REVIEW ARTICLE | https://doi.org/10.5005/jp-journals-10009-1659 |
What did We Learn from the Structural and Functional Development of Fetal Brain Using Four-dimensional Sonography?
1Department of Obstetrics and Gynecology, University of Zagreb, Zagreb, Croatia
2Department of Obstetrics and Gynecology, Private Clinic Veritas, Zagreb, Croatia; University SSST, Sarajevo, Bosnia and Herzegovina
3University of Athens, Alexandra Maternity Hospital, Athens, Greece
4Department of Obstetrics and Gynecology, Neonatal Unit, Medical, School University of Zagreb, University Hospital “Sveti Duh” Zagreb, Croatia; Department of Obstetrics and Gynecology, University Hospital, “Sveti Duh”, Zagreb, Croatia
5Clinic of Gynaecology and Obstetrics, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina; Department of Gynaecology, School of Medicine, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina
Corresponding Author: Asim Kurjak, Department of Obstetrics and Gynecology, University of Zagreb, Zagreb, Croatia, Phone: +385 91 4512096, e-mail: asim.kurjak@public.carnet.hr
How to cite this article Kurjak A, Spalldi Barišić L, Antsaklis P, et al. What did We Learn from the Structural and Functional Development of Fetal Brain Using Four-dimensional Sonography? Donald School J Ultrasound Obstet Gynecol 2020;14(3):245–261.
Source of support: Nil
Conflict of interest: None
ABSTRACT
Every human brain is a special, unique, and impressive organ and it does not fail to fascinate us every time with its endless possibilities and adaptation. New technology, such as four-dimensional ultrasound diagnostic devices, has gave us a chance to take a peek into the most complex, incredibly well-organized, and spectacular architecture of formation of fetal brain. Neuroscientists have made incredible discoveries about different structures and regions of the brain, and many elements of brain cognitive functions. However, what remains a great mystery is the interaction of different parts of the brain, in other words, that we are not entirely sure how individual parts of the brain exchange data and how and to what extent each is important and contributes to different patterns of behavior, feelings, or memory. Scientific research toward mapping the brain connections is on the way. Assessing fetal behavior in utero, its motor and cognitive functions, is one of the major challenges in perinatal medicine. Fetal behavior reflects the maturation and integrity of the fetal central nervous system (CNS). Understanding the course and timing of fetal neurodevelopmental events in relation to the development of motor and sensory systems is crucial to determining how environmental influences can affect certain structures as well as functions. With the Kurjak’s antenatal neurodevelopmental test (KANET) it is possible, for the first time ever, to evaluate the neurological state of the fetus in real time and to differentiate normal, borderline, and abnormal fetal behavioral patterns. If the KANET score is normal, that is highly predictive of favorable neurodevelopment of the infant. On the other hand, if the KANET score is borderline or abnormal in a high-risk pregnancy, the child’s postnatal development may appear abnormal. Thorough postnatal prospective neurodevelopmental (short- and long-term) follow-up of these children is highly recommended.
Keywords: Cerebral palsy, Fetal behavior, Fetal cognitive function, Fetal neurology, Four-dimensional ultrasound, Neurodevelopment.
INTRODUCTION
The human brain is the most mysterious and fascinating organ in so many different ways. Some of its cognitive functions, such as ability to learn, memorize, think, percept different sensations such as pain, to have emotions, process audiovisual inputs, and to coordinate reactions and movements, have been subjects of studies for many years.
It took the nature a few billion years in designing and constructing such a sophisticated architecture with infinitive scale of perfectly coordinated functions and amazing possibility to change and adapt. Yet, until recently, we could only make an assumption about what was going on with prenatal activities and fast construction of complex structures in the time frame of antenatal life.1
The assessment of the fetal behavior in utero, both motoric and cognitive functions, has been an outmost challenge in perinatal medicine. Fetal neurobehavior reflects the maturation and integrity of the fetal central nervous system (CNS). Understanding the course and timing of fetal neurodevelopmental events in correlation to motor and sensory system development is essential for determination how environmental effects can affect certain structures as well as functions.1,2
The cornerstones of human brain development are demonstrated in Table 1.
On the other hand, anatomic and functional development of the human brain is a uniquely complex and long-lasting procedure that goes through strictly structured developmental stages, which start from the second month of gestational age and continue up to adult life.3 During the fetal period, the brain develops swiftly with the rate of 250,000 neurons per minute.1,4 The neocortex is intensely under the construction,1,5 and about 99% is created during the fetal period of life.1,6,7
| Developmental event | Peak time of occurrence |
|---|---|
| 3–4 weeks antenatally |
| 5–6 weeks antenatally |
| |
| Cerebral | 2–4 months antenatally |
| Cerebellar | 2–10 months postnatally |
| |
| Cerebral | 3–5 months antenatally |
| Cerebellar | 4–10 months antenatally |
| |
| Axon outgrowth | 3 months—birth |
| Dendric growth and synapse formation | 6 months–1 year postnatally |
| Birth—years postnatally |
| Birth—years postnatally |
Most of 100 billion neurons and related major pathways found in adult brains have formed already in the fetal period and are present at birth.1,4,6 Every and each of these neurons are unique and different, and how the brain is build is secret design of each individual and clue to our diversity.1 However, the pattern of how circuits are designed is most likely species-specific.
These different connections (thalamocortical and corticocortical) and circuits in the brain are fundamental for cortical processing of sensory information and mental processes that coincide with the age limit for the premature baby survival.1,8
Antenatally, stating from the third trimester, formation of synapses (place where neurons communicate) speeds up to approximately 40,000 synapses per minute,1,9 to reach about 10 million synapses in adult life.
The number of neurons and related pathways are present at birth, their quantitative and qualitative features (synapthogenesis, axon networks, myelination) as well as strength of the connections still need fine-tuning and continue to develop during the postnatal life with continuous interaction with the environment.1,10 Capacities of the fetus to learn and memorize are prodigious.11 Accordingly, even though the neocortex is formed, it is still immature and continues to evolve for decades after birth. In addition, change and adaptation are lifelong processes.1,10
The fast evolution in three-dimensional (3D) and four-dimensional (4D) ultrasound technology, in the past three decades, brought the antenatal assessment of fetal structural, functional, and behavioral development on the totally new level.
