

Figure 8A.The distribution of dichotomized subsystem variables in the three study groups by the quantitative neonatal classification method.

Figure 8B. The distribution of dichotomized subsystem variables in the three study groups by the qualitative neonatal classification method.

0

5

10

15

20

25

GROSS MOTOR

BALANCE

FINE M

OTOR

HAND COORDIN

ATION

MUSCLE

TONUS

TENDON REFLE

XES

FACIAL-

ORAL M

OTOR

STRABISM

US

PR

OP

OR

TIO

N (

%)

OF

CH

ILD

RE

N W

ITH

AB

NO

RM

AL

PE

RF

OR

MA

NC

ES

NEOQUAL1

NEOQUAL2

NEOQUAL3

p=0,0018

p=ns

p=0,0178

p=ns

p=ns

p=0,0004

p=0,0118

p=0,0024

0

5

10

15

20

25

GROSS MOTOR

BALANCE

FINE M

OTOR

HAND COORDIN

ATION

MUSCLE

TONUS

TENDON REFLE

XES

FACIAL-

ORAL M

OTOR

STRABISM

US

PR

OP

OR

TIO

N (

%)

OF

CH

ILD

RE

N W

ITH

AB

NO

RM

AL

PE

RF

OR

MA

NC

ES

NEOQUAN1

NEOQUAN2

NEOQUAN3

p=0,0002

p=ns

p=0,0034

p=0,0306

p=ns

p=0,0036

p=0,0284

p=0,0006

95

The proportions of poor performance were greater among boys than girls in gross motor (12.4%/4.4%), fine

motor (13.8%/3.4%) and facial-oral motor function (5.8%/1.5%).

Very preterm children had the greatest proportion of poor performance in gross motor (19.5%/10.3%/8.1%)

and fine motor function (19.5%/11.6%/8.1%). They also had strabismus (11.6%/8.1%/3.8%) more often than

moderately preterm and full-term children.

30.3%/9.0%/8.1% of VLBW/LBW/NBW groups had poor performance in gross motor, 17.6%/11.3%/8.4%

in fine motor, 11.8%/7.5%/3.0% in facial-oral motor function and 11.4%/9.7%/3.9% had strabismus.

Moreover, 23.8% of the children with gross motor and 28.9% of those with fine motor problems, 31.6% of

those with impaired facial-oral motor function, and 37% of those with strabismus, were preterm children.

6.5.1.1.3. MILD NEUROLOGICAL DYSFUNCTION (MND)

The incidence of MND was greater in the quantitatively (33.8%) compared with the qualitatively (23.1%)

defined abnormal group (NeoQuan1, NeoQual1) (Figure 10, Table 28). The incidence did not differ between

the normal hospitalized (18.6%) (NeoQuan2, NeoQual2) and the normal non-hospitalized (15%) groups

(NeoQuan3, NeoQual3).

The proportion of boys with MND was two times greater compared with girls, 24.1% and 11.2%, respec-

tively (χ2 41.462, p<0.0001).

Of the three gestational age groups, 29.3%/21.4%/17.1% of very preterm/moderately preterm/full-term

children (χ2 6.177, p=0.0456) and of the three birth-weight groups, 35.3%/19.8%/17.4% of

VLBW/LBW/NBW groups (χ2 7.558, p=0.0228) had MND. Furthermore, one fourth of all MND came from

the preterm group, and the proportion was 58% by the quantitative and 44% by the qualitative method. The

proportions of MND in children with BW less than 2500 g were nearly the same (58% and 42%, respec-

tively).

Mild neurological dysfunction could not be defined in 16 children due to an insufficient number of attempted

items.

96

6.5.1.2. QUANTITATIVE ASSESSMENT

Non-optimal/abnormal neurological performance in quantitatively assessed test items (Appendix 6) in the six

study groups are presented in Table 25.

Table 25. Non-optimal/abnormal quantitative neurological findings in the six study groups

χ2-test, significance levels * p<0.05, ** p<0.01, *** p<0.001

Children in the quantitatively defined neonatally neurologically abnormal group (NeoQuan1) had most

problems in the individual gross motor test items. On the other hand, most differences in facial-oral motor

tests were observed between the qualitatively defined groups (NeoQual1-3). Instead, in the fine motor tests,

the differences between the three study groups were minor and not significant.

Effect of gender

In all individual test items, the boys failed more frequently than the girls. Statistically significant gender

differences were observed in tongue movements (χ2 p<0.0001), running (χ2 p=0.0016), standing on the right

leg (χ2 p<0.0001), on the left leg (χ2 p<0.0001), hopping on the right leg (χ2 p<0.0001), on the left leg (χ2

p<0.0001), hopping sideways (χ2 <0.0001), pro-supination left (χ2 p=0.03), forefinger-thumb tapping with

right hand (χ2 p<0.0001) and with left hand (χ2 p=0.0098).


NEOQUAN1 NEOQUAN2 NEOQUAN3 p NEOQUAL1 NEOQUAL2 NEOQUAL3 p

Pursing the lips % 18.8 10.2 9.7 17.4 9.9 8.7 **

Tongue position % 6.0 1.5 0.9 ** 3.4 1.4 0.9

Tongue movements % 28.8 20.1 18.8 29.3 19.0 18.4 **

Running % 5.9 3.4 1.7 4.9 3.4 1.3 *

Hopping sideways % 18.2 6.1 6.0 *** 12.1 6.0 5.7 **

Standing on one leg

Dominant right % 30.9 18.8 11.1 22.8 19.2 10.0 ***

Non-dominant left % 36.8 20.5 14.0 *** 28.3 19.9 14.0 ***

Hopping on one leg

Dominant right % 54.4 29.6 27.1 *** 35.0 30.6 26.5

Non-dominant left % 57.1 39.4 31.7 *** 45.5 39.7 30.7 **

Peg-board

Dominant right % 14.3 6.4 5.8 * 9.2 6.3 5.9

Non-dominant left % 7.4 9.3 6.4 12.6 8.3 6.6 *

97


In most of the individual test items, very preterm children had the most and full-term children the least

failures, although the differences did not reach statistical significance. The problems in standing (lin tr

p=0.0376) or hopping on the left leg (lin tr p=0.0347), hopping sideways (lin tr p=0.0005), pro-supination of

the left hand (lin tr p=0.0003), and peg-board on the right hand (lin tr p=0.0072) increased with decreasing

gestational age.

6.5.1.2.1. MOTOR COMPETENCE, PERCENTAGE SUM SCORE

The distribution of the mean percentage sum score of motor competence in the six study groups is shown in

Figure 9. On the average 81% of children in the NeoQuan1 versus 89% of those in the NeoQuan3 were

successful in the motor competence tasks. The percentages in the NeoQual1 and NeoQual3 were 85 and 89,

respectively. The differences in means between the three study groups, although low, were significant by

both classification methods (Figure 9).

In pairwise comparison, the performances of neonatally defined abnormal groups (NeoQuan1, NeoQual1)

were significantly (p<0.01) poorer than those of the two other groups (NeoQuan2-3, NeoQual2-3) by both

classification methods (Table 23).

In the linear regression analysis, using the total percentage sum score as a dependent variable and all individ-

ual test items as independent variables, 90% of motor competence was explained by five test items: hopping

on one leg, (both sides), standing on the right leg, tongue movements, and walking up stairs.

Effect of gender

Gender was a significant explanatory factor of motor competence (Table 26). The girls were clearly superior

to the boys. Even the girls in the qualitatively defined neonatally neurologically abnormal group (NeoQual1)

had a higher mean of the total percentage sum score (88.4) than the boys of the neonatally neurologically

normal non-hospitalized group (87.0, NeoQual3).

98

Table 26. The means of percentage sum scores of motor competence in boys and girls in the six study groups


MOTOR COMPETENCE


BOY GIRL BOY GIRL BOY GIRL BOY GIRL BOY GIRL BOY GIRL

N 49 21 505 421 235 240 121 63 448 393 220 226 1471

Mean 79.79 84.94 86.39 90.83 86.71 93.19 83.48 88.44 86.31 90.87 87.02 93.37 88.58

SD 13.4 22.0 12.3 11.5 13.1 8.6 12.41 15.69 12.43 11.54 13.36 8.23 12.31

ANOVA (two-way)

Group F 7.14 df 2.30 p <0.0029 F 7.83 df 2 p<0.0004

Sex F 22.48 df 1 p<0.0001 F 36.58 df 1.186 p<0.0001


When the mean scores of motor competence of very preterm infants (mean 83.86, SD 15.6), moderately

preterm infants (mean 87.35, SD 11.8) and full-term infants (mean 89.05, SD 12.2) were compared in one-

way ANOVA, the difference between the gestational age groups was significant (ANOVA, F=5.49, df=2,

p=0.0042). In post hoc pairwise comparison, very preterm infants had significantly lower means of total

scores compared with full-term infants (p<0.05), but they did not differ significantly from moderately

preterm children. Neither were moderately preterm children significantly different from their full-term

counterparts.

The group differences were maintained after adjusting for the effect of gestational age and birth-weight

(Table 27).

Table 27. Statistical significances of the differences between group means of percentage sum scores of motor compe-

tence in the six study groups after adjusting for the effect of gestational age or birth-weight (ANCOVA)


df F p df F p


Group 2 10.72 <0.0001 2 6.55 0.0015

GA 1 8.01 0.0046 1 7.53 0.0061

Birth-weight as covariate

Group 2 11.30 <0.0001 2 7.25 0.0007

BW 1 12.38 0.0004 1 11.43 0.0007

99

6.5.1.2.2. DEVIANT MOTOR COMPETENCE (DMC), DICHOTOMIZED VARIABLE

Also the incidence of DMC was greater in the quantitatively defined abnormal group (NeoQuan1, 25.7%)

than in the qualitatively defined (NeoQual1, 17.8%) abnormal group. The incidences in the normal hospital-

ized (NeoQuan2/NeoQual2) and non-hospitalized (NeoQuan3/NeoQual3) groups were similar, however

(Figure 10, Table 28). DMC increased linearly with increasing risk factors (e.g. neonatal morbidity and

neurological abnormality).

17.0% of the boys and 11.2% of the girls had DMC. 19.5% of very preterm infants, 15.9% of the moderately

preterm, and 10.6% of full-term infants had DMC. The proportion of preterms among children with DMC

was 29%; it was 39% by the quantitative and 42% by the qualitative method.

When the birth-weight groups were compared, 29.4% of VLBW, 16.1% of LBW and 10.7% of NBW

children had DMC. 56% vs. 52% of DMC came from the BW group less than 2500g by the quantitative and

qualitative methods, respectively.

Table 28 presents the proportions of children with MND and DMC.

MND and DMC did not always occur in the same children, but 7.4% of all assessed children had both MND

and DMC. 40.7% of those with MND had also DMC, and 62.9% of those with DMC had also MND.

Table 28. Total numbers and the proportions of children with mild neurological dysfunction and deviant motor compe-

tence in the six study groups



Mild neurological dysfunction

N 24/71 176/946 73/482 43/186 160/860 70/453 % 33.8 18.6 15.1 23.1 18.6 15.5

χ2 14.728 p=0.0006 χ2 5.411 p=0.0668 lin trend 10.190 p=0.0014 lin trend 5.309 p=0.0212

Deviant motor compe-tence

N 18/70 114/934 43/478 33/185 101/848 41/449 % 25.7 12.2 9.0 17.8 11.9 9.1

χ2 16.770 p=0.0002 χ2 9.556 p=0.0084 lin trend 11.841 p=0.0006 lin trend 8.786 p=0.0030

100

Figure 9. The distribution of the mean percentage sum score of motor competence in the three study groups by the quantitative and qualitative neonatal classification methods.

Figure 10. The distribution of MND (mild neurological dysfunction) and DMC (deviant motor competence) in the three study groups by the quantitative and qualitative neonatal classification methods.


ME

AN

S O

F T

OT

AL

PE

RC

EN

TA

GE

SU

M S

CO

RE

MOTOR COMPETENCE

p=0,0001p<0,0001

77

79

81

83

85

87

89

91

0

5

10

15

20

25

30

35

40

MND DMC

PR

OP

OR

TIO

N (

%)

OF

CH

ILD

RE

N W

ITH

AB

NO

RM

AL

PE

RF

OR

MA

NC

ES

NEOQUAN1

NEOQUAN2

NEOQUAN3

NEOQUAL1

NEOQUAL2

NEOQUAL3

p=0,0006

p=ns

p=0,0002

p=0,0084

101

6.5.1.3 HAND PREFERENCE

4.1%/5.7% of the children in the neonatally neurologically abnormal quantitative/qualitative groups (Neo-

Quan1/NeoQual1) were left-handed and 9.5%/6.2% were mixed-handed, respectively. In comparison, there

were with about 2% left-handed and 4% mixed-handed in the neonatally neurologically normal groups

(NeoQuan2-3, NeoQual2-3) (χ2 ns by the quantitative method, and χ2=13.380, p=0.0096 by the qualitative

method).

The children whose handedness was not yet established, were four times more often boys than girls (7.2% vs.

1.9%, χ2 p<0.0001) and three times more often very preterm than full-term children (12.2% vs. 4.3%, χ2 ns).

Mixed hand preference was associated with poor performance in fine motor function (p=0.0137). MND and

DMC were more common among children with mixed handedness, compared with right- and left-handed

children (MND:31% vs. 17%, 20%; DMC:24% vs. 11%, 3%, resp). Mixed handedness was also associated

with poor visual-motor function (VMI, F=9.21, df=2, p=0.0001), low test scores in CMM (CMM, F=13.01,

df=2, p<0.0001) and poor language comprehension (LSVTa, F=4.91, df=2, p=0.0075 and LSVTc, F=7.07,

df=2, p=0.0009) compared with right-and left-handed children in ANOVA analysis.

Left-handedness was observed in such a small number of children in the groups defined by neonatal neuro-

logical examination, that it was not possible to draw firm conclusions about the associations.

102


Results in the test of visual-motor integration (VMI) in standard deviations in the six study groups are

presented in Figure 11.

The means of the VMI test were 6.2 (SD 2.4), 7.0 (SD 2.3) and 7.5 (SD 2.2) for NeoQuan1-3 and 6.6 (SD

2.3), 7.0 (SD 2.3) and 7.5 (SD 2.2) for NeoQual1-3, respectively.

13.7% of the quantitatively defined (NeoQuan1) compared with 10.2% of qualitatively defined (NeoQual1)

neonatally neurologically abnormal children got scores below -2SD of the mean in the original control group.

In the neonatally neurologically normal non-hospitalized groups (NeoQuan3/ NeoQual3), the respective

frequencies were 2.7%/2.6%. The statistically significant difference in mean scores between the three study

groups was maintained by both classification methods even after excluding children with CP and SMR.

Figure 11. The distribution (%) of children according to standard deviations in the test of visual-motor integration (VMI) among the three study groups by the quantitative and qualitative neonatal classification methods.

13,7

6,12,7

10,8

5,62,7

20,5 21,5

17,118,6

21,8

17,3

65,8

72,4

80,2

70,672,6

80

0

10

20

30

40

50

60

70

80

90

100


"<-2SD

"-1SD --2SD

>-1SD

103

In pairwise comparisons the means of VMI scores of the neonatally neurologically abnormal groups

(NeoQuan1, NeoQual1) were significantly lower than those of the normal hospitalized (NeoQuan2, Neo-

Qual2, p<0.05) and non-hospitalized groups (NeoQuan3, NeoQual3, p<0.01) by both classification methods.

The neonatally neurologically normal non-hospitalized groups (NeoQuan3, NeoQual3) scored also signifi-

cantly better than the normal hospitalized groups (NeoQuan2, NeoQual2). After exclusion of the children

with cerebral palsy grade 2-4, the highly significant difference was maintained between the abnormal

(NeoQuan1, NeoQual1) and normal non-hospitalized (NeoQuan3, NeoQual3) groups (Table 23).

Effect of gender

In all three study groups, the girls had higher test means than the boys in visual-motor integration by both

classification methods (Table 29).


17.5% of very preterm, 6.2% of moderately preterm and 3.8% of full-term children had VMI scores below

-2SD of the original population mean. The difference was statistically significant (χ2=18.552, p=0.0001, lin

trend=14.083, p=0.0002).

Group differences were still significant in VMI after adjusting for the effects of gestational age and birth-

weight. After excluding children with CP and SMR, the significant difference remained by the quantitative,

but not by the qualitative method (Table 30). Gestational age and birth-weight were significant by both

methods (Table 30).

6.5.3. COGNITIVE/LANGUAGE TESTS

The distributions of children grouped according to standard deviations of the mean of the original population

control group in the different neonatal study groups in tests of CMM, AWST, LSVTA and LSVTC are pre-

sented in Figures 12-15.

The means of CMM were 43.6 (SD 13.8), 49.0 (SD 12.4) and 50.7 (SD 10.1) for the groups NeoQuan1-3 and

46.5 (SD 12.5), 49.2 (SD 12.5) and 50.7 (SD 10.1) for the groups NeoQual1-3, respectively.

18.0%/12.5% of the neonatally neurologically abnormal children (NeoQuan1/NeoQual1) compared with

8.6%/8.1% of the neurologically normal hospitalized (NeoQuan2/NeoQual2), and 4.4%/4.7% of the non-

hospitalized children (NeoQuan3/NeoQual3) by the quantitative/ qualitative method, respectively, had

performances below –2SD of the original control population mean in the CMM test. The group NeoQuan1

included the greatest proportion of children with performances below -3SD (9.7%) compared with 0.6-4.7%

in the other groups.

104

Figure 12. The distribution (%) of children according to standard deviations in the test of CMM among the three study groups by the quantitative and qualitative neonatal classification methods.

Figure 13.The distribution (%) of children according to standard deviations in the test of AWST among the three study groups by the quantitative and qualitative neonatal classification methods.

9,7

4,3

0,6

4,7 4,6

0,7

8,3

4,3 3,8

7,8

3,7 4

15,3

9,5 10,213,5

9,5 9,6

66,7

81,885,4

74

82,2

85,8

0

10

20

30

40

50

60

70

80

90

100


" < -3SD

"-3SD - 2SD

"-2SD - -1SD

" > -1SD

5,4 5,62,8 4,3 5,8

2,7

12,2 12,4 13,2 12,8 12,4 12,9

82,4 8284,1 82,9 81,7

84,4

0

10

20

30

40

50

60

70

80

90

100


"<-2SD

"-1SD --2SD

>-1SD

105

Figure 14. The distribution (%) of children according to standard deviations in the test of LSVTa among the three study groups by the quantitative and qualitative neonatal classification methods.

