REVIEW ARTICLE


https://doi.org/10.5005/jp-journals-10009-1919
Donald School Journal of Ultrasound in Obstetrics and Gynecology
Volume 16 | Issue 1 | Year 2022

Evolution of Assessment of Fetal Brain Function


Panos Antsaklis1, Sanja Malinac Malojčić2, Maria Papamichail3, Marianna Theodora4, George Daskalakis5

1,3-5Department of Obstetrics and Gynecology, Alexandra General Hospital, University of Athens, Greece

2Department of Gynecology and Obstetrics, Zabok General Hospital and Croatian Veterans Hospital, Zabok, Croatia

Corresponding Author: Panos Antsaklis, Department of Obstetrics and Gynecology, Alexandra General Hospital, University of Athens, Greece, Phone: +30 210 7112027, e-mail: panosant@gmail.com

ABSTRACT

Assessment of the structure and function of the fetal nervous system has been one of the greatest physicians’ challenges for decades. Advances in ultrasound techniques and especially the evolution of three-dimensional and four-dimensional (4D) ultrasound have made reality the evaluation of fetal anatomy and activity in real-time and in extreme detail. The process of human brain development and maturation is reflected by a specific behavioral pattern that undergoes changes and progresses reciprocal to each week of growth, mirroring the neurological integrity of the fetal brain. Therefore, evaluation of patterns of fetal behavior during the different stages of growth could make possible the distinction between normal and abnormal fetal neurodevelopment and more importantly facilitate early diagnosis of a wide variety of functional abnormalities of the fetal nervous system. To this direction, a pioneer test introduced by Kurjak; KANET (Kurjak Antenatal Neurodevelopmental Test) uses 4D ultrasound to assess fetal behavior and movements in a simulative way of postnatal neonatal neurological evaluation. Evidence from multicenter studies shows that the test indicates the potential to identify fetuses at risk for neurodevelopment impairment and it is applicable in everyday clinical practice.

How to cite this article: Antsaklis P, Malinac Malojčić S, Papamichail M, et al. Evolution of Assessment of Fetal Brain Function. Donald School J Ultrasound Obstet Gynecol 2022;16(1):66-78.

Source of support: Nil

Conflict of interest: None

Keywords: Brain development, Evolution, Fetal brain function, Ultrasound

INTRODUCTION

Assessment of the structure and function of the fetal nervous system has been one of the greatest physicians’ challenges for decades. Advances in ultrasound techniques and especially the evolution of three-dimensional (3D) and four-dimensional (4D) ultrasound have made reality the evaluation of fetal anatomy and activity in real-time.1 Development of the human brain is a very complicated and long-lasting procedure, evolving through strict and precise developmental steps, starting from the early first trimester and continuing for decades after birth.2 The process of human brain development and maturation is reflected by a specific behavioral pattern that undergoes changes and progresses reciprocal to each week of growth.2 Corresponding to its complexity, the human brain is very sensitive and vulnerable to a wide variety of factors that may be present during any of the phases of in utero and ex utero life-affecting brain function and development. Some of these factors are genetic factors or defects, external stimuli, pathological conditions, and environmental changes which are in the vast majority of the cases unable to be assessed and obstetricians cannot evaluate the degree of their consequences.1 Therefore, neurological impairment is one of the most feared perinatal complications and as data proved that cerebral palsy (CP) most often is the result of prenatal than perinatal or postnatal events,3 the antenatal diagnosis of neurological impairment and evaluation of fetal nervous system integrity have been the dream of obstetricians.4,5

The first steps to make this dream reality have been made by Kurjak et al. They realized that in order to evaluate and define neurological defects prenatally is more than important to comprehend firstly normal fetal behavior. Many scientists also noticed that neonatal behavior is not much different from fetal behavior.4 A pioneer test introduced by Kurjak; Kurjak Antenatal Neurodevelopmental Test (KANET) uses 4D ultrasound to assess fetal behavior and movements in a simulative way of neonatal assessment postnatal [Amiel-Tison neurological assessment at term (ATNAT test)] (Fig. 1).6 Many multicenter studies have been published since then, proving that the test has the potential to identify fetuses at risk for neurodevelopment impairment and it can be used in everyday clinical practice.6

Fig. 1: KANET test examines the fetal face and fetal extremities and evolution of technology reveals the potential of this test

Structural and Functional Development of Fetal Central Nervous System (CNS)

To understand fetal behavior and movement patterns it is more than important to comprehend the development of the fetus’ motor and sensory pathways, the chronology of their maturation, and myelination direction, as fetal cerebral growth and maturation is in accordance with fetal motility.7

Development of CNS begins approximately at the end of gastrulation. During the third postconceptional week, the neural plate is formed by the generation of the neuroectoderm from the ectoderm.8 Formation of the neural plate is succeeded by folding of its edges and formation of a neural tube, whose further growth and reshaping results in the formation of structures of CNS. In rapid succession, during the fourth postconceptional week, the forebrain components diencephalon and telencephalon can be detected. In all parts of the neural tube—from ventricular to pial surface—three embryonic zones: ventricular, intermediary, and marginal zone can be detected. The telencephalon contains two additional zones subventricular and subplate zone. The ventricular zone, as well as the subventricular zone of telencephalon, are the sites of neurogenesis: all the future neurons and glia originated from the telencephalon’s subventricular and subplate zones. The subplate zone plays also a key role in the developmental plasticity following perinatal brain damage, as it is a site for transient synapses and neuronal interactions.9 Moreover, at the 19th week of gestation, in the subplate zone the earliest cortical electric activity takes place. Interestingly, between weeks 13 and 25 of gestation, the subplate zone inhabits nearly half of the hemisphere.

