Donald School Fetal Brain Functioning Asim Kurjak
INDEX
Page numbers followed by f refer to figure and t refer to table
A
Advanced glycation end products 177
Alzheimer's diseases 173
Amiel-Tison neurological assessment at term 71, 194
Amiel-Tison postnatal test 76
Amniotic fluid 57, 125f
Antenatal corticosteroid administration 164
Anxiety 163
Apoptosis disorders 137
Appropriate-for-gestational age 90
Arm movement, isolated 4, 193
Attention-deficit hyperactivity disorder 65
Axon growth 72
B
Bardet-Biedl syndrome 141
Bleeding, intracranial 144f
Blood
brain barrier 175
impairment 175
pressure 172
Body
mass index 26, 179
movements 90
Brain
changes 170
defects, congenital 100
development 89
function 173, 175
assessment of 122
inflammatory disorders of 100
injury 174
maturation 89
overgrowth spectrum 43
C
Caffeine 107
Cajal-Retzius cells 41
Cardiovascular diseases 172
Central nervous system 1, 40, 53, 71, 90, 98, 120, 152, 170, 206
functional development of 1, 3
rapid development of 133
structural development of 1
Cerebellar neural
migration 72
proliferation 72
Cerebral artery, middle 23, 82
Cerebral blood flow 174
Cerebral cortex 48, 174
Cerebral disorders 41
Cerebral neural
formation 72
migration 72
Cerebral palsy 1, 8, 71, 96, 152
spectrum 76
Cerebrospinal fluid, stenosis of 139
Chiari malformation 139
Choroid plexus 49f
Clonic movements 193
Cobblestone lissencephaly 47
Cognitive
development 64
dysfunction 176
functions 53, 54, 170, 171, 178, 179, 181
impairment, mild 178
Corpus callosum 135, 137f
agenesis of 135, 137f
Cortical development, malformations of 40, 42, 44, 44t, 50, 133, 135
Corticotropin-releasing hormone receptors 64
Cranial dysraphism 133
Cranial suture and head circumference 16, 26, 78, 202
Cranial ultrasound 9
Craniofacial skeletal appearance 45f
Cry-face gestalt 123
Cysts, interhemispheric 137f
Cytomegalovirus 48, 138
D
Depression 163, 173, 182
cognitive aspects of 181
maternal 181
Depressive disorders 181
Development, stages of 71
Diabetes mellitus 83, 160, 175, 176, 182
gestational 84, 160, 175, 206
Dichorionic diamniotic twins 114, 115f
Diffusion-weighted imaging 9
Digits backwards score 171
Dopamine 180
Dystroglycanopathies 141
E
Eclampsia syndrome 172
Electroencephalography 95, 122, 170
Emotions 123
Encephalopathy 9
Epilepsy 163
Epileptogenicity 50
Ethnicity 153
Eye
blinking 18f
isolated 16, 26, 78, 202
movements 90
F
Face
grimacing 15f
movements 78
Facial
alteration 16, 18f, 26, 78, 79f, 80f, 156f, 202
awareness 120
expression 27f
Fetal
behavior 6f, 152, 153, 157, 160, 162-164, 192, 197f
assessment of 122
patterns, developmental sequence of 4t
body 90
brain
coronal section of 49f
development 152
function, evolution of assessment of 71
central nervous system 71
cognitive functions 53
craniofacial appearance 45f
eye 89, 90
face, three-dimensional surface rendering imaging of 125f
facial
alterations 157f
expression 6f, 126
growth restriction 89, 179
hand movements 57
three-dimensional ultrasonography images of 58f
holoprosencephaly, neurosonographic images of 136f
intracranial bleeding 144
learning 61
macrosomia 179
motoric activity 123
mouthing 89, 91f
movements 73, 193
nervous system
function of 1
structure of 1
neurobehavior 193
assessment of 26, 27f, 81f, 152
neurodevelopment 53
neurological
assessment 80f, 96
impairment 26
neurology 204t, 208
neonatal aspect of 8
pain 59
response 59t, 163
scowling 92f
self-awareness, investigation of 127
sensory perception 122
sex 157
smiling 92f
stress 64, 65
sucking 91f
tongue expulsion 92f
transfontanelle neuroimaging 134f
yawning 91f
Fetus 123
emotional development of 62
nervous system of 71
Fingers movements 17, 18f, 26, 78, 203
Focal cortical dysplasia 43
Fukuyama
congenital muscular dystrophy 141
syndrome 138
Functional magnetic resonance imaging 53, 122
G
General movements 73, 74, 78, 101
postnatal assessment of 10
Gestalt perception 11, 17, 78, 203
Gestational age 17, 78, 203, 206
assessment of 100
Gestational weight gain 180
Growth-restricted fetuses 89
H
Hammersmith infant neurological examination 33
Hand
head contact 193
movement 18f, 78
isolated 17, 26, 78, 203
to face movements 17, 26, 203
Head
anteflexion 4
isolated 16, 26, 78, 202
circumference 78
movements 193
retroflexion 4
rotation 4
Hemimegalencephaly, neurosonographic images of 45f
Hemiplegia 96
Hemorrhage
bilateral multiple intracranial 144f
intracranial 100
intraventricular 139
Hiccups 193
Holoprosencephaly 134
Hormone, adrenocorticotropic 64
Human brain, development of 2t, 72t, 95, 152
Hydrocephalus 139
normal-pressure 139
Hydrocephaly 100
Hyperglycemia 175, 177, 178
Hyperinflammation 176
Hyperinsulinemia 176, 177
Hypertension 172
chronic 172
diagnosis of 172
gestational 172
pregnancy-induced 85
Hypertensive diseases 171-174
classification of 172
Hypertensive disorders 89, 172
Hypoplasia, cerebellar 47
Hypothalamic-pituitary-adrenal axis 176
Hypothyroidism 162
Hypoxic-ischemic brain damage 100
I
In utero brain injury 142, 144f
Infant motor performance, test of 102
Insulin resistance 177
International Diabetes Federation 175
Intertwin contact 114, 115f
Intracranial pressure 139
Intrauterine fetal death 48
Intrauterine growth restriction 5, 23, 80, 162, 195, 206
J
Jaw movements 193
Joubert syndrome 141
K
Klinefelter syndrome 135
Kurjak's antenatal neurobehavioral test 1, 13, 15, 16t, 18f
normal 14f
Kurjak's antenatal neurodevelopmental test 13, 65, 71, 75, 76, 77f, 78t, 117, 120, 153, 157f, 158f, 192, 193, 194, 201f
abnormal 159f, 162f
application 78
complete 154f
evolution of 195
normal 156f
parameters of 27f, 196f
protocol of 202t
research, interpretation of 26
scores, interpretation of 17, 80t
Kurjak's antenatal neurological test 23, 28, 206
L
Laughter-face gestalt 123
Leukodystrophy 43
Lissencephaly 46, 47, 138
classic 47
classification of 47t
M
Macrocephaly 42, 43
Magnetic resonance
imaging 9, 95, 133, 170
spectroscopy 9
Magnetoencephalography 95, 122
Maternal thyroid function 162
Meckel syndrome 141
Megalencephaly
associated syndromes 141
capillary malformation-polymicrogyria syndrome 141
polymicrogyria-polydactyly-hydrocephalus syndrome 141
Membranes, preterm premature rupture of 23, 82
Mesencephalon 2
Metabolic syndrome 162f
Microcephaly 42, 43, 137
Microgravity 75
Microlissencephaly 47, 138
Migration 2, 72
disorders 46
Miller-Dieker lissencephaly syndrome 135, 138
Monochorionic diamniotic twins 114
Mood disorder 181
metabolic 182
Moro's reflex 5, 13
Motor development, prenatal 55
Motor reflex 59
Mouth opening 16, 26, 78, 202
Movements, type of 4
Muscle-eye-brain disease 138
Muscular dystrophies 141
Myelination 72
N
Near-infrared spectroscopy 955, 122
Neonatal behavioral assessment scale 102
Neonatal intensive care unit 99
network neurobehavioral scale 102
Neonatal neurological assessment 99
Nervous system 40f, 71
Neural development 72t
Neural tube 133
defects 133
Neurobehavioral test 1
Neurodevelopmental defects 75
Neurodevelopmental disorders 106
Neurogenesis 2
Neurologic thumb 13
Neurological assessment, postnatal signs of 104
Neuronal embryology 133
Neuronal migration disorder 46, 138
Neurons 192
formation of 72, 192
migration of 192
Neurosonogenetics 133
Neurulation
disorder 133
secondary 54
Neutral fetal face 91f
Nonstress test 163
Normal fetal behavior patterns, quantitative analysis of 7f
Norman-Roberts syndrome 138
O
Obesity 179, 180, 182
Obsessive-compulsive disorder 163
Oligogyria 46
Oral glucose tolerance test 84
P
Panic disorders 163
Perinatal period 95
Perisylvian bilateral polymicrogyria 139
Personality disorder 163
Polymicrogyria 48
Positron emission tomography 122, 178
Posterior reversible encephalopathy syndrome 172
Postmigrational disorders 48, 139
Postnatal death 108t
Post-traumatic stress disorder 173
Prechtl's fetal general movements 120
Prechtl's method 10, 102
Preeclampsia syndrome 172, 206
Pregnancy 170, 181
first trimester of 4t
hypertensive
diseases of 171-173
disorders of 89
neurobehavior assessment, third trimester of 201f
termination of 108t
Preterm infants
behavior, assessment of 102
neurological assessment of 101
Proliferation 137
disorders 43
Prosencephalic disorder 134
Prosencephalon, formation of 72, 192
Psychotropic drugs 163
R
Rapamycin, mechanistic target of 43, 44
Reverse face technique 13
Rhombencephalon 2
Rubella virus 138
S
Schizencephaly 49
Schizophrenia 163
Selective serotonin reuptake inhibitors 163
Sensory development, prenatal 59
Single intrauterine fetal death 143
Small-for-gestational age 93
Sonography, two-dimensional 114, 159
Stimuli, fetal perception of 59
Sucking 193
Swallowing 193
Sylvian fissure 46
abnormal 47f
angle 46
appearance of 138
Synapses
formation of 72, 192
organization of 72
Synaptogenesis 2
T
Teratogen exposure 48
Thanatophoric dysplasia 143f
Tongue expulsion 16, 19f, 78, 202
Transcranial Doppler ultrasonography 170
Trauma 48
Tuberous sclerosis complex 46
Tumor necrosis factor alpha 175
Twin
fetal
behavior 114
facial expressions 117
movements 116, 118
to-twin transfusion syndrome 143
U
Ultrasound
four-dimensional 3, 4, 5f, 6f, 8f, 90, 93, 114, 118, 122, 153, 192
three-dimensional 6f, 133, 153
two-dimensional 4, 160, 193
V
Ventriculomegaly 100, 139
isolated 141
Vibroacoustic stimulation 93, 163
W
Walker-Warburg syndrome 138, 141
White matter lesions 173, 174
Wisconsin card sorting test 176
Wolf-Hirschhorn syndrome 135
X
X-linked lissencephaly 47
Y
Yawning 16, 78, 202
Z
Zika viral infection 48
×
Chapter Notes

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From Structure to Function: A Long JourneyCHAPTER 1

Asim Kurjak,
Milan Stanojević,
Panagiotis Antsaklis
 
INTRODUCTION
For centuries understanding the structure and function of the fetal nervous system has been the dream of physicians. In the second part of the 20th century, this dream become a reality due to the pioneering efforts of Ian Donald in obstetric ultrasound. Early contribution of obstetric ultrasound focused on normal and abnormal structure. Initially, anencephaly was described and followed by increasingly subtle central nervous system (CNS) abnormalities like agenesis of the corpus callosum. For investigators in obstetric ultrasound there is a current and growing challenge to have similar success with the understanding of fetal neurological function. In many functional neurological abnormalities like cerebral palsy (CP) causes are poorly understood. There has also been noticed an escalating number of results which show that a large presence of neurological problems (like minimal brain dysfunction or attention deficit hyperactivity disorder, schizophrenia, epilepsy, or autism spectrum disorder), at least in part, come from prenatal neurodevelopmental problems. Clinical and epidemiological studies showed that CP most often results from prenatal rather than perinatal or postnatal causes.1
Although significant advances in prenatal and perinatal care are obvious, currently there is no mean to identify or expect the development of these disorders. Consequently, one of the most imperative tasks of contemporary perinatal medicine became the development of diagnostic strategies to avoid and condense the saddle of perinatal brain damage. Understanding of the prenatal neurodevelopmental events and possibly antenatal detection of CP and other neurological diseases might be improved by applying the new neurobehavioral test—Kurjak's antenatal neurobehavioral test (KANET).
 