Figure 15. The distribution (%) of children according to standard deviations in the test of LSVTc among the three study groups by the quantitative and qualitative neonatal classification methods.

13,9

6,7

2,8

7,9 6,8

2,9

23,6

16,2 16,1 16,3 16,7 16,3

62,5

77,1

81,1

75,8 76,4

80,8

0

10

20

30

40

50

60

70

80

90

100


"<-2SD

"-1SD --2SD

>-1SD

7,6

4,1 4,4 4,4 4,2 4,7

13,6 14,813,2

16,614,2 13,2

78,881,1

82,4

7981,6 82,1

0

10

20

30

40

50

60

70

80

90

100


"<-2SD

"-1SD --2SD

>-1SD

106

Verbal competence (AWST) did not differentiate the three study groups. 3-6% of the children performed

below -2SD. In verbal comprehension (LSVTa) the neonatally neurologically abnormal groups (NeoQuan1,

NeoQual1) had the most difficulties; 13.9% of the children in NeoQuan1 and 7.9% of the children in Neo-

Qual1 performed below -2SD of the population controls. The corresponding percentages for the neonatally

normal non-hospitalized groups (NeoQuan3, NeoQual3) were 2.8/2.9%.

Significant differences in the means of CMM and LSVTa between the three study groups were found by both

classification methods. In pairwise comparisons, neonatally neurologically abnormal groups (NeoQuan1,

NeoQual1) scored significantly lower than the other groups (NeoQuan2-3, NeoQual2-3) in CMM by both

classification methods. Also neurologically normal groups defined by quantitative neonatal neurological

examination (NeoQuan2 vs. NeoQuan3) differed significantly from each other (p<0.05). In LSVTa, a

significant difference (p<0.01) was found in post hoc pairwise comparisons between neurologically abnor-

mal and normal non-hospitalized groups (NeoQuan1 vs. NeoQuan3) by the quantitative method (Table 23).

Effect of gender

The girls had higher mean scores than boys in the tests of CMM, LSVTa and LSVTc. The boys, however,

were better than the girls in the test of AWST. Gender proved to be a significant source of variance in all of

the mentioned tests, except AWST, by the quantitative classification method. In spite of this significant

group differences were maintained in CMM and LSVTa (Table 29).


A statistically significant group difference was observed in CMM even after adjusting for the effects of

gestational age and birth-weight in children classified by the quantitative neonatal examination (Table 30). In

LSVTa, gestational age and birth-weight were not significant, but a group difference was observed in the

quantitatively defined neonatal group, while in LSVTc the situation was the opposite.

6.5.4. SPEECH PROBLEMS

Mild articulation defects were very common among the examined children. If missing or substitution of one

consonant/vowel was taken into account, an articulation defect was found in 36-45% of the children in the

six study groups, the greatest proportions in the neurologically abnormal groups. If distinctly articulated or

intelligible spoken single words or whole sentences were used as the criteria, the distribution of children with

articulation defects in the three study groups varied from 6.6-14.5% by the quantitative method and from 7.2-

9.1% by the qualitative method. Abnormalities in facial-oral motor function were linearly related to articula-

tion defects (lin trend p<0.001).

107

Table 29. The effect of gender on VMI, CMM, AWST, LSVTa, and LSVTc in the six study groups


NEOQUAN1 NEOQUAN2 NEOQUAN3 NEOQUAL1 NEOQUAL2 NEOQUAL3 BOY GIRL BOY GIRL BOY GIRL BOY GIRL BOY GIRL BOY GIRL

VMI

N 51 22 510 426 238 236 128 66 448 396 223 222

Mean 6.20 6.36 6.78 7.25 7.26 7.73 6.37 7.05 6.84 7.26 7.28 7.72

SD 2.28 2.63 2.24 2.25 2.19 2.12 2.27 2.28 2.24 2.25 2.16 2.16

ANOVA (two-way) Group F 12.13 df 2 p <0.0001 F 9.85 df 2 p=0.0001

Sex F 3.20 df 1 p ns F 12.95 df 1 p=0.0003

No interaction CMM

N 52 20 499 423 238 241 127 65 439 392 223 227

Mean 41.94 48.05 47.69 50.60 49.23 52.07 45.81 47.75 47.62 50.93 49.20 52.19

SD 11.93 17.30 12.69 11.86 10.51 9.48 11.87 13.53 12.87 11.73 10.53 9.54

ANOVA (two-way) Group F 5.55 df 2.31 p=0.0087 F 8.50 df 2.23 p=0.0003

Sex F 12.59 df 1 p=0.0004 F 13.41 df 1 p=0.0002

No interaction AWST

N 53 21 497 408 232 239 125 62 440 381 217 225

Mean 49.89 48.57 51.32 49.81 51.54 50.77 50.91 48.60 51.18 49.81 51.72 51.05

SD 10.60 9.90 10.74 10.11 9.49 9.26 10.17 8.21 10.81 10.26 9.57 9.37

ANOVA (two-way) Group F 1.18 df 2 p ns F 1.91 df 2 p ns

Sex F 1.59 df 1 p ns F 4.86 df 1 p=0.0274

No interaction LSVTa

N 51 21 502 423 232 240 126 64 444 394 217 226

Mean 10.08 11.24 10.75 11.73 11.24 11.96 10.91 11.63 10.66 11.70 11.20 12.03

SD 3.08 2.77 2.91 2.53 2.65 2.15 3.13 2.45 2.85 2.54 2.67 2.15

ANOVA (two-way) Group F 4.44 df 2.56 p=0.0162 F 3.93 df 2 p=0.0199

Sex F 13.63 df 1.56 p=0.0005 F 25.80 df 1.347 p<0.0001

No interaction LSVTc

N 46 20 464 408 220 234 119 62 406 380 205 220

Mean 8.15 9.25 8.49 9.60 8.62 9.72 8.52 9.11 8.45 9.63 8.60 9.79

SD 3.27 3.18 3.80 3.58 3.69 3.52 3.66 3.07 3.78 3.58 3.71 3.59

ANOVA (two-way) Group F 0.48 df 2 p ns F 0.64 df 2 p ns

Sex F 9.65 df 1 p=0.0019 F 19.09 df 1.403 p<0.0001

No interaction

108

Table 30. Statistical significances of the differences between group means of VMI, CMM, AWST, LSVTa, and LSVTc

after adjusting for the effect of gestational age or birth-weight (CP excluded, SMR excluded except in CMM)

QUANTITATIVE METHOD QUALITATIVE METHOD

df F p df F p


VMI

Group 2 3.19 0.0417 2 2.40 ns

GA 1 34.68 0.0000 1 35.06 0.0000

CMM

Group 2 5.77 0.0032 2 2.55 ns

GA 1 21.51 0.0000 1 21.86 0.0000

AWST

Group 2 0.13 ns 2 0.03 ns

GA 1 13.80 0.0002 1 12.72 0.0004

LSVTa

Group 2 4.15 0.0159 2 2.66 ns

GA 1 2.93 ns 1 4.05 0.0442

LSVTc

Group 2 0.23 ns 2 0.005 ns

GA 1 5.17 0.0229 1 5.19 0.0228

Birth-weight as covariate VMI

Group 2 3.81 0.0223 2 2.62 ns

BW 1 47.83 0.0000 1 48.08 0.0000

CMM

Group 2 6.92 0.0010 2 3.02 0.0491

BW 1 21.04 0.0000 1 20.97 0.0000

AWST

Group 2 0.40 ns 2 0.00 ns

BW 1 19.22 0.0000 1 18.03 0.000

LSVTa

Group 2 4.45 0.0118 2 2.70 ns

BW 1 1.97 ns 1 2.42 ns

LSVTc

Group 2 0.41 ns 2 0.06 ns

BW 1 6.31 0.0120 1 6.16 0.0131

109

6.5.5. THE EFFECT OF PARENTS’ EDUCATION ON PERFORMANCE IN VMI, CMM AND

LANGUAGE TESTS

When the three neonatally quantitatively or qualitatively defined study groups were analyzed in ANCOVA

using the neonatal group and gender as grouping factors, and the mother’s or father’s education as a covari-

ate, the education level of both parents had a highly significant effect on the VMI, CMM, AWST, LSVTa

and LSVTc results. The group and gender differences remained significant in VMI, CMM and LSVTa, and

gender difference in LSVTc by both classification methods, after adjusting for the effect of parental educa-

tion (Table 31).

6.6. OUTCOME AT 56 MONTHS OF AGE

6.6.1. MAJOR AND MINOR IMPAIRMENTS AMONG THE STUDY SUBJECTS

The proportions of major impairments in the six study groups are presented in Tables 32,33. Part of the data

on major impairments is based on inquiries, hospital records and earlier assessments (see Methods, Appendix

3). According to the hospital records, data were available on all children diagnosed as having CP and

belonging to the study population (Niemelä A, oral communication). Information on the other impairments

was available on 1760/2039 children.

6.6.1.1. CEREBRAL PALSY

Of 2039 children, 26 (1.3%) had cerebral palsy; 8 had spastic diplegia (4/8 independently walking), 7 had

spastic hemiplegia, 11 had spastic/dystonic tetraplegia (2 died before 56 months of age) and one child had

athetotic cerebral palsy (Table 32, Appendix 3). Mental retardation was associated with CP in 11 out of 26

children, and epilepsy in 9 out of 26 children. 18 children were preterm, of whom 10 were less than 32 com-

pleted weeks.

The proportion of children with CP was greatest in the neonatally neurologically abnormal groups (10.3%

NeoQuan1/4.2% NeoQual1). No child with CP was found in the neonatally neurologically normal non-hosp-

italized groups (NeoQuan3, NeoQual3). 5/9 children with diplegia (3 preterms, 2 full-terms) were abnormal

in neonatal neurological examination by both classification methods. Furthermore, 7/11 children with tetra-

plegia and 9/15 children with most severe, grade 3-4, cerebral palsy were abnormal in neonatal neurological

examination by both classification methods. The qualitative method selected 4/6 children with hemiplegia as

abnormal, whereas all of them appeared normal in the quantitative neurological examination.

110

Table 31. Statistical significances of the differences between group means of VMI, CMM, AWST, LSVTa and LSVTc in the six study groups after adjusting for the effect of gender and parents’ education ( ANCOVA)


df F P df F pVMI Group 2 10.46 <0.0001 2 8.45 0.0002

Sex 1 5.27 0.0217 1 14.84 0.0001

Education of mother 1 40.14 <0.0001 1 39.98 <0.0001 CMM Group 2 5.65 0.0036 2 5.73 0.0003

Sex 1 17.14 <0.0001 1 15.01 0.0001

Education of mother 1 48.06 <0.0001 1 76.10 <0.0001 AWST Group 2 0.56 ns 2 1.00 Ns

Sex 1 0.49 ns 1 4.67 0.0307

Education of mother 1 96.96 <0.0001 1 95.95 <0.0001 LSVTa Group 2 4.34 0.0132 2 3.48 0.0309

Sex 1 16.03 0.0001 1 24.53 <0.0001

Education of mother 1 14.28 0.0002 1 13.96 0.0002 LSVT c Group 2 0.34 ns 2 0.45 Ns

Sex 1 11.55 0.0007 1 17.36 <0.0001

Education of mother 1 16.30 0.0001 1 16.25 0.0001

VMI Group 2 10.14 <0.0001 2 9.65 0.0001

Sex 1 4.54 0.0331 1 12.82 0.0003

Education of father 1 64.74 <0.0001 1 65.26 <0.0001 CMM Group 2 5.98 0.0026 2 7.01 0.0009

Sex 1 15.11 0.0001 1 12.06 0.0005

Education of father 1 87.17 <0.0001 1 88.46 <0.0001 AWST Group 2 0.79 ns 2 1.07 ns

Sex 1 0.86 ns 1 5.98 0.0144

Education of father 1 74.39 <0.0001 1 75.05 <0.0001 LSVTa Group 2 4.34 0.0133 2 3.32 0.0365

Sex 1 15.16 0.0001 1 22.59 <0.0001

Education of father 1 9.39 0.0022 1 9.41 0.0022 LSVTc Group 2 0.34 ns 2 0.68 ns

Sex 1 11.91 0.0006 1 17.02 <0.0001

Education of father 1 23.67 <0.0001 1 24.41 <0.0001

111

Table 32. Neurological impairments in the six study groups at 56 months of age; also the children with indirect data are

included



TOTAL N 91 1106 553 228 1002 520 1750

CP

N a) 12 14 0 16 10 0 26

% 13.2 1.3 0 7.0 1.0 0 1.5

grade 1 0 2 0 0 2 0 2

grade 2 3 6 0 7 2 0 9

grade 3-4 9 6 0 9 6 0 15

Hemiplegia 0 6 0 4 2 0 6

Diplegia 4 4 0 4 4 0 8

Tetraplegia a) 7 4 0 7 4 0 11

Athetosis 1 0 0 1 0 0 1

SMR

N 7 13 0 9 11 0 20

% 7.7 1.2 0 3.9 1.1 0 1.1

EPILEPSY

N 4 11 2 4 11 2 17

% 4.4 1.0 0.4 1.8 1.1 0.4 1.0

HYDROCEPHALUS

N 0 2 0 1 1 0 2

% 0 0.2 0 0.4 0.1 0 0.1

VISUAL IMPAIRMENT

Blindness 0 0 0 0 0 0 0

Visus

< 0.3 0 1 0 0 1 0 1

0.3-0.6 5 62 18 12 56 17 85

> 0.6 52 751 403 150 677 379 1206

Strabismus 12 48 16 20 42 14 76

% 13.2 4.3 2.9 8.8 4.2 2.7 4.3

HEARING IMPAIRMENT

N 2 4 4 3 4 3 10

a) two children, who died after the neonatal period but before 56 months of age are included

112

6.6.1.2. MENTAL RETARDATION

Children with mental retardation caused by a specific syndrome or inherited disease were excluded from the

present study.

Severe mental retardation (SMR) was found in 20 of 1750 (1.1%) children. In 9 cases SMR was associated

with CP. 11 children with SMR without motor deficit had been diagnosed before 56 months of age. The

etiology of SMR in one child was fetal alcohol syndrome. The other children had no explanatory pre-

perinatal or hereditary factors for severe mental retardation. Seven of these 11 children were seen at 56

months of age.

7/20 (35%) and 9/20 (45%) of the children with SMR or 2/11 (18%) and 3/11 (27%) of the children with

SMR without motor deficit belonged to neonatally neurologically abnormal groups by the quantitative and

the qualitative method, respectively. None of the neonatally neurologically normal non-hospitalized children

had SMR. Two children who did not come to the 56-month-examination were known to have mild mental

retardation.

6.6.1.3. EPILEPSY

The percentages of children with epilepsy belonging to the six study groups are presented in Table 32. 17

children had epilepsy requiring antiepileptic medication. Nine of them did not come to the assessment at the

age of 56 months. 9 children had also CP, one preterm child had hydrocephalus with shunt after intraven-

tricular hemorrhage, and one child had congenital polycystic kidneys. 4/17 children were neonatally neuro-

logically abnormal and 2/17 children belonged to the non-hospitalized groups by both classification methods.

6.6.1.4. HYDROCEPHALUS

Three preterm children had hydrocephalus due to neonatal intraventricular hemorrhage. Two of them needed

a shunt. One child with dystonic tetraplegia and repeated episodes of ventriculitis died before the age of 56

months. The other child (GA 25 weeks) also had epilepsy. The third child without a shunt (GA 30 weeks)

was not examined in the neonatal period. His cognitive development was normal, but he had gross motor

clumsiness and problems in visual-motor integration.

113

6.6.1.5. VISUAL IMPAIRMENT

No child was observed to be blind. Two preterm infants with a gestational age of 25 completed weeks had a

mild form of retinopathy. The one who was not examined at 56 months had also squint and nystagmus. The

other one had hydrocephalus with shunt.

Nine (0.6%) children had visual acuity less than 0.3 at least in one eye, one of them in both eyes. 85 children

had visual acuity of at least 0.3, but not over 0.6 in both eyes. 886 (58.1%) children had visual acuity of 0.8

or better. The non-hospitalized groups (NeoQuan3, NeoQual3) had slightly lower frequencies with lowered

vision than did the hospitalized groups (NeoQuan1-2, NeoQual1-2), which did not differ from each other.

Strabismus was found in all 81 (4.6%) children. 76 of them were seen at 56 months of age, the information

on the other five was obtained from the parents or medical files. All five children were under ophthalmologic

care and/or waiting for an operation. Among the neonatally neurologically abnormal children, strabismus

was found in 15.4% (NeoQuan1) and in 10.2% (NeoQual1). Among the neonatally neurologically normal

non-hospitalized children (NeoQuan3, NeoQual3), strabismus was found in about 3%. 12.5% of the very

preterm children compared with 3.9% of full-terms had strabismus.

6.6.1.6. HEARING IMPAIRMENT

One child was deaf, as were also his parents. He was not seen at the age of 56 months. In the neonatal

neurological examination he was neurologically normal according to the quantitative method and abnormal

according to the qualitative method.

Five children had a hearing defect diagnosed before 56 months of age (three were considered to be congeni-

tal, and two consequences of neonatal problems). Two required a hearing aid; one of these two had also

diplegia.

The impaired hearing of four other children had been caused by repeated middle ear infections.

6.7. IMPAIRMENTS AND DISABILITIES AT THE AGE OF 56 MONTHS

For definitions of impairments/disabilities, used in the present study see Methods 5.6. The frequencies of

impairments/disabilities in the six study groups are presented in Table 33. The table includes also children

who were not seen, but on whom indirect data were available.

114

Table 33. The proportion of impairments and disabilities in the six study groups at 56 months of age. The children with indirect data are included.

