The assessment of fetal neurobehavior by

3D/4D ultrasound
Badreldeen Ahmed1, Asim Kurjak2, Ana Tikvica2, Berivoj Miskovic2, Oliver Vasilj2, Milan

Stanojevic2, Guillermo Azumendi3

1
Department of Obstetrics and Gynecology, Womens Hospital, Hamad Medical Corporation,

Doha, Qatar
2
Department of Obstetrics and Gynecology, Medical School, University of Zagreb, Sveti Duh

Hospital, Zagreb, Croatia

3
Clinica Gutenberg, Malaga, Spain

Introduction

For more than 40 years, ultrasound has been extensively used in medical imaging,

which has proved helpful for the diagnosis and staging of numerous diseases of different

organs and systems of human body. The development of real time two-dimensional (2D)

ultrasound has enabled the direct visualization of fetal anatomy and activity in utero. Analysis

of the dynamics of fetal behaviour in comparison with morphological studies has led to the

conclusion that fetal behavioural patterns directly reflect developmental and maturational

processes of the fetal central nervous system. Therefore, it was suggested that the assessment

of fetal behavior and developmental processes in different periods of gestation may make

possible the distinction between normal and abnormal brain development, as well as early

diagnosis of various structural or functional abnormalities (1). However, the two dimensional

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ultrasound was considered somewhat subjective method because information needs observer

interpretation. The latest development of three-dimensional (3D) and four dimensional (4D)

sonography that overcame some of the limitations of two-dimensional methods enables

precise study of fetal and even embryonic activity and behavior.

In the contrary to the 3D ultrasound which freezes the image of an object and therefore

does not provide information on movements, 4D enables the opportunity of simultaneous

visualization of the movements of the head, body, and all four limbs and extremities in three

dimensions, in a real-time mode. Therefore, the earliest phases of the human anatomical and

motor development can be visualized and studied simultaneously (2).

These new technologies have resulted in remarkable progress in visualization of early

embryos and in the development of sonoembryology that can assess both structural and

functional developments in the first 12 weeks of gestation more objectively and reliable.

Ultrasound examinations moved embryology from postmortem studies to the in vivo

environment.

Four-dimensional ultrasound or real-time three-dimensional ultrasound makes it

straightforward to comprehend some morphological dynamics, such as yawning, sucking,

smiling, crying and blinking. This offers a practical means for assessment of neurophysiologic

development, as well as for detection of anatomical pathology (4). Four-dimensional (4D)

ultrasound additionally provides a tool for observation of the fetal face (Figure 1).

Simultaneous imaging of complex facial movements was not possible using real-time 2D

ultrasound. 4D ultrasound integrates the advantage of the spatial imaging of the fetal face with

the addition of time. This new technology therefore allows the appearance and duration of

each facial movement and expression to be determined and measured.

In a relatively short period of time, 4D sonography has stimulated multicentric studies

on fetal and even embryonic behavior with more convincing imaging and data than those

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obtained by conventional ultrasonic and non-ultrasonic methods (Table 1). The visualization

of fetal activity in utero by 4D ultrasound could allow distinction between normal and

abnormal behavioral patterns which could make possible the early recognition of fetal brain

impairment (7). The purpose of this chapter is to review present knowledge on 4D ultrasound

fetal motoric activity imaging throughout the pregnancy.

Four-dimensional ultrasound

Recently de Vries published two overviews: one on normal fetal motility and second

on changes in fetal motility as a result of congenital disorders both assessed by two-

dimensional ultrasound after 35 years of real-time two-dimensional sonography (8, 9).

Although 2D sonography enhanced our understanding of fetal neuromuscular development,

the real breakthrough in studying fetal neurobehavior was achieved by introduction of four-

dimensional ultrasound. This technique has some additional advantages, such as the ability to

study fetal activity in the surface-rendered mode, and is particularly superior for fast fetal

movements (10). Its important advantage in comparison with two-dimensional ultrasound is

the ability to visualize the whole fetus continuously. Fetal movements such as yawning,

swallowing and eyelid movements cannot be displayed simultaneously, whilst, with four-

dimensional sonography, the simultaneous facial movements can be clearly depicted (11).