STRUCTURAL AND FUNCTIONAL DEVELOPMENT OF CENTRAL NERVOUS SYSTEM
 
Structural Development of Central Nervous System
Pomeroy and Volpe2 wrote that “the development of CNS begins around the end of gastrulation. The generation of the neuroectoderm from ectoderm during the third postconceptional week, results in formation of the neural plate. Thus, the neural epithelium of the embryo, which is a precursor of neurons and glia, is virtually the first part of organism that acquires the separate identity from other cells.”2
The formation of the neural plate is succeeded by the folding of its edges and formation of a neural tube, whose further growth and reshaping results in formation of structures of CNS. According to O’Rahilly and Muller, forebrain (prosencephalon), 2midbrain (mesencephalon), and hindbrain (rhombencephalon) can be distinguished in the rostral portion of the unfused neural folds3 earlier than it is usually referred to, approximately at 22nd postconceptional day. In the rapid succession, during the 4th postconceptional week, the forebrain components—diencephalon and telen-cephalon—can be detected. Three embryonic zones—ventricular, intermediary, and marginal zone (seen from ventricular to pial surface)—are present in all parts of neural tube, while telencephalon contains additional two zones, subventricular and subplate zone.3 Ventricular and subventricular zones of telencephalon are the site of neurogenesis and all the future neurons and glia are born in these structures.3 During migration toward the pial surface they form other transitional zones before reaching their genetically predetermined final destinations.3 Those destinations are cortical plate or different nuclei in the brain stem, diencephalon, and basal forebrain.1 One of the transitional structures, a subplate zone that is a site for transient synapses and neuronal interactions, can play a major role in the developmental plasticity following perinatal brain damage.4 Early appearance of interneuronal connections, given in Table 1, implicates a possibility of an early functional development.3,4 However, these first synapses exist only temporarily and disappear due to the normal reorganization processes. Most embryonic zones, types of neurons and glia, and early synapses, which play crucial role in certain periods of fetal brain development, eventually disappear, significantly changing structure and function of the brain.4 Reorganization processes include apoptosis, disappearance of redundant synapses, axonal retraction and transposition, and transformation of the neurotransmitters phenotype.4
Table 1 lists a significant overlap of neurogenesis, migration, and synaptogenesis in the embryonic and fetal life. At the time of delivery the development of human brain is not completed.3,4 In an infant born at term, characteristic cellular layers can be observed in motor, somatosensory, visual, and auditory cortical areas.1
While in a term infant proliferation and migration are completed, synaptogenesis and neuronal differentiation continue very intensively.5 Brainstem demonstrates high level of maturity, whereas all histogenetic processes actively persist in cerebellum.6 Therefore, only subcortical formations and the primary cortical areas are well developed in a newborn.6 Associative cortex which is barely visible in a newborn, is poorly developed in a 6-month-old infant.6 Postnatal formation of synapses in associative cortical areas, which intensifies between 8th month and 2nd year of life, precedes the onset of first cognitive functions, such as speech.1,6
TABLE 1   Dynamics of the most important progressive processes in the development of the human brain.3,4
Beginning
Most intensive activity
Ending
Neurogenesis
Early embryonic period (4th week)
8th–12th week
Approximately 20 weeks
Migration
Simultaneously with proliferation
18th–24th week
38th week
Synaptogenesis
6–7th week—spinal cord
8th week—cortical plate
13th–18th week, after 24th week, 8th month to 2 year of postnatal life
Puberty
3Following the second year of age, many redundant synapses are eliminated.6 The elimination of synapses begins very rapidly, and continues slowly until the puberty, when the same number of synapses as seen in adults is reached.6
 
Functional Development of CNS and Role of Four-dimensional Ultrasound
The first synapses appear in the spinal cord at 6–7 postconceptional weeks7 and in the cortical plate at 8 postconceptional weeks.8 This is the phase when the first electrical bustle and conduction of information take places. The earliest spontaneous fetal movements can be observed at 7.5 postconceptional weeks. These movements which consist of slow flexion and extension of the fetal trunk being accompanied by the inactive displacement of arms and legs and emerging in asymmetrical sequences, have been described as “vermicular”.9,10 They are substituted by various general movements (GMs) consisting of head, trunk, and limb movements, such as “rippling” seen at week 8, “twitching” and “strong twitching” at weeks 9 and 9.5, respectively, and “floating”, “swimming”, and “jumping” at week 10.11 Almost simultaneously with the GMs isolated limb movements emerge. At the same time with the beginning of spontaneous movements, at 7.5 postconceptional weeks, the initial motor reflex activity can be detected, permitting the hypothesis to be made of the existence of the first afferent-efferent circuits.7 Head tilting following perioral stimulation was noted at that time.7 The primary reflex movements are immense and signify a limited number of synapses in a reflex pathway.7 During the 8th week of gestation, these substantial reflex movements are replaced with local movements, possibly due to an increase in the number of axodendritic synapses.7 Hands become susceptible at 10.5 weeks and lower limbs start to contribute in these reflexes at around week 14.11,12 First sign of a supraspinal control on fetal motor activity is GMs.9,10 Brainstem which consists of the medulla oblongata, pons, and midbrain, begins to develop and mature in a caudal to rostral direction approximately at the 7 postconceptional weeks.68 As the medulla matures in advance of more rostral structures of brainstem, reflexive movements of the head, body, and extremities, as well as breathing movements and heart rate alterations, appear in advance of other functions.12 The amount and incidence of movements increase since the 10th week onward.12 Fetuses are highly active with the longest period between movements of only 5–6 minutes by 14–19 weeks.911 Fifteen singular types of movements can be observed in the 15th week.911 We can see general body movements and isolated limb movements, retroflexion, anteflexion, and rotation of the head.13 Furthermore, face movements, such as mouthing, yawning, hiccups, sucking, and swallowing, can be included to an ample repertoire of fetal motor activity at this stage.13 However, during the first half of pregnancy, a dynamic pattern of neuronal production and migration, as well as the immature cerebral circuits are considered too immature for cerebral involvement in the motor behavior.4 Merely at the end of this period do a quantifiable number of synapses appear in the structures preceding the cerebral cortex, perhaps forming a substrate for the first cortical electric activity, noted at week 19.4 At the 20th week, the spinothalamic tract is established and myelinized by 29 weeks of gestation while at 24–26 weeks the thalamocortical connections penetrate the cortical plate.14 At the 29th week evoked potentials can be detected from the cortex, suggesting that 4the functional connection between periphery and cortex operates from that time onward.14 In the second half of pregnancy, particularly during the last 10 weeks, the number of GMs gradually decreases.15 This decrease was first explained as a result of the reduction in amniotic fluid volume; however, it is now believed to be a result of maturation processes in the brainstem.12 An increase in facial movements, as well as opening or closing of the jaw, swallowing and chewing, can be observed simultaneously with the decline in the number of generalized movements.15 These activities can be seen mainly in the periods of absence of GMs. This pattern is considered to be a manifestation of the normal neurological development of the fetus.15 However, alterations not only in the number of movements, but also in their complexity, are revealed to be the result of cerebral maturation processes.12 It is important to point out that subunits of the brainstem remain the main regulators of all fetal behavioral patterns until delivery.12 Study of prenatal behavior is still in its infancy despite medical reports from 100 years ago and almost 40 years of systematic research initiated by Prechtl and colleagues.9,16-18 One of the most promising progress in the field of ultrasonography was the new four-dimensional ultrasound (4D US) technology. Its advance has been achieved in the last years giving visualizations in almost real time.19-22 In an extraordinary way the availability of new diagnostic data raised our knowledge about intrauterine life, substantially modifying some earlier interpretations.23 With conventional two-dimensional ultrasound (2D US) first spontaneous fetal movements can be observed around 8th gestational week, while the newly developed 4D US enables the visualization of fetal motility 1 week earlier (Table 2).24
TABLE 2   Developmental sequence of fetal behavioral patterns observed by four-dimensional ultrasound (4D US) in the first trimester of pregnancy.24
Postconceptional weeks
Type of movements
7
8
9
10
11
General movement
+
+
+
+
+
Startle
+
+
+
+
Stretching
+
+
+
+
Isolated arm movement
+
+
+
+
Isolated leg movement
+
+
+
+
Head rotation
+
+
+
Head anteflexion
+
+
+
Head retroflexion
+
+
+
General movements are the first complex fetal movement patterns observable by 2D US; however, assessment by 4D US is a considerable improvement. They can be recognized from the 8th to 9th week of pregnancy (Figure 1 showed by 4D US) and continue to be present until 16–20 weeks after birth.18
According to Prechtl, “these are gross movements, involving the whole body. They wax and wane in intensity, force, and speed, and they have a gradual beginning and end.”13,18 The majority of sequences of extension and flexion of the legs and arms is complex, and may be better assessed with 4D US.24 In the literature, there is a range between the 8th and 12th week regarding the first appearance of limb movements.13,18,20,25 De Vries found isolated arm and leg movements at the 8th week of gestation.13 With 4D US, limb movements were found at the 8th–9th week.24 By 4D sonography, Kurjak et al. found that from 13th gestational week onward, a “goal orientation” of hand movements appears and a target point can be recognized for each hand movement.19 It was noticed that more limb joints were active and moved simultaneously, like extension or flexion in arm and elbow or hip and knee.5
zoom view
Fig. 1: Four-dimensional ultrasound (4D US) imaging demonstrated fetus at 13 weeks of gestation showing general movement pattern.
Simultaneously, elevation of the hand, extension of the elbow joint, with a slight change in direction and rotation, could have been seen.26 The isolated limb movements which were seen at the 9th week are followed by the appearance of the movements in the elbow joint at 10 week, changes in finger position in the 11th week, and by easily recognizable clenching and unclenching of the fist at the 12th–13th week.26 Finally, isolated finger movements, as well as an increase in the activity and strength of movements of the hand or finger, can be seen at the 13th–14th week.26 Recent examination of fetuses in the last trimester of gestation which were performed by 4D US, has discovered an even wider range of movements of hand and face than was formerly explained.19 It has been also confirmed that the fetal movement patterns in the second half of pregnancy are about equal to those monitored after birth. However, the list of movements in the newborn consists of some patterns that cannot be observed in the fetus, such as the Moro reflex.27 In addition, at around the 20th gestational week, study of anencephalic fetuses have presented clear evidence for the influence of supraspinal structures on motor behavior. In these fetuses the number of movements was normal or even increased, but the complexity of the movement patterns distorted radically and movements were stereotyped and simplified.28
The eminence of fetal movement patterns is distorted in fetuses undergoing intrauterine growth restriction (IUGR). The activities become monotonous and slower, similar to cramps, and we can see that their variability in force and amplitude is reduced.29 These changes might designate the subsistence of brain lesions in growth-restricted and possibly hypoxic fetuses. Despite the premature postulations, the changes in the amplitude and complexity of movements in these fetuses do not show to be due to oligohydramnios. In cases of premature rupture of fetal membranes and 6a subsequently reduced volume of amniotic fluid, movements arise less frequently, but their complexity look likes that of movements achieved in the normal volume of amniotic fluid.16 Qualitative including quantitative analysis of fetal movements divulged the consistency of the fetal nervous system, and can be applied for the recognition of different cerebral dysfunctions, and probably neuromuscular ailments.28
The new technology, 4D US, when applied in the examination of fetal facial movements, revealed existence of a full range of facial expressions including grimacing, tongue expulsion, and eye-lid movements (Fig. 2) similar to emotional expressions in adults.27,30 Possibility of studying such subtle movements could open a new area of investigation.31
During the first trimester, it was noticed a tendency toward increased frequency of fetal GMs with increasing gestational age (Fig. 3A). While at the beginning of the second trimester, the fetuses began to display a tendency toward increased frequency of observed fetal facial expression up to the end of the second trimester. An oscillation and dispersion of the incidence of the facial expression as seen in the polynomial regression of isolated eye-blinking diagram is observable in Figure 3B.30
In the second trimester, the most frequent facial movement patterns were isolated eye blinking, grimacing, suckling, and swallowing, while yawning, mouthing, tongue expulsion, and smiling could be observed less frequently.25,30
zoom view
Fig. 2: Three-dimensional/four-dimensional ultrasound provides clear depiction of dynamic changes of fetal facial expression allowing study of fetal behavior during all trimesters of pregnancy.
7
zoom view
Figs. 3A to C: Quantitative analysis of normal fetal behavior patterns using four-dimensional ultrasound (4D US): (A) General movements; (B) Hand to face movement; (C) Isolated eye blinking.30
The fetuses began to display decreasing or stagnant incidence of fetal facial expression during the third trimester. From the beginning of the second trimester to the end of the third trimester, all types of head movements and hand to body contact indicated a tendency to decrease frequency (Fig. 3C).30
In this period, the investigations of fetal facial expressions established that all mechanisms of the fetal yawning pattern, prolonged jaw opening followed by a quick closure and accompanied by head flexion and elevation of arms, can easily be documented by 4D US (Fig. 4).32
If we compared fetal yawning in the third trimester with the yawning in the neonates during the first week of life, no differences in the frequencies of this reaction were found. It was noticed that the frequency of yawning steadily increased between 15th and 24th week, then from 24th to 26th week a short plateau was observed which was followed by a slight decrease toward the term.30 A gestational age-related tendency in the frequency of yawning could be assumed as the maturation of the brainstem and probably the gaining of control of more cranial structures over yawning pattern. These results gave new data about the route of neurodevelopment of this fascinating, but poorly implicit reflex.30 It still continues to be determined whether this is distorted in cases of neurodevelopmental disorders and whether such adaptations can give us impending into the function of fetal nervous system in high risk pregnancies. To what possibility are the facial motoric patterns related to the function and integrity of the CNS also stays to be determined. However, the fact that even in the embryonic stage, the identical inductive forces that cause growth and restyling of the neural tube influence the development of facial structures, and that many genetic disorders affecting the CNS are also described by dysmorphology and dysfunction of facial structures, underline the value of these studies.2,30,318
zoom view
Fig. 4: Four-dimensional ultrasound (4D US) image sequences of facial expression characterized by stereotyped yawning opening.
 