The benefits of high-resolution and 3D technology in obstetrical ultrasound mainly allow an extensive and more detailed examination of the fetal anatomy. However, the exceptional change and gain that was offered by the introduction of this technological accomplishment was that 4D ultrasound allowed the direct assessment of detailed structure and fetal behavior in real time, something that was not possible before.10–14 Fetal movements and the overall behavior of the fetus in utero could be studied in a similar way that a neonate is examined by neonatologists immediately after delivery, but also later on during its life as it develops its motoric system while growing. For example, a neonate born at 30 weeks is not expected to have the same nervous maturation and as a consequence the same behavior as a neonate born at 40 weeks. Similarly, a neonate during the first day of his life has a different behavioral pattern than it does after a month of life. If we apply this logic to fetal life, it is reasonable that a fetus at 14 weeks has a different neurobehavior than a fetus at 26 or at 36 weeks. We would expect to have identified these patterns and study them in detail.
Elaboration on neurodevelopmental correlates of cognitive functions, considering sensory, motor, emotional development, as well as ability of learning and to memorize in fetal life we described in detail elsewhere [for review, see/ref. 1 and 11]. What we should keep in mind is that the process of human brain development, apart from the fact that it is extremely structured and delicate, it is not predesignated, and at the same time is very sensitive. It can be modified by different genetic and epigenetic factors and can be influenced by incidents that may occur any time during the pregnancy, or even after the birth. A great point of concern, especially in fetal medicine, is that the degree at which the integrity of fetal brain development will be affected by external factors, in most cases, cannot be predicted prenatally. It is obvious why the assessment of the fetal neurological status remains one of the greatest challenges in perinatal medicine. We needed a screening test not only for low-risk pregnancies but also for cases that there may be a suspicion of neurological impairment prenatally. The severity of this condition most of the times cannot be defined. In these cases, we cannot be certain at what extent the fetus will be affected and finally in most cases we cannot identify the exact time that the impairment may have occurred, and most importantly we cannot be sure whether it may have happened during pregnancy, during labor, or sometime after delivery.3 A method that could assess fetal behavior and as a result assess the neurological integrity of the fetus would be a method that could provide useful information.15,16
A method that applies the benefits offered by 4D ultrasound technology and aims to assess the fetus in utero in a similar way that neonatologists assess a newborn is called Kurjak antenatal neurodevelopmental test (KANET). It has been used for the last 10 years; there were two international consensuses (Osaka, Bucharest) and it is accepted as a comprehensive and applicable method that is by now used in everyday clinical practice. By the application of 4D ultrasound, it assesses fetal behavior as a neonate is assessed postnatally, in a structured, complete, and objective way.
Assessment of Fetal Motoric and Cognitive Function
The cerebral growth and maturation of a fetus appears to be represented by its behavior in utero,17–19 while studies have shown that their movements are very good indicators of neurobehavioral organization and of the future neurological integrity of the fetus.20–27 Two-dimensional (2D) ultrasound allowed the evaluation of the fetal anatomy and gave the opportunity to view fetal movements. One the pioneering studies about the importance of fetal movements was published more than three decades ago offering the first knowledge in this new field of fetal medicine and at the same time the inspiration to study the fetal behavior as a whole in utero.28 Fetal motor activity through the assessment of fetal movements was firstly studied by De Vries et al. who followed and analyzed the qualitative and quantitative aspects of the movements in a more methodological way.
Based on the first analysis of fetal movements by 2D ultrasonography, de Vries29–31 classified movements into different patterns as follows:
Sideways Bending
Started between 7th and 8th gestational weeks, slow and small displacements at one or two poles of the fetus occur, lasting from 0.5 to 2 seconds, which usually occur as a single event and disappear through gestation.
Startle
A startle consists of a rapid-phase contraction of all limb muscles. It often spreads to the trunk and neck. It occurs frequently in the first trimester from 8 weeks on.
General Movements (GMs)
These movements are complex movements including neck, trunk, and limbs that are applicable if the whole body is moved but no distinctive patterning or sequencing of the body parts can be recognized. They wax and wane in intensity, force, and speed and they have gradual beginning and end. These movements are performed from 8 weeks and on.
Hiccups
These consist of a jerky contraction of the diaphragm. Hiccups appear from 9 weeks and on, often in series, for up to several minutes, and isolated arm and leg movements can be observed.
Breathing-like Movement
Fetal breathing-like movements are usually paradoxical in a way that every contraction of the diaphragm (which after birth leads to an inspiration) causes an inward movement of the thorax. The onset of fetal breathing-like movement is around the 10th week of gestation. Early in pregnancy, they are present continually and are associated with activity in the postural muscles of the neck and limbs.
Isolated Arm or Leg Movement
These movements appear around the 10th week of gestation and they vary in speed and amplitude. They involve extension, flexion, external and internal rotation, or abduction and adduction of an extremity, without movements in other body parts.
Twitches
Twitches are quick extensions or flexions of a limb or the neck. They are not generalized or repetitive.
Clonic Movements
These are repetitive movements of one or more limbs at a rate of about three per second.
Isolated Retroflexion of the Head
Retroflexions of the head are usually carried out slowly, but they can also be fast and jerky. These movements can be seen around the 10th week of gestation and on.
Isolated Rotation of the Head
Rotation of the head is carried out at a slow velocity and only exceptionally at a higher speed. The head may turn from a midline position to one side and back.
Isolated Anteflexion of the Head
Anteflexion of the head is carried out only at a slow velocity. The displacement of the head is small. The duration is about 1 second.
Jaw Movements
The onset of irregular jaw opening is at 11th week. The opening may be either slow or quick. The duration of opening varies from less than 1–5 seconds.
Sucking and Swallowing
At 13 weeks, rhythmical sucking movements, often followed by swallowing, occur in bursts indicating that the fetus is drinking amniotic fluid.
Hand-head Contact
In this pattern of movement, the hand slowly touches the face, and the fingers frequently extend and flex. These movements appear from 10th week onward and at first they usually represent an accidental contact of a hand with the face or mouth.
Subgroups of these movements are the following:
- Hand-to-head: When hand movement ends at contact of fingers with the parieto-occipitotemporal region of the head.
- Hand-to-mouth: When hand movement ends at contact of thumb or finger with the mouth, lips, or the immediate oral region.