QUANTITATIVE METHOD QUALITATIVE METHOD TOTAL


N 91 1106 553 228 1002 520 1750

NORMAL

N 23 533 293 88 485 276 849 % 25.3 48.2 53.0 38.6 48.4 53.1 48.5

IMPAIRMENT

Major N 25 122 30 39 109 29 175

% 27.5 11.0 5.4 17.1 10.9 5.6 10.0

Minor N 43 451 230 101 408 215 724 % 47.2 40.8 41.6 44.3 40.7 41.3 41.4

Multiple minor N 22 147 51 38 134 48 220 % 24.2 13.4 9.3 16.5 13.4 9.3 12.6

IMPAIRMENT WITH DISABILITY

Major N 18 77 10 21 75 9 105

% 19.8 7.0 1.8 9.2 7.5 1.7 6.0

Moderate N 12 80 30 27 66 29 122 % 13.2 7.2 5.4 11.9 6.6 5.6 7.0

Minor N 40 377 172 94 334 161 589 % 44.0 34.1 31.1 41.2 33.3 31.0 33.7

27.5% of the children in the neonatally defined abnormal group classified by the quantitative method

(NeoQuan1) compared with 17% of those by the qualitative method (NeoQual1) had major impairments at

56 months of age (Table 33). The proportions of major impairments among the neonatally neurologically

normal hospitalized (NeoQuan2, NeoQual2) and non-hospitalized (NeoQuan3, NeoQual3) groups were

similar by both classification methods, being 11% and 5% respectively. The differences between the three

study groups were statistically significant by both classification methods (p<0.0001). At least two major

impairments were observed in 19 (1.1%) children. One child had three, the others two major impairments.

Minor impairments were found in 47% in NeoQuan1 compared with 44% in NeoQual1. High frequencies of

minor impairments were found also in the other groups. The group differences were statistically significant

115

(p<0.05 and p<0.01). 24%/13%/9% of children in the quantitative groups (NeoQuan1-3) and

16.5%/13%/9% of those in the qualitative groups (NeoQual1-3) had multiple (more than three) minor

impairments.

The proportion of boys with major impairments (12.1%) was significantly (χ2 p=0.0044) higher than that of

girls (8.1%). As regards minor impairments, the difference was not so great, but was statistically significant

(p=0.0047).

The incidence of both major and minor impairments among very preterm children (31.7%/65.9%) was

significantly higher compared with more mature preterm (13.8%/52.8%) and full-term children

(8.6%/43.7%) (χ2 p=0.0007 and p=0.0047).

6.8. ASSOCIATION BETWEEN OUTCOME VARIABLES AT THE AGE OF 56 MONTHS

Pearson’s correlation matrix for all outcome variables at the 56-month examination is presented in Table 34.

The strongest correlations (r 0.42-0.52) were found between gross motor function, balance, fine motor

function and motor competence. The test of visual-motor integration correlated best with performance intel-

ligence (r 0.42), but also with fine motor function (r 0.34) and motor competence (r 0.30). Of the variables of

neurological/neuromotor assessment, fine motor function and motor competence were correlated best with

the cognitive and language tests (r 0.20-0.27), and also facial-oral motor function with AWST (r 0.20).

Table 34. Pearson’s correlation matrix for the outcome variables at the 56-month examination

GM Bal FM HandCoord

MT Refl F-O Strab MoCo VMI CMM AWST LSVTa

Bal 0.43

FM 0.35 0.21

Hand Coord 0.15 0.10 0.19

MT 0.33 0.15 0.20 0.19

Refl 0.22 0.11 0.17 0.15 0.23

F-O 0.29 0.14 0.26 0.13 0.27 0.17

Strab 0.15 0.11 0.08 0.16 0.17 0.08 0.13

MoCo 0.52 0.52 0.42 0.20 0.31 0.22 0.41 0.23

VMI 0.21 0.16 0.34 0.12 0.14 0.11 0.15 0.12 0.30

CMM 0.13 0.10 0.23 0.09 0.11 0.10 0.15 0.18 0.25 0.42

AWST 0.18 0.11 0.23 0.12 0.14 0.12 0.20 0.08 0.26 0.29 0.44

LSVTa 0.11 0.12 0.20 0.05 0.09 0.13 0.16 0.09 0.27 0.19 0.38 0.46

LSVTc 0.11 0.11 0.21 0.04 0.09 0.07 0.12 0.06 0.23 0.24 0.43 0.46 0.51 GM=gross motor, Bal=balance, FM=fine motor, Coord=coordination, MT=muscle tone, Refl=reflexes, F-O=facial-oral motor, MoCo=motor competence Correlation coefficient values over 0.10 were statistically significant at p <0.0001, values over 0.08 at p <0.001 and values over 0.04 at p <0.05.

116

After excluding children with CP, 34% of the children with gross motor problems also had fine motor

problems, and 41% of those who had difficulties in balance also had gross motor problems. 54% of the

children with gross motor problems, 42% of those with fine motor problems and 30% of those with abnormal

balance had deviancy in motor competence.

11-27% of the children with minor neurological problems had also poor performances in

VMI/CMM/language tests (Table 35). 12.5% of the children in the whole study series (N=1750) had multiple

minor impairments, i.e. an impairment in at least three different neurodevelopmental domains.

Table 35. The proportion of poor (<-2SD) test results in VMI, CMM, AWST, LSVTa and combined tests among children with abnormal function in the four subsystems of CNS, MND and DMC

VVMMII CCMMMM AAWWSSTT LLSSVVTTaa33//44

TTEESSTTSS44//44TTEESSTTSS

<<--22SSDD <<--22SSDD <<--22SSDD <<--22SSDD <<--22SSDD <<--22SSDD

GGrroossss mmoottoorr pprroobblleemmss %% 1166 1199 1133 1133 77 00..77

FFiinnee mmoottoorr pprroobblleemmss %% 2200 2211 1122 1133 66 11..33

FFaacciiaall--oorraall mmoottoorrpprroobblleemmss

%% 1199 2277 2200 22001111 11..66

SSttrraabbiissmmuuss %% 1155 2266 1122 1133 1100 22..55

MMNNDD %% 1144 1188 1111 1111 55 00..77

DDMMCC %% 1166 2233 1144 1166 77 11..00

6.9. BACKGROUND FACTORS OF ABNORMAL SUBSYSTEMS OF CNS, MILD NEURO-

LOGICAL DYSFUNCTION (MND) AND DEVIANT MOTOR COMPETENCE (DMC)

The background factors of abnormalities in the subsystems of CNS, MND and DMC were analyzed using

multivariate statistics. Tables 36 and 37 give a summary of the regression analyses.

In logistic regression analysis, PIVH (OR 6.5) and male gender (OR 3.1) showed the greatest risks for poor

gross motor performance, compared with a child with normal cranial ultrasound and female gender. Being

born outside neonatal intensive care facilities increased the risk for poor gross motor function 2.5-fold, and

fetal distress during delivery, defined as pathologic fetal heart rate pattern and fetal acidosis, increased the

risk 1.7-fold.

Smallness for gestational age and need for antibiotic therapy were significant risk factors for impaired

balance. Male gender was a 4.7-fold risk, and occurrence of repeated apnea and/or bradycardia a 3.0-fold risk

for poor fine motor function.

117

PIVH emerged as a risk for abnormal muscle tone with an odds ratio 36.6. Male gender showed an OR of 4.2

for difficulties in facial-oral motor function. Ventilatory treatment and toxemia also increased the risk

significantly.

Ventilatory treatment, maternal smoking or alcohol abuse during pregnancy, toxemia and antibiotic therapy

were significant independent risk factors for strabismus, with an OR of 1.9-2.6.

Table 36. Background factors in relation to abnormal performances in subsystems of CNS, MND and DMC (logistic

regression). Odds ratio (OR) and 95 per cent confidence limits (Cl95) are presented.

BACKGROUND VARIABLE

GROSS MOTOR

BALANCE FINE

MOTOR

HAND COORDI- NATION

MUSCLE TONE

REFLEX FACIAL-

ORAL MOTOR

STRA- BISMUS

MND DMC

Male gender ORCI95

3.1 2.0-4.8

4.7 2.9-7.5

1.9 1.2-3.1

3.2 1.4-7.4

4.2 2.0-8.8

2.7 2.0-3.6

3.5 2.4-5.1

Mother’s age <20y or >30y

ORCI95

1.7

1.1-2.6

Irregular prenatal care

ORCI95

2.7

1.2-5.9

Maternal smoking or alcohol abuse

ORCI95

2.5 1.5-4.1

Toxemia ORCI95

2.4

1.3-4.6 2.4

1.4-4.3

Fetal distress (delivery)

ORCI95

1.7 1.1-2.5

Smallness for gestational age

ORCI95

2.0 1.1-3.7

Ventilatory treatment

ORCI95

2.4

1.2-4.7 2.8

1.2-6.3 2.6

1.2-5.3 1.8

1.1-3.1

Apnea/ bradycardia

ORCI95

3.0 1.5-6.1

Antibiotic therapy

ORCI95

2.1 1.4-3.2

1.9

1.0-3.3

PIVH ORCI95

6.5 2.3-18.7

36.6

6.6-204 3.3

0.9-12.5

7.0 2.3-20.6

6.9 2.4-20.0

Outborn ORCI95

2.5 1.2-5.2

Father’s education

ORCI95

ORCI95

ORCI95

1.9 1.3-2.7

1.6 1.1-2.3

1.4 0.9-2.1

1.6 1.0-2.5

2.2 1.3-3.5

1.8 1.1-2.9

Hosmer-Lemeshow goodness of fit p

0.054 0.416 0.512 0.846 0.518 0.643 0.881 0.398 0.964

118

PIVH showed the greatest risk for MND with an OR of 7.0. Male gender (OR 2.7) and ventilatory treatment

(OR 1.8) also increased the risk for MND. Birth-weight and gestational age were not significant independent

risk factors. PIVH (OR 6.9) and male gender (OR 3.5) showed the greatest risks also for DMC, but male

gender had a stronger effect on DMC than on MND. Ventilatory treatment, instead, was not an independent

risk factor for DMC. Low education of the father was a risk, too. Birth-weight was among the variables,

which explained the variance in motor competence in the linear stepwise regression model. Irregular prenatal

care, placenta previa or ablation and intrapartum medication were the other background factors, accounting

altogether for 12% of the variance in motor competence.

Table 37. Background factors in relation to motor competence (stepwise linear regression)

BACKGROUND VARIABLE MOTOR COMPETENCE

b p R2

Male gender 5.296 <0.01 0.051

Low neurological optimality score

0.772 <0.01 0.090

PIVH 10.340 <0.01 0.102

Low birth-weight 0.001 0.01 0.107

Father’s education 0.724 0.01 0.111

Placenta previa/ablation -4.645 0.02 0.114

Irregular prenatal care 2.106 0.02 0.117

Intrapartum medication 1.692 0.03 0.120

b=regression coefficient at the last step Adjusted R2 = 0.115

6.10. ASSOCIATION OF NEONATAL NEUROLOGICAL EXAMINATION WITH RESULTS

OF NEURODEVELOPMENTAL EXAMINATION AT 56 MONTHS OF AGE

All single items of the neonatal neurological examination were analyzed separately with all outcome vari-

ables, i.e. the eight subsystem variables of CNS and motor competence, MND, DMC as well as VMI, CMM

and language tests, CP and major impairment. The results are summarized in Table 38.

Absent or poor visual fixation/tracking neonatally was associated with wide-ranging neurodevelopmental

problems including minor (fine motor and DMC) and major motor impairment, visual-motor problems, poor

language comprehension and lowered cognitive capacity. Absent or poor auditory response was associated

with major impairments and difficulties in language skills and lowered cognitive capacity.

119

Non-optimal findings in muscular resistance to passive movements were associated with minor (difficulties

in facial-oral motor function, MND, DMC) and major neurological abnormalities and poor performance in

the CMM test. Abnormal posture and muscle tone at rest were associated with both minor (MND) and major

neuromotor problems and low scores in CMM, whereas non-optimality in traction head was associated with

minor neurological problems and low scores in LSVT tests. An abnormal amount of spontaneous motility

was associated with minor impairments, and tremors with major impairments.

Table 38. The association between neonatal neurological findings and outcome variables at 56 months of age

GM Bal FM Coor MT Ref F-O Strab MND DMC VMI CMM AWST LSVTa LSVTc CP MAIMP

Head

Eye

Fix

AR

Glab

Posture

QuanSM

Inv Mov

MTat rest

MT resist

Tract head

Tract arm

Grasp H

Grasp F

Ref Knee

Ref Ankl

Ref Bic

Moro1

Moro2

Cry

GM=gross motor, Bal=balance, FM=fine motor, Coor=hand coordination, MT=muscle tone, Refl=reflexes, F-O=facial-oral motor, Strab=strabismus, MND=mild neurological dysfunction, DMC=deviant motor competence, CP = cerebral palsy, MAIMP = major impairment Eye=eye appearance, Fix=fixation/tracking, AR=acoustical response, Glab=glabella reflex, QuanSM=quantity of spontaneous motility, InvMov=involuntary movements, MT=muscle tone, H=hand, F=foot Significance levels according to t-test or χ2- test

120

The two components of the Moro response were different in their relations to the outcome variables. The

non-optimal first stage of the Moro response was associated with DMC, CMM and low AWST scores,

whereas the non-optimal second stage of the Moro response was associated with MND, CP and poor per-

formance in the VMI test. Abnormal cry was associated with cerebral palsy. On the other hand, CP was

associated with global neonatal neurological abnormality.

The neonatal neurological signs, which showed a risk for cerebral palsy in stepwise multiple logistic regres-

sion analysis, were non-optimality in plantar grasp (6-fold risk), head size and form (6-fold risk), eye move-

ments (4.5-fold risk), fixation/visual tracking (3.5-fold risk), involuntary movements (3-fold risk) and second

stage of the Moro response (2.7-fold risk).

Neonatal neurological signs, which emerged as a risk for CP, were different for full-term and preterm

children. The most powerful predictors of later CP were non-optimality in plantar grasp (35-fold risk), cry

(14-fold risk), and quality of spontaneous motility (9-fold risk) in full-term infants and that in posture (11.5-

fold risk) and eye movements (8-fold risk) in preterms.

When dichotomized variables (abnormal/normal) of the neonatal neurological examination (NeoQuan,

NeoQual) were analyzed with all outcome variables of the 56-month assessment, abnormal neonatal neuro-

logical assessment was significantly associated with abnormal neurological (gross motor, fine motor and

facial-oral motor function, strabismus, MND) and neuromotor (DMC) assessment. Abnormal neonatal

neurological examination was also highly significantly associated with abnormal visual-motor function

(VMI) and lowered cognitive ability (CMM). Most of the associations between abnormal neonatal neuro-

logical assessment and later language problems were non-significant. The only significant association was

found with comprehensive language (LSVTa) by the quantitative classification method (Tables 39,40).

By the quantitative classification method (NeoQuan1), 40.4% of the neonatally neurologically deviant

children were neurologically abnormal, i.e. had either CP or MND and/or DMC at 56 months of age. Of the

children regarded as neonatally abnormal by the qualitative method (NeoQual1), 30.3% were neurologically

abnormal in the follow-up (Table 40).

Finally, when looking at the outcome of children who were neonatally neurologically deviant by both

classification methods (N=77), the proportions of abnormal findings in the different domains were slightly

greater than those of the two neonatally defined abnormal groups. The rate of cerebral palsy was 16.4%

among them. MND was observed in 37.8% and DMC in 33.3% of those children. 15.6% had VMI problems.

20.5% had CMM scores, 9.1% LSVTa scores and 4.4% AWST scores that were below –2SD of the mean of

the original control population mean.

121

Table 39. Means and SDs of outcome variables in relation to abnormal/normal results of neonatal

quantitative and qualitative neurological assessment


ABNORMAL NORMAL ABNORMAL NORMAL

GROSS MOTOR

N 77 1417 189 1298

Mean 86.26 94.76 90.43 94.90

SD 23.33 13.06 19.59 12.78

t 3.17 p=0.0022 t 3.04 p=0.0026 FINE MOTOR

N 79 1434 192 1314

Mean 77.85 86.17 79.08 86.74

SD 28.71 22.07 25.82 21.82

t 2.54 p=0.0131 t 3.91 p=0.0001 FACIAL-ORAL MOTOR N 79 1435 194 1313

Mean 94.30 98.64 95.62 98.82

SD 19.22 7.36 15.25 6.83

t 2.00 p=0.0492 t 2.88 p=0.0044

STRABISMUS

N 83 1449 197 1328

Mean 84.34 95.58 89.85 98.78

SD 36.57 20.55 30.28 20.10

t 2.78 p=0.0068 t 2.67 p=0.0083 VMI

N 78 1413 194 1290

Mean 6.36 7.16 6.60 7.19

SD 2.37 2.24 2.29 2.24

t 3.06 p=0.0022 t 3.45 p=0.0006 CMM

N 77 1403 192 1281

Mean 43.90 49.59 46.47 49.72

SD 13.57 11.67 12.46 11.71

t 3.61 p=0.0005 t 3.55 p=0.0004 LSVTa

N 77 1399 190 1279

Mean 10.51 11.34 11.15 11.31

SD 2.99 2.68 2.93 2.66

t 2.65 p=0.008 t 2.93 p ns Significance levels according to t-test

122

Table 40. Probabilities of minor and major impairments in relation to abnormal/normal results of neonatal quantitative

and qualitative neurological assessment

6.11. THE PREDICTIVE POWER OF THE NEONATAL NEUROLOGICAL EXAMINATION

ON THE NEURODEVELOPMENTAL ASSESSMENT AT THE AGE OF 56 MONTHS

The sensitivity, specificity, as well as positive and negative predictive values for the neonatal neurological

examination are shown in Table 41. The sensitivity, and especially the predictive value of the abnormal

result of the neonatal neurological examination were very low for mild neurological abnormality, deviant

motor competence, cerebral palsy and all minor and major impairments. The sensitivity varied from 14-46%

by the quantitative classification method, and from 26-62% by the qualitative method for CP and major

impairments. The positive predictive values of the abnormal neonatal neurological examination for CP and

major impairments were 12-27% by the quantitative method and 7-21% by the qualitative method. The

sensitivity for minor impairments was even lower. The qualitative method displayed slightly higher sensitiv-

ity, but lower positive predictive values, compared with the quantitative method.