The early appearance of interneuronal connections (Tables 1 and 2) implicates a possibility of early functional development. However, those first synapses exist only temporarily and disappear due to the normal reorganization processes. Most embryonic zones, types of neurons, glia, and early synapses, which play a crucial role in certain periods of fetal brain development, eventually disappear, resulting in significant changes in the brain’s structure and function. Tables 1 and 2 show that there is a significant overlap of neurogenesis, migration as well as synaptogenesis in embryonic and fetal life.

Table 1: The most important progressive steps and landmarks of human brain development (Modified from Kurjak et al.11)
Beginning Most intensive activity Ending
Neurogenesis Early embryonic period (4th week) 8th-12th week Approximately at 20 weeks
Migration Simultaneously with proliferation 18th-24th week 38th week
Synaptogenesis Spinal cord: 6th-7th week
Cortical plate: 8th week
13th week to 2 years of postnatal life Puberty
Table 2: Major events in neural development (Modified by Kurjak et al.2)
Developmental event Peak time of occurrence
Primary neurulation (dorsal induction) 3-4 weeks antenatally
Procencephalic cleavage (ventral induction) 5-6 weeks antenatally
Cerebral neural proliferation 2-4 months antenatally
Cerebellar neural proliferation 2-10 months postnatally
Cerebral neural migration 3-5 months antenatally
Cerebellar neural migration 4-10 months antenatally
Neuronal differentiation (axon growth) 3 months birth
Neuronal differentiation (dendritic growth and synapse formation) 6 months-1 year postnatally
Synaptic rearrangement Birth-years postnatally
Myelination Birth-years postnatally

At the end of the first half of pregnancy, a quantifiable number of synapses appear in the structures preceding the cerebral cortex, forming a substrate for the first cortical electric activity, noted at the 19th week of growth.9 As the fetus grows, at the 20th week the spinothalamic tract is established and it is myelinated by the 29th week of gestation, while the thalamocortical connections penetrate the cortical plate at 24-26 weeks, playing a major role in the cortical processing of sensory information and mental processes.10 Moreover, functional connection between the periphery and cortex can be verified by evoked potentials from 29 weeks of gestation onward. In the third trimester, the formation of synapses could reach the speed of 40,000 synapses per minute. After the 32nd gestational week, the final neocortex appearance of six-layered lamination can be observed. Also, after 34th week of gestation, the sublate zone disappears.10 Finally, the neocortex is still immature and subunits of the brainstem remain regulators of all fetal behavioral patterns until delivery.

For an overview, the first and second trimesters of pregnancy are the most critical periods for cortical development, as proliferation, neuronal migration, organization, and connection take place. In the third trimester, growth and differentiation are the predominant events and continue after birth.11 In an infant born at term, you can observe characteristic cellular layers in motor, somatosensor, visual, and auditory cortical areas. Brainstem demonstrates a high level of maturity, while all histogenetic processes actively persist in the cerebellum.12 Although, proliferation and migration are completed in a term infant, synaptogenesis and neuronal differentiation continue really intensively.13

Fetal Movements Evaluated by U/S

Evolution of 4D Sonography Enables Fetal Movements Assessment

The primary assessment of fetal well-being was maternal registration of fetal movements. Nowadays, there is no doubt that the development of 4D ultrasound technology played a crucial role in the assessment of fetal behavior and movement patterns. According to Andonotopo et al.14 when 4D ultrasound is used, spontaneous fetal movements can be observed at the 7th gestational week, while the conventional 2D ultrasound can detect fetal motility a week later. Importantly, the evolution of ultrasound technology allowed depiction in extreme detail of fetal facial expressions, including grimacing, tongue expulsion, and eye-lid movements,15,16 as spatial recognitions of fetal face and visualizations of small facial structure such as fetal nose, eyebrows, mouth, and eyelids are possible due to 4D sonography. Furthermore, 4D technology can determine exactly the direction of the isolated limbs movements, hand movements, and target of the fingers.17 The possibility to study these subtle fetal movements opened a new area of investigation of fetal brain function by enabling us to develop measurable parameters of normal neurodevelopment.18

Fetal Movements throughout Pregnancy

Fetal behavior in utero should be evaluated as a whole, due to the fact that the different movement patterns of each week could define normal and abnormal neurodevelopment.6 According to Nijhuis and Arabin et al., fetal behavior can be described as any observable action or reaction to external stimuli, reflecting the activity of fetal CNS and early neuromuscular development.19,20

In the first trimester, as the fetal brain develops and matures fetal movement patterns are increasing.17 As Tables 1 and 2 show, the first synapses appear in the spinal cord at 6th to 7th postconceptional week and in the cortical plate at 8th postconceptional week. This is the phase when the first electrical bustle and conduction of formation takes place, and the time when the earliest spontaneous fetal movements make their appearance.21 These movements have been described as “vermicular,” as they consist of slow flexion and extension of the fetal trunk, accompanied by the inactive displacement of arms and legs and emerging in asymmetrical sequences.22,23 At the 7th postconceptional week approximately, the brainstem that consists of the medulla oblongata, pons, and midbrain, begins to develop, and mature in a caudal to rostra direction. Since the medulla matures in advance of more rostral structures of the brainstem, in advance of other functions reflexive movements of the head, body, and extremities, as well as breathing movements and heart rate alterations appear.24