- Hand-near-mouth: When movement ends with fingers in fluid between nose and shoulders/nipples or between both shoulders. Hands must be below eyes and within the area defined by the ears, less than a hand away from the mouth.
- Hand-to-face: When movement ends with hand in contact with the face (cheeks, chin, and forehead).
- Hand-near-face: When movement ends with finger in fluid in front of the face but not in the mouth region.
- Hand-to-eye: When movement ends with hand or palm or fingers in the eye region.
- Hand-to-ear: When movement ends at hand contact with the ear.
Stretching
This movement is a complex motor pattern, which is always carried out at a slow speed and consists of the following components: forceful extension of the back, retroflexion of head, and external rotation and elevation of the arms. It retains an identical movement form into adult life.
Yawning
This motor activity is similar to the yawning observed after birth: prolonged wide opening of the jaws followed by quick closure, often with retroflexion of the head and sometimes elevation of the arms. This movement pattern is nonrepetitive and it appears around 11th week. The anatomical criterion for fetal yawning is retraction of the tongue, whereas yawning in adults is characterized by an extended tongue.
Rotation of the Fetus
Rotation of the fetus occurs around the sagittal or transverse axis. A complete change in position around the transverse axis, usually with a backward somersault, is achieved by a complex GM, including alternating leg movements, which resemble neonatal stepping.
This was a classical way, which of course had several limitations as the fetus was studied in 2D way and not through direct observation of fetal movements. The revolution in the examination of fetal movements was started by the introduction of 4D ultrasonography. Four-dimensional ultrasound changed the way fetal behavior was assessed in utero, as obviously it is a more objective and realistic method than 2D ultrasound.20–26 Three- or four-dimensional ultrasound has become routine in everyday clinical practice; it is part of routine assessment of most fetal medicine units and it has been proved to allow better observation of fetal movements.
Where 4D ultrasound mainly makes a difference is at the examination of small movements such as finger and toe movements but also for the study of the fetal face. Details like facial movements and facial expressions (such as smiling, crying, eye blinking) cannot be demonstrated with 2D ultrasound, and have only been documented with 3D and 4D ultrasound.27–29
It has been suggested that distinguishing between types of fetal movements and behavior according to each trimester could help to dissever routine normal fetal behavioral patterns, from possible pathological patterns.30–33 The face represents the most visible part of the human being. All major senses are facilitated in this region and expressed through facial expressions. The long-term study of fetuses with 4D ultrasound allowed the production of measurable units that could be finally applied systematically for the assessment of fetal behavior.34 One of the greatest advantages of 4D ultrasound compared to 2D, as we mentioned earlier, is the detailed views of the fetal face (e.g., smiling, crying, mouthing, and blinking), something that cannot be achieved with 2D ultrasound. When comparing assessment of fetal behavior by 2D and 4D US, the advantage of 4D is better depiction of fetal facial expressions in three dimensions (3D)35–37 with the possibility to assess them in almost real time with the new sophisticated ultrasound machines having fast frame rates.
There are now studies that prove that. With the use of 4D ultrasound differences in fetal behavior can be indeed identified and with these findings eventually abnormal characteristics can be identified too.38–40 The commencement of fetal movements has been shown by ultrasound studies that occur very early in fetal life and much earlier than pregnant women can start feeling them.41,42 Studies regarding neonatal neurology have shown that the neonatal behavioral examination can give more information about a possible impairment than a typical neurological examination. That initiated a series of studies that aimed to find out the exact pattern of the development of fetal behavior for each trimester, in order to define what is a normal behavior from what could be different and possibly abnormal pattern.3,12–14,30–32,43–46
Almost 10 years ago, Kurjak et al. developed a methodical system for assessing the integrity of the nervous system of fetuses in a complete and objective way, by applying 4D ultrasound.47 This test was named KANET, standing for Kurjak’s antenatal neurodevelopment test. Its innovation is that it aims to assess the fetus by application of 4D ultrasound almost the same way the neonatologists assess the integrity of the nervous system of newborns, using similar parameters.30,44,45,48–50 Two-dimensional ultrasound is a good classical method for the assessment of fetal movements; however, the KANET aims to improve this method and fill in the gaps that 2D technology has in the assessment of fetal movements. It is a complete test that consists of some general parameters, such as GMs of the fetus but it also adds some parameters that are used postnatally for neonatal assessment, incorporated by the Amiel-Tison Neurological Assessment at Term (ATNAT) signs.31,44 So while 2D US is used only for the assessment of fetal startles and GMs, KANET enabled assessment of movements with the addition of some signs used in postnatal neurological assessment, like cranial sutures, head circumference, and finger movements of the hand for the detection of neurological thumb (adducted thumb in the clenched feast).
Assessment of Fetal Motoric and Cognitive Function through Multicenter Studies
Timely diagnosing the brain impairment is the main reason why so many studies have been conducted regarding the anatomical and functional integrity of the fetal nervous system as well as the understanding of their reactions. The results that these studies showed gave the motivation for the development of a structured way of assessing fetal behavior in a similar way that neonatal assessment is done.12 The KANET is a new pioneering method of fetal evaluation by 4D ultrasound that shows a relationship between fetal behavior and neurodevelopmental processes in different periods of pregnancy, making possible to distinguish between normal and abnormal brain development.47,51 It consists of general parameters such as GMs of the fetus and some parameters that are used postnatally for neonatal assessment incorporated by the ATNAT signs.30,31,44,45,48,52 The following parameters are included in the KANET: 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 GMs (overall perception of the body and limb movements with their qualitative assessment).
Studies show a continuity of the behavioral pattern that follows a fetus from its in utero life to its postpartum attitude and it has been observed that all movements that are present in neonates are also present in fetal life, with the exception of Moro’s reflex, which cannot be demonstrated in fetuses.53 The absence of Moro’s reflex can be attributed to the differences of the environment in which a fetus develops compared to the postnatal environment, and these differences concern mainly the differences of gravity in the two environments.16 The parameters finally decided to be used for the KANET were the result of long-term multicenter studies regarding neurological assessment and the GM’s emergence of the fetuses.52,54
The KANET is an integrated test consisting of parameters that concern in utero behavior and movements, but also signs that are used postnatally for detection of neurodevelopmental impairment (neurological thumb, overlapping sutures, and small head circumference).55 The KANET is a test that has been standardized, and studies show that it is a method with good reproducibility and the learning curve is very reasonable for physicians and medical staff with a good ultrasound background.55 Regarding the gestational age at which KANET should be performed, it has been decided that the best period is the third trimester of pregnancy, and particularly after 28 weeks. The test is proposed to last about 15–20 minutes, and it has been decided that it is best to be performed at periods that the fetus is awake. If this is not achievable because the fetus goes through its sleeping period, the test should be repeated in 30 minutes or the following day, at a minimum period of 14–16 hours.