NEONATAL ASPECT OF FETAL NEUROLOGY
In our previous publications, we have extensively discussed obstetric aspects of fetal neurology.19-25,27-31 In order to come to better understanding of fetal neurobehavioral patterns, we have learned a lot from basic studies of brain development and from clinical postnatal studies of neonates. Now, when we have reached the edge of fetal behavioral investigation by 4D US in normal fetuses, we intend to find some new ideas and ways of investigation presenting neonatal aspect of fetal neurology.
Cerebral palsy is an “umbrella” term for disorders of development, movement, and posture, resulting in limitations of activity due to nonprogressive impairment of developing brain.33 The diagnosis of CP is retrospective and it is exceptionally made before the age of 6 months in only most severely affected infants, and the specificity of the diagnosis will improve as the child ages and the nature of the disability evolves.34 CP does not result from a single event but rather there is a 9sequence of interdependent adverse events providing to the condition.35
We should take into account this time frame of evolving adverse events when considering the possibility of CP diagnosis in infants.34,35 The understanding of the profile of a child's disability across multiple domains is an ongoing process which is necessary for proper treatment and future planning.34 This theoretical statement is sometimes very difficult to be implemented in practice. In every patient an attempt to make early diagnosis of CP should be followed with factors related to pathogenesis, impairment, and functional limitations.34 To identify pathogenesis of the process, neuroimaging methods should be used. In very low-birthweight premature infants and in term infants with encephalopathy, cranial ultrasound, magnetic resonance imaging (MRI), magnetic resonance (MR) spectroscopy, and diffusion-weighted imaging are the most frequently used.34 Impairment of organs or systems by clinical assessment of muscle tone, strength, and control of voluntary movements for early detection of infants with the risk for CP is frustrating since 43% of 7-year-old children with CP had a normal newborn neurological examination.34,36 Is it possible to change this discouraging fact resulting from our failure to diagnose neurological impairment early enough to intervene? Among ultrasonographers using 4D US interests in diagnosis of neurological impairment have been recently shifted toward prenatal period.23,37 Question is whether there is any possibility to improve timing of postnatal diagnosis of neurologically disabled infant? It is probably easier to perform postnatal assessment than prenatal, by using a simple and suitable for everyday work screening clinical test with good reliability, specificity, and sensitivity. Such tests are still not widely used. However, those complicated and time-consuming are used mostly for clinical research purposes. There is a possibility for the early and simple neurological assessment of the term and preterm newborns with the aim to detect associated risks and anticipate long-term outcome of the infant, and to establish a possible causative link between pregnancy course and neurodevelopmental outcome.38 Since CP is a disorder of movement and postural control resulting in functional limitations, its diagnosis could help in detection of early impairment.34 Clinical neurological assessment which was proposed and practiced by Amiel-Tison, could be very useful in the early detection of newborns at risk.38 Development of CNS is a very complex and long-lasting process, therefore the assessment of its developmental optimality is something which should be assessed in order to investigate whether the infant is neurologically normal or damaged. Neurological assessment at term by Amiel-Tison (ATNAT) is taking into account neurological maturation exploring so called lower subcortical system developing earlier from the reticular formation, vestibular nuclei, and tectum and upper cortical system developing from the corticospinal pathways.39 The role of lower system is to maintain posture against gravity, while the upper system is responsible for the control of erect posture and for the movements of the extremities.39 At the corrected age of 40 gestational weeks optimality assessment consists of head circumference measurement, assessment of cranial sutures, visual pursuit, social interaction, sucking reflex, raise-to-sit and reverse, passive tone in the axis, passive tone in the limbs, finger movements and thumbs outside the fist, and autonomic control during assessment.39 The ATNAT is increasing 10accuracy in assessing CNS function in the neonate by using simple scoring system, focusing on the most meaningful items, promoting a clinical synthesis at term, for term and preterm infants.39 It was recognized that clinicoanatomic correlations using high-resolution neuroimaging techniques could be helpful in the neurological assessment of newborns, while the neurological examination and the functional assessment of the developing CNS are bringing a new perspective of CNS status in neonatal period.40
 
POSTNATAL ASSESSMENT OF GENERAL MOVEMENTS
In the last 30 years objective assessment of videotaped GMs by Prechtl's method has been shown to be predictive of later CP.9,16,18,41 The quality of GMs at 2–4 months post-term (so-called fidgety GM age) has been found to have highest predictive value in the detection of the infants at risk for development of CP.42 It seems that assessment of the quality of GM is a window for early detection of children at high risk for developmental disorders.17,42 Method is simple and it is based on the so called Gestalt perception of GM complexity and variation.17,41,42 Assessment of GMs at 2–4 months post-term at so called fidgety GM age has been found to have the highest predictive value for development of CP if abnormal.17,41,42
Heinz Prechtl's work enabled that spontaneous motility during human development has been brought into focus of interest of many perinatologists prenatally and developmental neurologists postnatally.9,16,18,41,42 According to the research preceding Prechtl's ingenious idea, during the development of the individual the functional repertoire of the developing neural structure must meet the requirements of the organism and its environment.41 This concept of ontogenetic adaptation fits excellently to the development of human organism, which is during each developmental stage adapted to the internal and external requirements.41 Prechtl stated that spontaneous motility, as the expression of spontaneous neural activity, is a marker of brain proper or disturbed function.41,42 The observation of unstimulated fetus or infant which is the result of spontaneous behavior without sensory stimulation is the best method to assess its CNS capacity.41 All endogenously generated movement patterns from unstimulated CNS could be observed as early as from 7 to 8 weeks of postmenstrual age, with developing a reach repertoire of movements within the next two or three weeks, continuing to be present for 5–6 months postnatally.13 This remarkable fact of the continuity of endogenously generated activity from prenatal to postnatal life is the great opportunity to find out those high-risk fetuses and infants in whom development of neurological impairment is emerging. The most important among those movements are GMs involving the whole body in a variable sequence of arm, leg, neck, and trunk movements, with gradual beginning and the end. They wax and wane in intensity, force, and speed being fluent and elegant with the impression of complexity and variability. GMs are called fetal or preterm from 28 to 36 to 38 weeks of postmenstrual age, while after that we have at least two types of movements: (1) writhing present to 46–52 weeks of postmenstrual age and (2) fidgety movements present till 54–58 weeks of postmenstrual age.18,41,42 Main characteristics of mildly abnormal GMs are lack of fluency and existence of considerable variation and complexity.43 We are dealing with definitely abnormal GMs when complexity, variation, and fluency are absent.43
The quality of each individual movement includes speed, amplitude, and force combined in one complex perception.13,18,41-44 Investigation of normal and neurologically 11impaired preterm infants showed that except for higher incidence of clonuses in the abnormal group, there was no marked difference in the quantity of different motor patterns studied.44,45 However, video analysis of another group of sick preterm infants revealed a “reduction of elegance and fluency as well as variability, fluctuation in intensity and speed rather than any change in incidence of distinct motor patterns.”44-46 Based on postnatal studies, it would be very important to seek for abnormal quantity and quality of prenatal movements in order to find fetuses neurologically at risk.46
Some facts are very important in the assessment of GMs. The first important fact is that evaluation of GMs should be based on the video-recorded movements either pre- or postnatally. The second fact is that when assessing GMs examiner should use so called “gestalt perception”, which could be described as overall impression of GMs with standardized procedure.41 During the perception one should recognize the movement patterns of GMs, than assess their complexity, variability, and fluency.41,42 According to Hadders-Algra, GMs could be classified as (A) normal-optimal, (B) normal-suboptimal, (C) mildly abnormal, and (D) definitely abnormal.42 This modality of GM assessment is important for the prenatal and postnatal observation of GMs. It is not so important to assess the quantity of GMs, while the assessment of their quality is of utmost importance in terms of the prognosis of neurodevelopmental outcome. They can better foresee neurodevelopmental outcome than classical neurologic examination alone.47
It can be concluded that prenatal and postnatal assessment of GMs according to Prechtl's method, gives quite new awareness on the function and development of CNS. We are aware that this important modality is time-consuming and requires some technology and expertise to be practiced; however, advantages of its application in prenatal and postnatal life are very promising and encouraging in terms of its prognostic value. Prenatal assessment of GMs is well developed and established. However, prenatal assessment needs sophisticated real-time 4D ultrasonographic or other technology in order to support more precise assessment of GM quality in fetuses.
 
CONTINUITY OF GENERAL MOVEMENTS FROM PRENATAL TO POSTNATAL LIFE
Postnatal studies of neonatal behavior have taught us that the assessment of behavior is a better predictor of neurodevelopment disability than neurological examinations.46 It is important to mention that postnatal observation of movement patterns was launched by Prechtl and coworkers. They have been observing spontaneous movements of the infant using video typing and “off-line” analysis of quantity as well as quality of the movement.17,48 They have shown that assessment of GMs in high-risk newborns has significantly higher predictive value for later neurological development than neurological examination.46,47,49 Kurjak and coworkers performed a study by 4D US and were able to confirm earlier findings made by 2D US, that there is behavioral pattern continuity from prenatal to postnatal life.27 Assessment of neonatal behavior has been shown a better method for early detection of CP than neurological examination alone.50 It is being speculated that intrauterine detection of encephalopathy would improve the outcome. Many fetal behavioral studies have been conducted; however, it is still uncertain whether the assessment of continuity from 12fetal to neonatal behavior could improve our ability of early detection of brain pathology. Early detection could possibly rise an opportunity to intervene and even prevent the expected damage.
 
COULD SOME POSTNATAL SIGNS OF NEUROLOGICAL DISABILITY BE USED PRENATALLY?
Fact that ultrasonography is a powerful tool in the assessment of fetal behavior has been proven by 4D US-enabled visual observation of the fetus, particularly in two especially important domains: fetal finger movements and facial expressions.19,51 This new technology is not only a tool of fetal observation but a very useful tool to evaluate the development of fetal CNS in normally developing fetuses and those at high risk. A basic understanding of fetal neurology includes: (1) defining of motor pathways involved, (2) chronology of their maturation, and (3) direction of myelination.52,53 This information helps clinician to better interpret fetal movements. The experience acquired with the ATNAT helps us in interpretation of fetal movements.39,54,55
The domain of fetal neurology is already too extensive, but the focus of interest is mainly second trimester, despite the fact that spontaneous fetal mobility emerges and has already became differentiated at a very early age.56 This means that we will take into a consideration period of pregnancy from 20 till 40 weeks of gestation, including the end of the neuronal migration and the postmigratory phase corresponding to the development of neocortex.4,57
As already mentioned, CP describes a group of disorders of the development of movement and posture, causing limitations in activity, which are attributed to nonprogressive disturbances occurring at the time of development of fetal brain.58-65 Motor disorders which occur in patients with CP are often accompanied by disturbances of sensation, cognition, communication, perception, behavior, and/or with seizure disorder.58-65 “Disturbances” is a term which refers to events or processes influencing in some way the expected pattern of brain maturation.55 Those events or processes are many, with consequences varying from very conspicuous to very subtle. We should always keep in mind what many neurologists emphasize that morphology does not always correspond to neurological outcome.39,54,55 The opposite view is the one from pediatricians and neurophysiologists. They are involved in long-term follow-up studies, and they are certainly not that optimistic. It would be wise to consider long run prognosis, for each specific type of fetal brain damage and make appropriate decisions for conservative management.
Hopes have been headed toward MR, but in many cases brain changes cannot be detected as early as the first year of life, like for example, pathological gliosis which causes secondary hypomyelinization.
While examining the fetal head by 4D, sonographer should examine bony structures and fetal cranial sutures. If they are folding over one another, it is considered to be a bad sign as previously described by Amiel-Tison.39,55 The same sign should be searched for postnatally, as a part of neurological examination.62
The majority of pediatricians believe that the main obstacle for early prediction of CP based on a functional observation of the fetus such as visual observation by 4D US, is due to the “precompetent” stage of most of the motor behavior observed in utero.39,55 One of the possible signs detected could be high-arched palate, described by Amiel-Tison, in clinical assessment of the infant nervous system.39,55 What was believed as undetectable became visible by 4D. Recently, the three-dimensional 13(3D) “reverse face technique” has been described. This technique overcomes shadowing the fetal face by rotating the frontal facial image through 180° along the vertical axis, so that the palate, nasal cavity, and orbits become visualized.63,64
Pooh and Ogura, in their early work, examined 65 normal fetuses by 3D/4D. The purpose of their study was to investigate the natural course of fetal hand and finger positioning.26 During 9th week and at the beginning of 10th week fetal hands were placed in front of the chest and no movements of wrists and fingers could be visualized. Active arm movements were present from the middle of 10th week.26 This study is very important since it is showing that movements of fingers and thumbs begin in the early stage of human life, long before the maturation of the upper system. Therefore, this motor activity depends on the lower system and not before 30–32 weeks switches to the upper control.
Amiel-Tison also described so called “neurologic thumb” squeezed in a fist. Clenched fingers can also be found by 4D US, as well as overlapping cerebral sutures.19,26
According to de Vries and coworkers, head anteflexion becomes visible during 10th and 11th gestational week.56 However, the activity of flexor muscles will depend on the upper system since 34 weeks of gestation. The absence of active head flexion explored by the raise-to-sit maneuver is one of the major neurological signs at 40 weeks of gestation.39,54,62
 