General movements are the first sign of a supraspinal control on fetal motor activity and they consisted of the 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 10.25 Depiction of isolated limb movements could be present almost simultaneously with the general movements. Substantial reflex movements are replaced with local movements during the 8th weeks of gestation, possibly due to an increase in the number of axodendritic synapses. Nevertheless, 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.9 Since, the 10th week and onwards the amount and incidence of movements increase, and head anteflexion, retroflexion, and rotation can also be observed. Additionally, the first eye movements and mouth opening make their appearance at week 10, when in the 12th week swallowing reflex is present. The most frequent movement at 10-11 weeks is the isolated arm movement while at 12-13 weeks jumping movements can be noticed more often.26

During the second trimester, fetuses are very active and the longest period without observation of any movement is only 5 to 6 minutes. Furthermore, this period is characterized by the increased complexity of movements. Zagreb group proved that as early as the 13th gestational week, a “goal orientation” of hand movements appears and a target point can be recognized for each hand movement.17 According to their spatial orientation, these movements could be characterized further as hand to head, hand to mouth, hand near the mouth, hand to face, hand near face, hand to eye, and hand to ear.17 In the 15th week, 15 singular types of movement can be observed, as the development continues, new movements make their debut. Therefore, during the period starting from 13th-16th gestational week, there are prolonged episodes of position alterations, while after 17th week jerky or slow flexion and extension movements of the fetal trunk can be accompanied by isolated limb movements. The general body movements, as well as isolated limb movements, retroflexion, anteflexion, and rotation of the head, are still present and harmonized. Additionally, facial expressions make their first appearance at 16th-18th gestational week and they are now part of the repertoire of fetal motor activity; mouthing, yawning, hiccups, sucking, and swallowing.21 All types of facial expressions display a top frequency at the end of the second trimester, except isolated eye blinking which begins to consolidate at the 24th-26th week of gestation.27

In the second half of pregnancy and especially during the last 10 weeks,28 the number of general movements gradually decreases while the resting periods last longer. This decrease was first attributed to the reduction of volume of amniotic fluid, but now it is believed to be the result of maturation processes in the brainstem.24 Simultaneously with the number of generalized movements decline, one can notice an increase in facial movements, such as blinking, opening or closing of the jaw, tongue expulsion, smiling, swallowing, and chewing, while during the third-trimester mouthing was the most frequent expression. Interestingly, according to Patrick et al.29 starting from the 30 gestational weeks, fetuses begin to stretch and roll. These activities can be seen mainly in the periods when general movements were absent, and this pattern is considered to be a manifestation of normal fetal neurological development.24

To sum up, fetal movements have their debut in the embryonic life, which is much earlier than when the mother feels them. They start as gross, synchronized movements involving the whole fetal body and by the end of the third-trimester fetal activity changes from random movements to well-organized and detailed behavioral patterns, accompanied by harmonized facial expressions.30

General Movements (GM)

General movements have to be discussed further, as they reflect directly brain function.31 These movements are smooth and complex, with fluctuation on their amplitude, involving the head, trunk, arms, and limbs,7 lasting from a few seconds to a minute. Changes in their fluency, elegance, variability, fluctuation of intensity, and speed being monotonous and chaotic are signs of brain activity impairment and one of the first signs of supraspinal control of motor activity.31 Additionally, the quality of GM at 2-4 months postnatal has the highest predictive value for the diagnosis of infants at risk for CP and other neurodevelopmental disorders.32

Continuity from Fetal to Neonatal Behavior

As it mentioned several times above, synaptogenesis, neural differentiation, myelination, and the dynamic connection between neurons is a life-long procedure, continuing throughout pregnancy, birth, and adult life.33 Hence, it is logical to be continuity of fetal and neonatal behavior.34 Although fetal movements are present from the 7th week of gestation, fetal movement behavior of the second half of pregnancy should be taken into consideration when fetal behavior is compared to the neonatal, as during this period neuronal migration and development of the neocortex is complete.21

According to Stanojevic et al.4 “all neonatal movements are also present in utero, especially in terms of isolated eye blinking movements, mouth and eyelid opening, yawning, tongue expulsion, smiling, scowling, and hand movements directed to other parts of the face.”24 Concerning general movements, their amplitude and pattern remain identical until the second month after birth.35 There is only one reflex that cannot be assessed on fetuses: the Moro reflex. This differentiation has been attributed to the different environments to which the fetus and the neonate are exposed: inside the uterus, the fetus lives in a microgravity environment and after birth, neonate meets the “tyranny of gravity.” This statement has been doubted by many scientists because the perception of the fetus living in a gravity-free environment cannot be applied to the whole pregnancy since it is exposed to the force of gravity after the confinement of the fetus to the uterus.36 Nevertheless, to the longest part of gestation, until the end of pregnancy, the fetus is not in major contact with the uterine walls and amniotic sac. Therefore, sensory input arising from antigravity is not present, simulating a microgravity environment.37 However, gravity forces have a significant role in normal musculoskeletal development of the fetus and neonate and the appearance of the earliest antigravity movements take place within the first month of life. There is no doubt that “the fetus and the neonate are the same person in different environments.”4