The specificity (87-96%) and predictive value of the normal result of the neonatal neurological examination

(91-99%) for CP and major impairments were fairly high. The specificity for CP reached 99%, and the

negative predictive value of normal neonatal neurology for major impairments and death reached 91% by

both neonatal classification methods. Minor impairments showed similar specificities. The quantitative

MND DMC CP CP+ MND

CP+ MND+ DMC

Minor Imp

Major Imp

Major Imp+ Death

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

QUANTITATIVE METHOD

NABN

%

24 33.8

47 66.2

1825.7

5274.3

12 12.1

87 87.9

35 35.4

64 64.6

4040.4

59 59.6

55 60.4

36 39.6

25 27.5

6672.5

27 27.3

72 72.7

NNORM

%

249 17.4

1179 82.6

157 11.1

1255 88.9

14 0.8

1652 99.2

263 15.8

1403 84.2

323 19.4

1343 80.6

680 41.0

979 59.0

150 9.0

1509 91.0

150 9.0

1516 91.0

χ2 12.162 13.642 81.935 25.496 25.265 13.399 32.561 34.567

p 0.0005 0.0002 <0.0001 <0.0001 <0.0001 0.0003 <0.0001 <0.0001

QUALITATIVE METHOD

NABN

%

43 23.1

143 76.9

3317.8

152 82.2

16 6.7

222 93.3

58 24.4

180 75.6

7230.3

166 69.7

116 50.9

112 49.1

39 17.1

189 82.9

41 17.2

197 82.8

NNORM

%

230 17.5

1083 82.5

142 10.9

1155 89.1

10 0.7

1517 99.3

240 15.7

1287 84.3

291 19.1

1236 80.9

619 40.7

903 59.3

136 8.9

1386 91.1

136 8.9

1391 91.1

χ2 3.431 7.379 52.234 10.985 15.797 8.481 14.705 15.799

p 0.0640 0.0066 <0.0001 0.0009 0.0001 0.0036 0.0001 0.0001

123

method showed higher specificity compared with the qualitative method, but the negative predictive values

did not differ from each other.

The sensitivity was low. As many as 54-91%/38-84% of the children with neurological problems at the age

of 56 months could not be identified in a single quantitative/qualitative neonatal neurological examination at

term age, respectively. One third of the children with later CP were normal in the qualitative, and a half of

them in the quantitative neonatal neurological examination.

High specificity and negative predictive values, on the other hand, meant that if the result of the neonatal

neurological examination was normal, neurological problems were unlikely to occur later. High specificity

meant also that there were proportionately very few `wrong positives´.

Table 41. Sensitivity, specificity, and positive and negative predictive values of abnormal/normal neonatal neurological

assessment vs. abnormal/normal outcome at the age of 56 months.

GROUPING FACTOR MAJOR IMPAIR- MENT AND

DEATH

MAJOR IMPAIR- MENT

MINOR IMPAIR- MENT

CP MND DMC VMI CMM AWST LSVTa

QUANTITATIVE

Sensitivity % 17 14 7 46 9 10 13 11 6 12

Specificity % 96 96 96 95 96 96 96 96 95 96

PPV % 33 27 60 12 34 26 14 18 5 14

NPV % 91 91 59 99 83 89 95 93 95 95

QUALITATIVE

Sensitivity % 26 26 16 62 16 19 26 21 12 18

Specificity % 88 88 89 87 88 88 88 88 87 87

PPV % 21 21 51 7 23 18 11 13 4 8

NPV % 91 91 59 99 88 89 95 93 95 95

PPV=positive predictive value, NPV=negative predictive value

124

7. DISCUSSION

7.1. SUBJECTS AND METHODS

The study design fulfilled the methodological demands for a population study (Aylward et al. 1989b, Mutch

et al. 1989, Largo et al. 1990a, Ornstein et al. 1991). The residence of the mothers of the enrolled infants was

strictly geographically defined. The sample collection was performed during one year, which was short

enough to guarantee the uniform attending practice, yet long enough to prevent bias of the study cohort. The

control group was randomly selected simultaneously and examined together with the index children. Data on

neonatal background factors were collected prospectively. The size of the study population was large enough

to define the prevalence of uncommon impairments (e.g. CP), which was beyond the primary scope of the

present study, however. All the children were examined at the same ages. The follow-up to the age of 56

months was not long enough, however, to detect all aspects of developmental dysfunction, e.g. specific

learning difficulties.

7.1.1. STUDY POPULATION

The enrolment criterion of the original index population was admission to a neonatal ward for any reason

defined by a permanent hospital physician, and was not based on a specifically defined neonatal risk factor

or morbidity. For minor neonatal morbidity problems, the admission practice may have varied according to

the hospital or the physician on duty. Consequently, the hospitalized group consisted of a heterogeneous

population of high-risk and low-risk preterm and full-term infants. The regional enrolment of a study popula-

tion makes possible selection bias non-operative, however (Kiely and Paneth 1981). The only inclusion

difference between the study and control groups was a medical concern of any kind, but not pre- or perinatal

risk factors.

7.1.2. NEONATAL NEUROLOGICAL EXAMINATION METHODS

The neonatal neurological examination was based on the concept of Prechtl (1977), which has proven to be

useful in predicting severe and minor neurological impairments and language/speech problems in earlier

follow-up studies (Calame et al. 1976, Bierman-van Eendenburg et al. 1981, Touwen et al. 1982, Hadders-

Algra et al. 1986, 1988a, Forslund and Bjerre 1989, Touwen 1990, Ferrari et al. 1990, den Ouden et al.

1990, Weisglas-Kuperus 1992, Soorani-Lunsing et al. 1993).

125

The limit of neurological normality and abnormality is not always easy to define. Consequently, the concept

of optimality (Prechtl 1980) was used in the neurological assessments, both neonatally and at 56 months of

age. As to the concepts of optimal and normal, optimal is more narrow as concerns the limits of normality.

The classification methods, quantitative and qualitative, were derived from the same standardized neuro-

logical examination. The two methods were selected to compare the value of quantification of non-optimal

neurological signs and responses (i.e. non-weighted) and clinical judgment of neurological normality and

abnormality in predicting later neurodevelopmental outcome. The former was based on a strictly predefined

examination protocol, and the latter on the examiner’s experience and clinical knowledge of neurological

abnormalities. No such study could be found in the previous literature.

The classification of an infant as abnormal (group NeoQual1) was based on definite neonatal neurological

abnormalities in order to minimize the bias of an inconsistent interpretation of mildly abnormal findings. The

neonatal neurological optimality score was used as a quantitative measure (group NeoQuan1) of the neuro-

logical examination with a cut-off point for reduced optimality, as proposed by Stave and Ruvalo (1980), and

applied by Forslund and Bjerre (1983) and Aylward et al. (1989a). With this cut-off point of 25% of the

maximum total score, the number of abnormal infants defined by the quantitative neurological assessment

was smaller (N=117) than the number of abnormal infants defined by the qualitative assessment (N=282).

However, due to the more strict concept of optimality compared with normality, the situation would have

been expected to be vice versa. Indeed, the optimality of only 77 children in the qualitatively abnormal group

had fallen by more than 25%. The main reason for the greater numbers of infants in the qualitatively abnor-

mal group was the inclusion criterion related to brain nerve signs: 11% of the qualitatively abnormal group

(NeoQual1) had only one non-optimal sign (eye appearance, visual fixation/ tracking, auditory response,

sucking), 23% had two non-optimal signs.

The quantitatively and qualitatively defined neurologically abnormal groups were compared with two

neurologically normal groups, one with (NeoQuan2 and NeoQuan2) and the other without (NeoQual3 and

NeoQuan3) neonatal general morbidity. The purpose was to evaluate the possible specific features of

neurologically abnormal infants as concerns background factors and future development, compared with sick

neonates without neurological abnormality. Another aim was to find out what kind of impact neonatal

morbidity without neurological abnormality has on later outcome.

7.2.3. ASSESSMENT METHODS AT 56 MONTHS

The outcome measures included major impairments, but also specific and minor problems in neurological

and neuromotor area, visual-motor integration, general reasoning, speech and language. All the examinations

126

were performed by one of the four pediatricians in a standardized manner. Neuropsychological tests, which

require trained psychologists to administer the test, were not used in the present study due to a lack of

resources.

The neurological examination at 56 months was developed to detect functional abnormalities in the eight

subsystems of CNS, MND and DMC. Touwen’s neurological assessment method - suitable for children from

3-12 years of age - has been widely used for detecting minor neurological dysfunction among preterm and

full-term children (Noble-Jamieson et al. 1982, Hadders-Algra et al. 1986, Forslund and Bjerre 1989,

Marlow et al. 1989, Astbury et al. 1990, Largo et al. 1990a, Herrgård 1993, Jongmans et al. 1997, Lacey and

Henderson-Smart 1998). In the present study, the predefined optimal findings and abnormal alternatives were

assumed to decrease interobserver differences, which have been reported (Kakebeeke et al. 1993). Further-

more, the cut-off points in the present study were based on the performance of the representative randomized

control group. Because the interpretation of both minor neurological signs and motor impairment is partly

subjective, a simultaneously blindly assessed control group can give a better reference than standardized test

norms of other populations (Lindahl 1987, Marlow et al. 1989). Although not more than four pediatricians

were examining the children, some interobserver variation was nevertheless observed. Undetected systematic

errors in the interpretation, possible in one-researcher studies, were avoided, however.

Assessment of motor competence consisted of age-appropriate tasks in oral motor and fine motor functioning

and co-ordination of the whole body, including balance. Partly similar tasks have been used in other methods

evaluating motor clumsiness among preschool-school-aged children (Gillberg et al. 1982, Henderson and

Sugden 1992).

The calculation of a percentage sum score of successful tasks according to the suggestion of Aylward et al.

(1989a, 1989b) was done to lessen the overestimation of abnormalities in the cases of incomplete perfor-

mances. All the distributions of neurological/neuromotor percentage scores were skewed due to a ceiling

effect in the good performances. The cut-off points for mild abnormality in the eight subsystems of CNS and

for deviant motor competence were based on the lowest 10% of the control group of the original study popu-

lation, as in other studies on mild neurological abnormalities or motor competence (Vähä-Eskeli et al. 1990,

Hall et al. 1995). Minor neurological dysfunction was defined, weighting performances in gross motor

function, balance and fine manipulative ability (Riegel et al. 1995). Hadders-Algra et al. (1988a) and Lacey

and Hendersson-Smart (1998) used quite similar definitions of minor neurological dysfunction in children

with abnormal performance in one or two of five to six subsystems or clusters as mildly neurologically

abnormal.

The test of visual-motor function (VMI) has recently been standardized for Finnish children, and the results

of the original control group of the study population were in accordance with the standardization.

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The cognitive ability (CMM) and language tests (AWST, LSVT) were standardized among German children,

but had no previous Finnish standards. The performances in CMM were found to be similar in the two

countries, as the cumulative distributions of raw scores of Bavarian and Finnish regional normative samples

were congruent (t-test t=0.58, ns) (Riegel et al. 1995). Instead, the pictures of AWST-test material did not

match the experience and typical vocabulary of Finnish children, which probably explained why the results

were below those of German children (Riegel et al. 1995). The second part of the LSVT-test (part-C) proved

to be too difficult for many of the examined children, who interrupted the test or refused to do it. Missing or

incomplete data in that test amounted to 8.1%, while in other tests it ranged from 2.1-4.3%.

The normative data of normally distributed visual-motor, cognitive and language tests were also based on the

performance of the randomized control group of the original study population. These data, in addition to the

standardized assessment situation were considered to provide a more reliable reference than the outmoded

test norms. This has also been observed in other studies (Bill et al. 1986, Astbury et al. 1987, Gaily et al.

1990, Herrgård 1993, Wolke et al. 1994).

The present classification of impairments and disabilities is based on WHO recommendations. For defining

the severity of impairments and disabilities of visual-motor, cognitive and language domain, standard

deviations were used as cut-off points according to the Bavarian Study Group (Riegel et al. 1995) and recent

follow-up studies (Johnsson et al. 1993, Victorian study group 1995). The chosen cut-off value is important

because it influences the rates of impairment and the comparison between different studies.

7.1.4. DROPOUTS

In the original hospitalized or control groups there was no difference as to gender, birth-weight, gestational

age, family status or the educational level of the parents between the surviving infants who were and were

not examined in the neonatal period. In the hospitalized group the obstetric optimality score was significantly

higher (more optimal, less risk factors) among infants missed in the neonatal examination due to early

discharge, but the neonatal optimality score was not different.

The attrition rate at 56 months of age was high (24.4%) as in other regional follow-up studies (Olsen et al.

1998, Pinto-Martin et al. 1999) in spite of active efforts to contact the parents by letter and by phone. Indirect

data on health and development were available on nearly half of the children not seen at the age of 56

months, and only 13% of the children were not traced. No child untraced at 56 months of age had a severe

motor impairment or was definitely delayed in his/her cognitive development at 20 months of age, when

90.6% of the study population was seen.

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There was no statistically significant difference between the examined children and dropouts in birth-weight,

gestational age, obstetrical or neonatal optimality scores. Instead, the presence of impairment and the low

education of the parents affected participation negatively, as in Bavaria, too (Wolke et al. 1995). 9.6% of the

children with indirect data available, compared with 1.6% of those examined, had a major developmental

disorder or impairment, diagnosed after the neonatal period. Furthermore, of the ten most severely disabled

cerebral palsy children, only one child was seen at 56 months of age. In the lowest educational group of the

mothers, 69% of the children were examined, 17% not traced, compared with 80% and 10% in the highest

educational group, respectively. 54% of the children of single parents were seen, while one fourth of them

could not be traced.

Because major developmental disabilities are likely to be found before 2 years of age (Amiel-Tison 1989), it

can be assumed that the incidence of major disabilities in the present study is not underestimated. Instead, it

is not possible to detect minor impairments with certainty at very early age, and environmental factors are

known to be associated especially with minor neurodevelopmental abnormalities. A slight underestimation as

to minor impairments is therefore possible.

7.2. SURVIVAL

The survival rate of the whole study population was similar to that of the Bavarian population (95.4%,

VLBW 70.7%), but the survival rate of VLBW infants was slightly lower. The Scottish Low Birthweight

Study Group (1992a) reported a population-based 4.5-year survival rate of 62% for VLBW infants and of

29.4% for ELBW infants born in 1984. The survival rate of the ELBW infants was distinctly lower compared

with that found in the present study. Long-term survival in a low birth-weight (<1750g) population reported

in Northern Finland from the same time period was 73%, i.e. exactly the same as in the present study (Olsen

et al. 1998).


The neonatal neurological examination was performed as close to the 40-week post conceptual age as

possible. This proved to be difficult, however, because many preterm infants were discharged before the term

age, and additional visits were not possible to arrange after discharge from hospital. The mean examination

age in the whole study population was 39.5 (SD 2.3) gestational weeks, ranging from 38.7-40.2 weeks post

conceptual age in the six study groups. It was lowered mainly by moderately preterm infants, since the mean

examination age of the tiniest infants with gestational age less than 29 completed weeks (N=28) was greater

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(mean 37.8) than that of the whole preterm group (mean 36.5). The reason for this was the longer hospitaliza-

tion of the tiniest infants, which was on average 78 days compared with 22 days for moderately preterm

infants. However, the examination age did not confound the results in statistical analysis, because the slopes

of the regression lines of raw and assessment-adjusted neurological optimality scores predicting motor

outcome were almost equal (r=1.553 and r=1.529).

In all 18 (4.2%) preterm infants had their neonatal neurological examination before 34 weeks postmenstrual

age. 7 (38.9%) of them were neurologically abnormal by the quantitative method and 12 (66.7%) by the

qualitative method, compared with 23.7% and 69.5% abnormal of those examined at term, respectively.

Consequently, 2-3 preterm infants would have moved from the quantitatively abnormal group to the normal

group, if they had been examined at term age, whereas the influence on qualitative method probably was not

significant. In addition, three of 17 severely ill infants who were not examined until at 44 weeks gestational

age or more, were moved from the neurologically abnormal to the normal group due to the results of the

latest neurological examination. Consequently, because the numbers of neurologically abnormal and normal

infants did not change, and all infants could be considered high-risk infants as to adverse developmental

outcome, this hardly had any significant effect on the final results. Indeed, 6 of the 7 quantitatively abnormal

children examined early were seen at 56 months of age; two of them had motor impairment (1 CP, 1 MND),

the others displayed normal motor development. Moreover, we had information on 11 of the children

examined later, and 2 of them had motor impairment (1 CP, 1 MND).

Of the neonatal neurological individual signs, deviant passive and active muscle tone, visual fixa-

tion/tracking, auditory orientation, Moro response, spontaneous motility, and involuntary movements were

observed significantly more often in hospitalized than in control infants. These signs were found more often

in boys than in girls, and in very preterm infants more than in full-term ones. These signs also associated

with adverse neurodevelopmental outcome, confirming previous studies (Nelson and Ellenberg 1979,

Molteno et al. 1995).

During neurological maturation, passive muscle tone evolves gradually in the caudocephalic direction from

global hypotonia at 28 weeks gestation to the acquisition of flexor tone at term age. (Amiel-Tison and

Grenier 1986, Brown et al. 1997). Strengthening of active tone also progresses to equalization of the extensor

and flexor tone of the axis at term age (Amiel-Tison and Grenier 1986). This development has been reported

to show very little biologic variability (Saint-Anne Dargassies 1966). By term age, visual tracking of an

object is possible horizontally, vertically and sometimes also in an arc (Mercuri and Dubowitz 1999). In

addition, acoustical orientation includes shifting of eyes, cessation of movements and often head turning. The

Moro reflex in term infants consists firstly of abduction and extension, and secondly adduction and flexion

of upper extremities with equal amplitude (Volpe 1995, Mercuri and Dubowitz 1999). Complexity, variabil-

ity and fluency of spontaneous motility is a property of the normal nervous system at all ages (Touwen 1990,

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Prechtl 1997). Abnormalities in these abilities at term age reflect either somatic or neurologic morbidity of

an infant; hypotonia is a common sign also in cardio respiratory, metabolic or infectious diseases. Because

the Moro reflex is sensitive to the level of alertness, the absence of a whole Moro reflex is associated with

generalized CNS disturbance (Volpe 1995). Absence of the second stage is often associated with exaggerated

first stage of the Moro reflex and extensor hypertonia. Involuntary movements, such as tremors and startles,

brisk tendon reflexes and exaggerated Moro reflex are related to hyperexcitability condition in an infant

(Prechtl 1977, Volpe 1995). Isolated, jerky and monotonous movements are markers of brain dysfunction.

According to recent brain imaging studies, all these clinical deviant neurological signs have been reported as

important markers of the main neonatal brain lesions such as IVH, cystic PVL and HIE (Mercuri et al. 1995,

Katz-Salamon et al. 1997, Mercuri and Dubowitz 1999, Cioni et al. 2000).