When the test is abnormal or the score is borderline, the test should be repeated every 2 weeks until delivery. Very important features are facial movements and eye blinking because the face is also called “the mirror of the brain.” The overall number of movements must be documented in all cases and compared with normal values as presented in previous studied and reviews52,54 (Figs 1 to 8).
Figs 1A to C: Sequences of images of fetal face (profile) at 30 weeks of gestation; images extracted from the 4D ultrasound recording and KANET assessment in surface mode. Typical fetal facial expressions as seen during the performance of KANET: Notice: Open eyes and smiling
Figs 2A to C: Sequences of images of fetal face (profile) at 31 weeks of gestation; images extracted from the 4D ultrasound recording and KANET assessment in HDlive surface mode. KANET assessment. Notice: Open eyes, opening the mouth, tongue expulsion, grabbing the foot and licking it. These are all complex and planned movements and important parameters of KANET showing normal neurological development
Examiners who apply KANET should have proper training and adequate experience in low- and high-risk pregnancies. Interobserver and intraobserver variability has to be documented. The suggestion regarding the ultrasonographic machines use is to have a frame rate of at least 24 volumes/second. The KANET consists of eight parameters (Table 2). The results of KANET are divided in three groups: (1) abnormal, when the score is 0–5, (2) borderline for a score from 6 to 13, and finally (3) normal for a score 14–20 (Table 3). A 2-year follow-up should be available and documented for all fetuses that KANET has been applied, in order to draw safe conclusions.
The aim of the KANET is to evaluates fetal motoric activity and through that the development of the nervous activity. The KANET depends on realistic images compared to the traditional 2D ultrasound and maternal perception of fetal movements, as it can demonstrate fetal movements in real time. As mentioned above, parameters used by KANET are a mixture of GMs and signs adopted by ATNAT, and these are based on the fact that there is a continuity from fetal life to neonatal life after delivery, plus the fact that the integrity of the fetal nervous system is up to a point represented by the quality and quantity of the movements that a fetus has in utero and its overall behavior.31,56–61
Studies show62–67 that KANET can identify severe motoric impairment in fetuses with already diagnosed anatomical CNS abnormalities or chromosomal abnormalities. Also it has been proven that the results of KANET in both low- and high-risk populations correspond to a very high extent with the final outcome and particularly in high-risk populations; KANET can be a very useful tool providing information regarding the prognosis and the grade of impairment of these cases.68 The KANET constitutes the first test applying 4D ultrasound, which has been standardized attempting to simplify things and offers a scoring system, with an aim to be introduced in the clinical practice.69–72 Regarding the applicability of KANET, studies show that it is relatively easy to learn and well accepted by pregnant women. The KANET appears to offer useful information about fetal neurobehavior and has the potential to detect and discriminate normal, borderline, and abnormal fetal behavior mainly in high-risk pregnancies, so it can be a valuable diagnostic tool for fetal neurological assessment.51,55,75–80 So far KANET has proven its usefulness in standardization of neurobehavioral assessment, with the potential of prenatal detection of fetuses with severe neuronal dysfunction.51 According to the Bucharest consensus statement81 on KANET, an experienced ultrasound specialist needed to perform about 80 KANETs in order to be familiar with the KANET assessment of the fetus with 4D US in 20 minutes. It was calculated that one needs 10–15 cases in 7 days in order to learn the basics of the technique, which can be reproducible. The number of tests was comparable with other ultrasound tests like nuchal translucency screening (40 tests by experienced ultrasound specialist) and anomaly scan (100–200 tests by experienced specialist). In a study where 1,712 KANETs were performed on 655 patients, the success rate of the test ranged between 91% and 95%. The success rate for the assessment of particular signs of the KANET was between 88% for isolated eye blinking and 100% for mouth opening and isolated leg movement. The KANET had almost 100% negative predictive value. Interobserver agreement between two examiners for different components of the KANET was assessed by calculation of Kappa values, which were lowest for the facial expression (K = 0.68) and highest for the finger movements (K = 0.84), proving that KANET is a reliable method to be used with confidence in everyday clinical practice after appropriate education of an experienced examiner. What is even more appropriate as educational courses with certificate of completion on the performance of KANET that are organized by the Ian Donald School of Ultrasound.
Figs 3A to F: Sequences of images of fetal face (profile) at 34 weeks of gestation; images extracted from the 4D ultrasound recording and KANET assessment in HDlive surface mode. Notice: Fetus awake, open eyes, smiling (look at the nasolabial fold), an important parameter of KANET and a good sign of normal neurological development
Figs 4A and B: Fetus at 28 weeks of gestation. KANET assessment with 4D surface rendering mode. Notice: Fetal hand and finger movements, touching the right eye. Detailed movements are very indicative of the neurological maturation and very important parameter of KANET
Figs 5A and B: Fetus at 29 weeks of gestation. Visualization of hand movements, touching the umbilical cord, opening the eyes in (B)
The KANET has a dual purpose: first of all to assess the motoric function of the fetus and second by assessing the motoric function of the fetus and its behavior, to draw conclusions regarding the cognitive function of the fetus and the integrity of its nervous activity (Figs 1 and 2). Compared to the classical 2D ultrasound assessment of fetal movements and the so-called maternal perception of fetal movements, KANET offers a more objective method as it relies on realistic images and it demonstrates fetal activity in real (or near real) time.