WHAT IS KURJAK'S ANTENATAL NEURODEVELOPMENTAL TEST?
Kurjak's Antenatal Neurobehavioral Test is a new scoring system for the assessment of fetal neurobehavior which is based on prenatal evaluation of the fetus by 3D/4D US.66 Test is a combination of several parameters consisting of fetal GMs and of postnatal ATNAT signs, which can be easily visualized prenatally by using 4D US, as described earlier.25,38 As mentioned before, following parameters have been incorporated in the KANET test: isolated head anteflexion, overlapping cranial sutures, head circumference, isolated eye blinking, facial alterations, mouth opening (yawning or mouthing), isolated hand and leg movements, thumb position, and Gestalt perception of GMs (overall perception of the body and limb movements with their qualitative assessment).
Several papers have shown that there is a continuity of behavior from pre- to postnatal life. It has been observed that all movements which are present in neonates are also present in fetal life, with the exception of Moro's reflex, which cannot be demonstrated in fetuses.67 This is probably due to a different environment to which fetus and neonate are exposed. The fetus lives in an environment of microgravity, while the newborn is exposed to full gravity, which creates certain obstacles for neurodevelopment in the first months of life.68-70 The parameters were chosen based on developmental approach to the neurological assessment and on the theory of central pattern generators of GMs emergence. They were the product of multicentric studies conducted for several years.25,30 KANET is a combination of assessments of fetal behavior, GMs, and three out of four signs which have been postnatally considered as symptoms of possible neurodevelopmental impairment (neurological thumb, overlapping sutures, and small head circumference).68,69
Kurjak's Antenatal Neurobehavioral Test has been standardized, it is reproducible and easily applied by fetal medicine specialists.68 Recommendation is to perform KANET in the third trimester of pregnancy, between 28 and 38 weeks. Optimal duration of the examination is between 15 and 20 minutes, and fetus should be examined while awake. If the fetus 14is in the sleeping period, the assessment should be postponed for 30 minutes or for the following day, at a minimum period of 14–16 hours. In cases of grossly abnormal or borderline score, the test should be repeated every 2 weeks until delivery. Special attention should be paid to the facial movements and to eye blinking, which are prenatally very informative and important (the face is the mirror of the brain).
zoom view
Figs. 5A and B: (A) Normal Kurjak's antenatal neurobehavioral test (KANET) score at 34 weeks of pregnancy; (B) Normal KANET score at 32 weeks of pregnancy—the impact of the evolution of ultrasound technology on the quality of fetal assessment.
15
zoom view
Figs. 6A to C: Face grimacing.
Overall number of movements should be defined in very active or inactive fetuses and compared with normal values of previous studies (Figs. 5 and 6).25,30
For the application of KANET test all the examiners should have extensive hands-on education, both in low- and high-risk pregnancies. Interobserver and intraobserver variability should be available. It is advisable to use 4D US machines, with frame rate of minimum 24 volumes/sec. KANET consists of eight parameters (Table 3).68
A score range of 0–5 is characterized as abnormal, a score calculated from 6–13 is considered borderline, and a score range of 14–20 is normal (Table 4).1,21,68 After that neonates should be followed up postnatally for neurological development for a 2 years period.
The test evaluates quantitative as well as qualitative aspects of fetal motor behavioral patterns. The parameters examined by this test are a combination of GMs and parameters adopted from ATNAT.70,71 It is believed that the criterion of quality and quantity of spontaneous GMs has excellent reliability in evaluating the integrity of fetal CNS.72,73 Furthermore a continuity of behavioral patterns from prenatal to the postnatal period has been proven.27,74,75 Both those facts support the choice of the parameters used in this test which make KANET theoretically appropriate for the assessment of fetal behavior. According to previous reports28,29,76-79 KANET easily detects serious functional impairment associated with structural abnormalities. Studies have shown that application of KANET in both low- and high-risk populations has given good results. Especially in high-risk populations, KANET may provide useful information regarding the neurological outcome of these fetuses.80 KANET is the first test which is based on 4D US, with an original scoring system and has been standardized. Therefore, it can be implemented in everyday practice, overcoming the difficulties and covering the gaps of methods that were used in the past for the evaluation of fetal behavior.16,81,82 Studies show that KANET is easily applicable to most pregnancies. Furthermore, the learning curve is reasonable for physicians who already have training in obstetrical ultrasound. Actual duration of KANET ranges from 15 to 20 minutes.83 All of these show strong evidence that it can be widely implemented in everyday clinical practice.84
Kurjak's Antenatal Neurobehavioral Test has been introduced in training and it has been calculated that the number of KANET tests needed to be performed by experienced ultrasound specialist in order to be familiar to assess a fetus with 4D US in 20 minutes is 80.85 The success rate of the test ranges from 91 to 95%. Further study of each parameter revealed a success rate for the assessment of particular signs of 88% for isolated eye blinking and 100% for mouth opening and isolated leg movement.8516
TABLE 3   Proposal for the new Kurjak's antenatal neurobehavioral test (KANET) assessment tool consisting of eight parameters.68,84
Sign
Score
Sign score
0
1
2
Isolated head anteflexion
zoom view
Abrupt
Small range (0–3 times of movements)
Variable in full range, many alteration (>3 times of movements)
Cranial sutures and head circumference (HC)
zoom view
Overlapping of cranial sutures
Normal cranial sutures with measurement of HC below or above the normal limit (–2 SD) according to GA
Normal cranial sutures with normal measurement of HC according to GA
Isolated eye blinking
zoom view
Not present
Not fluent (1–5 times of blinking)
Fluency (>5 times of blinking)
Facial alteration (grimace or tongue expulsion)
zoom view
Not present
Not fluent (1–5 times of alteration)
Fluency (>5 times of alteration)
or
Mouth opening (yawning or mouthing)
zoom view
Isolated leg movement
zoom view
Cramped
Poor repertoire or small in range (0–5 times of movement)
Variable in full range, many alteration (>5 times of movements)
Isolated hand movement
zoom view
17
or
Hand to face movements
zoom view
Cramped or abrupt
Poor repertoire or small in range (0–5 times of movement)
Variable in full range, many alteration (>5 times of movements)
Fingers movements
zoom view
Unilateral or bilateral clenched fist, (neurological thumb)
Cramped invariable finger movements
Smooth and complex variable finger movements
Gestalt perception of GMs
Definitely abnormal
Borderline
Normal
Total score
(GA: gestational age; GM: general movement; SD: standard deviation)
TABLE 4   Interpretation of Kurjak's antenatal neurobehavioral test (KANET) scores.68,84
Total score
Interpretation
0–5
Abnormal
6–9
Borderline
10–16
Normal
KANET has almost 100% negative predictive value, interobserver variability was satisfactory with lowest being for the facial expression (K = 0.68) and highest for the finger movements (K = 0.84).85
 