With four-dimensional ultrasound, it is now feasible to study a full range of facial expressions

including smiling, crying, scowling and eyelid movement (11, 12). The observation of facial

expression may be of scientific and diagnostic value and this scientific approach opens an

entirely new field. Recently, multicentric studies of fetal brain function have been carried out

(5, 7, 11), the aim of which was to establish the standards of fetal peripheral and body

movements, and facial expressions as additional diagnostic criteria for prenatal brain

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impairment. It is our belief that four-dimensional ultrasound will have its place in everyday

obstetric practice, combining patient acceptance and sensitivity of diagnosis.

Fetal behavior

Although more than 100 years of curiosity in fetal behavior and almost three decades

of sustained awareness and research, the study of fetal behaviour has achieved widespread

acceptance in perinatal medicine. For centuries, maternal registration of fetal movements and

obstetrician auscultation of fetal heartbeats were the only methods of the follow up of fetal

well being in utero. It has been shown that fetal activity occurs as early as the late embryonic

period, which is far earlier that a mother can sense it. A turning point in the assessment of

fetal behavior was the introduction of real-time ultrasound and from that time we can say that

fetal behavior can be defined as any fetal activity observed or recorded with ultrasonographic

equipment. As it is not yet possible to assess functional development of the CNS directly,

investigators have started to analyze fetal behavior as a measure of neurological maturation

icluding properties of fetal hemodynamics and the muscular system, as well (13). This

technique allowed the investigation of spontaneous fetal motor activity in utero. For the first

time, studies of spontaneous prenatal movements and behavior in utero were performed and

published. Since fetal body movements give important information about the condition of the

fetus, their quantitative as well as qualitative aspects were analyzed.

Classification of movement patterns

According to the literature data, movement patterns could be classified in different

activities (15, 16):

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1. Sideways bending. Between 7 and 8 weeks postmenstrual age, slow and small

displacements at one or two poles of the fetus occurs, lasting from half a second to two

seconds, which usually occurs as a single event and disappears through gestation.

2. 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.

3. General movements. 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.

4. Hiccup. A hiccup consists 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.

5. Breathing. Fetal breathing 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 torax. The onset of fetal breathing is around the 10 th week of gestation. Early

in gestation, they are present continually and are associated with activity in the postural

muscles of the neck and limbs.

6. Isolated arm or leg movement. These movements appear around 10 th 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.

7. Twitches. Twiches are quick extensions or flexions of a limb or the neck. They are not

generalized or repetitive.

8. Clonic movements. These are repetitive movements of one or more limbs at a rate of about

three per second.

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9. Isolated retroflexion of the head. Retro-flexions of the head are usually carried out slowly,

but they can also be fast and jerky. These movements can be seen around 10th week and on.

10. 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.

11. 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 s.

12. Jaw movements. The onset of irregular jaw opening is at 11 th week. The opening may be

either slow or quick. The duration of opening varies from less than 1 s to 5 s.

13. Sucking and swallowing. At 13 weeks, rhythmical sucking movements, often followed by

swallowing occur in bursts, indicating that the fetus is drinking amniotic fluid.

14. Handhead contact. In this pattern of movement, the hand slowly touches the face, and the

fingers frequently extend and flex. These movements appear from 10 th week and on and at

first they usually represent an accidental contact of a hand with the face or mouth (Figure 2).

15. Stretch. A stretch 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 retaines an indentical movement form into

adult life.

16. Yawn. This movement is similar to the yawn 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 non-repetitive and it appears around 11th week

(Figure 3). The anatomical criterion for fetal yawning is retraction of the tongue, whereas

yawning in adults is characterized by an extended tongue.

17. 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 backwards somersault,

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is achieved by a complex general movement, including alternating leg movements, which

resemble neonatal stepping.

The integration of the breathing movements, wide body movements, eyes movements

and the FHR pattern enabled Nijhuis to describe certain behavioral states in the human fetus,

these being level 1F to 4F (17). These states were first reported to emerge at 38 weeks with

the organization of movements develop into fetal behavioral states, including sleep-wake

episodes, with a stable temporal organization towards the end of pregnancy (17). Thereafter

evidence was found that they appear at 36 weeks, and the change of no coincidence of the

state parameters to coincidence with short transition time develops gradually over the time

period of 28 weeks until term from 1F to 4F. However, abnormal behavioural state is

considered to be highly unspecific sign that is hard to use for the assessment of fetal

neurobehavioral (19).