Figs 6A to D: Fetus at 28 weeks of gestation. KANET assessment with 4D surface rendering mode. Notice: Fetal hand and finger movements, touching the left eye. Mouth opening, yawning. Notice as well umbilical cord around the fetal neck. Detailed movements are very indicative of the neurological maturation and very important parameter of KANET
Figs 7A to D: Normal KANET—test - facial alterations mouthing, eye blinking and hand movements toward the face, hand opening and closing, forming the fist. Notice: Thumb outside the fist in Figure D. Good neurological signs
Figs 8A and B: Abnormal KANET score: (A) Mouth movements were identified, but otherwise facial alterations were minimal and the KANET score was abnormal. No leg movements were seen and forced position of the hands was seen (arrow); (B) Similar case abnormal KANET: Specific signs: Neurological thumb and overlapping of index and 3rd finger of the left hand (arrow) were identified
Prenatal Assessment of Motoric and Cognitive Function of the Fetus: Results from Multicenter Studies
The first form of the KANET scoring system was applied by Andonotopo et al.67 and Zagreb group. Their aim was to assess whether facial expression and body movements could be of any diagnostic value regarding cerebral palsy in growth-restricted fetuses. They studied 50 pregnancies with intrauterine growth restriction (IUGR) after 28 weeks of pregnancy. They noted decreased motor activity in the IUGR fetuses compared to the non-IUGR. This preliminary study motivated further studies about the usefulness of 4D ultrasound in the assessment of fetal behavior. Introduction of KANET as a method that could identify characteristics in fetal behavior or movement manifested some degree of brain impairment as well. For the development of this test, several neonates with variable forms of neurological impairment were examined and compared with “normal” neonates. The idea was to try and identify similarities and differences during in utero life in order to diagnose brain impairment prenatally. The KANET was applied retrospectively in 100 low-risk pregnancies and all fetuses were assessed and after delivery, with the score 14–20 characterized as normal. Then the test was applied to 120 high-risk pregnancies according to the postnatal assessment, and neonates were divided into three groups: normal, mildly or moderately abnormal, and abnormal. According to the results, the scoring system was divided to prenatal score 14–20 (normal), 5–13 (mildly or moderately abnormal), and 0–5 (abnormal). From the abnormal cases, four were diagnosed with alobar holoprosencephally, one with severe hydrocephaly, one with thanatotrophic dysplasia, and four cases with multiple severe structural abnormalities. Following this preliminary study (Table 4), many studies applied KANET and assessed its usefulness for the detection of neurological impairment during in utero life.39,82
| Sign | Score | Sign score | ||
|---|---|---|---|---|
| 0 | 1 | 2 | ||
| 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 circumference | 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 | Not present | Not fluent (1–5 times of blinking) | Fluency (>5 times of blinking) | |
 | ||||
| Facial alteration (grimace or tongue expulsion) | Not present | Not fluent (1–5 times of alteration) | Fluency (>5 times of alteration) | |
 | ||||
| or Mouth opening (yawning or mouthing) | ||||
 | ||||
 | ||||
| Isolated hand movement | Cramped or abrupt | Poor repertoire or small in range (0–5 times of movement) | Variable in full range, many alteration (>5 times of movements) | |
 | ||||
| or Hand-to-face movements | ||||
 | ||||
| Fingers movements | 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 | ||||
| Total score | Interpretation |
|---|---|
| 0–5 | Abnormal |
| 6–9 | Borderline |
| 10–16 | Normal |
In one of the studies, out of 288 high-risk pregnancies, 7 abnormal cases were included—also 25 cases with borderline KANET score, yielding 32 fetuses at neurological risk. There were also 11 cases with abnormal KANET, of which 6 fetuses died in utero and 5 were terminated. The seven remaining neonates with abnormal KANET were followed up postnatally at 10 weeks and from these neonates, three had confirmed pathological ATNAT score postpartum. These three cases included a neonate with arthrogryposis, a neonate with cerebellar vermian complete aplasia, and one case with a history of cerebral palsy in a previous pregnancy.
| Author | Year | Study | Study design | Study population | Indication | No. | GA (weeks) | Time (minutes) | Result | Summary |
|---|---|---|---|---|---|---|---|---|---|---|
| Kurjak et al.15 | 2008 | Cohort | Retrospective | High-risk | Multiple | 220 | 20–36 | 30 | Positive | Introduction of scoring system was proposed for antenatal assessment of fetal neurobehavior. |
| Kurjak et al.43 | 2010 | Multicenter | Prospective | High-risk | Multiple | 288 | 20–38 | 30 | Positive | KANET appeared to be prognostic of identification of neurological impairment in utero. KANET also identified fetuses with severe anatomical anomalies, especially related to neurological damage. |
| Miskovic et al.31 | 2010 | Cohort | Prospective | High-risk | Multiple | 226 | 20–36 | 30 | Positive | Correlation between antenatal (KANET) and postnatal (ATNAT) results identified. KANET showed variations in the neurobehavior of fetuses from high- to low-risk cases. |
| Talic et al.30 | 2011 | Multicenter Cohort | Prospective | High-risk | Multiple | 620 | 26–38 | 15–20 | Positive | KANET test had prognostic value in discriminating normal from borderline to pathological neurobehavior. Abnormal KANET scores were predictable of both intrauterine and postnatal death. |
| Talic et al.44 | 2011 | Multicenter Cohort | Prospective | High-risk | Ventriculo-megaly | 240 | 32–36 | 10–15 | Positive | Statistically significant difference in KANET scores between normal pregnancies and pregnancies with ventriculomegaly. Cases with pathological result and majority of cases with borderline results were noted in cases with severe ventriculomegaly, especially when combined with other anomalies. |
| Honemeyer et al.63 | 2011 | Cohort | Prospective | Unselected | Unselected | 100 | 28–38 | N/A | Positive | KANET result had a significant predictive value of a good postpartum neurological evaluation. |
| Lebit et al.29 | 2011 | Cohort | Prospective | Low-risk | Normal 2D examination | 144 | 7–38 | 15–20 | Positive | A specific mode of in utero neurobehavior corresponding to each stage of pregnancy was noted. |
| Abo-Yaqoub et al.54 | 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.64 | 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 had normal score, for high-risk pregnancies → 78.5% of fetuses had a normal score. |
| Honemeyer et al.65 | 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 risk. |
| Kurjak et al.83 | 2013 | Cohort | Prospective | High and low risk | Multiple | 869 | 28–38 | 20 | Positive | Statistical differences regarding the distribution of normal, abnormal, and borderline results of KANET between low-risk and high- risk groups found. Fetal behavior was significantly different between the normal group and the high-risk subgroups. |