INTRODUCTION OF KANET

It has been well confirmed that fetal behavioral patterns are related directly to the developmental and maturation stages of the human brain.3,38 Additionally, many studies present data proving that the quantity and quality of fetal movements reflect the neurological integrity of the fetal brain.39 Therefore, evaluation of patterns of fetal behavior during the different stages of growth might produce the demarcation between normal and abnormal fetal neurodevelopment40-43 and more importantly facilitate early diagnosis of a wide variety of functional abnormalities of the fetal nervous system.1,44 Moreover, postnatal studies evaluating neonatal behavior, proved that behavior is a better indicator of neurodevelopmental impairment than neurological examinations.44 Finally, the continuity from fetal to neonatal behavior is established.21

Neurodevelopmental defects and especially CP are one of the most feared perinatal complications. The main reason for this concern is the delay in its diagnosis and because neurological deficits and their effects accompany both the patients and their environment for a lifetime. Additionally, the high prevalence of CP, the lack of effective treatment, and its doubtful cause are the factors that made CP a great field for clinical research. CP proved to be a heterogeneous condition, with different clinical expressions, causes, and comorbidities. Therefore, nowadays the term “Cerebral Palsy Spectrum” (CPS) is recommended. Interestingly, although cesarean section rates have been launched during the 21st century, CP incidence did not change in the last 50 years, with its prevalence staying stable at 2-2.5/1,000 births.45 Therefore, it is obvious that CP is not related to the mode of delivery.

Considering the parameters above, Kurjak et al. introduce a new, pioneering scoring system for the assessment of fetal neurobehavior. It is based on prenatal evaluation of the fetus using 3D and 4D sonography. The primary aim of this new test is the detection of normal and abnormal brain development in utero, by the assessment of fetal motoric activity and through that, fetal neurodevelopment. This test was named [Kurjak Antenatal Neurodevelopmental Test (KANET)] and it consists of parameters regarding fetal behavioral patterns in terms of general movements and aspects of postnatal ATNAT.46

Kurjak Antenatal Neurodevelopmental Test includes the following parameters: isolated head anteflexion, overlapping cranial sutures, head circumference, isolated eye blinking, facial alterations, mouth opening (yawning or mouthing), isolated hand and leg movements and thumb position, and gestalt perception of general movements (Figs 2 and 3) (Table 3). Three of the parameters KANET evaluates—neurological thumb, overlapping sutures, and small head circumference are also postnatal signs of neurological impairment.35 Special attention has to be taken to facial expressions, as “the face is the mirror of the brain.” When the score is between 10 and 16 the test considers normal, between 6 and 9 borderlines, and between 0 and 5 abnormal (Table 4).

Table 3: KANET parameters (Standardized by Bucharest Consensus)
Score
Sign 1 2 3
Isolated head anteflexion Abrupt Small range (0-3 times of movements) Variable in full range, many alteration (>3 times of movements)
Cranial sutures and head circumferences Overlapping 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 Not present Not fluent (1-5 times of blinking) Fluency (>5 times of blinking)
Facial alteration (grimace or tongue expulsion) or Mouth opening (yawning or mouthing) Not present Not fluent (1-5 times of alteration) Fluency (>5 times of alteration)
Isolated led movements Cramped Poor repertoire or small in range (0-5 times of movements) Variable in full range, many alterations (>times of movements)
Isolated hand movements or hand and face movements Cramped or abrupt Poor repertoire or small in range (0-5 times of movement) Variable in full range, many alternation (>5 times of movements)
Fingers movements Unilateral or bilateral clenched fist, (neurological thumb) Cramped invariable finger movements Smooth and complex, variable finger movements
Gestalt perception of GM Definitely abnormal Borderline Normal
Table 4: Interpretation of KANET scores
Total score Interpretation
0-5 Abnormal
6-9 Borderline
10-16 Normal

Fig. 2: Facial alterations, grimacing, yawning and tongue expulsion can be altered permanently or transiently by different maternal or environmental conditions

Fig. 3: Facial alteration is a landmark of fetal neurological assessment

Kurjak Antenatal Neurodevelopmental Test has been standardized through the first and second consensus in Osaka and Bucharest, respectively, and over the years has undergone simplified modifications. Its value in the application of everyday routine has been established as a powerful tool for early diagnosis of neurological impairment. KANET should be performed during the third trimester, between weeks 28 and 38, and when the fetus is awake. If the fetus is 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. The duration of the examination should last between 15 and 20 minutes. If the result of the case is grossly abnormal or borderline, the test should be repeated every 2 weeks until delivery.35 Furthermore, fetuses that have undergone KANET assessment should be followed-up for 2 years in order to conclude in safe results.