Onset of specific fetal behavioural patterns

The first trimester

In the first trimester of pregnancy, 3D US allow precise morphological examinations,

important for early detection of serious fetal malformations, such as anencephalic fetus and

spina bifida (21) (Figure 4). The early embryonic development is characterized by the

immobility of an embryo. Most types of movement pattern emerge between 7 and 15 weeks

of gestation. From the 15th week onwards, distinct patterns can be seen (22). These

movements remain present during the entire intrauterine development. Just discernible

movements were found between 7 and 8 weeks of gestation by de Vries and co-workers (15).

They reported not only how to describe a particular movement, but also how these movements

were performed in terms of speed and amplitude (15, 23). Goldstein and colleagues found

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embryonic body movements between 8 and 9 weeks of gestation by two-dimensional

transvaginal sonography (24). Their results are in agreement with those of others (14, 15, 25).

First spontaneous fetal movements were descried as consisted of slow flexion and extension

of fetal trunk accompanied by the displacement of arms and legs and appearing in irregular

sequences was described as vermicular (26). The earliest signs of fetal motility coincide

with the occurrence of first synapses, around the seventh postconceptional week and with the

earliest electrical activity and transmission of information.

The Zagreb group has evaluated the advantages of four-dimensional over two-

dimensional real-time sonography in the assessment of early fetal behavior (4, 27). The

introduction of high-frequency transvaginal transducers has resulted in remarkable progress in

ultrasonographic visualization of early embryos and fetuses and the development of

sonoembryology. Furthermore, introduction of three-dimensional and four-dimensional

ultrasounds combined with the transvaginal approach has produced more objective and

accurate information on embryonal and early fetal development. For the first time parallel

analyses of structural and functional parameters in the first 12 weeks of gestation become

possible (27).

With four-dimensional transvaginal sonography these authors found body movements

at 7 weeks of pregnancy (4). The observed body movements consisted of the changing

position of the head towards the body. Therefore, this technology enables the visualization of

the moving phenomenon 1 week earlier than two-dimensional ultrasound. However,

embryonic movements are not frequent and consist mainly of moving of the head towards the

rest of the body. At 8-9 weeks, the head is less flexed and the changes of the position of the

head towards the body are clearly visible (28). Vermicular movements are visible for less than

2 weeks. A startle is the next movement with participation of the fetal body. Startles were

found between 8 and 9 weeks of gestation, and lasted for about 1 s (29). Observations were

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performed using transabdominal sonography, and it is entirely possible that, with better

resolution of the transvaginal transducer (either two-dimensional or four-dimensional), some

of these movements may already be present at a somewhat younger age.

In a little while, these first simple movements are replaced by different general

movements, that include head, trunk and limb, such as rippling seen at 8th week,

twitching and strong twitching at 9th and 9,5th week respectively, and floating

swimming and jumping at 10th week (26). Isolated limb movements emerge almost

simultaneously with the generalized movements.

After the ninth gestational week the repertoire of movements expands rapidly. Hiccups

appear, often in series, for up to several minutes, and isolated arm and leg movements can be

observed. This is remarkable in two respects. First, that the young fetus is able to perform

isolated movements of one limb at an age when one would expect a longer period of diffuse

and generalized motor activity. The second is the unexpected finding of the simultaneous

onset of arm and leg movements, unexpected because of the long held principle of a

cephalocaudal development in spinal motor functions. After ten weeks, head movements of

various types can be seen. They consist of lateral rotation of the head and overextension of the

neck (30). At about the same age, hand-face contact is seen for the first time. Usually, this is

an accidental contact of a hand with the face or the mouth. Between 10.5 and 12 weeks the

fetus starts to make breathing movements. At 11 weeks three new patterns, namely the

opening of the jaw, bending forward of the head and complex stretch movements, are added to

the repertoire. Somewhat later than the irregular jaw movements, yawns occur. These have the

same pattern as in children and adults and hence are easily recognizable (30).

Previously, the Zagreb group showed that several movement patterns, such as sideway

bending, hiccup, breathing movements, mouth opening and facial movements could be

observed only by 2D sonographic technique in the first trimester. They concluded that both

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2D and 4D methods are required for the assessment of early fetal motor development and

motor behavior (31).