WHAT HAVE STUDIES ABOUT KANET SHOWN SO FAR?
One of the first studies which used a preliminary form of the KANET scoring system was that by Andonotopo et al. in 2006. They aimed to assess fetal facial expression and quality of body movements and examine if they are of diagnostic value for brain impairment in fetuses with growth restriction. In that prospective study of 50 pregnancies with IUGR fetuses in the third trimester of pregnancy, there has been noted a tendency of less behavioral activity in IUGR than normal fetuses.29 Future investigation of the use of 4D US for quantitative and qualitative assessment of fetal behavior as possible indicators of the neurological condition in IUGR fetuses was encouraged by the results of this study (Figs. 7 to 10).29
In 2008, the Zagreb group were the first to introduce the KANET for the assessment of neurological status of the fetus, aiming to the detection of fetal brain and neurodevelopmental alterations due to in utero brain impairment.86,8718
zoom view
Figs. 7A to I: Hand and finger movement.
zoom view
Fig. 8: Kurjak's antenatal neurobehavioral test (KANET)—facial alterations mouthing, eye blinking, and hand movement.
19
zoom view
Fig. 9: Tongue expulsion and mouthing.
zoom view
Fig. 10: Smiling.
20
In order to develop the new scoring system they identified neonates with severe brain damage and neonates with good neurological condition and then compared the neonatal findings, with corresponding findings in utero.86,87 In the group of 100 low-risk pregnancies they retrospectively applied KANET. After delivery, postnatal neurological assessment (ATNAT) was performed and all neonates assessed as normal reached a score between 14 and 20, assumed to be the score of optimal neurological development.86,87 New scoring system was applied in the group of 120 high-risk pregnancies in which, based on postnatal neurological findings, three subgroups of newborns were identified: normal, mildly or moderately abnormal, and abnormal. Based on this, findings a neurological scoring system has been proposed.86,87 All normal fetuses reached a score from 14 to 20. Ten fetuses who were postnatally described as mildly or moderately abnormal achieved a prenatal score of 5–13, while another 10 fetuses postnatally assigned as neurologically abnormal had a prenatal score 0–5.86,87 Among this group, four had alobar holoprosencephaly, one had severe hypertensive hydrocephaly, one had thanatophoric dysplasia, and four fetuses had multiple malformations.86,87 This study inspired a large series of multicenter studies (Table 5) that used the KANET in order to assess the usefulness of this promising new scoring system for the assessment of neurological status in fetuses and the recognition of signs of early brain impairment in utero.86,87
The first application of KANET was on growth-restricted fetuses,29 where mainly facial expressions and body movements were studied. A decreased behavioral activity in the IUGR fetuses compared to normal growth cases was noticed.29 The study that followed was the first with complete neurologic postnatal assessment for all studied fetuses. According to the used criteria neonates were divided into three groups: (1) normal, (2) mildly or moderately abnormal, and (3) abnormal.29 Based on these groups, it was decided to form the first KANET scoring system which was as follows: 14–20 (normal), 5–13 (mildly or moderately abnormal), and 0–5 (abnormal). All the following studies were designed based on this scoring system.84,86,87
The first study which included a large number of high-risk pregnancies identified 32 fetuses at neurological risk: 7 cases with abnormal score were identified and 25 with a borderline KANET score.88 There were also 11 cases which either died in utero or had a termination of pregnancy and all of these cases had an abnormal KANET score.88 The seven remaining neonates with abnormal KANET were followed up postnatally at 10 weeks of neonatal life and three had confirmed pathological ATNAT score.88 These three cases included a neonate with arthrogryposis, a neonate with cerebellar vermian complete aplasia, and one case with a history of CP in a previous pregnancy.88 Among the parameters that KANET uses, facial expressions appeared to be most pathological—the fetal faces, due to lack of expressions on 4D US, were characterized by the authors as “masks.”88 The remaining four pathological KANET cases had normal postnatal assessment. However, these four cases had complications of pregnancy.88 There was one case with ventriculomegaly, one case with pre-eclampsia, one case with maternal thrombophilia, and one case with oligohydramnios.88 From 25 cases diagnosed with borderline KANET result, 22 neonates showed a borderline ATNAT score and were followed up.8821
TABLE 5   List of studies that have applied KANET test to different populations.
Author
Year
Study
Study design
Study population
Indication
No
GA (weeks)
Time (mins)
Result
Summary
Kurjak et al.86,87
2008
Cohort
Retrospective
High risk
Multiple
220
20–36
30
Positive
A new scoring system was proposed for the antenatal assessment of fetal neurological status
Kurjak et al.88
2010
Multicenter
Prospective
High risk
Multiple
288
20–38
30
Positive
KANET appeared to be prognostic of antenatal detection of serious neurological fetal problems. KANET also identified fetuses with severe structural abnormalities, especially associated with brain impairment
Miskovic et al.89
2010
Cohort
Prospective
High risk
Multiple
226
20–36
30
Positive
Correlation between antenatal (KANET) and postnatal (ATNAT) results was found. KANET showed differences of fetal behavior between high- and low-risk pregnancies
Talic et al.90
2011
Multicenter
Cohort
Prospective
High risk
Multiple
620
26–38
15–20
Positive
KANET test had a prognostic value in discriminating normal from borderline and abnormal fetal behavior, in normal and in high-risk cases. Abnormal KANET scores were predictable of both intrauterine and postnatal death
Talic et al.91
2011
Multicenter
Cohort
Prospective
High risk
Ventriculomegaly
240
32–36
10–15
Positive
Statistically significant difference was identified in KANET scores between normal pregnancies and pregnancies with ventriculomegaly. Abnormal KANET scores and most of the borderline scores were noted in fetuses with severe ventriculomegaly, especially associated with additional abnormalities22
Honemeyer et al.92
2011
Cohort
Prospective
Unselected
Unselected
100
28–38
N/A
Positive
Normal prenatal KANET scores had a significant predictive value of a normal postnatal neurological evaluation
Lebit et al.93
2011
Cohort
Prospective
Low risk
Normal 2D examination
144
7–38
15–20
Positive
A specific pattern of fetal neurobehavior corresponding to each trimester of pregnancy was identified
Abo-Yaqoub et al.94
2012
Cohort
Prospective
High risk
Multiple
80
20–38
15–20
Positive
Significant difference in KANET scores was noted. All antenatally abnormal KANET scores had also an abnormal postnatal neurological assessment
Vladareanu et al.95
2012
Cohort
Prospective
High risk
Multiple
196
24–38
N/A
Positive
Most fetuses with normal KANET → low-risk, those with borderline → IUGR fetuses with increased MCA RI and most fetuses with abnormal KANET → threatened PTD with PPROM. Difference in fetal movements was identified between the two groups. For normal pregnancies → 93.4% of fetuses achieved normal score, for high-risk pregnancies → 78.5% of fetuses had a normal score
Honemeyer et al.96
2012
Cohort
Prospective
High and low risk
Multiple
56
28–38
30
max
Positive
Introduction of the average KANET score → combination of the mean value of KANET scores throughout pregnancy. Revealed a relationship of fetal diurnal rhythm with the pregnancy risk23
Kurjak et al.97
2013
Cohort
Prospective
High and low risk
Multiple
869
28–38
20
Positive
Statistically significant differences in the distribution of normal, abnormal, and borderline KANET scores between low-risk and high-risk groups were found. Fetal behavior was significantly different between the normal group and the high-risk subgroups
Predojevic et al.98
2013
Case study
Prospective
High risk
IUGR
5
3139
30
Positive
KANET could recognize pathologic and borderline behavior in IUGR fetuses with or without blood flow redistribution. Combined assessment of hemodynamic and motoric parameters could enable in better diagnosis and consultation
Athanasiadis et al.99
2013
Cohort
Prospective
Unselected (High and low risk)
Multiple
(IUGR, PET, GDM)
152
2nd and 3rd trimester
N/A
Positive
The neurodevelopmental score was statistically significant higher in the low-risk group compared to the high-risk group (p < 0.0004). The diabetes subgroup score was statistically significantly higher compared to the IUGR and the pre-eclampsia subgroup (p = 0.0001)
(KANET: Kurjak's antenatal neurological test; No: number of patients; IUGR: intrauterine growth restriction; MCA: middle cerebral artery; PTD: preterm delivery; PPROM: preterm premature rupture of membranes; PET: pre-eclampsia; GA: gestational age; GDM: gestational diabetes mellitus)
24The three remaining cases showed normal ATNAT result.88 There was an interesting paper which studied a case of a fetus with prenatally diagnosed acrania.88 The authors studied the fetal behavior and managed to document how it altered from 20 weeks of gestation onward.88 It was noticed that as pregnancy progressed and the control center of motoric activity shifted from the lower to the upper part, KANET score was decreasing respectively, suggesting that neurological damage in later pregnancy is possible.88
A study with 226 cases, including different study populations, identified three cases with pathological KANET score.89 All three cases had chromosomal abnormalities and all three of them postnatally also had an abnormal ATNAT score.89 Scores from antenatal KANET and postnatal ATNAT were compared between low- and high-risk groups, and they showed differences between them, for 8 out of the 10 parameters—these included: head anteflexion, eye blinking, facial expressions—grimacing, tongue expulsion, mouth movement such as yawning, jawing, swallowing—isolated hand movements, hand to face movements, fist and finger movements, and GMs.89
The comparison of the two tests revealed correlation between them and proved that the neonatal examination (ATNAT) was a satisfactory confirmation of the prenatal ultrasound examination (KANET), stating that KANET could offer useful information about the neurological status of the fetus and can be applied in clinical practice.89
One of the largest studies regarding KANET included 620 cases, of both low- and high-risk populations (100 low-risk and 520 high-risk cases) and it showed differences in the scores between the two groups.90 The study showed interesting results that most abnormal cases were noted from pregnancies with a previous history of CP (23.8%) and that most borderline scores were noted in cases with possible chorioamnionitis (56.4%).90 There parameters of KANET that were more notably different between the two groups were: overlapping cranial sutures, head circumference, isolated eye blinking, facial expressions, mouth movements, isolated hand movements, isolated leg movements, hand to face movements, finger movements, and GMs.90 This study confirmed the relationship of pathological KANET with increased risk of perinatal mortality and neurological impairment and showed that the results can be confirmed and are reproducible postnatally.90
A very interesting study which tried to shed some light on the clinical dilemmas caused by the prenatal diagnosis of ventriculomegaly, compared fetuses with ventriculomegaly91 with apparently low-risk fetuses (normal CNS appearance on ultrasound examination). A significant difference was noted between the two groups, with the KANET score decreasing as the degree of ventriculomegaly was increasing.91 For isolated cases of mild or moderate ventriculomegaly no pathological KANET scores were noted and postnatal evaluation confirmed the prenatal KANET, offering valuable information for the more complete assessment of these fetuses and better counseling regarding their prognosis.91
A recent study with a complete follow- up92 postnatally up to 3 months of life, having complete postnatal documentation in all cases, showed that a normal KANET score is very reassuring of a good neonatal outcome, confirming the consistency of prenatal and postnatal assessment.92 It was a great challenge to understand the evolution of fetal movements by 4D US throughout pregnancy, and how these movements reflect the 25development and integrity of fetal nervous system.92 It was shown that during the first trimester of pregnancy the development of the frequency and the complexity of fetal movements is more important, while during the second trimester, the variation of fetal movements develop, with more detailed movements (facial expressions and eye blinking) appearing at the end of this trimester.93 Finally at the end of third trimester, the number of fetal movements declines as a result of the increase of fetal rest periods, due to fetal cerebral maturation, and this is something that most pregnant women notice near term.7781
Abo-Yaqoub et al.94 aimed to study how practical is to apply 4D ultrasonography for the assessment of fetal neurobehavior and also how useful it is for the prediction of neurological impairment.94 Their results showed agreement of prenatal scores with postnatal assessment. The parameters that were significantly different between the two groups were: isolated head anteflexion, isolated eye blinking, facial expressions, mouth movements, isolated hand movements, hand-to-face movements, finger movements, and GMs.94 The difference was not statistically significant regarding isolated leg movements and cranial sutures.94
Vladareanu et al.95 noted that the majority of normal KANET scores derived from low-risk populations that they studied, while the majority of cases with borderline or pathological KANET scores derived from the high-risk groups and in some cases were related to abnormal values of Doppler studies in IUGR fetuses.95 The authors concluded that KANET can be useful for the detection of neurological impairment which could become obvious during the antenatal or postnatal period.95
The average KANET score was introduced for fetuses who had more than one assessments in order to have a more complete picture of the behavior of these fetuses.96 The average KANET score derived from the mean calculation of KANET scores for each fetus throughout pregnancy, since these fetuses had more than one KANET assessments.96 What was new from this study was the association of KANET score with fetal diurnal rhythm.96 For the high-risk group 89% of the borderline scores were recorded at times that the mothers characterized them as active periods, compared with 33.3%, respectively in the low-risk pregnancies.96
Another important goal was to compare all parameters of KANET between high- and low-risk pregnancies and observe differences in fetal behavior between them. For pathological KANET score 5 out of 8 parameters were significant different: isolated head anteflexion, cranial sutures and head circumference, isolated hand movement or hand to face movements, isolated leg movement, and fingers movements.9799 Further results showed that only high-risk patients had abnormal scores (8.5%), while comparing high- and low-risk groups it was noticed that 80.6% of high-risk patients had borderline results while 85.3% of low-risk patients were normal, both being statistically significant.9799 For abnormal KANET results (score between 0 and 5), some were related to pregnancy complications (pre-eclampsia, threatened preterm labor, and drug abuse) and some were related to fetal condition (trisomy 13, 18, and 21 and IUGR).9799
Other studies confirmed the feasibility of neurodevelopment assessment by 4D US and showed further evidence that KANET test is useful in early identification of fetuses prone to neurological impairment.100,10126
When comparing Caucasian to Asian populations in order to check for ethnic differences, the total KANET score was normal in both populations, but there was a difference noted in total KANET scores between these two populations.102 When individual KANET parameters were compared, significant differences were observed in four fetal movements: (1) isolated head anteflexion, (2) isolated eye blinking, (3) facial alteration or mouth opening, and (4) isolated leg movement.102 No significant differences were noted in the four other parameters: (1) cranial suture and head circumference, (2) isolated hand movement or hand to face movements, (3) fingers movements, and (4) gestalt of GMs, showing that ethnicity is a parameter that should be considered when evaluating fetal behavior, especially during assessment of fetal facial expressions.102 The authors concluded that although there was a difference in the total KANET score between Asian and Caucasian populations, all the scores in both groups were within normal range proving that ethnical differences in fetal behavior do not affect the total KANET score, but close follow-up should be continued in some borderline cases.102
Unpublished data from Greece collected from 655 singleton pregnancies, showed that KANET is a method which is feasible in everyday clinical practice, with a success rate of 95% and a very low negative predictive value. There were the cases where KANET could not be completed. The reason for that was severe oligohydramnios, fibroid uterus (difficult imaging), very high body mass index (BMI) and a case that due to vasovagal reaction-supine hypotensive syndrome ultrasound examination could not be completed. From the 655 cases, 1,712 KANET were performed from only two operators and the interobserver variability was calculated showing adequate results for all parameters, with the lowest being for facial alterations (K = 0.68) and the highest for finger move-ments (K = 0.84). This study was primarily designed to compare the neurological status of pregnancies complicated by diabetes, compared to low-risk pregnancies and it did show that there was a difference between the fetal neurobehavior of these two groups, with the diabetic pregnancies having lower scores.103
Figures 11 to 13 are illustrating important parameters of KANET depicted by high-definition (HD) 4D US.
 
Interpretation of KANET Test Research
Assessment of fetal neurobehavior and detection of fetal neurological impairment in utero is one of the greatest challenges in perinatal medicine. KANET is the first method that applied 4D US for the assessment of the fetus in the same way like a neonate is assessed neurologically after birth by neonatologists. It appears to be a powerful diagnostic method for the detection of neurological impairment and for the assessment of fetal neurobehavior, conditions that were not accessible with the traditional prenatal diagnostic methods which were used so far.67 Studies have proved the validity of this method,27,28,84 that it can be applied in everyday clinical practice, especially for high-risk cases, showed how and by whom it should be performed, what is the value of the result of KANET, and how it should be managed. It is very difficult to make diagnosis of neurological impairment prenatally and usually all these diagnosis are made postnatally, even months or years after delivery. Moreover, neurological conditions such as CP, are not adequately understood and they are falsely attributed to incidents during labor, although it has been proven that the majority of CP cases originate sometime during in utero life and are not related to intrapartum events.27
zoom view
Figs. 11A to C: Mouthing as part of the assessment of fetal neurobehavior [high-definition four-dimensional ultrasound (4D US)].
zoom view
Fig. 12: Parameters of Kurjak's antenatal neurodevelopmental test (KANET): mouthing, yawning, and hand movements [high-definition four-dimensional ultrasound (4D US)].
zoom view
Fig. 13: Facial expression and grimacing [high-definition four-dimensional ultrasound (4D US)].
28
All these things lead to delayed diagnosis of neurological conditions. The later a neurological impairment is diagnosed the less is the possibility of an effective intervention. In order to increase a possibility of an effective intervention or even treatment, it would be extremely challenging to have a timely diagnosis of such conditions. KANET offers a possibility to detect prenatally fetuses at risk for neurological problems, offering a possibility of even an in utero intervention or at least an early postpartum intervention.84 The earliest physiotherapy is commenced and intervention programs are applied in neonates that are born prematurely or with neurological problems the better the neurodevelopmental outcome of these neonates, with the cognitive benefits persisting into preschool age. KANET appears to be able to offer this advantage of early identification of these fetuses with neurological problems, so that they could be put under treatment as early as possible, aiming to a better outcome.86,87,104,105
Even more, the explicitly detailed pictures obtained by the new ultrasound machines but also the advanced techniques of molecular genetics, many times brings us, as ultrasound specialists, across findings (anatomical and chromosomal) of uncertain clinical significance and prognosis, especially regarding the neurological integrity of the fetus.106,107 A method like KANET offers a more comprehensive diagnostic approach to such dilemmas and hopefully in the near future with more data we could form a complete neurosonobehavioral assessment of the fetus and a more complete counseling of these couples.108
Many centers for the assessment of fetal neurobehavior of not only high-risk pregnancies but also low-risk pregnancies have introduced KANET in everyday clinical practice.
Studies show that the sensitivity and specificity of the test are satisfactory, as are the positive and negative predictive values and the inter- and intraobserver variability of this method. The KANET has been introduced into systematical training and ultrasound specialists have already been certified to perform this examination. Hopefully, application of KANET on larger populations, both high- and low-risk, will give more knowledge regarding early detection of fetuses at risk for neurological impairment, in order to allow accurate diagnosis prenatally, and as a consequence prompt intervention that could possibly improve the outcome of some of these neonates.
 