| Predojevic et al.84 | 2014 | Case study | Prospective | High risk | IUGR | 5 | 31–39 | 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.85 | 2013 | Cohort | Prospective | Unselected (high and low risk) | Multiple (IUGR, PET, GDM) | 152 | Second and third trimester | N/A | Positive | The neurodevelopmental trimester score was statistically significant higher in the low-risk in comparison to that of high-risk group (p %3C; 0.0004). The KANET results in the diabetes subgroup was higher when compared to that of the IUGR and the preeclampsia subgroup (p = 0.0001). |
| Neto et al.86 | 2014 | Cohort | Prospective | High and low risk | Multiple | 51 | Third trimester | 20 | Positive | Statistical significance between high- and low-risk cases. All abnormal results come from high-risk cases. |
| Hanaoka et al.87 | 2015 | Cohort | Prospective | Mixed (Asian and Caucasian) | Multiple | 167 | Third trimester | N/A | Positive | Differences in pattern movements in different racial groups so that ethnicity should be considered when performing KANET. |
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, preeclampsia; GDM gestational diabetes mellitus
The main characteristic of these three cases was the facial expressions that appeared significantly diminished—these faces are characterized as masks due to lack of expressions noted at the time of ultrasound examination. The remaining four cases with pathological KANET did not show abnormal ATNAT postnatally and the examiners characterized the neurological assessment as normal. These four cases included a case of ventriculomegaly, a case complicated by preeclampsia, one case with maternal thrombophilia, and one case complicated by oligohydramnios. From the 25 cases diagnosed with borderline KANET result, 22 neonates showed a borderline ATNAT score and were followed up, while the 3 remaining cases showed normal ATNAT result. These three cases were complicated by ventriculomegaly, chorioamnionitis, and maternal thrombocytopenia, respectively. The cases with pathological prenatal score and normal postnatal ATNAT were characterized by the following risk factors: ventriculomegaly, Dandy–Walker malformation, skeletal dysplasia, increased amniotic fluid, gestational diabetes, hydrocephaly, thrombophilia, preeclampsia, achondroplasia, oligohydramnios, nonimmune hydrops, chorioamnionitis, growth restriction, Down’s syndrome, and thrombocytopenia.
From the three cases with pathological KANET, at neonatal assessment with ATNAT two showed confirmed abnormal Prechtl’s GMs (these were the cases with arthrogryposis and with cerebellar vermis aplasia) while there were six more cases that were characterized as pathological (history of previous neonate with CP, Dandy–Walker syndrome, hydrocephaly, Down’s syndrome, ventriculomegaly, nonimmune hydrops). From the remaining 21 neonates, all of them had normal optimal or suboptimal GMs.
An interesting case was that of a fetus with acrania and by studying this pregnancy they managed to document how fetal behavior altered from 20 weeks of gestation. The remarkable thing was that as pregnancy progressed and the control center of motoric activity shifted from the lower to the upper part, the KANET score was becoming lower and lower, suggesting that neurological damage in later pregnancy is possible.62
A study with66 226 cases, including different study populations, identified three cases with pathological KANET. All three cases had chromosomal abnormalities and all three postnatally had also an abnormal ATNAT. Scores from antenatal KANET and postnatal ATNAT were compared between low- and high-risk groups, and showed differences between them, for eight out of the ten 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.
The comparison of the two tests revealed correlation between them, proving that the neonatal exam (ATNAT) was a satisfactory confirmation of the prenatal ultrasound examination (KANET), stating that possibly with further studies this antenatal test could offer useful information about the neurological status of the fetus and be applied in clinical practice.
One of the largest studies of KANET65 includes 620 cases, of both low- and high-risk populations (100 low-risk and 520 high-risk cases). This study did not include fetuses with anatomical anomalies that were studied between 26 weeks and 38 weeks of gestation. The high-risk group included the following cases: threatened preterm delivery with or without preterm rupture of membranes (PPROM), previous history of CP, pregnancy hypertension, preeclampsia, gestational diabetes, IUGR, polyhydramnios, Rhesus alloimmunization, placental abruption, and maternal fever %3E;39°C.
Analysis revealed differences in the average KANET scores between high- and low-risk groups. The most cases of pathological KANET were identified in the cases that were characterized by a previous history of CP (23.8%), while the most cases of borderline KANET were noted in cases with maternal fever, which were possibly related to chorioamnionitis (56.4%). The 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. This study concluded that an abnormal KANET score is related with an increased risk of both intrauterine and neonatal mortality, but also with an increased risk of neurological impairment. What they also mentioned is that KANET is indicative of normal but also abnormal fetal neurobehavior, which can be demonstrated in postpartum life.
A study by Honemeyer and Kurjak72 with 100 cases and a very good postnatal follow-up of the neonates not only exactly at the time of delivery, before discharge from the hospital, but also at routine follow-up at 3 months of life showed that a good KANET score confirms up to a great extent an also normal neurological examination of the neonate at the time of delivery and at 3 months of age. A study by Lebit et al.88 included 144 low-risk pregnancies, which they followed up antenatally from as early as 7 weeks up to 38 weeks, in order to define a specific pattern of fetal behavior that would be characterized as normal and correspond to each trimester. It appears that during the first weeks of pregnancy the number of fetal movements increase as does their complexity. In the second trimester, the fetal motoric activity increases in number and different types of movements develop. More detailed movements such as facial grimacing and eye blinking tend to make their appearance during the middle of second trimester. Many women sustain that their perception of fetal movements decrease near term; that is because at that time fetal movements indeed decline in frequency as the duration of fetal rest periods increase as a result of fetal cerebral maturation rather than the fact as many people believe that the amniotic fluid decreases at the end of pregnancy.41,82 Fetal behavior may reflect the level of CNS maturation and integrity and as a result KANET that assesses fetal behavior may offer useful information.88 A study that applied KANET in 140 fetuses with ventriculomegaly68 and compared them with 100 fetuses with normal CNS appearance during 32–36 weeks of gestation showed a big difference of abnormal KANET scores between the two groups (6% abnormal KANET in the low risk-control group compared to 34.9% in the group with ventriculomegaly). The greatest degree of ventriculomegaly correlated with the lowest KANET score, especially when other anomalies were present.