To investigate the natural course of fetal hand and finger positioning Pooh and Ogura

(34) examined 65 normal fetuses by 3D/4D ultrasound. Each appearance of fingers, thumb,

and wrist was confirmed by viewing on three orthogonal planes. At 9 weeks and the

beginning of the 10th week, fetal hands were located in front of the chest and no movements

of wrists and fingers were visualized. Fetal digits including thumbs are located on the same

layer at this stage. From the middle of 10th week of gestation, active arm movements were

observed associated with active body and lower limb movement. Despite active movements of

glenohumeral and elbow joints at this stage, wrist and finger movements were not visualized

in most cases. At 11 weeks, a change in finger positioning was seen. At this stage, all fetuses

still opened their palms, but five digits were no longer on the same layer. Mild adduction of

the thumb and atonic fingers were observed and the palm appearance was clearly different

from that at 9 and 10 weeks. At 12 weeks of gestation, fetuses started to mildly clench and

unclench their fists (32).

In the first trimester one could notice a tendency towards an increased frequency of

fetal movement patterns with increasing gestational age. Only the startle movement pattern

seemed to occur stagnantly during the first trimester (33).

The second trimester

Only a few studies are available on fetal movement patterns during the second

trimester (15, 34, 35). De Vries and colleagues studied fetal movements from 20 and from 24

postmenstrual weeks onward (15). During the second trimester of pregnancy, the incidence of

body movements increases considerably. The periods of quiescence become longer and eye

movements are clearly visible (36). The incidence of hiccups startles and stretches decreased,

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whereas other movement patterns (jaw movement, handface contacts, and head movements)

showed no clear developmental changes (34). At 28 postmenstrual weeks, Roodenburg and

associates presented the following ranges and median values based on 1-h observations: jaw

movements, 60460, median300; handface contact, 30190, median 95; head rotations, 20

125, median 37; head retroflexions, 429, median 12 (29). From a developmental point of

view, one could say that in the second trimester the development continues, but there are no

new movements appearing for the first time.

Zagreb group determined the incidence of each subtype of isolated hand to head

movements between 13 and 16 weeks of gestation (37). A total of 25 fetuses in uncomplicated

pregnancies were analyzed; 15 fetuses at 13 to 16 weeks and 10 fetuses at 30 to 33 weeks of

gestation were studied with abdominal 4D-US. After standard assessment in two dimensional

(2D) real-time B mode, a 4D mode was switched on. Further examination lasted a maximum

of 15 minutes. Isolated hand movement and subtypes of hand movements were easily

recognized by 4D-US. The sub-types of hand to head movement are: hand to head, hand to

mouth, hand near mouth, hand to face, hand near face, hand to eye and hand to ear. All

subtypes of hand to head movement can be seen from 13 weeks of gestation, with fluctuating

incidence. Facial activities and different forms of expression were also easily recognized by

4D-US. Among these, two types could be easily differentiated: smiling and scowling. One

could recognize that the amount of isolated arm movements decreased gradually from 13

through 16 weeks. The incidence of hand to head movement decreased, followed by a plateau

at 14 weeks of gestation. The highest range of hand at mouth was found at 15 weeks of

gestation, at 13 weeks a plateau was observed and with mild fluctuations the plateau

continued until 16 weeks. In contrast to most other movement patterns, hand near mouth

movements decreased gradually from 13 weeks onwards with a single fluctuation in the 14th

week. One can recognize that the incidence of hand near face movement is stable between 13

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and 16 weeks of gestation with a slight increase at 14 and 15 weeks. At 13 weeks the range

was the widest (0 to 12, with a median value of 3). The incidence of hand to ear movement

showed a rapid trend of decrease between 13 and 16 weeks while the incidence of the hand to

eye movement pattern showed the same developmental trend as the hand to head and hand to

face movement patterns (37). The authors concluded that 4D-US is superior over real-time

two-dimensional ultrasound (2D-US) for qualitative, but inferior for quantitative analysis of

hand movements. Thus 4D-US makes it possible to determine exactly the direction of the fetal

hand, but the exact number of each type of hand movements could not still be determined.

In another study, the same group of authors confirmed that in the second trimester, the

number of head and hand movements decreased gradually compared with the first trimester.