The method of the test has good reproducibility.4 Finger movements had the highest interobserver agreement (K = 0.84), while facial expressions had the lowest (K = 0.68). The learning curve is also reasonable for physicians experienced in the field of fetal medicine. Importantly, the examiners should have proper training and experience in Fetal-Maternal Medicine. In addition, it has been calculating that the examiner has to perform 80 KANET tests in order to get acquainted with the test method, a number that is comparable with other prenatal US tests. KANET test presents extremely high negative predicting value (100%) and acceptable sensitivity and specificity.11

There is an increasing number of evidence proving that CP and other neurological disorders such as schizophrenia, epilepsy, and autism have their origin in fetal life.35 Also, Palmer et al.47 claimed that among 7-year-old children having CP, neonatal neurological examination was normal. Introduction of the KANET test and its capability to diagnose in utero. neurological impairment carries significant advantages. The most important is that as this test has the potential of the very early detection of the fetuses in-risk for neurodevelopmental defects, intervention can occur much earlier resulting in a better outcome, if not treatment,4 for example, early physiotherapy has been proved to have a significant role on cognitive and motor outcomes, even in infancy. Moreover, physiotherapy can improve infant self-regulation, postural stability, coordination, and strength. Additionally, timely counseling from a psychologist could have long-term advantages for both the baby and its environment, regarding better parental mental health with less stress, improved parental-infant relationship, and also children in preschool age present less internalizing behaviors. As there is little that could be done for the management of the infant with neurological retardation and because the effectiveness of treatment is not optimal, the timely intervention is crucial for the better outcome.4 Nevertheless, further research has to take place to define the ideal intervention which provides the optimal outcome.

Review of Studies: 10 Years’ Experience of KANET Application

Since the introduction of the KANET more than 10 years of clinical use have passed, many studies have been published and hundreds of tests have been performed globally the evidence they provide is really promising, as it seems that the KANET is able to detect severe neurological defects in utero. and its results are in extreme accordance with the postnatal neurological outcome. Hence, the KANET has the potential to become a very useful tool that provides information concerning the prognosis of pregnancies at high risk for neurodevelopmental impairment such as CP, autism spectrum disorder (ASD), and others.6

Even before KANET introduction for fetal neurological assessment, Andonotopo et al. in 2006 studied prospectively fetal expressions and quality of fetal movements with 4D imaging, in fetuses with normal growth and in fetuses complicated with growth restriction. Their goal was to assess whether these aspects of fetal behavior could predict the incidence of CP in growth-restricted fetuses. The authors concluded that Intrauterine Growth Restriction (IUGR) fetuses tended to be less active and they encouraged further investigation of the potential of 4D sonography to evaluate fetal behavior and therefore brain impaiment.48

The first multicenter study was published in 2010 and involved 288 high-risk pregnancies from four centers (Zagreb-Croatia, Istanbul-Turkey, Bucharest-Romania, and Doha-Qatar). Fetuses underwent KANET prenatally and ATNAT test on the first to the third day of life. Concerning the KANET test, seven cases had abnormal scores while 25 cases were borderline, identifying 32 fetuses in high-risk for the neurological defects. The seven neonates with the abnormal score were followed-up postnatal since the 10th week of life and three of them (3/7) had also an abnormal ATNAT tests. These fetuses had arthrogryposis, vermis aplasia, and sibling with CP, respectively. The facial expressions of these fetuses were significantly decreased: the authors characterized them as masks due to the total absence of any expression during the examination. The other four neonates were believed normal (preeclampsia, thrombophilia, ventriculomegaly, and oligohydramnios). A total of 22 out of the 25 fetuses with borderline KANET scores had also borderline ATNAT score. The underlying causes were: ventriculomegaly, Dandy-Walker syndrome, skeletal dysplasia, polyhydramnios, hydrocephaly, diabetes in pregnancy, nonimmune hydrops, intra-amniotic infection, IUGR, trisomy 21, thrombocytopenia, thrombophilia, preeclampsia, achondroplasia, and oligohydramnios. The remaining three (3/25) were cases with ventriculomegaly, in amniotic infection, and maternal thrombocytopenia, that had normal ATNAT scores. There were also six fetuses that died in utero and five were terminated. The authors drew the conclusion that the KANET has the potential to diagnose prenatally fetuses at high risk for neurodevelopmental impairment, especially in high-risk pregnancies.49

Miskovic et al. published in 2010 an article with really promising results. They studied 226 fetuses from both high-and low-risk and they identified three cases having abnormal KANET scores. All these fetuses had chromosomal defects and also abnormal ATNAT tests. The parameters of the KANET test had also been assessed individually and there was found a statistically significant difference for eight of them between low and high-risk pregnancies: isolated anteflexion of the head, eye blinking, facial expressions—grimacing, tongue expulsion, mouth movement (yawning, jawing, swallowing), isolated hand movements, hand to face movements, fist and finger movements, and general movements. When KANET and ATNAT tests were compared, a moderate but statistically significant correlation between them was noticed, confirming that the postnatal ATNAT test agrees with the findings of the prenatal test.50