What is interesting is that no cases of pathological KANET score were identified when the degree of ventriculomegaly was mild or moderate and no other anomalies were present. The study showed agreement of prenatal KANET with the postpartum neonatal evaluation and also application of KANET in cases of ventriculomegaly offered the opportunity to identify fetuses who would not only have a structural anomaly but also their motoric activity would be affected, so that a complete assessment of the nervous system could be achieved, not only anatomically but also functionally. That is extremely important especially in cases of ventriculomegaly. The question: if, how and to what degree will it affect a neonate, is not always clear and still not well understood.
A study of64 40 cases with increased risk for neurological anomalies applied KANET between 20 weeks and 38 weeks of gestation and compared the results with a control group of 40 low-risk cases. They aimed to define the usefulness and feasibility of 4D ultrasonography in the assessment of fetal neurobehavior and also in the prediction of neurological impairment.
The two groups had significant differences in their KANET scores and the study showed that in all cases where the KANET score was abnormal also postnatally there was some degree of neurological impairment, while when the KANET score was normal or even borderline the neurological outcome postnatally was also normal. The parameters that were significantly different between the two groups were isolated head anteflexion, isolated eye blinking, facial expressions, mouth movements, and isolated hand movements, hand-to-face movements, finger movements, and GMs. Regarding isolated leg movements and cranial sutures, the difference was not significant.
Vladareanu et al.89 applied KANET in 196 singleton pregnancies (61 low-risk and 135 at-risk patients) from 24 to 38 weeks. The study lasted for 3 years. Most fetuses in the study who obtained normal KANET score belonged to the low-risk group. The majority of cases with borderline scores belonged to the IUGR group that also had high resistance index (RI) in the middle cerebral artery (MCA) while the majority of cases with pathological KANET score belonged to cases of threatened preterm labor with preterm premature rupture of membranes (PPROM).
There was statistical significant difference in fetal movements in the two groups. In normal pregnancies, most fetuses (93.4%) achieved a normal KANET score compared to 78.5% of the fetuses from high-risk pregnancies. Borderline and abnormal scores were dominant in high-risk pregnancies. In the high-risk pregnancy group, most abnormal KANET scores were noted in cases of threatened preterm delivery with PPROM (25%). Most fetuses with pregnancies complicated by IUGR with middle cerebral artery resistance index (MCA RI) changes and with hypertension above 160/100 mm Hg achieved borderline score (50%). The highest percentage of normal fetal movements was found in pregnancies complicated by Rhesus alloimmunization without hydrops fetalis (96%). The characteristics of reduced speed and amplitude were found in the threatened preterm delivery group. There was a reduction of both number and duration of GMs in the IUGR group. The IUGR fetuses moved less and their GMs were poorly organized. Alterations in the quality of fetal movements were accompanied by considerable decrease in the quantity of fetal movements. The authors concluded that KANET can be useful in the detection of neurological impairment that could become obvious during the antenatal or postnatal period. Honemeyer et al.90 studied 56 singleton pregnancies (24 low-risk and 32 high-risk cases) between 28 and 38 weeks of gestation and applied serial KANETs on them, performing a total of 117 tests in total. They did not identify any abnormal KANET scores, but two-thirds of the borderline scores occurred in the high-risk pregnancies. Because they performed more than one KANET in each pregnancy, they introduced the average KANET score, which derived from the scores of each fetus during pregnancy. Only one fetus had a borderline average KANET score, and this fetus who belonged to the high-risk group was the only 1 out of 56 pregnancies who had an abnormal early neurological outcome. When the authors compared all the 18 borderline KANET scores with fetal diurnal rhythm based on maternal observation, they noticed that 89% of the borderline scores of the at-risk group were recorded at times that the mothers characterized them as active periods, compared with 33.3% in the low-risk pregnancies. The authors concluded that KANET is suggestive of expressing the risk for neurodevelopmental fetal disorders, but the connection of fetal diurnal rhythm and pregnancy risk status should be investigated further.
Kurjak et al.83 studied 869 high- and low-risk singleton pregnancies taking under consideration the results of the Doppler studies of umbilical and middle cerebral arteries, and noticed that fetal behavior was significantly different between the normal group and the following subgroups of fetuses: IUGR, gestational diabetes mellitus, threatened preterm birth, antepartum hemorrhage, maternal fever, sibling with cerebral palsy (CP), and polyhydramnios. The authors concluded that their study showed a new clinical application of the KANET test in early identification of fetuses prone to neurological impairment.
Athanasiadis et al.91 studied with KANET 152 pregnancies of both low and high risk. According to the maternal background risk, there were 78 low-risk and 74 high-risk pregnancies (12 with IUGR fetuses, 24 with diabetes mellitus, and 38 with preeclampsia). The study showed that 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 preeclampsia subgroup (p = 0.0001). The authors concluded that the neurodevelopment fetal assessment by 4D ultrasound appears to be a feasible technique in the evaluation of high-risk pregnancies and the detection of differences in these populations.91
Moreira Neto51 performed a pilot study in Brazil by applying KANET to 17 high-risk pregnancies and 34 low-risk pregnancies and compared the results. He noticed that for KANET score 0, five out of eight parameters were significantly different: isolated head anteflexion, cranial sutures and head circumference, isolated hand movement or hand-to-face movements, isolated leg movement, and fingers movements. All abnormal KANET result derived from high-risk pregnancies (17.6%). No low-risk pregnancies presented with KANET score 0, concluding that there were important differences in fetal behavior between low- and high-risk pregnancies.51
Hanaoka et al.74 assessed with KANET 89 Japanese (representative of Asians) and 78 Croatian (representative of Caucasians) pregnant women and studied the total value of KANET score and values of each parameter (eight parameters) in the different populations. Total KANET score was normal in both populations, but there was a significant difference in total KANET scores between Japanese and Croatian fetuses. When individual KANET parameters were compared, significant differences were observed in four fetal movements (isolated head anteflexion, isolated eye blinking, facial alteration or mouth opening, and isolated leg movement). No significant differences were noted in the four other parameters (cranial suture and head circumference, isolated hand movement or hand-to-face movements, fingers movements, and gestalt of GMs), showing that ethnicity should be considered when evaluating fetal behavior, especially during assessment of fetal facial expressions. The authors concluded that although there was a difference in the total KANET score between Japanese and Croatian 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.74,78
Antsaklis et al. studied with a strict protocol the differences in fetal neurobehavior between diabetic and nondiabetic patients. They studied 60 pregnancies with gestational diabetes under treatment with insulin and compared them with 60 nondiabetic cases, and it appeared that the diabetic group showed lower scores in KANET than the nondiabetic group, proving that there are differences in the fetal behavior between diabetic and nondiabetic fetuses, and also identified the specific parameters—movements that were different between the two groups.