The highest incidence was registered for head retroflexion pattern, with range of 15 to 42 and

median of 25. Among facial expressions, the highest incidence was found for sucking, with

the range between 3 and 30 and median of 9 (38).

Recently, Kuno and co-workers evaluated fetal behavioral patterns in the early second

trimester in 11 healthy pregnant women at 14 18 weeks of gestation and they found that the

most active fetal behavioral pattern was arm movement in each fetus, whereas the least active

was mouth movement. Each fetal movement was synchronized and harmonized with other

fetal movements during this period of pregnancy (35).

Kurjak et al. reported the first study that described the 4D US techniques used for

obtaining longitudinal standard parameters of fetal neurological development in all trimesters

of a normal pregnancy (39). Valid reference ranges appropriate for gestational ages are

essential for comparisons with former or future measurements of patients. For that purpose a

group of 100 healthy normal singleton pregnancies were recruited for longitudinal 4D US

examinations to evaluate fetal neurodevelopmental parameters between 7 to 40 weeks

gestation. In the first trimester 8 fetal movements patterns were analyzed and 14 parameters

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of fetal movement and fetal facial expression patterns recorded thereafter for the construction

of fetal neurological charts. Standard parameters of fetal movements and facial expressions in

all trimester of pregnancy are presented in Figures 5 and 6. The statistical analysis of the

incidence of fetal movements and facial expressions studied in the first trimester revealed

statistically significant changes in general movements, stretching, isolated arm and leg

movement, head retroflexion, head rotation and head retroflexion (Figure 5). At the first

trimester, a tendency towards increased frequencyof fetal movement patterns with increasing

gestational age has been noticed. Only in the startle movement pattern, it seemed to occur

stagnantly during first trimester (Figure 5b). In this type of movement, there is no significant

correlation with gestational age, as shown by the large dispersion of scatter points around the

regression line (rs0.673; Ps0.506). At the first trimester, a tendency towards increased

frequency of fetal movement patterns with increasing gestational age was noticed. During the

second and third trimester, multiple regression and polynomial regression revealed

statistically significant changes in tongue expulsion, grimacing, swallowing, head movements,

and all hand to body contact movements (P-0.05) (Figure 6). The authors found a tendency

towards an increase in the frequency of fetal movement patterns at the beginning of the

second trimester. They noticed fluctuation and dispersion of the incidence of all facial

expressions as seen in the polynomial regression diagram (Figures 2, i-n). All of types of

facial expressions display a peak frequency at the end of the second trimester, except in

isolated eye blinking which increases at the beginning of 24th week. At the beginning of the

third trimester, the fetuses display decreasing or stagnant incidence of fetal facial expression.

However, all types of head movements and hand to body contact movements indicated a

decrease in frequency from the beginning of the second trimester to the end of the third

trimester. Results from Yigiter and co. are similar to that study, as they found a significant

correlation between all head movements and hand to body contact patterns during the second

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and third trimesters except for head anteflexion, which did not show a significant change

during the second half of pregnancy (33). It has also been suggested that there is a tendency

towards decreased frequency of observed facial expressions and movement patterns with

increasing gestational age (39). All of types of facial expressions display a peak frequency at

the end of the second trimester, except in isolated eye blinking which increases at the

beginning of 24th week (39).

The third trimester

The parameters that could be detected and analyzed during the third trimester are fetal

heart rate pattern, and eye and body movements (13). The association of these movements

increases steadily and, in the last weeks of pregnancy, fetal behavior can almost completely be

described in terms of behavioral states, which are stable over time and recur repeatedly, not

only in the same infant, but also in similar forms in all infants (17, 40, 41). The concept of

behavioral states has been used as a descriptive categorization of behavior, and also as an

explanatory concept in which states are considered to reflect particular modes of nervous

activity that modify the responsiveness of the infant (17).

By term, normal number of generalized movements per hour was found to be

approximately 31 with the longest period between movements ranging from 50-75 minutes

(15). This reduce is considered a result of cerebral maturation processes, rather than a

consequence of the decrease in the amniotic fluid volume. Simultaneously with the decrease

in the number of generalized movements, an increase in the facial movements, including

opening/closing of the jaw, swallowing and chewing can be observed. These movements can

be seen mostly in the periods of absence of generalized movements and that pattern is

considered to be the reflection of the normal neurological development of the fetus (15).