A large multicenter study was held by Talic et al. The authors studied 620 singleton pregnancies, between 26 and 38 weeks of gestation. They excluded fetuses with congenital malformations and multiple pregnancies. They grouped the fetuses in two teams: the low-risk group (n = 100) and the high-risk group (n = 520). For the high-risk group inclusion criteria were: threatened preterm delivery with or without preterm premature rupture of membranes (PPROM), a previous child diagnosed with CP, hypertension in pregnancy with or without preeclampsia, diabetes before pregnancy or gestational diabetes, intrauterine growth restriction, polyhydramnios, Rhesus isoimmunization, placental bleeding and maternal fever >39C. Their results were in accordance with the first multicenter study, as KANET scores present also a statistically significant difference between the two groups. Interestingly, in the subgroup of patients having a previous child diagnosed with CP, the largest incidence of abnormal KANET scores was found, while fetuses whose mother was in fever had the largest incidence of borderline scores. When the parameters of the KANET test were evaluated one by one, 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 general movements were found to be statistically different between high and low-risk pregnancies. In this study, there was another observation: abnormal KANET score has predictive value for both intrauterine and neonatal death, as there were two intrauterine deaths of fetuses with low KANET scores (3 and 4, respectively) and one neonatal death where KANET score was 2. They identified 36 fetuses having abnormal KANET tests and during follow-up, 10 of them were found to have severe generalized spasticity, confirming the strength of the predicted value of the KANET. Therefore, there were two conclusions concerning this study: an abnormal KANET score can predict not only neurological impairment but also intrauterine and neonatal mortality.51

Honemeyer et al. performed the KANET in 100 fetuses up to three times between the 28th and 38th gestational week. The fetuses were followed up with a complete neurological assessment by a neonatologist immediately after birth and at 12 weeks of life The KANET score results and the postnatal findings have been compared, concluding that a normal KANET score has a significant predicting value of normal postnatal neurological examination of both the newborn and the 12 weeks old infant.52

Talic et al. ran an interesting trial, investigating movement behavior with the usage of KANET in normal fetuses (n = 100) and in fetuses with cerebral ventriculomegaly (n = 140), between 32nd and 36th gestational week. Only 6% of the fetuses in the normal brain structure had abnormal KANET scores, while in the group of ventriculomegaly this percentage was 34.9%. The largest number of abnormal KANET scores was present in fetuses with severe ventriculomegaly, accompanied with other structural malformations (Dandy-Walker, Arnold-Chiari, agenesis of the corpus callosum, holoprosencephaly, encephalocele, spina bifida, choroid plexus cyst, osteogenesis imperfecta type II, thanatophoric dysplasia type I, and Meckel Gruber syndrome). Interestingly, there were no abnormal KANET scores in fetuses with isolated mild and moderate ventriculomegaly. KANET results were in accordance with the postnatal neurological outcome. From this study, several important conclusions could be drawn: firstly, it is proved that the KANET can predict the postnatal outcome of fetuses with ventriculomegaly, identify fetuses with abnormal behavior, adding a functional aspect of CNS evaluation to brain structure. Secondly, it was clear that coexisting malformations besides ventriculomegaly affect KANET score and therefore neurological outcomes. As ventriculomegaly is a finding whose clinical significance is not well-defined, KANET might give valuable data enabling correct parental counseling and management.53

Abo-Yaqoub also evaluated the role of 4D ultrasound in the prenatal assessment of neurodevelopment.54 The authors concluded to same results as the studies mentioned above: the KANET has a statistically significant difference between low- and high-risk pregnancies. In addition, fetuses with abnormal KANET scores have higher odds to remain abnormal postnatal, while there was a tendency for fetuses with borderline KANET scores to normalize after birth. Moreover, they found that the following parameters were considerably different between the two groups: isolated head anteflexion, isolated eye blinking, facial expressions, mouth movements, isolated hand movements hand-to-face movements, finger movements, and general movements. The difference was not significant as regards isolated leg movements and cranial sutures.

Additionally, Vladareanu et al. performed the KANET test in 196 pregnancies, both low (n = 61) and high (n = 135) risk for neurological impairment between the 24 and 38 weeks of gestation. They came to the conclusion that KANET scores as long and fetal movements differed significantly between the two groups; 93.4% of fetuses on the low-risk group achieved a normal KANET score, while 78.5% of fetuses on the high-risk group had a normal score. Accordingly, borderline scores resulted from fetuses in the high-risk group and more specifically from the subgroup of growth restriction and affected Middle Cerebral Artery Resistance Index (MCA RI) index or maternal hypertension. Concerning fetuses with abnormal KANET scores, the vast majority of them were complicated with PPROM. The predominant part of fetuses with Rh isoimmunization achieved a normal KANET score. Furthermore, when the subgroup of IUGR fetuses were assessed, it was noticed that both the quantity and quality of their movements have been significantly decreased; the number and duration of GM in addition to their organization were affected. Therefore, the authors ended up to the conclusion that the KANET could be used for timely diagnosis of neurological defects.33

Honemeyer et al. in their second study applied a series of KANET evaluations in 56 singleton pregnancies- both low and risk- during 28 and 38 weeks of gestation, performing a total of 117 tests. As one fetus underwent more than one test, they introduced the term “average KANET score.” Although they do not find any abnormal average scores, the vast majority (2/3) of the borderline scores were presented in the high-risk group. Only one fetus with a borderline score was found to be abnormal at postnatal neurological evaluation. The authors concluded that “KANET is suggestive of expressing the risk for neurodevelopmental fetal disorders.”55