Why are Prenatal Diagnoses of Neurodevelopmental Disorders that Affect Motoric and Cognitive Function of the Fetus Important?
Once the diagnosis of neurological impairment is made in neonates the interventions available in everyday clinical practice are very limited and usually they prove to be ineffective. The KANET offers the possibility of very early, prenatal detection of fetus at risk for neurological problems.77 As soon as it becomes possible to detect abnormalities by prenatal ultrasound, the question arises of what can and should be done. This very early detection of these high-risk fetuses may be the key for the management of these cases, as the earlier you have a diagnosis, the earlier you may possibly intervene and as a result increase the possibility if not for treatment, for an improved outcome. It has been suggested, for example, for many years that early application of physiotherapy can be of some significance and that it can improve neurodevelopmental outcome. The KANET can also make a valuable contribution to the detection, diagnosis and sometimes prognosis of many fetal syndromes.76,77 In Cochrane meta-analysis, it has been stated that early intervention programs for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with the cognitive benefits persisting into preschool age.78 Of course, further research is needed to determine which early developmental interventions really make a difference in improving the cognitive or motoric function of neonates. In one of the programs, the primary caregivers have been educated about evidence-based interventions for improving infant self-regulation, postural stability, coordination and strength, parent mental health, and the parent–infant relationship. A therapy team consisting of a physiotherapist and psychologist delivered the nine sessions of the program (each session was 1.5–2 hours long) in the family home over the infant’s first year of life. Infants and their caregivers have selective long-term benefits, with caregivers experiencing fewer anxiety symptoms and lower odds of an anxiety disorder and preschoolers showing fewer internalizing behavior problems. It is obvious that we do not have many effective treatment options for cases of neurological impairment, but it appears that the earlier you apply these treatments, the better the results, and the earlier you have a diagnosis then indeed you can apply earlier these treatments to the correct group of people, and this is an area where definitely KANET can be a pioneer.75–80,81,92
DISCUSSION
The study of motoric and cognitive function of the fetus remains one of the most challenging issues in perinatal medicine. Maternal perception in combination with the application of 2D ultrasound offered some valuable information regarding fetal movements, leaving however many unanswered questions about the overall motoric activity of the fetus and offering very limited information regarding the cognitive function of the fetus. A more complete approach for the assessment of the motoric function of the fetus was offered by KANET. It was the first method that applied 4D ultrasound for the assessment of the fetus, in a similar way that a neonate is assessed neurologically after birth by neonatologists. So apart from assessing the motoric system of the fetus, it allows the assessment of its neurological status. So far KANET has been proven a strong diagnostic method of great potential, particularly for the detection of problems that were inaccessible by any other method until now, such as functional fetal brain impairment and neurodevelopmental alterations.53 Of course as a new method, it has to be further tested and more, larger studies are required in order to draw safe conclusions and for this test to be ready for introduction in clinical practice.
Ongoing studies aim to further investigate the potential of this new method setting the guidelines for a complete fetal neurosonography and neurobehavioral assessment.84 The continuous knowledge that we gain by studying fetal neurobehavior in a systematic way with the application of a standardized method such as KANET, in combination with the unrelenting technological advantage of 4D ultrasonography gives the impression that in the near future perinatal medicine will be able to study in explicit detail the functional development and maturation of the fetal nervous system, something that until today has not been achieved.
CONCLUSION
One of the greatest challenges of obstetrical ultrasonography is the better understanding of fetal neurological function, a field with still many unanswered questions. We have to keep in mind that still all these diagnoses are made postnatally, and that can be months or even years after delivery. What is more neurological conditions, such as CP, are not adequately understood and falsely attributed to intrapartum incidents, even though it has been proven that the majority of CP cases originate sometime during in utero life and are not related to intrapartum events.93–95 All these things lead to delayed diagnosis of various forms of neurological conditions. However, the later a neurological impairment is diagnosed the possibility of an effective intervention is decreased.
The distinction between normal and abnormal fetal neurological behavior and the development of an accurate method for the assessment of the function of fetal nervous system is a great challenge in obstetrics, and that was made possible with the introduction of 4D ultrasound, which offered the opportunity to study the fetus in real time and with explicit detail.
The KANET is the first method that applied 4D ultrasound for the assessment of the fetus in the same way that a neonate is assessed neurologically after birth by neonatologists. The KANET offers an objective scoring system that divides the fetuses according to the severity of the ultrasound findings and studies show that it can identify fetal signs that could predict its neurological development. What is more in cases of anatomical findings of uncertain significance and consequences on the neurological integrity of the fetus, like for example in cases of ventriculomegaly, it offers the possibility of a more complete assessment of the fetus and therefore a more comprehensive counseling of the couples with an affected fetus. A great innovation would be to have a method that would allow a timely diagnosis of such conditions, even during in utero life, in order to increase the possibility of an effective intervention or even treatment. The KANET offers the possibility of prenatal detection of fetuses at risk for neurological problems, allowing at the same time the possibility of in utero or early postpartum intervention. It is known for example that when physiotherapy is commenced early rather than late and intervention programs are applied correctly in neonates that are born prematurely or with neurological problems, their neurodevelopmental outcome is improved, with the cognitive benefits persisting into preschool age. The KANET appears to be able to offer this advantage of early identification of fetuses with neurological problems so that they could be put under treatment as early as possible, aiming to a better outcome.
The KANET is currently used by many centers in clinical practice as the investigational tool for normal and high-risk fetuses. It has acceptable sensitivity and specificity, and adequate positive and negative predictive value and also inter- and intraobserver reliability and can be easily learned by ultrasound specialists with access to 4D ultrasound machines.95 What is 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.
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. 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. This will enable a more precise diagnosis prenatally, and thus a prompt intervention either pre-or postnatally that could improve the outcome of some of these newborns.
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