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However, not only the changes in the number of movements, but also in their complexity are

shown to be the result of maturational processes.

The incorporation of 3-dimensional ultrasound (3DUS) technology into clinical

practice has resulted in remarkable progress in visualization and anatomic examination of the

fetal face. Four-dimensional ultrasonography (4DUS), in turn, provided for the first time an

opportunity to evaluate subtle fetal facial expressions, which can be used to understand fetal

behavior (42). 4DUS has additional advantages in studying fetal activity in the surface

rendered mode and is particularly superior for fast fetal movements. With 2DUS, fetal

movements such as yawning, swallowing and eyelid movements cannot be displayed

simultaneously, whereas with 4DUS, the simultaneous facial movements can be clearly

depicted. Because of its curvature and small anatomic details, the fetal face can be visualized

and analyzed only to a limited extent with 2DUS (5). 3DUS has the capability of

demonstrating planes of section that cannot be obtained with 2DUS and, thus, allows for a

comprehensive evaluation of facial anatomy (27, 43, 44) (Figure 7). The standardized image

display helps sonologists to understand fetal anatomy better and to communicate complex

observations to both parents and less-experienced observers. The entire face cannot be seen on

a single 2DUS image. 3DUS allows spatial reconstruction of the fetal face and simultaneous

visualization of all facial structures such as the fetal nose, eyebrows, mouth, and eyelids.

4DUS opened, for the first time, the possibility of visualizing the full range of facial

expressions, including subtle grimaces similar to emotional expressions in adults (38). It is not

only a useful tool in appreciating the severity of a fetal defect, but also provides more

convincing evidence of a normal fetus than does conventional 2DUS in recurrent surface

malformation cases. This technique does not replace conventional real-time 2DUS imaging,

but rather supplements it. 3DUS requires an investment of additional time in each case;

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therefore, it is predominately used, presently in conjunction with 2DUS, as a problem-solving

tool.

Although facial movements, which are controlled by V and VII cranial nerves, appear

around 10 and 11 weeks, the exact onset of facial expressions has not been determined and it

is still unclear whether their appearance is gestational age related (42).

An important diagnostic aim of the observation of facial expression is prenatal

diagnosis of facial paresis. The criterion for the diagnosis is asymmetric facial movement and

detectionof the movements limited to only 1 side of the face. Unfortunately, during the

relaxed phase it is not possible to evaluate the status of the facial nerve. Therefore, during the

active phase, the fetus should be scanned by 4DUS. Because the origin of facial expression

can be influenced by external forces, before the final diagnosis, examiners should be aware of

this pitfall. For example, force of the fetal hand can alter the facial expression on 1 side of the

face, causing asymmetry. This kind of asymmetry, however, should be differentiated from

pathologic features such as unilateral facial paresis (42).

Zagreb group evaluated fetal behavioral patterns in the third trimester between 30 and

33 weeks of gestation in ten gravidas (38). The incidence of eyelid movements ranged

between 4 and 20 with a median value of 17, mouthing movements ranged between 2 and 19

with a median value of 12, and mouth and eyelid movements ranged between 0 and 13 with a

median value of 5. The incidence of pure mouth movement such as mouth opening ranged

between 4 and 13 with a median of 5, tongue expulsion ranged between 0 and 2 with a median

of 2, yawning ranged between 0 and 2 with a median of 1 and pouting ranged between 0 and 9

with a median of 3. The incidence of facial expressions such as smiling ranged between 2 and

7 with a median of 2, and scowling between 2 and 4 with a median of 2. It is evident that

eyelid and mouthing movements dominate at this gestational age (37). The next study by this

team showed the ability of 4D sonography to depict different facial expressions and

16
movements, which might represent fetal awareness (45). This was based on the consideration

that the face predicts the brain because of the same embryologic origin for many facial and

encephalic structures (46). The study included 99 patients, 40 of whom were in the second

and 59 in the third trimester of pregnancy . Following movements of the fetal face structures

were analyzed during a 30-min observation period: forehead, brows, nasal soft tissue and

nasolabial folds, upper lip, oral cavity and tongue, lower lip and chin, eyelids and eyes, mouth

and mouth angles, and facial expression. A tendency towards increased frequency of observed

facial expressions with increasing gestational age was noted, but the difference between

second- and third-trimester fetuses was not significant due to the low frequency of

movements. As at that time the images were only near real-time they were only able to study

the quality and not the quantity of facial movement patterns with the possibility that some

very subtle facial movements may have been missed.