In the present study, the strong associations, observed between the non-optimal individual neonatal neuro-

logical signs and the adverse outcome measures, might be related to early brain injury. Noteworthy were the

significant associations between absent visual fixation/tracking and fine motor and visual-motor problems,

lowered cognitive ability and difficulties in verbal comprehension, as well as between absent acoustic

response and lowered cognitive ability and verbal capacity. Of the few studies that have dealt with the

respective associations, Wallace et al. (1995) also found a positive association between neonatally detected

deviant visual following and auditory orienting, and low cognitive test scores among VLBW children at 6

years of age.

The effect of gestational age was found in the neonatal neurological examination at term age, as in earlier

studies (Howard et al. 1976, Kurtzberg et al. 1979, Palmer et al. 1982, Majnemer et al. 1992); increasing

non-optimality was related to decreasing gestational age, as also noted by Aylward et al (1984). The effect of

gestational age was evident, even though the full-term infants were examined at the age of 5-7 days, when

differences between preterms and full-terms due to postnatal adaptation are considered to be minimal

(Palmer et al. 1982).

The proportion of definitely abnormal infants by the quantitative method was 5.7% and that by the qualita-

tive method 13.8%. Although preterm (<37 gwks) infants comprised only 21% of the whole study popula-

tion, 48% of the infants in the quantitatively abnormal group and 41.5% of those in the qualitatively abnor-

mal group were preterm. Very preterm infants (<32 gwks) comprised 3.2% of the total population, while

their proportion among neurologically abnormal infants was 15.4% in the quantitatively abnormal and 10.3%

in the qualitatively abnormal group. On the other hand, of the full-term infants, comprising 79% of the whole

study population, 3.8% and 10.2% were abnormal by the quantitative and qualitative method, respectively.

Consequently, the quantitative method selected a greater proportion of preterm and especially very preterm

infants as abnormal, compared with the qualitative method. On the other hand, the qualitative method

selected a greater proportion of full-term infants as abnormal, compared with the quantitative method.

131

Comparison of the incidences of neonatal neurological abnormality between different studies is difficult. The

quality of the neonatal population is a crucial factor. As shown in the present study, the severity of neonatal

morbidity is strongly associated with neonatal neurological abnormality. Consequently, in high-risk popula-

tions - such as neonatal intensive care graduates - the incidences will be higher than in low-risk populations.

Furthermore, hospital-based studies are assumed to have higher incidences than regional studies. The

incidences are also influenced by the methods and definitions used.

In some studies – including one nationwide study – Prechtl’s neonatal neurological examination method has

been used (Jurgens-van der Zee et al. 1979, Forslund and Bjerre 1983, Aylward et al. 1984, den Ouden et al.

1990). The present study is comparable with the Groningen hospital-based study ten years earlier (Jurgens-

van der Zee et al. 1979), which has the same kind of study design including mainly full-term infants. The

proportion of neurologically abnormal newborns, based on Prechtl’s neurological syndromes, was 5.3%

(4.7% of full-terms and 17% of preterms) compared with 13.8% (10.2%, 27.3%, respectively) in our study.

Our method was a modified version of the original Prechtl method, and the criteria for abnormality were

different, as we did not define the distinct neurological syndromes.

Smaller percentages of neurological abnormality were found also in the Dutch nationwide study in the mid

1980s (den Ouden et al. 1990) on newborns less than 32 gestational weeks and/or birth-weight less than

1500g. In their study, 8.1% of very preterms, compared with 43.9% in our, were neonatally neurologically

abnormal in an examination based on Prechtl’s syndromes. It is probable that the different criteria for

neurological abnormality – not exactly described in the study reports - explain the different rates between the

studies.

Similar or higher rates than in the present study have been reported among preterm populations measured by

other qualitative methods. Dubowitz et al. (1984) noted that 31% of preterm infants less than 35 gestational

weeks were definitely neurologically abnormal according to their own examination method, compared with

34% in the present study. Stewart et al. (1988) found 42% of preterms of less than 33 gestational weeks to be

neurologically abnormal, compared with 35% of the preterms of the same age in the present study. Allen and

Capute (1989) found 40% of their high-risk preterm (<37 weeks) infants to be clinically neurologically

abnormal.

A few studies have used neurological optimality scores in defining neonatal neurological abnormality.

Forslund and Bjerre (1983) found 26% of preterms of less than 35 weeks gestational age to be neurologically

abnormal according to reduced optimality of more than 25% (27 items in Prechtl’s method) compared to

20% in our study. The proportion of neurologically abnormal full-terms was 3.8%, i.e. exactly the same as in

the present study. Njiokiktjien and Kurver (1980) examined `healthy´ preterm and full-term newborns using

Prechtl’s method, and found 18% of them to be sub optimal. They used a cut-off point of 86% for sub

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optimality. Had we used the same cut-off point for our non-hospitalized newborn infants, 13.9% of them

would have been sub optimal. Our proportion of sub optimality was lower, but we used 27 items, instead of

42 used by Njiokiktjien.

The incidences of neonatal neurological abnormality in the present study are within the great variability

observed in other studies. The reasonably high proportion of neurological abnormality is not a major problem

in the present study, however, because of the randomly chosen and similarly assessed control group.

7.4. BACKGROUND FACTORS OF NEONATAL NEUROLOGICAL ABNORMALITY

The neonatally neurologically abnormal infants were those who had the greatest perinatal risk and who were

the sickest as measured by obstetrical or neonatal optimality scores or Casaer’s intensity scores, compared

with the two neurologically normal groups. This confirms the relationship between serious morbidity and

neurological abnormality; the sicker the neonate the more probable for him/her to be neurologically abnor-

mal.

The quantitatively and qualitatively defined neurologically abnormal groups were different in respect to their

obstetric and neonatal morbidity background factors. Quantitatively defined neonatal neurological abnor-

mality was, in the univariate analysis, significantly associated with both prematurity-related factors, such as

previous preterm birth, preterm contractions, low gestational age, and also acute catastrophic intrapartum

events.

Previous preterm birth carries a risk for preterm delivery in the following pregnancies, and preterm contrac-

tions may sometimes start a preterm delivery. Furthermore, as regards prematurity-related neonatal morbidity

factors, ventilatory treatment was an independent predictor of quantitative neurological abnormality, but it

did not increase the risk of qualitative neurological abnormality. 57.2% of all ventilated neonates were

preterm, one third of the quantitatively abnormal infants needed ventilatory assistance. Prematurity as a

background factor in the quantitatively abnormal group was supported by a long duration of ventilatory

treatment and high rate of neonatal morbidity. Also in the study of premature infants by Katz-Salamon et al.

(1997) prolonged ventilatory treatment was observed to have an adverse effect on neonatal neurological

examination at term age, especially on passive tone, palmar/plantar grasping and sucking/swallowing.

Ventilatory treatment predisposes a premature infant to fluctuations in cerebral blood flow and IVH, or

chronic hypoxia (Volpe 1995). The relationship between prolonged mechanical ventilation and cranial MRI

abnormalities has also been demonstrated (Krägeloh-Mann et al. 1999, Sie et al. 2000). Sie et al. (2000)

observed a complicated neonatal period with sepsis, prolonged ventilatory treatment or recurrent bradycardia

in most of the preterm infants with PVL in cranial MRI.

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The starting event in the cellular mechanisms of birth asphyxia is impaired gas exchange with hypoxemia

and hypercapnia, leading to a cascade of failure in energy metabolism, cytotoxic reactions, reperfusion

injury, and finally neuronal death. The sequence of clinical signs associated with these cellular events

includes abnormal fetal heart rate, fetal acidosis, low Apgar scores, delay and problems in maintaining

respiration, neurological deviant signs, and seizures (Blair 1993). In the present study all these delivery-

related factors, in addition to the need for instrumental delivery in about half of the cases, associated signifi-

cantly with quantitative neonatal neurological deviancy. Fetal intrapartum distress, defined as pathologic

CTG and fetal acidosis, as well as seizures, were significant independent predictors of quantitative neuro-

logical abnormality also in multivariate analysis. Intrapartum events as a clinical pathway to neonatal

neurological deviancy are thus of major concern.

The background factors relating to maternal or neonatal infection were more common among neurologically

deviant groups than normal groups. Maternal fever during delivery (7% of mothers in the neurologically

abnormal vs. 0.6% of those in the normal non-hospitalized groups) was a significant independent risk factor

for quantitative neurological abnormality in linear regression. Badawi et al. (1998) reported maternal pyrexia

in labor to increase the risk for neonatal encephalopathy almost 4-fold. Moreover, in the present study,

antibiotic therapy neonatally increased the risk for both quantitative and qualitative neonatal neurological

abnormality in multivariate analysis. These findings are noteworthy because intrauterine infection via

neurotoxic mediators has been reported in the development of cerebral white matter damage and cerebral

palsy (Murphy et al. 1995, Perlman et al. 1996, Zupan et al. 1996, Yoon et al. 1997).

Also qualitative neonatal neurological abnormality was significantly associated with asphyxia-related

factors, such as meconium-stained amniotic fluid, low 5-min Apgar scores, the need for immediate ventila-

tory assistance, and seizures. These factors were more prevalent in full-terms. Low 5-min Apgar scores

presented a slight independent risk for qualitative abnormal neurology. If the children who were neurologi-

cally abnormal by only one classification method were compared with each other, 7.8% of the infants had

scores less than 6, 2.1% less than 4, by the qualitative method, compared with 2.6% and none by the quanti-

tative method. Low Apgar scores may be associated with neonatal neurological abnormality via prematurity

or asphyxia. Holden et al. (1982) found a 5-min Apgar score less than 7 to be significantly related to me-

conium staining and seizures. In the present study, 45% of the 93 surviving neonates whose 5 min Apgar

scores were 6 or less presented with neonatal neurological signs, such as deviancy in responsiveness and

muscle tone and sucking problems, suggesting HIE; 15% of these infants had also seizures. Apgar scores are

reported to be related to gestational age, and therefore to have different implications for full-term and

preterm infants (Catlin et al. 1986). Nevertheless, post-asphyctic encephalopathy with respiratory depression,

hypotonia and seizures typical for full-term infants has been reported also among preterm infants (Niijima

and Levene 1989). However, in the present study 67% of all neonates with Apgar scores less than 6 were

full-term infants. Brain injury of the basal ganglia and thalamus in MRI at preterm age and that reaching

134

from the internal capsule to the perirolandic cortex at term age have been described after profound perinatal

asphyxia (Martin and Barkovich 1995).

Moreover, qualitative neurological abnormality was associated with prenatal problems, such as toxemia,

multiple pregnancy, vaginal bleeding and poly/oligohydramnios. Pre-eclamptic toxemia, i.e. hypertension

with proteinuria, is a common cause of intrauterine growth retardation. It may thus predispose an infant to

intrapartum or postnatal complications (Stanley et al. 2000). Multiple pregnancy, today an increasing

phenomenon resulting from fertility treatment, is also associated with preterm birth and delivery complica-

tions. Furthermore, prenatal cerebral damage because of co-fetal death has been suggested as a cause of

cerebral palsy (Pharaoh and Cooke 1997). Antenatal hemorrhage has been associated with newborn encepha-

lopathy and white matter damage (Leviton and Paneth 1990, Sinha et al. 1990, Zupan et al. 1996, Badawi et

al. 1998). Poly- and oligohydramnios are often related to congenital malformations. In addition, the infants

with abnormal maternal amniotic fluid volume have been reported to have lower birth-weight, shorter

gestational age, lower placental weight, more frequent chromosomal aberrations and higher maternal gesta-

tional morbidity (hypertension, diabetes) than infants with normal maternal amniotic fluid volume (Martinez-

Frias et al. 1999).

Large head size, male gender and seizures predicted independently both quantitative and qualitative neonatal

neurological abnormality. After excluding infants with congenital hydrocephalus or spina bifida, 4% of

neonates had head size above 2SD of the mean for gestational age at birth, and associated with birth weight

above 2SD in one third of them. 5% of these infants had 5-min Apgar scores less than 4 compared with 1.5%

of infants with a normal or small head size. The need for immediate ventilatory assistance occurred in 11.6%

and 6.7%, respectively. However, the manner of delivery was not different, as instrumental delivery was used

in about one third of both groups. Although the differences in the proportions of emergency situations im-

mediately after delivery were not statistically significant, macrocephalic infants were nevertheless found to

be at increased risk for neonatal neurological morbidity.

Seizures are mainly observed among full-term neonates (Mizrahi and Kellaway 1987). Hypoxic-ischemic en-

cephalopathy is the most common etiological factor; cerebrovascular lesions, infections and metabolic

disorders are others (Mizrahi and Kellaway 1987, Scher et al. 1993, Mercuri et al. 1995, Leth et al. 1997). A

strong correlation has been found between neonatal seizures and ischemic brain lesions (Sinha et al. 1985).

Moreover, localized cerebral infarcts, observed in early MRI examinations (Bouza et al. 1994, Mercuri et al.

1995), have been reported to be more common than earlier known. Because seizures may increase systemic

blood pressure and consequently cerebral venous pressure, IVH may play a contributing role (Perlman,

Volpe 1983). An ischemic background for seizures is supported by the close relationship between acidemia

and seizures, as reported by Perlman et al. (1993). They observed 17% of 47 infants with severe acidemia

(ph<7.0) to have seizures. In the present study, 64% of the 55 surviving infants with clinical seizures were

135

full-term, and 16% very preterm infants. 35%/47% were abnormal in the neonatal neurological examination

by the quantitative/qualitative method. Correspondingly, 11%/16% were neurologically abnormal and had

5min Apgar scores below 7, and probably HIE was a cause of their seizures. However, ischemic or hemor-

rhagic brain lesions in MRI have been observed also in neonates with seizures, but normal Apgar scores

(Mercuri et al. 1995).

In the present study 53/55 infants with seizures underwent neonatal ultrasound examination. 22% of them

had mild to severe peri-intraventricular hemorrhage or cystic PVL, of which 83% were observed among

preterms. Consequently, most of the infants with seizures, especially full-terms, showed no cerebral damage

in US. On the other hand, about one third (36%) of the 31 surviving infants with PIVH in cranial ultrasound

(77% preterms) had seizures.

Incomplete coverage of ultrasound examinations may be the reason for the unexpected finding that PIVH had

no predictive effect on neonatal neurological abnormality, when prematurity and other related problems were

more important. Moreover, seizures probably mediated some of the effect of PIVH. Katz-Salamon et al.

(1997) also found IVH to have only a weak influence on neonatal neuromotor status among preterm infants

at 40 weeks postconceptional age. However, they observed cystic or large white matter echogenicity to have

a negative effect on the control of head, neck and trunk, and the development of sucking and swallowing. At

the time of the present study, subtle periventricular echodensities, other than cysts, were technically not

possible to detect. Aylward et al. (1989a) and den Ouden et al. (1990), however, found a significant correla-

tion between IVH and the neurological condition of preterm infants at 40 weeks conceptional age or at

preterm age.

In spite of the same severity of general neonatal morbidity in boys and girls, boys had nearly a 2-fold risk for

neonatal neurological abnormality as also noted by others (Aylward et al. 1984, Hadders-Algra et al. 1986).

Instead, in a very preterm group, den Ouden et al. (1990) did not find male gender to be a significant risk for

neonatal neurological abnormality. In the present study, gender differences were observed in single test

items, such as better visual fixation/tracking among girls, and more tremors among boys, in line with the

findings of Aylward et al. (1984). In the assessment of the subsystems of CNS, however, gender differences

were insignificant (NeoQual1). The mean of the neurological optimality scores of single nonoptimal signs

was nevertheless lower among the boys than girls (NeoQuan1).

Parental education had no influence on neonatal neurological examination, as reported also by Hadders-

Algra et al. (1986). Neither did Aylward et al. (1989a) find any influence of SES on neonatal neurological

examination at term age.

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7.5. ASSESSMENT AT 56 MONTHS OF AGE

7.5.1. ABNORMALITIES IN SUBSYSTEMS OF CNS, MILD NEUROLOGICAL

DYSFUNCTION (MND) AND DEVIANT MOTOR COMPETENCE (DMC)

Neonatal neurological deviancy was significantly associated with adverse neurological outcome at 56 months

of age, confirming the results of earlier studies (Dubowitz et al. 1984, Hadders-Algra et al. 1986, Allen and

Capute 1989, den Ouden et al. 1990, Molteno 1995, Lacey and Hendersson-Smart 1997). Many of these

infants, however, were considered to be neurologically normal at preschool age.

Voluntary movements are complex motor patterns, which are initiated and controlled by the cortical motor

areas in neural connection with the posterior parietal and prefrontal association cortices. Prefrontal motor

cortex and the basal ganglia are involved in planning movement sequences and in coordinating the function-

ing of the different sides of the body. The cerebellum improves the accuracy of movement by integrating

motor commands and sensory feedback. All these brain structures participate in motor learning and re-

cording. The thalamus acts as a relay nucleus between the cerebral cortex and the two subcortical systems

(DeLong 1993, Diamond 2000, Soinila 2001). An injury to any part of this interconnected neural system may

produce abnormal motor function. Particularly, the cerebral cortex, basal ganglia, thalamus, hippocampus,

brain stem and the cerebellum are reported to be sensitive to pre- and perinatal asphyxia or hypoxia (Volpe

1995, Yokochi 1997, Mercuri et al. 1999b).

The children, regarded neonatally as neurologically abnormal, even after exclusion of those with CP, had

gross motor, fine motor and facial-oral motor problems and strabismus 2-4 times more often than neonatally

neurologically normal children. Hand coordination was normal in most of the children, as observed also by

Huttenlocher et al. (1990) among 5-year-old children. Also Forslund and Bjerre (1989) and Lacey and

Henderson-Smart (1998) reported a high pass rate in the finger-nose test among 4-6-year-old children. In

addition, very few cases of mild hypotonia, which is difficult to assess (Amiel-Tison and Stewart 1989),

were found.

Because of the MND criteria of the present study, stressing performances in gross motor and fine motor tasks

and balance, most children who fulfilled the criteria, had a simple form of MND (Hadders-Algra et al. 1988a,

2000). Only 1.2% of the children had problems in at least three subsystem areas, and could be considered as

having complex MND, also called borderline CP (Hadders-Algra 2000).