Kurjak et al. have studied 869 high-and low-risk singleton pregnancies. In their study, they took under consideration the results of the Doppler studies of umbilical and middle cerebral arteries. They noticed a significant differences in fetal behavior between the normal group and the following subgroups of fetuses: fetal growth restriction, gestational diabetes mellitus (DM), threatened preterm birth, antepartum hemorrhage, maternal fever, sibling with CP, and polyhydramnios. This made the authors conclude that it is possible to introduce a new clinical application of the KANET test in the early identification of fetuses at risk for adverse neurological outcome.56

Athanasiadis et al. applied the KANET in 152 pregnancies of both low (n = 78) and high (n = 74) risk. Inclusion criteria for the high risk group were IUGR (n = 12), DM (n = 24), and preeclampsia (n = 38). When the scores of the two groups were compared, the low-risk group presented statistically significant higher scores in comparison with the high-risk group. Additionally, when the subgroups on the high-risk team were compared, fetuses whose pregnancies were complicated with DM achieved higher KANET scores than pregnancies complicated with IUGR or preeclampsia. Therefore, the authors stated that the KANET is a feasible technique for neurological assessment of pregnancies with a high risk for adverse neurological outcome.57

Neto et al. run a pilot study with 17 high-risk and 34 low-risk pregnancies aiming to compare KANET scores of the two groups. They noticed that all abnormal KANET scores came from high-risk pregnancies, concluding that fetal behavior between fetuses in low and high-risk pregnancies differ significantly.58

Hanaoka et al. performed a trial in 89 Japanese (Asian) and 78 Croatian (European) pregnant women, in order to evaluate the total value of the KANET score and each of its parameters in different populations and ethnicities. Although a statistically significant difference concerning the total KANET score between Japanese and Croatian fetuses was found, all of them achieved a normal score. When the authors compared individual KANET parameters, they observed significant differences in four fetal movements. Those were: isolated head anteflexion, isolated eye blinking, facial alteration or mouth opening, and isolated leg movement. Regarding the four remaining parameters (cranial suture and head circumference, isolated hand movement or hand-to-face movements, fingers movements, and gestalt of general movements), no significant differences were noticed. This study drew the interesting conclusion that when evaluating fetal behavior, ethnicity should be considered, especially while assessing fetal facial expressions. Nevertheless, the total KANET score is not affected by ethnical differences in fetal behavior.59

Hata et al. from Kagawa, Japan, published the study with the longest follow-up so far. They applied the KANET in 353 fetuses with uncomplicated pregnancies and they followed up with them for 2 years. 95.4% (337/353) of fetuses achieved normal scores and the remaining 4.6% (16/353) resulted in a borderline score. Hence, there were not any abnormal scores. Five out of the 337 (1.48%) of fetuses with normal scores were found to present postnatal developmental disability. The diagnoses of these fetuses were: Werdnig-Hoffmann disease (diagnosed immediately after birth), neurodevelopmental delay (diagnosed at 3 months), Ullrich congenital muscular dystrophy (diagnosed at 9 months), developmental delay (diagnosed at 18 months), and ASD (diagnosed at 24 months). Concerning fetuses with borderline scores, three out of 16 (18.75%) had also neurological defects: motor developmental delay (diagnosed at 6 months), Duchenne Muscular Dystrophy (diagnosed at 18 months), and ASD (diagnosed at 30 months). The authors noticed a statistically significant difference in the incidence of postnatal developmental impairment between fetuses with normal and borderline KANET scores and they reached the conclusion that the KANET can be used as a diagnostic tool for the prediction of postnatal neurodevelopmental defects.60

Vladereanu et al. in their second trial performed KANET in 280 pregnancies between 26 and 38 weeks of gestation. About 195 of them were assigned in the low-risk group and the remaining 85 in a high-risk group for neurological impairment. Of 195 low-risk fetuses, 2 (1.0%) were found with abnormal KANET scores and nine (4.6%) had borderline scores, while 184 (94.4%) had normal scores. The two fetuses having abnormal scores were found to have intrauterine growth restriction with normal postnatal neurological findings. Concerning the nine fetuses from the low-risk group with the borderline test, one of them had Prader-Willi syndrome and another one had spinal muscular dystrophy type 1. The remaining seven had a normal postnatal neurological assessment. When the high-risk group is considered, five out of the 85 high-risk pregnancies, (5.9%) had abnormal scores, 20 (23.5%) had borderline scores, and 60 (70.6%) had normal scores. Postnatal outcomes of all other infants, from both groups low-risk and high-risk, were uneventful.45

Neto et al. after their pilot study performed a prospective cohort trial with 631 fetuses from singleton pregnancies which were divided into low (n = 406) and high-risk (n = 225) groups. They assessed the KANET test to the fetuses between 28 and 28 weeks’ gestation and they followed up the neonates in order to evaluate the postnatal outcomes. KANET scores between the two groups and the postnatal outcomes were compared. In the low-risk group, 348 (85.8%) of fetuses had normal KANET scores and 58 (14.2%) had borderline KANET scores, while abnormal KANET scores were not found. Abnormal KANET scores were present only in the high-risk group. About 19 out of 225 fetuses (8.5%) had an abnormal scores and in 57 (25.3%) of them, borderline scores were found, with the remaining 149 (66.2%) fetuses achieving normal KANET scores. For the 19 fetuses with abnormal scores, five were related to pregnancy condition (preeclampsia, PPROM, and drug abuse) while the remaining 14 fetal condition was responsible (IUGR and trisomies 13,18,21). Follow-up was available for only 212 of the fetuses and according to the parents’ knowledge, none of them has been diagnosed with severe neurodevelopmental disability so far.45