The Most Recent Research Data on the KANET Test
The data of fetal prenatal neurological testing from nine centers by nine investigators from seven countries which were performed from May 2010 till April 2020, with the number of 25–1,344 fetuses from singleton pregnancies are presented.109 Altogether there were 3,709 fetuses of whom 1,573 (42.4%) completed the pregnancy of which 1,556 were eligible for postnatal follow-up, while in 2,136 mostly low-risk pregnancies for 2,094 the data were missing while in 42 the pregnancies were still ongoing (Table 6). From the group of 3,709 fetuses 3,206 (86.5%) had normal, 379 (10.2%) borderline, and 124 (3.3%) abnormal KANET scores, respectively, while in those after completed pregnancy 153 (9.7%) had borderline and 52 (3.3%) had abnormal KANET scores (Tables 6 and 7).
The inter-rater reliability was substantial for low-risk pregnancies and moderate for high-risk pregnancies.29
TABLE 6   The results of the KANET+ test from nine centers: the date of the introduction of KANET, number of patients investigated, total number of borderline and abnormal scores, number with postnatal follow-up, number of borderline and abnormal cases in all fetuses, and those postnatally followed-up.109
Name of the investigator/country
Introduction of KANET+
Number of fetuses
All fetuses
Postnatal follow-up
KANET+ scores
Number of children
KANET+ scores
Borderline
Abnormal
Borderline
Abnormal
Lara Spalldi Barisic, Croatia*
May,
2010
1,344
98
(7.3%)
52
(3.9%)
482
(35.9%)
36
(7.5%)
19
(3.9%)
Panos Antsaklis, Greece19
January,
2012
1,180
105
(8.9%)
40
(3.4%)
520
(44.1%)
47
(9.0%)
19
(3.7%)
Raul Moreira Neto, Brazil17
November,
2014
631
115
(18.2%)
19
(3.0%)
212
(33.6%)
39
(18.2%)
6
(3.0%)
Suada Tinjić Tuzla, B and H18
May,
2015
141
38
(27.0%)
5
(3.5%)
60
(42.6%)
16
(27.0%)
2
(3.5%)
Sonal Panchal, India33
October,
2015
160
3
(1.9%)
0
145
(90.6%)
3
(1.9%)
0
Dorota Bomba Opon, Poland18
July,
2017
63
6
(9.5%)
3
(4.8%)
26
(41.3%)
2
(9.5%)
1
(4.8%)
Gigi Selvan, India*
July,
2018
64
0
1
(1.6%)
35
(54.7%)
0
1
(1.6%)
Sertac Esin, Turkey18
February,
2019
25
4
(16.0%)
1
(4.0%)
17
(68.0%)
3
(16.0%)
1
(4.0%)
Edin Medjedovic, B and H*
July,
2019
101
10
(9.9%)
3
(3.0)
76
(75.2%)
7
(9.2%)
3
(3.9%)
Total
May, 2010–July, 2019
3,709
379
(10.2%)
124
(3.3%)
1,573
(42.4%)
153
(9.7%)
52
(3.3%)
+KANET: Kurjak's Antenatal Neurodevelopmental Test
*Unpublished data
(B and H: Bosnia and Herzegovina)
There were 2,502 (67.5%) fetuses from low-risk pregnancies and 1,207 (32.5%) fetuses from high-risk pregnancies (Table 7). Compared to the fetuses from low-risk pregnancies, fetuses from high-risk pregnancies had higher frequencies of borderline and abnormal KANET scores, which was statistically significant. We could speculate that a hostile intrauterine environment is affecting adversely fetal neurobehavior, which can be detected by the KANET test. Dropout rate in the investigation was high (47.6%), respectively, which is a severe constraint of the investigation. Most of the dropouts were from the low-risk pregnancies with low rates of borderline or abnormal KANET scores and high probability of normal postnatal development.
Out of 1,556 fetuses who were born after KANET testing the distribution based on age is presented in Table 3. Most of the children were older than 3 years (819 out of 1,556 or 52.6%). Most of the infants were developing normally (1,530 or 98.3%), 8 (0.5%) had slight and moderate developmental delay, while 18 (1.2%) had severe developmental delay.30
TABLE 7   The data on KANET& scores from low- and high-risk pregnancies shown as normal, borderline, and abnormal, comparing abnormal and borderline score prevalence depending on the pregnancy risk.109
Name of the investigator
Risk of the pregnancy
KANET score
Total number
Normal
Borderline
Abnormal
Lara Spalldi Barisic, N* = 1,344
Low
1,017
31
0
1,048
High
177
67
52
296
Panos Antsaklis, N = 1,180
Low
772
23
0
795
High
263
82
40
385
Raul Moreira Neto, N = 631
Low
348
58
0
406
High
149
57
19
225
Suada Tinjic, N = 141
Low
96
33
0
129
High
2
5
5
12
Sonal Panchal, N = 160
High
157
3
0
160
Dorota Bomba Opon, N = 63
Low
30
0
0
30
High
24
6
3
33
Gigi Selvan, N = 64
Low
30
0
0
30
High
33
0
1
34
Serac Esin, N = 25
High
20
4
1
25
Edin Medjedovic, N = 101
Low
64
0
0
64
High
24
10
3
37
Subtotal low risk
2,357
(94.2%)
145
(5.8%)
0
2,502
(67.5%)
Subtotal high risk
849
(70.3%)
234
(19.4%)
124
(10.3%)
1,207
(32.5%)
Total
3,206
(86.5%)
379
(10.2%)
124
(3.3%)
3,709
χ2 = 457.36; d.f.+ = 2; p < .01
&Kurjak's Antenatal Neurodevelopmental Test
*N = total number of pregnancies
+d.f. = degrees of freedom
The severe and moderate developmental delay could develop more frequently in the group of infants who as fetuses had abnormal KANET scores which are presented in Table 8, which was statistically significant.
Most of the infants with abnormal KANET scores were from high-risk pregnancies, they had severe congenital malformations, often IUGR, and had more chance to die in utero. To investigate the validity of the KANET test for the prediction of developmental delay and CP, we made predictive value calculations from sensitivity, specificity, and prevalence for all age groups with developmental delay and only for the age group above 2 years for the CP and severe developmental delay. The calculations showed that the KANET test has low sensitivity for the detection CP, and lower sensitivity for the detection of slight, moderate, and severe developmental delay, than for only severe developmental delay.31
TABLE 8   Postnatal follow-up of infants who as fetuses had borderline and abnormal KANET& scores from low- and high-risk pregnancies including termination of pregnancy and postnatal death.109
Name of the investigator (N*)
KANET score (N*)
Postnatal developmental delay (N*)
Comment
No
Slight
Moderate
Severe
Lara Spalldi Barisic,
N = 482
Borderline N = 36
33
0
0
2
1 IUD+
Abnormal N = 19
15
0
0
4
All severe congenital malformations
Panos Antsaklis,
N = 520
Borderline N = 47
45
0
0
1
1 IUD+
Abnormal N = 19
7
0
0
1++
5 died
6 terminated
Raul Moreira Neto,
N = 212
Borderline N = 39
39
0
0
0
-
Abnormal N = 6
3
0
0
3
One case of trisomy 13, 18, and 21
Suada Tinjic,
N = 60
Borderline N = 16
16
0
0
0
-
Abnormal N = 2
1
1
0
0
IUGR** one with slight developmental delay
Sonal Panchal,
N = 145
Borderline N = 3
0
0
2
1
-
Abnormal N = 0
0
0
0
0
-
Dorota Bomba Opon,
N = 26
Borderline N = 2
2
0
0
0
-
Abnormal N = 1
0
0
0
1
One with severe delay Kagami Ogata syndrome
Gigi Selvan,
N = 35
Borderline N = 0
0
0
0
0
-
Abnormal N = 1
0
0
1
0
IUGR**
Serac Esin,
N = 17
Borderline N = 3
3
0
0
0
-
Abnormal N = 1
0
0
0
1
Trisomy 18, died in the first day of life
Edin Medjedovic,
N = 76
Borderline N = 7
7
0
0
0
-
Abnormal N = 3
3
0
0
3
Two severe congenital malformations and one IUGR**
Subtotal normal KANET
1,351 (86.8%)
1,348
(99.8)
0
2 (0.1%)
1 (0.1%)
One with severe delay Kagami Ogata syndrome
Subtotal borderline
KANET
153 (9.8%)
145
(94.8%)
0
2 (1.3%)
4 (2.6%)
2 IUD (1.3%)
Subtotal abnormal
KANET
52 (3.3%)
26
(50.0%)
1 (1.9%)
1 (1.9%)
13 (25.0%)
11 terminated or died
(21.2%)
Total
1,556 (100.0%)
1,519
(97.6%)
1 (0.1%)
5 (0.3%)
18 (1.2%)
13 (0.8%)
χ2 = 315.28; d.f.+++ = 6; p <0.01
&Kurjak's Antenatal Neurodevelopmental Test
*N: Number of infants
+IUD: Intrauterine death
++One infant with CP (with previous case of cerebral palsy in the family)
**IUGR: Intrauterine growth restriction
+++d.f. = Degrees of freedom32
Specificity was rather high for detection of CP, it was lower for the detection of developmental delay. In concordance, positive predictive value and the false positive rate were high. The negative predictive value was high and the false negative rate was low. If the KANET score is normal, then there is a huge probability of postnatal normal development, with a very small chance that it is false negative meaning that the probability of abnormal postnatal development is low if KANET was normal. There is a problem with the interpretation of abnormal and borderline KANET scores which appears to have very low sensitivity and positive predictive value and high false positive rate. This means that based on the borderline or abnormal KANET score one cannot predict the neurodevelopmental outcome, although there is a higher tendency of developmental disorders to occur in infants with abnormal KANET scores from high-risk pregnancies, however, it cannot be concluded concerning the type and severity of the disorder, especially not CP. As it has been pointed out many times in the papers published up to now by our team, the most important aim of KANET introduction was to early predict the development of CP in order to intervene early enough to decrease possible consequences of the condition on individual, family, societal, and public health level. We were aware that early diagnosis of CP was and is not easy even postnatally. There is a rule saying that making the diagnosis of CP is inversely proportional to the age, undermining confidence in diagnosing CP early. Possible barriers in postnatal early diagnosis could be110-119:
  • There are no clinical signs on the clinical examination which can confirm or rule out the diagnosis.
  • High probability of false positive diagnosis
  • Lack of specific biomarkers, genetic, or other tests helpful in making the diagnosis
  • Due to grief and the stigma of the family with the child diagnosed with CP, there is the desire of the healthcare providers to rule out every treatable condition first by wide differential diagnosis
  • There are no curative treatments and evidence of the efficacy of the early intervention is scarce.
Another important recurrent discussion lasting for decades on CP is when the earliest diagnosis of CP could be made to avoid the development of deformities connected with the disease.110-119 For many years from the 1970s, it is accepted that it is almost impossible to make the diagnosis of CP in infancy, and that acceptable age for the diagnosis is between 3 and 5 years.110-119 It has been claimed that in a well-developed healthcare system the diagnosis of CP could be made in one of five children at the age of 6 months and in more than half of the cases after the first year of life.117 There is a belief that CP is neurologically silent in the first few months of age and almost impossible to be diagnosed. This was the reason for the development of the concept of GMs by Prechtl et al. which enabled detection of neurological impairment by the recording of GMs by a camera and assessing them off-line. The assessment was time-consuming and not practical or clinically applicable for everyday clinical practice. However, in the recently published guidelines for the early diagnosis (by the age of 5 months in high-risk infants) of CP the following criteria have been mentioned110-119:33
  • General movements assessment {sensitivity 98% [95% confidence interval (CI) 74%–100%]; specificity 91% (95% CI 83%–93%)} at fidgety age26
  • Magnetic resonance imaging at term equivalent age (sensitivity 86%–100%, specificity 89%–97%)
  • Hammersmith Infant Neurological Examination (HINE) (sensitivity at 3 months 96%, specificity 85%, CI not reported).119
Mentioned criteria is aimed for high-risk infants, while infants with CP who do not have newborn detectable risks, and are seemingly healthy at birth, are less likely to be followed up, and there is a need for identifying these infants and administering best practice tools in order not to miss the diagnosis of CP, which is nowadays in low-risk population very often overlooked and missed.110-119 For such term and high-risk preterm infants automated computer assisted/smartphone GMs assessment tool is under development,119 which will make a time-consuming assessment of GMs more practical, standardized, and clinically applicable.
We are aware of weaknesses of our study: nine investigators included, high dropout rate, heterogeneity of the investigation group in terms of nationality and race, inhomogeneous groups of pregnant women in terms of risk of pregnancy, social status, age, parity, and many other characteristics. Although KANET was standardized and it was advised to be used in everyday clinical practice, it would be much better if all those weaknesses could have been avoided.69,98
The main weakness of the investigation is the postnatal follow-up of infants, which was dependent on local circumstances, and the information for infants who had developmental delays has been obtained from the parents and available medical charts. Such an approach may cause that some children with developmental delay may have been missed, without awareness of the investigator(s). That is why the results of the study should be taken with due caution.
Based on the results of the study we can conclude that if the KANET score is normal then there is a high probability that the development of the infant will be normal, with a very low probability that the child with developmental delay would have been missed. However, if the KANET score is borderline and especially if abnormal in high-risk pregnancy, postnatal development of the child may appear abnormal. Due to a high false-positive rate in those fetuses, thorough postnatal prospective neurodevelopmental follow-up especially in high-risk infants with a positive family history on CP should be advised.110-119 To make an early diagnosis of CP in high-risk cases, the protocol proposed by Novak et al. should be followed,117 while for low-risk infants with abnormal KANET scores the protocol should be individualized and follow-up established on a case by case basis. The future development of fetal neurology should be multidisciplinary with special emphasis on scrutinized postnatal follow-up of infants who had abnormal and borderline KANET scores and were born from high-risk pregnancies.
REFERENCES
  1. Salihagic-Kadic A, Kurjak A, Medic M, Andonotopo W, Azumendi G. New data about embryonic and fetal neurodevelopment and behavior obtained by 3D and 4D sonography. J Perinat Med. 2005;33(6):478–90.
  1. Pomeroy SL, Volpe JJ. Development of the nervous system. In: Polin RA, Fox, WW (Eds). Fetal and Neonatal Physiology. Philadelphia-London-Toronto-Montreal-Sydney-Tokyo: WB Saunders Company;  1992. pp. 1491–509.