The 33.8%/23.1% rate of MND among neonatally neurologically abnormal infants and about 15% of neuro-

logically normal non-hospitalized infants, defined quantitatively/qualitatively, was higher than that observed

in the Groningen study. 12.7% of the neonatally neurologically abnormal infants in that study had MND at

137

the age of 4 years, compared with 7.5% of the controls (Touwen et al. 1982). At six years the incidence rose

to 30% in the abnormal group. Among the preterm population, the rate of MND (according to Touwen’s test)

was 31% (Jongmans et al. 1997).

Tests of motor competence measure quantified tasks of motor skills, which require the child to voluntarily

control his/her neuromotor system, as distinguished from neurological responses, which are passively elicited

(Henderson 1993). Adequate motor competence is important because it affects the child’s performance in

everyday tasks and activities. The observed 9% incidences of deviant motor competence or clumsiness in

non-hospitalized groups are between those reported by others (Henderson and Hall 1982, Kadesjö and

Gillberg 1999).

MND and DMC did not always coexist; consequently a child with DMC could be normal in the neurological

qualitative examination, and a child with MND could have normal motor competence. This is in agreement

with the study of Jongmans et al. (1997) who concluded that the qualitative and quantitative measures of

neurological assessment examine different aspects of neurological functioning. Both are thus necessary for

getting an overall impression of a child’s neurological problems. Hadders-Algra (2000) recently presented

her hypothesis on the relationship between the theoretical concept of motor development and MND or

clumsiness (Developmental Coordination Disorder, DCD). She suggested that CP and the severe form of

MND (dysfunction of several clusters of CNS subsystem areas) were associated with a limited repertoire of

primary (sub)cortical neuronal networks. Abnormalities of simple MND and DCD, on the other hand, were

restricted to the level of secondary variability, i.e. selection of neuronal groups on the basis of afferent

information produced by behavior and experience.

Gestational age and birth-weight had a significant effect on the differences in neurological/neuromotor

performance observed between the three neonatally defined study groups, gestational age having a greater

effect. The problems in preterm and low birth-weight children increased with decreasing GA or BW, as

observed also by others (Marlow et al. 1989, Hall et al. 1995, Pinto-Martin et al. 1999). Strabismus was

common among preterm children even without cerebral palsy, but the greatest problems were observed in

fine motor function, especially among very preterm children who were significantly inferior to moderate

preterms, too. The poorer performance of nondisabled preterm children compared with full-term controls at

4-6 years of age has been found in gross motor function, balance, coordination and fine motor function also

in previous studies (Halsey et al. 1993, Pinto-Martin et al. 1999) assessed by Touwen’s method (Forslund

and Bjerre 1989, Largo et al. 1990a, Herrgård et al. 1993).

21% of the assessed children were preterms. However, one third of those with strabismus and problems in

fine motor and facial-oral motor function, and one fourth of those with gross motor problems, were preterm.

Furthermore, of the 3% proportion of assessed VPT children, about 6% of the problems in the same domains

138

were composed of this group. However, the majority of all the children with minor motor impairment were

full-terms.

7.5.2. HAND PREFERENCE

Mixed-handedness, occurring especially in boys and very preterm children, was associated more often with

neonatal morbidity and neurological abnormality than normality, and different neurodevelopmental problems

at preschool age. The proportion of mixed-handed children was greater than that of left-handed ones, whose

total number was small. The same trend was noted by Stewart et al (1989) among VLBW children at 4-5

years of age, and by Astbury et al (1990) among ELBW children.

The etiological factors behind hand preference are still unresolved. Recent evidence points to prenatal

development of behavioral lateralization in the human fetus (McCartney and Hepper 1999). Perinatal

complications have long been suggested to contribute to delayed or altered predisposition to right-

handedness (Bakan 1977, Schwartz 1988). Associations between non-right-handedness and preterm birth,

neurological impairment, visual problems, low IQ or impaired language development have also been reported

(Ross et al. 1987, Saigal et al. 1992, Powls et al. 1996). Levene et al. (1992) demonstrated a statistically

significant relationship between ultrasound appearance of germinal matrix-intraventricular hemorrhage with

prolonged flares and impairment of manual dexterity. In the present study, 23% of the 22 nondisabled

children with PIVH/cystic PVL in neonatal ultrasound were non-right-handed, compared with 7% non-right-

handed children in the whole study population. The numbers were too small for drawing firm conclusions,

but the association of non-right-handedness with several areas of brain function disturbances suggests injury

to the dominant left hemisphere.

7.5.3. BACKGROUND FACTORS OF SUBSYSTEMS OF CNS, MILD NEUROLOGICAL

DYSFUNCTION (MND) AND DEVIANT MOTOR COMPETENCE (DMC)

Abnormal neonatal cranial ultrasound, ventilatory treatment and male gender were the leading predictors of

mildly impaired neurological or neuromotor function at 56 months of age in the present study; only few

obstetric factors were significant, confirming the results of earlier studies (Drillien 1980, Ounsted et al. 1986,

Hadders-Algra et al. 1986, Lindahl et al. 1988a, den Ouden et al. 1990, Fawer and Calame 1991, Levene et

al. 1992, Herrgård et al. 1993, Jongmans et al. 1993, Fazzi et al. 1994, Lacey and Hendersson-Smart 1998,

Pinto-Martin et al. 1999). Moreover, differences in the background factors of the eight subsystems of CNS,

MND and DMC were observed.

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Although it was not possible to include neonatal cranial ultrasound into the present study design, it was done

to 86% of the very preterm, 35% of the moderately preterm, and 13% of the full-term infants. Abnormal find-

ings in cranial ultrasound, especially when mild (Grades 1-2) changes were included, predicted poor perfor-

mance in gross and facial-oral motor function, abnormal muscle tone, MND and DMC, as also observed by

others (Fawer and Calame 1991, Levene et al. 1992, Jongmans et al. 1993, Fazzi et al. 1994). Several studies

have shown that parenchymal involvement of hemorrhage or cystic PVL carries a risk for cerebral palsy (de

Vries et al. 1985, Weindling et al. 1985, Cooke et al. 1987, Fawer et al. 1987, Graham et al. 1987, Fazzi et al.

1994). Milder forms of the PVL spectrum (echodensities, prolonged flares) or small focal PVL changes have

been reported to associate with minor neurological abnormalities (Fawer and Calame 1991, Levene et al.

1992, Jongmans et al. 1993). Although ischemic flares were not possible to be observed at the time when the

present study series were examined, a significant relationship between abnormal ultrasound appearance and

minor neurological/neuromotor abnormalities suggests an organic basis for these mild impairments.

Impaired gross motor function (without cerebral palsy), was predicted also by acute fetal distress during

delivery (detected as pathologic fetal heart rate and fetal acidosis), which is an important cause of hypoten-

sion and diminished brain perfusion, and known to be associated with ischemic or hemorrhagic brain lesions

(Volpe 1995). Damage in the vascular boundary zones, watershed areas, in the cerebral cortex and subcorti-

cal white matter or periventricular white matter among full-term and preterm infants is a known etiology of

major motor impairment after hypoxic-ischemic injury (Volpe 1995).

Being born outside of neonatal intensive care facilities associated with a 2.2-fold risk for neonatal neuro-

logical abnormality, but also with a 2.5-fold risk for poor gross motor function. An increased risk for peri-

intraventricular hemorrhage has been connected with outborn status (Finer et al. 1983, Ichord 1992, Volpe

1995). One third of all neonates treated in NICU had been transferred from other hospitals. 21% of them

were preterm infants and 7.8% very preterm infants, all of whom had PIVH in early cranial ultrasound. 11%

of outborn infants compared with 1% of inborn infants had 5-min Apgar scores 3 or less, and 18% vs. 2%,

respectively, had seizures neonatally. 7.6% of outborn compared with 1.6% inborn infants later had cerebral

palsy. Furthermore, 21% vs. 8% had minor gross motor problems. Transportation of a pregnant mother,

instead of a resuscitated newborn infant, to the perinatal center seems to bear a lower risk for the future out-

come of the child. One aim of the original study was to examine the benefit of centralizing the care of high-

risk pregnant mothers. In Finland this had been in practice, but in Germany, it was just being planned. The

results of the present study confirm the importance of centralizing risk deliveries to hospitals that have facili-

ties for neonatal intensive care.

Differing distinctly from other subsystems, poor fine motor function was predicted by recurrent neonatal

apnea and/or bradycardia. Apneic episodes may lead to reduced systemic blood pressure and diminished

cerebral blood flow (Perlman and Volpe 1985), cerebral deoxygenation (Urlesberger et al. 1999) and an

140

increased risk (3-4-fold) for ischemic brain lesions among preterm infants (Sinha et al. 1985, deVries et al.

1988). In the present study, 73% of the infants with apneic episodes were preterms, and about a half of them

very preterm infants that were most impaired of all in the fine motor domain. The result parallels earlier

reports describing fine motor problems to be more common among preterm children than full-term controls

(Elliman et al. 1991, Herrgård et al. 1993), or to be associated with extreme prematurity, RDS and long

ventilatory treatment (Goyen et al. 1998) or ischemic brain lesions (Skranes et al. 1997).

Still at 56 months of age, ventilatory treatment emerged as a risk for difficulties in facial-oral motor function

and hand coordination, strabismus and MND. Pinto-Martin et al. (1999) proposed that namely the duration of

ventilatory treatment correlated significantly with motor performance at later ages. Ventilatory treatment is

often associated with severe neonatal morbidity and several other problems such as hemodynamic, fluid-

balance, metabolic and nutritional problems. Katz-Salamon et al. (1997) demonstrated an adverse effect of

prolonged ventilatory assistance on complex motor patterns of rooting, sucking and swallowing. They

suggested that injury to the nasopharynx and trachea caused by long intubation might disturb the develop-

ment of normal oral motor function, thus predisposing infants to feeding problems and undernutrition (Lucas

et al. 1990, Adamkin 1998) at a time of most rapid brain myelination (Volpe 1995). Prolonged ventilatory

treatment has also been reported to be a risk for ophthalmologic abnormalities (Herrgård 1993). Thus for, it

has not been possible to prevent entirely the damaging effect of prolonged oxygen administration on imma-

ture retinal vessels, especially among tiny preterms.

The background factors of MND and DMC were somewhat different, suggesting at least partly different

neurological entities and possibly different etiologies. The need for mechanical ventilation due to any

respiratory problems, suggesting acute compromise of an infant, and also prematurity, was a risk factor for

MND, but not for DMC, as also reported by Lindahl et al. (1988a). In linear regression, low birth-weight

emerged as a significant independent risk factor for DMC, and in univariate analysis DMC was significantly

associated with SGA (p=0.0435), but this association was not found for MND. Furthermore, low education

of the father (stressing perhaps the genetic aspect of social influence), increased the risk for DMC). The

greater influence of environmental and psychosocial factors on DMC, as compared with MND, was sup-

ported by the finding (in linear regression analysis) that the mother’s irregular prenatal care was also a

significant independent risk factor for DMC. Pregnant women who had participated seldom or never in

prenatal care, were reported to be mostly single, less educated, and younger than those who participated

regularly (Viisainen et al. 1998). Indeed, environmental disadvantage with limited stimulus has been sug-

gested to be associated with symptoms of DCD without MND (Hadders-Algra 2000).

Several authors have observed the relationship between subtle neurological/neuromotor problems and mild

PVL or hemorrhagic changes detected in neonatal ultrasound in preterm populations (Fawer and Calame

1991, Levene et al. 1992, Jongmans et al. 1997, Pinto-Martin et al. 1999). Stronger morphological evidence

141

for brain lesions behind minor neurological abnormalities has been brought out in MRI studies done at later

ages. Skranes et al. (1997) observed significantly poorer performance in gross motor function among non-

disabled 6-year-old VLBW children with gliosis in the centrum semiovale in brain MRI, compared with

those without such findings. The children with gliosis, including periventricular occipital white matter, had

problems also in balance and fine motor function, as a result of damage in both pyramidal and visual path-

ways, according to their speculation. They did not examine facial-oral motor function, but the close anatomi-

cal location of the motor pathways of the face and the hand could explain coexisting problems of facial-oral

motor function. Visual impairments, ranging from strabismus to cerebral blindness, are commonly observed

in premature born and full-term children, and especially in children with cerebral palsy after hemorrhagic-

ischemic brain lesions (Graham et al. 1987, Scher et al. 1989, Fazzi et al. 1994, Eken et al. 1995, van Hof-

van Duin et al. 1998). Optic radiations are often involved in PVL (Eken et al. 1995, Cioni et al. 2000), and

visual impairments are reported to be associated with motor signs and PVL (Scher et al 1989, Gibson et al

1990, Eken et al. 1995, Jakobson et al. 1996, Krägeloh-Mann et al. 1999).

The superiority of girls over boys in neurological/neuromotor performance has been observed in the present,

and in numerous other studies among 4-9-year-old risk children (Neligan et al. 1976, Drillien 1980, Ounsted

et al. 1986, Ahonen 1990, Largo et al. 1990a, Elliman et al. 1991, Vähä-Eskeli 1992, Herrgård et al. 1993,

Hulkko et al. 1996, Pinto-Martin et al. 1999). This suggests that motor maturation of preschool boys lags

behind that of girls, and boys would thus require norms of their own. If the difference, instead, results from

brain damage, it seems obvious that, taking into account neonatal morbidity, which did not differ between

boys and girls, the boys are more fragile for risk factors, or male gender itself bears a developmental risk.


The neonatally neurologically abnormal children had problems in visual-motor function about four times

more often than `healthy´ newborns, and two times more often than hospitalized, but neonatally neurologi-

cally normal children.

Problems in visual-motor function have often been reported among preterm children, especially among the

tiniest ones (Klein et al. 1985, Calame et al. 1986, Saigal et al. 1990, Teplin et al. 1991, Halsey et al. 1993,

Damman et al. 1996, Goyen et al. 1998, Luoma et al. 1998, Olsen et al. 1998). Also in the present study

decreasing gestational age and birth-weight, in addition to male gender, were associated with problems in

visual-motor integration. 11% of the very preterm children, 4.6% of the moderately preterm, and 3.6% of the

full-term children with normal cognitive capacity and without cerebral palsy had visual-motor scores less

than -2SD below the mean of the control group.

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Normal visual-motor integration requires complex brain function for integrating visual stimuli and motor

performance. Inadequate voluntary control of the hand, poor precision of tactile-kinesthetic perception and

memory, and poor ability to shift movements fluently have been described as deficiencies of visuomotor

dysfunction (Luoma et al. 1998). The relationship between visual-perceptual impairment and ischemic PVL

lesions, visualized in cerebral MRI as a reduced amount of peritrigonal white matter reaching the parietal

lobe, and ventricular enlargement, have been reported in preterm children with or without spastic diplegia

(Koeda et al. 1992, Goto et al. 1994, Ito et al. 1996, Olsen et al. 1998). Posterior peritrigonal regions include

optic radiations and association fibers between the parietal and occipital lobes and other brain structures.

Also early damage to the thalamus has been related to visual-perceptual impairment (van den Hout et al.

2000). Goto et al. (1994) demonstrated the relationship between reduced parietal white matter and spatial

and visual deficits among preterm children. They speculated on the role of visual, auditory and somesthetic

association fibers in the development of visual perceptual disorders. The relationship between visual-motor

problems, poor fine motor function, and deficiency in voluntary eye movements observed among non-

disabled children in the present study may be explained to result from injury to these interacting fibers.

7.5.5. COGNITIVE AND LANGUAGE TESTS

Neonatal neurological abnormality was associated also with lowered cognitive ability and impaired language

comprehension at pre-school age in accordance with previous results (Hadders-Algra et al. 1986, Lindahl et

al. 1988a). The means of CMM were 7/4 points lower, and the proportions of poorest performances signifi-

cantly higher (9.7%/4.7% vs. 0.6%/0.7%) among neurologically abnormal quantitative/qualitative neonatal

groups, compared with those of the non-hospitalized groups. There were only three children with perfor-

mances below -3SD in the neurologically normal non-hospitalized groups, compared with higher numbers in

the hospitalized groups. However, the differences between the three study groups were smaller in perfor-

mances above –3SD but below -1SD, and they did not differ at all between the neonatally neurologically

normal groups. The findings of the present study indicate that neonatal morbidity has a greater effect on

marked than on mild developmental delay, which, instead, has been shown to be more influenced by, for

instance, genetic and environmental factors (Paneth and Stark 1983, Aicardi 1992, Yeargin-Allsop et al.

1997).

3.1% and 5.8% of all the examined children performed poorly (below -2SD) in the tests of verbal compe-

tence and language comprehension, respectively. Comparison with other studies is difficult due to differ-

ences in the assessment methods used, but a 4-7% rate of expressive or receptive language disorder, reported

among preschool children (Silva et al. 1983, Weindrich et al. 1998), are in accordance with the prevalences

of the present study.

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Boys were superior to girls in verbal competence (AWST), which at 56 months was the only test in which

boys were more skillful than girls. Perhaps the contents of the test favored boys.

The negative effect of low gestational age and birth-weight on performances in CMM is in line with other

studies (Aylward et al. 1989b, Scottish Low Birthweight Study Group 1992b, Johnsson et al. 1993). In the

present study, the mean score of the very preterm children was six points lower than that of the full-term

children. It was in the normal range though significantly lower than in the full-terms. Several previous

studies have been pointed out that although the means of DQ/IQ scores of all low birth-weight children differ

from those of control children, both scores are within average range, however (Drillien 1980, Hirata et al.

1983, LLoyd et al. 1984, Michelsson et al. 1984, Aylward et al. 1989b, Marlow et al. 1989, Abel-Smith and

Knight-Jones 1990, Ornstein et al. 1991, Luoma et al. 1998, Olsen et al. 1998). Gross IQ measurements

therefore do not give the correct picture of the difficulties or specific deficits among risk children, and cog-

nitive subareas such as language, VMI, perception and memory ought to be better defined (Aylward et al.

1989b). Problems in several developmental domains among neonatally neurologically abnormal children, and

very preterm children, noted in the present study, confirm the requirements of comprehensive assessment.

The effect of parental education on cognitive ability and language competence was observed in the present

study. The influence of environmental factors has been reported in several earlier studies (Drillien et al.

1980, Escalona et al. 1982, Lindahl et al. 1988a, Aylward et al. 1989b, Leonard et al. 1990, Fawer and

Calame 1991, Damman et al. 1996).