In the recent study by Yan and his group, 10 healthy fetuses aged from 28 to 34 weeks

were recorded continuously for 15 min with a 4-D ultrasonographic machine and the

occurrence rates of blinking, mouthing, yawning, tongue expulsion, smiling, scowling, and

sucking were evaluated (47). As in previous reports mouthing was found to be the most active

facial expression during this gestational period (37, 45). However, the frequency of blinking

was lower in this study. This could be due to the differences in the characteristics of the

samples recruited and differences in interpreting the definition of each facial expression.

During the last trimester of pregnancy, signicant developmental changes in specific movement

patterns can be observed. Isolated eye movements can be registered from 16 gestational

weeks onward and rapid eye movements from 19 weeks (48). The eye movement patterns

begin to consolidate at 2426 weeks of gestation, and the periods of eye movements (EM)

begin to alternate with non-eye movement periods (NEM). During the last 10 weeks of

gestation, both switching and maintaining mechanisms responsible for this ultradian rhythms

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mature, and constant mean values of duration of (EM) and (NEM) periods are achieved by

3738 weeks. At that time, EM and NEM last 2729 and 2324 minutes respectively, which is

similar to the values in the neonate (49). From 33 weeks onward, both rapid eye movement

(REM) pattern and slow, rolling movement (SEM) pattern can be registered, and the periods

of REM alternate with periods of NEM. At 3638 weeks of gestation, they become integrated

with other parameters of fetal activity, such as heart rate and fetal movements, into organized

and coherent behavioral states (7, 50).

Fetal behaviour in high risk fetuses

Recently de Vries evaluated the literature on fetuses determined to be at high risk for

motor anomalies, particularly congenital ones, by means of real-time two-dimensional

sonography (9). The study revealed that fetal motor activity can be affected in quantitative

and qualitiative way depending on the underlying disorder (9). The same group stated detailed

high risk factors that can lead to complications followed by abnormalities of fetal movement

(51). Obviously, risk does not necessarily mean that a problem will occur, but indicates the

need for extra vigilance. Although there is considerable overlap in this approach, it has the

advantage of ensuring that both maternal and fetal are taken into account. A healthy mother

may develop problems during pregnancy and, conversely, an individual pregnancy may

proceed uneventfully despite the presence of a significant past medical or obstetric history.

However, determining a pregnancy as high risk may lead to unnecessary anxiety when the

outcome is ultimately uneventful (52).

Ahmed and his group established a behavioral state profile in the eight high risk

fetuses by 4D US recording (51). Their procedure included the 30 minute observation of fetal

movement activity and fetal facial expression. Variables of maternal and fetal characteristics

including gestational age, amplitude, participating body parts in GM, quality and quantity of

18
eight fetal movement patterns in the first trimester and 14 parameters of fetal movement and

fetal facial expression patterns from the second through the third trimesters were observed. In

anencephalic case (Figure 8) and cephalocele case, they noticed excessive hypertonic

movements, while fetuses affected by homocystinuria and Meckel Grubber syndrome

demonstrated hypotonia. The sequence of occurrence of behavioral parameters was clearly

abnormal in those fetuses affected by anencephalic and cephalocele. These findings fully

agree with their previous case report on the behavior of an anencephalic fetus (21). They also

noted normal quantity and quality of behavioral parameters in fetuses affected by prune belly,

diaphragmatic hernia, and hydrothorax. The quality and quantity of fetal movement in the

fetus affected by anchondrogenesis were normal, but it was difficult to observe the movement

of extremities due to abnormal fetal posture (52).