  1. 34 O'Rahilly R, Muller F. Minireview: Summary of the initial development of the human nervous system. Teratology. 1999;60(1):39–41.
  1. Kostovic I, Judas M, Petanjek Z, Simic G. Ontogenesis of goal-directed behavior: anatomo-functional considerations. Int J Psychophysiol. 1995;19(2):85–102.
  1. Schaher S. Determination and differentiation in the development of the nervous system. In: Kandel ER, Schwartz JH (Eds). Principles of Neural Science, 2nd edition. New York: Elsevier Science Publishing;  1985. pp. 730–2.
  1. Kostovic I. Prenatal development of nucleus basalis complex and related fiber systems in man: a histochemical study. Neuroscience. 1986;17(4):1047–77.
  1. Okado N. Onset of synapse formation in the human spinal cord. J Comp Neurol. 1981; 201(2):211–9.
  1. Kostovic I. Zentralnervensystem. In: Hinrichsen KV (Ed). Humanembryologie. Berlin: Springer-Verlag;  1990. pp. 381–448.
  1. Prechtl HF. Ultrasound studies of human fetal behavior. Early Hum Dev. 1985;12(2):91–8.
  1. Ianniruberto A, Tajani E. Ultrasonographic study of fetal movements. Semin Perinatol. 1981;5(2):175–81.
  1. Goto S, Kato TK. Early movements are useful for estimating the gestational weeks in the first trimester of pregnancy. In: Levski RA, Morley P (Eds). Ultrasound ‘82. Oxford: Pergamon Press;  1983. pp. 577–82.
  1. Joseph RG. Fetal brain behavior and cognitive development. Dev Rev. 2000;20(1):81–98.
  1. de Vries JI, Visser GH, Prechtl HF. The emergence of fetal behavior. I. Qualitative aspects. Early Hum Dev. 1982;7(4):301–22.
  1. Kostovic I, Rakic P. Development of prestriate visual projections in the monkey and human fetal cerebrum revealed by transient cholinesterase staining. J Neurosci. 1984;4(1):25–42.
  1. D'Elia A, Pighetti M, Moccia G, Santangelo N. Spontaneous motor activity in normal fetuses. Early Hum Dev. 2001;65(2):139–47.
  1. Prechtl HF, Einspieler C. Is neurological assessment of the fetus possible? Eur J Obstet Gynecol Reprod Biol. 1997;75(1):81–4.
  1. Roodenburg PJ, Wladimiroff JW, van Es A, Prechtl HF. Classification and quantitative aspects of fetal movements during the second half of pregnancy. Early Hum Dev. 1991;25(1):19–35.
  1. Prechtl HF. Qualitative changes of spontaneous movements in fetus and preterm infant are a marker of neurological dysfunction. Early Hum Dev. 1990;23(3):151–8.
  1. Kurjak A, Azumendi G, Vecek N, Kupesic S, Solak M, Varga D, et al. Fetal hand movements and facial expression in normal pregnancy studied by four-dimensional sonography. J Perinat Med. 2003;31(6):496–508.
  1. Andonotopo W, Stanojevic M, Kurjak A, Azumendi G, Carrera JM. Assessment of fetal behavior and general movements by four-dimensional sonography. Ultrasound Rev Obstet Gynecol. 2004;4(2):103–14.
  1. Kurjak A, Stanojevic M, Azumendi G, Carrera JM. The potential of four-dimensional (4D) ultrasonography in the assessment of fetal awareness. J Perinat Med. 2005;33(1):46–53.
  1. Kurjak A, Pooh RK, Merce LT, Carrera JM, Salihagic-Kadic A, Andonotopo W. Structural and functional early human development assessed by three-dimensional and four-dimensional sonography. Fertil Steril. 2005;84(5):1285–99.
  1. Kurjak A, Miskovic B, Andonotopo W, Stanojevic M, Azumendi G, Vrcic H. How useful is 3D and 4D ultrasound in perinatal medicine? J Perinat Med. 2007;35(1):10–27.
  1. Andonotopo W, Medic M, Salihagic-Kadic A, Milenkovic D, Maiz N, Scazzocchio E. The assessment of fetal behavior in early pregnancy: comparison between 2D and 4D sonographic scanning. J Perinat Med. 2005;33(5):406–14.
  1. Kurjak A, Stanojevic M, Andonotopo W, Scazzocchio-Duenas E, Azumendi G, Carrera JM. Fetal behavior assessed in all three trimesters of normal pregnancy by four-dimensional ultrasonography. Croat Med J. 2005;46(5):772–80.
  1. Pooh RK, Ogura T. Normal and abnormal fetal hand positioning and movement in early pregnancy detected by three- and four-dimensional ultrasound. Ultrasound Rev Obset Gynecol. 2004;4(1):46–51.

  1. 35 Kurjak A, Stanojevic M, Andonotopo W, Salihagic-Kadic A, Azumendi G, Carrera JM. Behavioral pattern continuity from prenatal to postnatal life—a study by four-dimensional (4D) ultrasonography. J Perinat Med. 2004;32(4):346–53.
  1. Andonotopo W, Kurjak A, Kosuta MI. Behavior of an anencephalic fetus studied by 4D sonography. J Matern Fetal Neonatal Med. 2005;17(2):165–8.
  1. Andonopo W, Kurjak A. The assessment of fetal behavior of growth restricted fetuses by 4D sonography. J Perinat Med. 2006;34(6):471–8.
  1. Kurjak A, Andonotopo W, Hafner T, Salihagic-Kadic A, Stanojevic M, Azumendi G, et al. Normal standards for fetal neurobehavioral developments—longitudinal quantification by four-dimensional sonography. J Perinat Med. 2006;34(1):56–65.
  1. Kurjak A, Azumendi G, Andonotopo W, Salihagic-Kadic A. Three- and four-dimensional ultrasonography for the structural and functional evaluation of the fetal face. Am J Obstet Gynecol. 2007;196(1):16–28.
  1. Walusinski O, Kurjak A, Andonotopo W, Azumendi G. Fetal yawning assessed by 3D and 4D sonography. Ultrasound Rev Obstet Gynecol. 2005;5:210–7.
  1. Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, et al. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl. 2007;109:8–14.
  1. Palmer FB. Strategies for the early diagnosis of cerebral palsy. J Pediatr. 2004;145(2 Suppl): S8–S11.
  1. Walstab JE, Bell RJ, Reddihough DS, Brennecke SP, Bessell CK, Beischer NA. Factors identified during the neonatal period associated with risk of cerebral palsy. Aust N Z J Obstet Gynecol. 2004;44(4):342–6.
  1. Nelson KB, Ellenberg JH. Neonatal signs as predictors of cerebral palsy. Pediatrics. 1979;64(2):225–32.
  1. Amiel-Tison C, Gosselin J, Kurjak A. Neurosonography in the second half of fetal life: a neonatologist's point of view. J Perinat Med. 2006;34(6):437–46.
  1. Gosselin J, Gahagan S, Amiel-Tison C. The Amiel-Tison Neurological Assessment at Term: conceptual and methodological continuity in the course of follow-up. Ment Retard Dev Disabil Res Rev. 2005;11(1):34–51.
  1. Amiel-Tison C. Update of the Amiel-Tison neurologic assessment for the term neonate or at 40 weeks corrected age. Pediatr Neurol. 2002;27(3):196–212.
  1. Volpe JJ. Neurological examination: Normal and abnormal features. In: Volpe JJ (Ed). Neurology of the Newborn, 4th edition. Philadelphia: WB Saunders;  2001. p. 127.
  1. Einspieler C, Prechtl HFR, Bos AF, Ferrari F, Cioni G. Prechtl's Method on the qualitative assessment of general movements in preterm, term and young infants. MacKeith Press:  Cambridge; 2004. p. 104.
  1. Hadders-Algra M. General movements: a window for early identification of children at high risk for developmental disorders. J Pediatr. 2004;145(2 Suppl):S12–8.
  1. Hadders-Algra M, den Niewcendijk AKV, Martijn A, van Eyken LA. Assessment of general movements: towards a better understanding of a sensitive method to evaluate brain function in young infants. Dev Med Child Neurol. 1997;39(2):89–98.
  1. Bekedam DJ, Visser GH, de Vries JJ, Prechtl HF. Motor behavior in the growth retarded fetus. Early Hum Dev. 1985;12(2):155–65.
  1. Cioni G, Prechtl HF. Preterm and early postterm motor behavior in low-risk premature infants. Early Hum Dev. 1990;23(3): 159–91.
  1. Seme-Ciglenečki P. Predictive value of assessment of general movements for neurological development of high-risk preterm infants: comparative study. Croat Med J. 2003;44(6):721–7.
  1. Cioni G, Prechtl HF, Ferrari F, Paolicelli PB, Einspieler C, Roversi MF. Which better predicts later outcome in full-term infants: quality of general movements or neurological examination? Early Hum Dev. 1997;50(1):71–85.

  1. 36 Einspieler C, Prechtl HF, Ferrari F, Cioni G, Bos AF. The qualitative assessment of general movements in preterm, term and young infants—review of the methodology. Early Hum Dev. 1997;50(1):47–60.
  1. Ferrari F, Cioni G, Einspieler C, Roversi MF, Bos AF, Paolicelli PB, et al. Cramped synchronized general movements in preterm infants as an early marker for cerebral palsy. Arch Pediatr Adolesc Med. 2002;156(5):460–7.
  1. Prechtl HF. State of the art of a new functional assessment of the young nervous system. An early predictor of cerebral palsy. Early Hum Dev. 1997;50(1):1–11.
  1. Kurjak A, Jackson D (Eds). An Atlas of Three- and Four-Dimensional Sonography in Obstetrics and Gynecology. London: Taylor & Francis Group;  2004. p. 216.
  1. Sarnat HB. Anatomic and physiologic correlates of neurologic development in prematurity. In: Sarnat HB (Ed). Topics in Neonatal Neurology. New York: Grune and Stratton;  1984. pp. 1–24.
  1. Sarnat HB. Functions of the corticospinal and corticobulbar tracts in the human newborns. J Pediatr Neurol. 2003;1(1):3–8.
  1. Amiel-Tison C. Clinical assessment of the infant nervous system. In: Levente MI, Chervenak FA, Whittle M (Eds). Fetal and Neonatal Neurology and Neurosurgery, 3rd edition. London: Churchill Livingstone;  2001. pp. 99–120.
  1. Salisbury AL, Fallone MD, Lester B. Neurobehavioral Assessment from Fetus to Infant: The NICU Network Neurobehavioral Scale and the Fetal Neurobehavioral Coding Scale. Ment Retard Dev Disabil Res Rev. 2005;11(1):14–20.
  1. de Vries JIP, Visser GHA, Prechtl HFR. Fetal motility in the first half of pregnancy. In: Prechtl HFR (Ed). Continuity of Neural Functions from Prenatal to Postnatal Life. Oxford: Blackwell;  1984. pp. 46–63.
  1. Kostović I, Seress L, Mrzljak L, Judaš M. Early onset of synapse formation in the human hippocampus: a correlation with Nissl-Golgi architectonics in 15- and 16.5-week-old fetuses. Neuroscience. 1989;30(1):105–16.
  1. Mutch L, Alberman E, Hagberg B, Kodama K, Perat MV. Cerebral palsy epidemiology: where are we now and where are we going? Dev Med Child Neurol. 1992;34(6):547–51.
  1. Bax M, Goldstein M, Rosenbaum P, Leviton A, Paneth N, Dan B, et al; Executive Committee for the Definition of Cerebral Palsy. Proposed definition and classification of cerebral palsy, April 2005. Dev Med Child Neurol. 2005;47(8):571–6.
  1. Sankar C, Mundkur N. Cerebral palsy-definition, classification, etiology and early diagnosis. Indian J Pediatr. 2005;72(10):865–8.
  1. Shapiro BK. Cerebral palsy: a reconceptualization of the spectrum. J Pediatr. 2004;145(2 Suppl):S3–7.
  1. Amiel-Tison C, Gosselin J, Infante-Rivard C. Head growth and cranial assessment at neurological examination in infancy. Dev Med Child Neurol. 2002;44(9):643–8.
  1. Pooh RK, Pooh K, Nakagawa Y, Nishida S, Ohno Y. Clinical application of three-dimensional ultrasound in fetal brain assessment. Croat Med J. 2000;41(3):245–51.
  1. Campbell S, Lees C, Moscoso G, Hall P. Ultrasound antenatal diagnosis of cleft palate by a new technique: the 3D “reverse face” view. Ultrasound Obstet Gynecol. 2005;25(1):12–8.
  1. DiPietro JA. Neurobehavioral assessment before birth. Ment Retard Dev Disabil Res Rev. 2005;11(1):4–13.
  1. Yigiter AB, Kavak ZN. Normal standards of fetal behavior assessed by four-dimensional sonography. J Matern Fetal Neonatal Med. 2006;19(11):707–21.
  1. Rees S, Harding R. Brain development during fetal life: influences of the intra-uterine environment. Neurosci Lett. 2004;361(1-3): 111–4.
  1. Kurjak A, Carrera JM, Stanojevic M, Andonotopo W, Azumendi G, Scazzocchio E, et al. The role of 4D sonography in the neurological assessment of early human development. Ultrasound Rev Obstet Gynecol. 2004;4(3):148–59.