7.5.6. MAJOR IMPAIRMENTS/DISABILITIES

Higher proportions of major impairments were observed in neonatally neurologically abnormal children

compared with neonatally neurologically normal children, very preterm children compared with moderately

preterm and full-term children, and boys compared with girls; this is in agreement with previous results

(Drillien 1980, Touwen et al 1982, Rantakallio and von Wendt 1985, Teplin et al 1991, The Scottish Low

Birthweight Study Group 1992a, Stanley et al 1993, Roeleveld et al 1997).

Among the 28/27 children who were responsible for the proportion of major impairments among `healthy´

newborns by the quantitative/qualitative classification method, respectively, one child had deafness of

probably hereditary origin, and the others had CMM scores more than 2SD below the mean of the original

control population. No child had cerebral palsy. On the other hand, the neonatally neurologically normal

hospitalized groups consisted of children with cerebral palsy and severe mental retardation. The findings

suggest that any kind of neonatal morbidity may have great impact on the integrity of the central nervous

system, even though it cannot be detected from the neonatal neurological behavior or verified before matura-

144

tion proceeds.

The rates of major impairments among neurologically abnormal neonates, 27.5%/17.1% by quantita-

tive/qualitative method, respectively, parallel those of Gross et al. (1978) and Molteno et al. (1995), observed

at 1-5 years of age. The proportions in the present study are higher, compared with the 10% rate of major

impairments observed by Touwen et al. (1980) in neonatally neurologically abnormal children at 4 years.

Their control group was free of cerebral palsy and severe mental retardation, as was the non-hospitalized

group in the present study.

The rates of major impairment among neonatally neurologically abnormal children and very preterm children

in the present study are exceeded by the rate reported by Allen and Capute (1989) in high-risk preterm

children (38% CP). Also Dubowitz et al. (1984) reported the rate of 65% among preterm infants less than 35

gestational age at 1 year of age, and den Ouden et al. reported (1990) the rate of 50% among the neonatally

neurologically abnormal very preterm and/or VLBW children at 2 years of age. However, the above-

mentioned studies concerned selected high-risk preterm populations born slightly earlier than the infants in

the present study.

26 (1.3%) of all the neonatally neurologically examined 2039 children in the present study had cerebral

palsy. One child with congenital hydrocephalus and later hemiplegia was excluded. During the study period,

one preterm diplegic child, whose mother resided in the region, was born outside the region. Furthermore, six

children with hemiplegia, who did not fulfill the inclusion criteria neonatally, are missing from the figures.

The population incidence for CP, after including these children, was 2.2/1000 live births (or neonatal

survivors) (Niemelä A, oral communication). This is slightly less than that reported by Hagberg et al. (1993)

in 1983-1986 in Sweden, or the prevalence rate of 2.5/1000 live births reported by Riikonen et al. (1989)

during 1978-1982 in western Finland. Incidence per survivors was almost the same (2.1/1000) as observed

by Pharoah et al. (1998) in 1984-1989 in England and in Scotland. The rate of CP was 0.5% for full-terms,

4.2% for preterms, and 18.2% for very preterms, in line with previous studies (Powell et al. 1986, Marlow et

al. 1987, Herrgård et al. 1993).

The proportion of CP was greatest in the neonatally neurologically abnormal groups (12.8%/6.4%, quantita-

tive/qualitative, respectively) compared with neonatally neurologically normal hospitalized groups

(1.1%/0.9%). Thus 46%/62% of all CP children could be picked out in the neonatal neurological examina-

tion at term age by the quantitative/qualitative classification method, respectively. The proportion was not

greater in a large study series from the 1950s consisting of about 40,000 mainly full-term infants, where 23%

of 128 children with moderate or severe CP at seven years of age had been considered definitely abnormal as

neonates (Nelson and Ellenberg 1979). 69% of the children with CP in the present study were preterm, and

about half of them were abnormal in neonatal neurological examination at or near term age. In smaller

145

hospital-based series, Allen and Capute (1989) found 80% of the high-risk preterm infants with CP at one

year of age to be abnormal in the neonatal neurological examination. Dubowitz et al. (1984) were able to

pick out all infants with evidence of CP at one year of age by means of the term neonatal neurological

examination of preterm infants, and only two of the 10 infants with dystonia had been normal in the neuro-

logical examination.

The children with CP of grades 3-4 (9/15 children by both classification methods) were most often consid-

ered as neonatally neurologically abnormal. Half (4/8) of the children with diplegia and 7/11 of the children

with tetraplegia were abnormal in the neonatal neurological examination by both classification methods. 6/9

of the children with later CP, who were missed by both methods in the neonatal neurological examination,

were moderately preterm infants (32 to 36 weeks gestational age). One third of the children with the most

severe form of cerebral palsy were considered normal in the neonatal neurological examination, both clini-

cally and by using optimality scores. They had neither `classical major neurological signs´ nor several single

non-optimal signs. The qualitative method picked out 4/6 of the hemiplegic children, but all of them had

neonatal neurological optimality scores within the normal range. Three of them were definitely hypotonic,

and one had absent visual tracking in the neonatal neurological examination. No children with later hemiple-

gia had definite asymmetry in the neonatal neurological examination. Also Bouza et al. (1994) found it

difficult to demonstrate signs of hemiplegia in full-term infants in the neonatal neurological examination,

even though unilateral hemispheric lesions had been detected in brain imaging soon after birth. 2/5 of their

hemiplegic infants were hypotonic as newborns.

7.6. INTERRELATIONSHIP BETWEEN THE OUTCOME MEASURES AND IMPLICATIONS

OF ABNORMAL PRESCHOOL EXAMINATION

Abnormalities in gross and fine motor function, MND and DMC were most significantly associated with

poor visual-motor function and lowered cognitive ability. Strabismus was negatively associated with VMI

scores. Facial-oral motor dysfunction was associated with poor performance in expressive language, reflect-

ing dyspraxia. These associations have been observed also by others (Ford et al. 1989, Marlow et al. 1989,

Huttenlocher et al. 1990, Jongmans et al. 1997, Goyen et al. 1998, Trauner et al. 2000).

Diamond (2000) has underlined the close interrelation of motor and cognitive development. The cerebellum

and the caudate nucleus of the basal ganglia, which are important for controlling movements and for novel

motor and cognitive learning, and the dorsolateral prefrontal cortex, which is responsible for the most

complex cognitive functions and working memory, are interconnected parts of a neural system; they have an

important role both in motor and in cognitive functions (Diamond 2000). This has been demonstrated by co-

146

activation of the prefrontal cortex and the cerebellum in functional MRI during the performance of cognitive

tasks (Paulesu 1995). It is also evidenced by a reduction in the size of the cerebellum or by reduced caudate

activity in ADHD children (Lou et al. 1990, Berquin et al. 1998, Mostofsky et al. 1998), or by cerebellar

atrophy observed in MRI among very preterm children with mental subnormality (Krägeloh-Mann et al

1999).

The major goal of preschool developmental screening is to find sufficiently early the children with coexisting

impairments in different neurodevelopmental domains, because co-morbidity, such as DAMP, is known to

expose a child to learning problems at school. The present study supports the accumulating tendency of

various neurodevelopmental problems, as 12.5% of the children had multiple minor impairments in different

neurodevelopmental areas. Behavioral or attentional deficits were not included in the present analysis.

However, also isolated motor-perceptual difficulties can cause considerable learning difficulties especially

during the early school years (Gillberg and Rasmussen 2001). 5.6% of the children in the present study had

DMC associated with VMI and language problems, fulfilling partially the criteria of DAMP dysfunction.

This incidence corresponded to that reported in Sweden (Gillberg and Rasmussen 1982, Landgren et al.

1996).

According to previous studies, minor neurodevelopmental abnormalities found at 5 years of age were still

observable in 85% of the children at 8-9 years of age, or they were associated with minor neuromotor-

/neurological deviancy in 43-68%, or they were associated with school problems in 46% of children (Clayes

et al. 1984, Lindahl et al. 1988b). In half of the children with motor clumsiness, observed at the age of five,

the clumsiness persisted until 11 years of age (Ahonen 1990). Poor neurological performance or motor skills

at 5-6 years were the strongest predictors of school problems at 8-9 years among high-risk or VLBW children

(Lindahl et al. 1988b, Marlow et al. 1989). As regards class placement at age seven, 86% of these children

were either one grade below normal or in a special class (Huttenlocher et al. 1990). 74% of the clumsy chil-

dren had difficulties in at least one of the areas of reading, writing or arithmetic, compared with 26% of the

controls. Clumsy children had also more behavioral problems, such as inattentiveness, passivity, immaturity,

low frustration threshold, as well as difficulties in peer relations (Ahonen 1990). Problems in visual/auditory

perception, visual-motor and fine-motor function, speech and language comprehension at 4-5 years of age

predicted problems in language, cognitive, reading and mathematical skills at school at 6-9 years (Clayes et

al. 1984, Lindahl et al. 1988b, Bloch-Petersen et al. 1994). Moreover, 58% of 8-year-old preterm children

with MND had problems in learning compared with 13% of the neurologically normal preterms (Olsen et al.

1998).

Taking into account the highly significant associations between MND or DMC, on the one hand, and poor

performance in visual-motor, language or cognitive tests, on the other hand, found in the present as well as

earlier studies, it appears that many of these children with neurological or neuromotor problems, especially

147

very preterm and male children, will presumably have motor and/or specific learning problems at early

school age. It is therefore crucial to identify at preschool age those with multiple problems by examining

neurological and neuromotor performance, visual-motor function, speech and language skills, and other areas

of cognition of risk children. These problems might be alleviated by means of early rehabilitation.

7.7. PREDICTIVE VALIDITY OF THE NEONATAL NEUROLOGICAL EXAMINATION

Sensitivity refers to the ability of a test instrument to identify correctly those who will be abnormal, and

specificity, correspondingly, to identify those who will be normal in follow-up. High sensitivity is connected

with few false negatives, and high specificity with few false positives. The positive predictive value (PPV) of

a test is the proportion of true positives among all those with positive results. (Low PPV means that many

normal children are classified as abnormal according to a test). Negative predictive value is the proportion of

true negatives among all those with negative results. The prevalence of a disorder influences the predictive

values but not sensitivity nor specificity. The optimality of predictive values depends also on the cut-off

scores of a test instrument.

Sensitivity in the present study was very low for all outcome measures by both classification methods,

suggesting the presence of false negatives. Specificity, on the other hand, was high, indicating few false

positives. The tendency of a term neonatal neurological examination to miss children who later will be ab-

normal has been found also by other authors. Ferrari et al. (1990) observed the neurological assessment of

some preterm infants with brain lesions to become falsely negative around term age, mainly because of

normal resistance to passive movements. Term age as a transitional period from hypotonia to hypertonia

among preterm infants has been reported by others, as well as difficulty of identification especially in

symmetrical cases (Dubowitz and Dubowitz 1988, Stewart et al. 1988). Furthermore, Cioni et al. (1997a)

have demonstrated improved sensitivity of consecutive neurological examinations after term age among

high-risk preterm infants. In the present study, which was based on the results of a single neurological

examination at term age, 10/14 and 8/10 of the missed CP children were preterms by the quantitative and

qualitative methods, respectively. The problem of false negatives with a sensitivity of 21% for later death

and major handicaps was reported also in a large nationwide follow-up study of high- and low-risk preterm

infants (den Ouden et al. 1990). Higher specificity compared with sensitivity for one-year outcome was also

observed by Stewart et al. (1988) and Molteno et al. (1995) among high-risk full-term or preterm children,

and also for nine-year outcome in large hospital series by Hadders-Algra et al. (1988a). Among high-risk

populations with neonatal neurological abnormality, up to 52-57% higher sensitivities for various outcome

measures at 2-6 years of age have been reported (Majnemer and Rosenblatt 1995, Cioni et al. 1997a).

Because the sensitivity and the specificity of a test consist of a continuum depending on a cut-off point, the

148

cut-off value of the optimality score in the quantitative method could have been higher. Sensitivities and

specificities were calculated also using other cut-off values. It was possible to increase sensitivity, losing at

the same time some specificity (and increasing also false positives), but the increase was not so meaningful

that the screening practice would have essentially benefited from it. A cut-off point for abnormality, used in

the present study, was defined according to an earlier study (Stave and Ruvalo 1980), where namely the num-

ber of false positives was aimed to be minimized. An optimal balance between sensitivity and specificity, i.e.

the balance between missing a child with abnormal outcome, or mislabeling a normal child as abnormal, is

however, crucial in clinical work. High specificity, observed in the present study, was clinically important,

because proportionally few normal children were labeled as abnormal.

The positive predictive values were also low, but the negative predictive values were high, especially for

major impairments, which meant that most of the neonatally neurologically normal neonates were free of

major impairments. The positive (39-46%) and the negative (88-95%) predictive values for CP in the present

study are comparable with those reported by Allen and Capute (1989). Also the trend that normal neonatal

neurological examination results predict better normal outcome, than abnormal examination results predict

abnormal outcome, was in accordance with previous studies (Touwen et al. 1980, Dubowitz et al. 1984,

Hadders-Algra et al. 1988a, Stewart et al. 1988, Allen and Capute 1989, Majnemer and Rosenblatt 1995). It

is worth noting, however, that the positive and negative predictive values are influenced by the prevalence of

abnormalities (a disorder in the population). This explains, on the one hand, that the positive predictive

values in the present study were higher for minor than for major impairments and, on the other hand, that

among NICU high-risk populations the positive predictive values will be higher than in regional population

such as ours.

7.8. USEFULNESS OF THE TWO NEONATAL NEUROLOGICAL

CLASSIFICATION METHODS

The two comparison groups by the two neonatal classification methods turned out to be different from each

other, in respect to both perinatal risk and outcome. Furthermore, during the statistical analysis, the grouping

variable (NeoQuan, NeoQual) proved to be by nature ranking order, picking out different groups of infants

with a linearly increasing trend of risk factors and poor performance with increasing neonatal morbidity and

neurological abnormality. In other words, neonatal general morbidity increased the risk for adverse outcome,

especially when associated with neurological abnormality.

As to the quantitative method, the impact of each individual response, according to the optimality concept,

was as important. However, several non-optimal responses were required for global `abnormality´. On the

other hand, when defining global `abnormality´, some non-optimal major neurological signs may have been

149

underestimated, in spite of the fact, pointed out by Prechtl (1980), that the optimality score is self-weighting,

i.e., non-optimal performance in one task is often followed by non-optimal performance in several other

tasks. It may also be speculated that more severe brain lesions produce symptoms from several subsystems of

CNS. The qualitative method, instead, was sensitive for certain individual responses (e.g. cranial nerve

signs), which by themselves could classify an infant into an abnormal group.

The qualitative method consequently picked out proportionally more full-term infants with various levels of

severity of neurological morbidity. On the other hand, the quantitative method picked out proportionally

more preterm infants who were, during the neonatal neurological examination at term or near term age,

overcoming their acute illness and showing sequalae of brain injury. Up to 90% of periventricular-

intraventricular hemorrhage occurs during the first three days of life (Trounce et al. 1986). Instead, ischemic

lesions develop over several weeks, and the clinical signs reveal the evolution of ischemic injury (Ichord

1992, Mercuri and Dubowitz 1999). Consequently, though the neonatal neurological classification was based

on the same single examination, the neonatal neurological non-optimality profiles of the abnormal quantita-

tive and qualitative groups showed some differences. The neonatal neurological profile of the quantitative

abnormal group was modified by the differences observed in the neurological behavior between preterm and

full-term infants, resembling more that of preterms, whereas the profile of the qualitative abnormal group

paralleled that of full-terms.

The background factors of the two neonatally defined abnormal groups were also different. Severe morbid-

ity, known to associate with acute intrapartum hypoxia and preterm birth, emerged as a risk for quantitative

neonatal neurological abnormality, or significantly differentiated the quantitatively abnormal group from the

neurologically normal groups. On the other hand, the prenatal problems and asphyxia-related factors mainly

observed in full-term infants increased the risk, or differentiated the qualitative abnormal group from neuro-

logically normal groups.

In the follow-up assessment at 56 months of age, the developmental profiles of minor impairments of the

children in the neonatally neurologically abnormal groups by the two methods were different. The neurologi-

cal problems in the quantitative abnormal group were related to gross motor function and strabismus,

whereas the qualitative abnormal group showed more dyspractic problems, e.g. problems in fine and facial-

oral motor function. The developmental profile of the quantitative abnormal group included disturbances in

visual-motor integration, language comprehension, and cognitive ability, while that of the qualitative abnor-

mal group displayed disturbances in visual-motor function and cognitive ability.

Neurological morbidity constitutes the continuum from mild to severe impairments (Amiel-Tison et al. 1998,

Hadders-Algra 2000). Mild motor problems involving the lower more than the upper extremities, observed in

the quantitative abnormal group in the present study, followed the pattern described by Volpe (1995, 1997)

150

for major motor impairments after periventricular leucomalacia among preterm infants. Because the lesion is

typically located in the periventricular region, the more medially located fibers of the lower extremities, com-

pared to those of the upper extremities, descending from the motor cortex are destroyed first. Morphological

evidence of ischemic brain injury as an etiological factor of minor neurological, visual, visual-motor or

cognitive deficits has been obtained from numerous MRI studies (Gibson et al. 1990, Koeda and Takeshita

1992, Goto et al. 1994, Eken et al. 1995, Skranes et al. 1997, Olsen et al. 1998, Krägeloh-Mann et al. 1999).

Moreover, in the white matter lesions, an altered structural differentiation and functional maturation of

partially isolated gray matter will occur because of the destruction of axonic fibers, and consequently the

postinjury neocortical dysplasia play a role in the pathogenesis of adverse neurological outcome (Marin-

Padilla 1997).

Volpe (1995) described major motor signs and associated developmental deficits after ischemic injury also in

full-term infants. Parasagittal cerebral injury and more diffuse selective neuronal necrosis are manifestations

of hypoxic-ischemic injury (Hill and Volpe 1982, Volpe 1995). Parasagittaly located lesions at watershed

border zones cause involvement of the upper extremities more than of the lower extremities. Visual-

perceptual deficits were assumed to arise if the lesions reach associative fibers in posterior-parietal-temporal

regions.

Ischemic brain injury is assumed to be the main etiological factor of minor neurological impairments in the

neonatally defined neurologically abnormal quantitative and qualitative groups. This view takes into account

the neonatal background factors and the similar neurological impairment profiles as those described earlier

for major motor impairments in preterm and asphyctic full-term infants. In future, MRI studies will probably

be able to determine the more precise relationship between neuroimaging correlates and the whole spectrum

of mild forms of adverse neurodevelopmental profiles after ischemic brain injury in preterm and full-term

infants.