Bomba-Opon et al. did a fetal neurobehavioral assessment with KANET in 36 pregnant women between 28 and 36 weeks of gestation, before and after acoustic stimulation of the fetus (Fig. 4). The intention of the study was to evaluate the benefits of acoustic stimulation on the KANET score. They were motivated by previous studies claiming that the nonreactive antenatal cardiotocography test can be reduced due to fetal vibroacoustic stimulation. Moreover, there is evidence proving that acoustic stimulation evoked significantly more fetal movements than mock stimulation.61 After acoustic stimulation, the percentage of fetuses with normal KANET scores decreased from 77-69%, while the percentage of fetuses with abnormal KANET scores increased from 6-14%. In none of the fetuses the improvement of test scoring was recorded. The parameters that were statistically significantly affected with acoustic stimulation were: grimacing, eye blinking and mouth opening, lower and upper extremity movements. The authors concluded that acoustic stimulation during KANET testing did not evoke more fetal activity and it is not useful for KANET testing.

Fig. 4: Assessment of fetal neurobehavior. 4D ultrasound allows assessment of the fetus similarly to neonatal assessment

Tinjic et al. in Bosnia and Herzegovina performed a prospective cohort study which included 141 pregnant women from 28-38 weeks’ gestation. 129 of them were considered as high-risk and the other 12 as low-risk. In five out of 12 fetuses from high-risk pregnancies group, abnormal KANET scores were observed. These cases were complicated with severe IUGR with oligohydramnios and type I DM. In another five out of 12, borderline scores were observed, while the remaining 2 out of 12 high-risk fetuses achieved normal KANET scores. Concerning the low-risk pregnancies, 96 fetuses (74.4%) had a normal KANET score and 33 fetuses (25.6%) had a borderline KANET score. None of the fetuses in the low-risk group had abnormal KANET score. The authors followed-up the neonates, however postnatal outcomes are not published yet.

Antsaklis et al. in Greece published a study including 40 pregnant women with preexisting insulin-dependent DM or insulin-dependent gestational diabetes mellitus (GDM) and applied antenatal neurological assessment with KANET. The authors compared these results with KANET scores from 40 low-risk pregnant women without DM or GDM. Maternal characteristics concerning maternal and gestational age were not statistically significant differences between the two groups. KANET scores in the nondiabetic group were statistically significant higher. Hence, there were also differences of fetal behavior between the two groups. When further analysis of the parameters of KANET test was done, isolated eye blinking, facial expressions, and finger movements were noted to have the biggest difference between the two groups.62

Panchal et al. in India conducted a prospective study in order to evaluate the value of KANET in high-risk pregnancies. They included 135 singleton high-risk patients. Inclusion criteria were: DM (n = 13), GDM (n = 18), pregnancy-induced hypertension (n = 31), thyroid gland pathology (n = 16), infection during pregnancy (n = 8), and cardiac disease (n = 1). KANET was done twice: between 28 and 32 weeks of gestation and between 34 and 36 weeks of gestation. A total of 134 fetuses had normal KANET scores and only one had a borderline score. Neonates were routinely assessed at birth and a pediatrician performed postnatal follow-up at the age of 24 hours, 1, 3, 6, 9, 12, 18, and 24 months. Four infants whose pregnancy was complicated with GDM and pregnancy-induced hypertension and during prenatal neurodevelopmental assessment had normal scores, at 16 and 17 months of age showed delayed milestones. Increased risk for delay in the milestones was also found in patients in whom the KANET score significantly decreased between the two KANET assessments. Additionally, fetuses whose score on the second assessment was lower than the first score were also considered to be at a higher risk than those who increased their score on the second scan. Fetuses with a score above 14 were considered to be at a lower risk for any post-birth neurological defect than fetuses with scores between 11 and 14. The authors drew the conclusion that KANET is able to detect fetuses at increased risk for neurodevelopmental delay.45

Honemeyer et al. reported two really interesting cases of fetal akinesia deformation sequence. Examiners were surprised by the total immobility of the otherwise structural normal fetuses. When KANET was applied, both fetuses had extremely low scores (3 and 2, respectively).60

CONCLUSION

Although it is clear that dynamic and complicated processes of functional CNS development are not easy to be assessed, there is no doubt that fetal movement patterns reflect the brain’s maturation progress of every week of growth. Additionally, as sonography technology has made huge steps, introducing the 4D ultrasound in clinical routine, we are approaching the era when physicians could be able to have a clearer insight into the mysterious development of the human brain.

The KANET test can make the neurological evaluation for fetuses and neonates just two tests in series. The primary goal of the KANET is the evaluation of fetal nervous system integrity and the timely diagnosis of functional and structural neurological impairment. So far, data from many multicenter studies are very promising, showing that the KANET is able to identify functional aspects of fetal behavior, enabling the detection of normal and abnormal fetal neurodevelopment. This information could be really valuable for timely intervention, better and more accurate parental counseling. Nevertheless, further research is necessary for the establishment of the KANET in everyday clinical practice. Worldwide, many studies have been started and very interesting results regarding the potential of KANET assessment on the timely diagnosis of fetuses at high risk for neurodevelopmental defects are yet to be published.

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