  1. 37 Eidelman AI. The living fetus—dilemmas in treatment at the edge of viability. In: Blazer S, Zimmer EZ (Eds). The Embryo: Scientific Discovery and Medical Ethics. Basel: Karger;  2005. p. 351e70.
  1. Stanojevic M, Zaputovic S, Bosnjak AP. Continuity between fetal and neonatal neurobehavior. Semin Fetal Neonatal Med. 2012;17(6):324–9.
  1. Haak P, Lenski M, Hidecker MJC, Li M, Paneth N. Cerebral palsy and aging. Dev Med Child Neurol. 2009;51(Suppl 4):16–23.
  1. Einspieler C, Prechtl HFR. Prechtl's assessment of general movements: a diagnostic tool for the functional assessment of the young nervous system. Ment Retard Dev Disabil Res Rev. 2005;11(1):61–7.
  1. Moster D, Wilcox AJ, Vollset SE, Markestad T, Lie RT. Cerebral palsy among term and postterm births. JAMA. 2010;304(9):976–82.
  1. Almli CR, Ball RH, Wheeler ME. Human fetal and neonatal movement patterns: Gender differences and fetal-to-neonatal continuity. Dev Psychobiol. 2001;38(4):252–73.
  1. DiPietro JA, Bronstein MH, Costigan KA, Pressmen EK, Hahn CS, Painter K, et al. What does fetal movement predict about behavior during the first two years of life? Dev Phychobiol. 2002;40(4):358–71.
  1. DiPetro JA, Hodson DM, Costigan KA, Johnson TR. Fetal antecedents of infant temperament. Child Dev. 1996;67(5):2568–83.
  1. DiPietro JA, Costigan KA, Pressman EK. Fetal state concordance predicts infant state regulation. Early Hum Dev. 2002;68(1):1–13.
  1. Thoman EB, Denenberg VH, Sievel J, Zeidner LP, Becker P. State organization in neonates: developmental inconsistency indicates risk for developmental dysfunction. Neuropediatrics. 1981;12(1):45–54.
  1. St James-Roberts I, Menon-Johansson P. Predicting infant crying from fetal movement data: an exploratory study. Early Hum Dev. 1999;54(1):55–62.
  1. de Vries JI, Visser GH, Prechtl HF. The emergence of fetal behavior. II. Quantitative aspects. Early Hum Dev. 1985;12(2):99–120.
  1. de Vries JI, Visser GH, Prechtl HF. The emergence of fetal behavior. III. Individual differences and consistencies. Early Hum Dev. 1988;16(1):85–103.
  1. Nijhuis JG (Ed). Fetal Behavior: Developmental and Perinatal Aspects. Oxford: Oxford University Press;  1992.
  1. Kurjak A, Antsaklis P, Stanojevic M, Porovic S. Fetal behavior assessed by four-dimensional sonography. Donald School J Ultrasound Obstet Gynecol. 2017;11(2):146–168.
  1. Stanojevic M, Talic A, Miskovic B, Vasilj O, Shaddad AN, Ahmed B, et al. An Attempt to Standardize Kurjak's Antenatal Neurodevelopmental Test: Osaka Consensus Statement. DSJUOG. 2011;5(4):317–29.
  1. Kurjak A, Antsaklis P. 4D in functional studies of the fetus. Donald School J Ultrasound Obstet Gynecol. 2019;13(1):23–33.
  1. Kurjak A, Tikvica A, Stanojevic M, Miskovic B, Ahmed B, Azumendi G, et al. The assessment of fetal neurobehavior by three-dimensional and four-dimensional ultrasound. J Matern Fetal Neonatal Med. 2008;21(10):675–84.
  1. Kurjak A, Miskovic B, Stanojevic M, Amiel-Tison C, Ahmed B, Azumendi G, et al. New scoring system for fetal neurobehavior assessed by three- and four-dimensional sonography. J Perinat Med. 2008;36(1):73–81.
  1. Kurjak A, Luetic AT. Fetal neurobehavior assessed by three-dimensional/four-dimensional sonography. Zdr Varst. 2010;79(11):790–9.
  1. Miskovic B, Vasilj O, Stanojevic M, Ivanković D, Kerner M, Tikvica A. The comparison of fetal behavior in high risk and normal pregnancies assessed by four-dimensional ultrasound. J Matern Fetal Neonatal Med. 2010;23(12):1461–7.
  1. Talic A, Kurjak A, Ahmed B, Stanojevic M, Predojevic M, Salihagic-Kadic A, et al. The potential of 4D sonography in the assessment of fetal behavior in high-risk pregnancies. J Matern Fetal Neonatal Med. 2011;24(7):948–54.
  1. Talic A, Kurjak A, Stanojevic M, Honemeyer U, Badreldeen A, DiRenzo GC. The assessment of fetal brain function in fetuses with ventriculomegaly: the role of the KANET test. J Matern Fetal Neonatal Med. 2012;25(8): 1267–72.

  1. 38 Honemeyer U, Kurjak A. The use of KANET test to assess fetal CNS function. First 100 cases. 10th World Congress of Perinatal Medicine 8-11 November 2011. Uruguay: Poster Presentation. p. 209.
  1. Lebit FD, Vladareanu R. The role of 4D ultrasound in the assessment of fetal behavior. Maedica (Bucur). 2011;6(2):120–7.
  1. Abo-Yaqoub S, Kurjak A, Mohammed AB, Shadad A, Abdel-Maaboud M. The role of 4-D ultrasonography in prenatal assessment of fetal neurobehavior and prediction of neurological outcome. J Matern Fetal Neonatal Med. 2012;25(3):231–6.
  1. Vladareanu R, Lebit D, Constantinescu S. Ultrasound assessment of fetal neurobehavior in high-risk pregnancies. DSJUOG. 2012;6(2):132–47.
  1. Honemeyer U, Talic A, Therwat A, Paulose L, Patidar R. The clinical value of KANET in studying fetal neurobehavior in normal and at-risk pregnancies. J Perinat Med. 2013;41(2):187–97.
  1. Kurjak A, Talic A, Honemeyer U, Stanojevic M, Zalud I. Comparison between antenatal neurodevelopmental test and fetal Doppler in the assessment of fetal wellbeing. J Perinat Med. 2013;41(1):107–14.
  1. Predojević M, Talić A, Stanojević M, Kurjak A, Salihagić-Kadić A. Assessment of motoric and hemodynamic parameters in growth restricted fetuses—case study. J Matern Fetal Neonatal Med. 2014;27(3):247–51.
  1. Athanasiadis AP, Mikos T, Tambakoudis GP, Theodoridis TD, Papastergiou M, Assimakopoulos E, et al. Neurodevelopmental fetal assessment using KANET scoring system in low and high risk pregnancies. J Matern Fetal Neonatal Med. 2013;26(4):363–8.
  1. Neto RM, Kurjak A. Recent results of the clinical application of KANET test. DSJUOG 2015 Oct-Dec;9(20):420–425. 78.
  1. Neto RM. KANET in Brazil: first experience. Donald School J Ultrasound Obstet Gynecol 2015 Jan-Mar;9(1):1–5.
  1. Hanaoka U, Hata T, Kananishi K, Mostafa AboEllail MA, Uematsu R, et al. Does ethnicity have an effect on fetal behavior? A comparison of Asian and Caucasian populations. J Perinat Med 2016 Mar;44(2):217–221. 79.
  1. Antsaklis P, Porovic S, Daskalakis G, Kurjak A. 4D assessment of fetal brain function in diabetic patients. J Perinat Med. 2017;45(6): 711–5.
  1. Pooh RK, Pooh K. Assessment of fetal central nervous system. Donald School J Ultrasound Obstet Gynecol 2013;7(4):369–84.
  1. Kurjak A, Ahmed B, Abo-Yaquab S, Younis M, Saleh H, Shaddad AN, et al. An attempt to introduce neurological test for fetus based on 3D and 4D sonography. DSJUOG. 2008;2(4):29–44.
  1. Kuno A, Akiyama M, Yamashiro C, Tanaka H, Yanagihara T, Hata T. Three-dimensional sonographic assessment of fetal behavior in the early second trimester of pregnancy. J Ultrasound Med. 2001;20(12):1271–5.
  1. Koyanagi T, Horimoto N, Maeda H, Kukita J, Minami T, Ueda K, et al. Abnormal behavioral patterns in the human fetus at term: correlation with lesion sites in the central nervous system after birth. J Child Neurol. 1993;8(1):19–26.
  1. Kurjak A, Abo-Yaqoub S, Stanojevic M, Yigiter AB, Vasilj O, Lebit D, et al. The potential of 4D sonography in the assessment of fetal neurobehavior—multicentric study in high-risk pregnancies. J Perinat Med. 2010;38(1):77–82.
  1. Stanojevic M, Antsaklis P, Panchal S, Porovic S, Salihagic-Kadic A, Barisic LS, et al. A critical appraisal of Kurjak Antenatal Neurodevelopmental Test: five years of wide clinical use. DSJUOG. 2021;14(4):304–10.
  1. Hepper PG. Fetal behavior: who so sceptical? Ultrasound Obstet Gynecol. 1996:8(3):145–8.
  1. Greenwood C, Newman S, Impey L, Johnson A. Cerebral palsy and clinical negligence litigation: a cohort study. BJOG. 2003;110(1): 6–11.
  1. Strijbis EMM, Oudman I, van Essen P, MacLennan AH. Cerebral palsy and the application of the international criteria for acute intrapartum hypoxia. Obstet Gynecol. 2006;107(6):1357–65.

  1. 39 de Vries JIP, Fong BF. Changes in fetal motility as a result of congenital disorders: an overview. Ultrasound Obstet Gynecol. 2007;29(5):590–9.
  1. de Vries JIP, Fong BF. Normal fetal motility: an overview. Ultrasound Obstet Gynecol. 2006;27(6):701–11.
  1. Rosier-van Dunné FM, van Wezel-Meijler G, Bakker MP, de Groot L, Odendaal HJ, de Vries JI. General movements in the perinatal period and its relation to echogenicity changes in the brain. Early Hum Dev. 2010;86(2):83–6.
  1. te Velde A, Morgan C, Novak I, Tantsis E, Badawi N. Early diagnosis and classification of cerebral palsy: an historical perspective and barriers to an early diagnosis. J Clin Med. 2019;8(10):1599.
  1. Novak I, Morgan C, Adde L, Blackman J, Boyd RN, Brunstrom-Hernandez J, et al. Early, accurate diagnosis and early intervention in cerebral palsy: advances in diagnosis and treatment. JAMA Pediatr. 2017; 171(9):897–907.
  1. Romeo DMM, Cioni M, Palermo F, Cilauro S, Romeo MG. Neurological assessment in infants discharged from a neonatal intensive care unit. Eur J Pediatr Neurol. 2013;17(2):192–8.
  1. Kwong AK, Eeles AL, Olsen JE, Cheong JL, Doyle LW, Spittle AJ. The Baby Moves smartphone app for General Movements Assessment: Engagement amongst extremely preterm and term-born infants in a state-wide geographical study. J Pediatr Child Health. 2019;55(5):548–54.