Because the two methods used in the present study were different in selecting neurologically abnormal

infants, it is not possible or even relevant to compare the superiority of the methods. This was pointed out

also in estimating predictability, which was about the same by both methods. The most severe neonatal

neurological morbidity with a poor prognosis was best screenable by both methods, and the neonatal neuro-

logical normality with a good prognosis was screenable with great reliability. However, neither of the

methods was valid in predicting the outcome of neonates with various signs in between the two extremes.

Neither was any notable increase in predictability gained, when the children who were neonatally neurologi-

cally abnormal by both methods were evaluated. One reason for the difficulty in predicting the outcome is

brain plasticity. Corticospinal axons, which are characteristically disrupted in PVL, are described to retain a

high degree of plasticity during axonal growth and synaptic development (Eyre et al. 2000). Also substituting

branching from undamaged motor cortex has been described (Farmer et al. 1991). On the other hand, taking

151

into account the requirements of neonatal neurological examination, it is possible that all the abnormal

neurological findings were not real signs of brain injury.

Based on the results of the present study, it can be said that neonatal neurological examination ought to be

comprehensive, and that final conclusions cannot be drawn on the basis of major signs only. Because a single

neonatal neurological examination at term age is not a sufficient tool for predicting the future outcome of any

individual infant, the abnormal neurological condition should be controlled later on. Cioni et al. (1997a)

found an examination at two months of age to predict later outcome better than a neonatal examination. Also

video recording of general movements at term age was found to predict major disabilities better than neuro-

logical examination (Cioni et al. 1997b). Recent neuroimaging and neurophysiological studies have been

promising in predicting minor impairments such as motor, visual-motor and visuospatial functions (Jong-

mans et al. 1993, Majnemer and Rosenblatt 1995, Olsen et al. 1998).

152

8. CONCLUSIONS

1. The quantitative and qualitative neurological classification methods selected neonatally neurologically

different abnormal infants in respect to pre-perinatal risk and gestational age. The quantitative method

included more preterm infants with several non-optimal neurological signs, whereas the qualitative method

included more full-term infants who displayed fewer, but clinically significant, non-optimal signs.

Preterm infants, particularly the smallest ones, differed from full-term infants in their neurological behavior

at term conceptional age, depending on the severity of the medical complications.

2. Different profiles of minor neurological impairments were found to associate with the neonatally neurolo-

gically abnormal quantitative and qualitative groups at 56 months of age. These profiles resembled those

described earlier in the literature in preterm and full-term asphyxiated infants with respect to major motor

impairments. Ischemic pre-perinatal brain injury is assumed to be a main etiological factor of minor neuro-

logical impairments in the neonatally defined neurologically abnormal quantitative and qualitative groups. It

appears that there is a similar but milder spectrum in the continuum of neurological impairments after

ischemic brain injury for preterm and full-term children.

MND as a qualitative measure and DMC as a quantitative measure of minor neurological abnormality at 56

months of age did not overlap entirely. Consequently, MND and DMC are presumed to describe different

aspects of minor neurological disorders, and are thus essential for the assessment of the whole spectrum of

minor neurological morbidity.

3. Male gender, prematurity- and asphyxia-related obstetric and neonatal morbidity were most important risk

factors for neonatal and 56 months’ neurological abnormalities.

At 56 months of age, very preterm children compared with full-term children, and boys compared with girls,

had significantly more often minor neurological abnormalities, especially poor fine motor function.

4. MND and DMC were significantly associated with deviancy in visual-motor function, and cognitive and

language skills. Consequently, according to the present study, MND and DMC can be considered to be

concomitant to learning problems. Of all subsystems of CNS, fine motor function correlated best with

cognitive capacity and language skills.

5. Neonatal neurological abnormality, significantly more often than neonatal neurological normality, was

associated with MND, DMC, CP and problems in visual-motor integration, and poorer performance in

cognitive ability and language comprehension tests, and with major and minor impairments at preschool age.

153

Among the neonatal neurological normal infants, early neonatal morbidity increased the probability of future

developmental problems.

An abnormal result in a single age-specific neonatal neurological examination at term postmenstrual age did

not predict reliably the future development of an individual child. Instead, a normal result in an infant who

had no neonatal morbidity risk factors predicted development without major impairments with high certainty.

6. In order not to overestimate the performance of high-risk children, a randomly selected control group is a

prerequisite especially in neurological studies, in which the subjectivity of an examiner influences the

evaluation.

154

9. ACKNOWLEDGEMENTS

The present study was carried out, as a part of bi-national Bavarian-Finnish regional study, in the Uusimaa

county at the Department of Pediatrics (presently the Hospital for Children and Adolescents), Departments I

and II of Obstetrics and Gynecology, University of Helsinki, at the State Maternity Hospital, and at Jorvi,

Porvoo and Tammisaari District Hospitals.

I am greatly indebted to Professor Kalle Österlund, the former head of neonatology at the Department of

Obstetrics and Gynecology, University of Helsinki, my supervisor and the leader of the Finnish project. He

introduced the study project to me, and suggested the subject for my dissertation. His kind support, warm

encouragement and understanding are appreciated.

I express my deepest and warmest thanks to Elina Liukkonen, M.D., Ph.D., my other supervisor, for her

enormous patience in reading thoroughly and revising my manuscript over and over again. Her expert

guidance, indispensable help and optimistic encouragement during all these years enabled me to tackle the

challenges and ensured the successful completion of my thesis.

My respectful gratitude is due to Professor Niilo Hallman, former head of the Department I of Pediatrics,

University of Helsinki, who skillfully took care of the administrative matters during the early phases of this

project; his support and interest in my work are acknowledged.

In Bavaria, the study project was initiated by Professor Klaus Riegel, to whom I express my sincere apprecia-

tion for the opportunity to participate in the project, and for his kind encouragement. My gratitude is also to

Barbara Ohrt, M.D., who designed the neurological part of the multicenter study. I am most grateful to

Professor Märta Donner, the neurological advisor of the Finnish study group, for her guidance and kind

interest in my work.

I wish to thank my co-workers Anja Niemelä, M.D., Juha Peltola, M.D., and Timo Vartia, M.D., for their

excellent collaboration in collecting the Finnish data. I acknowledge gratefully the assistance offered by

Marina von Flittner, M.D., and Carl Stråhlman, M.D., for neonatal data collection at Tammisaari and Porvoo,

respectively.

I owe my thanks to Ms Anneli Eronen and Ms Sirkka Weckström for their skillful assistance in collecting

pre-perinatal data and interviewing the parents, and especially to Ms Maija Eklund for creating a positive

unconstrained atmosphere during the assessments, and for her friendship.

155

I am grateful to Professor Matti Iivanainen, former head of the Department of Child Neurology for his

constantly supportive attitude towards the project throughout the years. I owe my gratitude also to Professor

Lennart von Wendt, head of the Department of Child Neurology, for his invaluable help in kindly revising

and suggesting structural improvements to my preliminary manuscript.

I express my sincere gratitude to Professor Mijna Hadders-Algra and Docent Kirsti Heinonen for their

advice, constructive criticism and professional encouragement in revising the manuscript. It was a privilege

to have such expert reviewers.

I wish to express my warm gratitude to Professor Pirkko Santavuori, my first teacher, who aroused my

interest in child neurology, for her expert guidance and empathetic support. I am also grateful to Docent

Helena Pihko, my second teacher, for her professional advice and help during the final stages of my work.

I am very grateful to Pertti Keskivaara, M.A., for his guidance and kind help with statistical questions. I also

owe my thanks to Marjut Schreck, IT-analyst, who did an enormous job in working up the huge amount of

data into microcomputer files, and to Kauko Heikkilä, systems analyst, for changing them into BMDP files.

I want to express my thanks to Ms. Terttu Kaustia, M.A., for the thorough revision of the English language.

I am deeply grateful to the children and their families for participating in the study, and for their pleasant co-

operation. Assessing the children was enjoyable and rewarding for me. I want to express my gratitude to the

staff of all the participating hospitals for their kind help and collaboration. I also thank my friends and

colleagues at the Department of Child Neurology for their support and interest.

I wish to thank my brother, Docent Aarno Hautanen, for his guidance and valuable help at the early phase of

my scientific work. I also thank my parents of whom my father did not see this work becoming accom-

plished, and my parents-in-law for taking care of our children and their loving support.

Most of all, my heartfelt gratitude goes to my loving husband Tapio for his unceasing confidence, support

and patience during these years. I also want to thank our children Juhana, Henrik and Heidi-Maaria, who

have filled our home with joy and music, for their never-ending understanding.

This study was financially supported by grants from the Ministry of Research and Technology of The

Federal Republic of Germany and the Foundation for Pediatric Research, Finland.

Espoo, November 2002

157

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11. APPENDICES

Appendix 1. Causes of death of infants

N Gestational age

DEATHS DURING PRIMARY HOSPITALIZATION * <32 gwk 32-36

gwk >36 gwk

Chromosomal abnormality 6 2 2 2Congenital heart defect 6 - - 6 Other congenital abnormality 8 1 3 4Metabolic disease 1 - - 1 Infection 10 6 1 3Meconiumaspiration 2 - - 2 Asphyxia, pulmonary hypertension 5 1 - 4Intraventricular hemorrhage 9 8 1 - IRDS, BPD 7 6 1 -Immaturitas 2 2 - - Thrombosis of venae cavae 1 1 - -Congenital nephrosis 1 - 1 - Total 58 27 9 22 DEATHS AFTER PRIMARY HOSPITALIZATION Complications of prematurity or labour 3 2 - 1Chromosomal abnormality, hypotonia NUD 1 - - 1 Metabolic disease 1 - - 1Congenital spinal atrophy 2 - 2 - Complications of a surgical measure 2 2 - -SIDS 1 - - 1 Total 10 4 2 4

*49 infants were not given a neurological examination, 9 infants were examined, 4 of which were excluded (one trisomy, one MMC, one Down syndrome, one Ellis van Creveld) The infant with SIDS belonged to the control group

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Appendix 2.

Pre-, peri- and neontal items used in defining obstetric and neonatal optimality scores

Before pregnancy:

Maternal age <20 or >30 year

Treatment for sterility

Previous abortions >1

Previous pregnancies complicated

Previous preterm birth

Previous stillbirth or anomalic infant

Severe chronic disease (DM, kidney disease)

Parity 1. or >2

Single mother

During present pregnancy:

First visit at maternity health center >12gwk or irregular prenatal care

Psychosocial stress

Smoking or abusus of alcohol or drugs

Urinary infection or infectious disease

Hyperemesis, severe illness, trauma, anesthesia

Cerclage/Tokolysis

Multiple pregnancy

Toxemia (edema, proteinuria 1g/l or more, RR>140/90)

Vaginal bleeding

Preterm contractions <37gwk

Polyhydramnion/Oligohydramnion

Fetal distress - intrauterine growth retardation/ pathologic CTG before birth/ placental insufficiency (pathological estriol

excretion)

Anemia (Hb<100g/l)

During delivery and immediately postpartum:

Premature rupture of membranes >12h before regular contractions

Amniotic fluid meconium stained

Placenta previa or ablation

Fetal distress (pathological CTG, acidosis in micro sample)

Fever during delivery (temp=/> 36.0 C)

Breech or other abnormal presentation

Weak contractions

Intrapartum medication (oxytocin, opiate, narcotics)

Duration of the first stage <3h/>12h

Duration of the second stage <10min/>60min

Cord complications

180

Instrumental delivery (vacuum, sectio, forceps)

Gestational age <37gwk/>41gwk

SGA<-2SD/LGA>2SD

Apgar 1min<8/5min<9

Ventilatory assistance(mask/intubation)

Medical correction of acidosis or volume substitution

Neonatal morbidity factors:

Mechanical ventilation

Apnea/bradycardia

Shock

Hyperbilirubinemia requiring phototherapy

Anemia requiring blood transfusion

Symptomatic hypoglycemia

Suspect/verified sepsis

Operation

Catheterization

Pneumothorax indicating pleural suction

Seizures

Intracranial hemorrhage

Outborn

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Appendix 3. 230 children with indirect follow-up data

N179 HEALTHY AND NORMAL DEVELOPMENT

20 MAJOR IMPAIRMENTS 11 cerebral palsy 8 spastic/ dystonic tetraplegia with MR 1 spastic diplegia 1 spastic hemiplegia 1 athetosis 4 severe mental retardation 3 unknown etiology 1 with macrocephalia, tremor, nystagmus 1 social deprivation with severe developmental delay 2 epilepsy with anticonvulsant therapy 1 shunted hydrocephalus 1 deaf (hereditary)

20 MINOR IMPAIRMENTS 2 mild mental retardation 14 speech/ language problems 4 strabismus

6 SOMATIC DISEASE 3 congenital heart disease 1 polycystic kidneys 2 bronchial asthma (one st p BPD)

5 CONGENITAL DISORDER OR PROGRESSIVE DISEASE

1 Moebius syndrome 1 brain malformation 1 Angelman syndrome 1 IOSCA 1 Salla disease

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Appendix 4. The neonatal neurological examination form *

ITEM RESPONSE OR FINDING

OPTIMAL NON-OPTIMAL/ABNORMAL

1 The head size and form optimal size < -2SD or > 2 SD form abnormal, (miscellaneous) 2 Fontanelles and cranial sutures optimal non-optimal/abnormal (miscellaneous)

FACE (state/alertness) 3 Pupils symmetric, round, middle size yes asymmetric, smaller right/left 4 Reaction of pupils to light fast, symmetric yes incomplete , slow, absent right/left 5 Position of eyes central, no deviation, yes strabismus,nystagmus,sun setting conjugated eye movements right/left 6 Fixation and horizontal tracking (ad 300) yes no 7 Acoustical response: certain uncertain/ absent eyes open / stands still / frightens 8 Mimic symmetrical, facial expressions variable, yes no normal tonus of facial muscles 9 Glabella reflex immediate, strong yes weak, absent right/left 10 Sucking reflex rhythmical, strong yes weak, absent 11 Swallowing undisturbed yes difficult, absent I

SENSORIMOTOR SYSTEM (state/alertness) 12 Posture in supine symmetric, stable body

control, the limbs semi-flexed and occasionally off the

surface, the hands slightly twisted or opened yes abnormal: head,body,arms,legs Spontaneous motor activity 13 The quantity medium, continual movements yes increased/decreased/ no spontaneous movements The quality 14 the type of movements yes abnormal: arms right/left mainly alternating, variable, symmetric, legs right/left medium wideness 15 the progress of movements yes mainly sudden, jerky, too wide, mainly harmonic, symmetric, continual weak and slow, miscellaneous 16 Involuntary movements no tremor: high frequency in fingers, hands, toes, chin; coarse in arms, legs Muscular tone at rest 17 Assessed by the posture: optimal, symmetric yes decreased: arms, legs, body increased: arms, legs, body 18 Assessed by resistance against passive

movements: yes

lowered: head, body, arms, legs

moderate resistance increased: head, body, arms, legs

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The traction response 19 Head control: remains 1-2 sec at the body

niveau yes

head lags flaccid, miscellaneous

20 Arms symmetric, moderately flexed at the elbow yes flaccid, fully extended, misc.

REFLEXES / RESPONSES (state/alertness) 21 Palmar grasp fast, symmetric, medium intensity yes absent, interrupted, tremor, misc. 22 Plantar grasp fast, symmetric, medium intensity yes absent, interrupted, tremor, misc. 23 Knee jerk fast, symmetric, medium inten-

sity/threshold yes

exaggerated, weakened, absent

24 Ankle jerk 25 Biceps jerk Moro response 26 Stage 1 (abduction, extension of the elbows) yes exaggerated (full extension) fast, symmetric, medium intensity/threshold diminished, absent 27 Stage 2 (adduction, flexion of the elbows) yes exaggerated, diminished, absent fast, symmetric, medium intensity/threshold 28 CRYING medium intensity, normal pitch yes weak, groaning, high-pitched, no sounding

SUMMARY: 1 CNS irritability: responses to stimulus normal mildly slowered/diminished slightly strengthened apathy, coma hyperexcitability, convulsions 2 Quantity of spontaneous motility normal mildly/definitely abnormal 3 Quality of spontaneous motility normal mildly/definitely abnormal 4 Muscle tone normal, symmetric mildly/definitely abnormal 5 Cranial nerves normal abnormal 6 Asymmetry no yes modified from the Prechtl’s concept by Bavarian Study Group (Riegel, Ohrt 1988, Riegel et al. 1995)

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Appendix 5. Qualitative variables in 56 months examination

ITEM NON-OPTIMAL / ABNORMAL

I Gross motor function speed, smoothness, adequacy of

movements asymmetry or missing smoothness in

1 walking 2 running 3 walking up and down stairs 4 walking on tiptoe 5 walking on heels 6 the position of feet during walking II Balance of trunk missing stability of the control of

position in 1 walking 2 on stairs 3 walking along a straight line III Fine motor function smoothness, adequacy of movements missing smoothness on 1 peg-board 2 drawing 3 muscle power during peg-sticking too loose or too tight IV Hand coordination definite deviations or misplacings in 1 finger-tip nose test (R/L) 2 finger-tip touching test (R/L) 3 tremor V Muscular tone definite hypotonia VI Tendon reflexes definitely abnormal 1 Biceps jerk (R/L) 2 Knee jerk (R/L) 3 Ankle jerk (R/L) VII Facial-oral motor function definitely abnormal 1 asymmetry, tone, power at rest, during voluntary movements 2 drooling 3 mouth and tongue movements VIII Visual system 1 eye movements not conjugated (strabismus)

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Appendix 6. Quantitative variables in 56 months examination

ITEM ABNORMAL 1 pursing the lips to whistle not possible 2 tongue position maintained when

sticked out not possible

3 imitates the tongue movements with difficulty/ not possible 4 running only slowly 5 going upstairs only with support/ even pace 6 sideways hopping less than two jumps 7 standing on one leg (R/L) <5 sec/ not possible 8 hopping on one leg (R/L) <5 sec/ not possible 9 forefinger-thumb tapping (R/L) jerky/ not possible 10 finger-opposition (R/L) not possible 11 peg-board (R/L) one hand slower than 95% of the

controls 12 hand pro-supination (R/L) no rhythm 13 simultaneous handclapping no rhythm 14 alternate handclapping no rhythm

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