A delay of the appearance of fetal movement patterns by 12 weeks has been found in

generally well controlled studies in women with type-1 diabetes mellitus (53). Delayed

behavioral state development has been found both in growth restricted fetuses (54) and in

fetuses of insulin-dependent diabetic women (55). The Zagreb group assessed the

neurobehavior of 50 growth restricted fetus in the third trimester of pregnancy (56). In their

prospective study they used specially designed 4D ultrasound observation in order to assess

whether functional brain impairment and fetal growth restriction had prenatally occurred by

the utilization of several behavioural patterns. Fourteen parameters of fetal movements and

facial expressions on 30 min observation were analyzed. Normal movements were defined as

synchronized movements showing fluency and elegance of the movements and create the

impression of complexity and variability. Three categories of abnormal movements were

distinguished as follows: 1) poor repertoire: the sequence of successive components is

monotonous and movements do not occur in the complex manner observed in normal

movements; 2) cramped-synchronized: movements look rigid and lack the normal smooth and

19
fluent character, 3) chaotic: movements look chaotic in their sequence without any fluency

nor smoothness. It was noted a tendency that IUGR fetuses have less behavioral activity than

normal fetuses in all observed movement patterns. Correlation reached statistical significance

between normal and IUGR fetuses in the third trimester in hand to head, hand to face and

head retroflexion (64). Poor repertoire of movement patterns was found in 11 cases of IUGR.

The movements were monotony with lack of complexity of the sequence of successive

movement components. Although parameters such as amplitude and speed were reduced, it

must be emphasized that the overall monotony and predominantly small range of amplitude

were the most impressive features in this group. In 39 out of 50 growth restricted fetuses, no

abnormalities in the quality of general movements were observed. These results indicate an

uncomplicated intrauterine growth restriction and as such does not necessarily affect the

quality of general movements.

Abnormal fetal state cycling has been found in fetuses of cocaine addicted mothers

and a fetus exposed to maternal alcohol abuse (57).

Fetal behavior as an indicator of fetal brain impairment

Even after the fetal brain anatomy can be visualized by ultrasound and the

development of the fetal brain is well understood, not much is known about the functional

development of the fetal CNS. In other words, the function of fetal CNS is not accessible. It is

possible only to ascertain the output of the CNS, i.e. fetal behavior. Observation of fetal

behavior provides a direct assessment of the most important human organ. It is possible to

look closely at the functioning of the CNS and the brain. Even after delivery, behavioral

patterns frequently provide the most useful indicators of brain function in spite of having

extending acces to neurological, physiological and pharmacological measures (22). Prenatal

20
motility is considered to reflect the developing nervous system but also involves functional

and maturational properties of fetal hemodynamic and the muscular systems (22).

The major problem with the study of fetal behavior is that it is very time consuming

and not enough functional for routine clinical practice. The question of subjectivity should be

overcome using recording of information . Nevertheless, there is no other possibility of

assessing the function of the CNS in utero, and this is needed for understanding of the hidden

information in the neurodevelopmental pathways of the fetal CNS. Only if normal behavior is

fairly understood, is it possible to identify and to perceive abnormal behavior before birth (4,

5).

First reports on fetal behavior obviously suggested that these studies should be

standardized as much as possible. An objective analysis with strict application techniques and

the use of valid reference ranges appropriate for the gestational age are essential (13). Without

such standardization, comparisons with former or future measurements of patients and

comparable studies cannot be made. In order to achive this goal the Zagreb group published

the first study which describes the 4D sonographic techniques used for obtaining longitudinal

standard parameters of fetal neurological development in all trimesters of a normal pregnancy

(39). Measurement of 7 parameters in the first trimester and 11 parameters in the second and

third trimesters correlated with gestational age. Those parameters have been followed

longitudinally through all trimesters and showed increasing frequency of fetal movements

during the first trimester. A tendency towards decreased frequency of facial expressions and

movement patterns with increasing gestational age from second to third trimesters has been

confirmed (39).

Despite the longstanding conclusion that it is possible to make valid conclusion about

brain function from observed, no generalized antenatal behavior screening has been

developed to identify fetuses that may have central nervous system defects. Recent study from

21
Morokuma tried to produce screening test that would be less time consuming and in that way

cost effective as compared to their previous study (58). They devised a brief ultrasound

examination to distinguish fetuses with compromised central nervous system function from

the general population and evaluated it with their study (59). The study design compared

findings on five behavioral patterns obtained by retrospectively reviewing the ultrasound

examinations of 5 fetuses that had abnormal behavior with prospectively obtained findings of

29 normal fetuses. Median time for brief examination criteria was 50 min (range, 30-60 min)

with the only case undetectable by this brief ultrasound examination had an eye-movement

period significantly longer than the normal upper limit.

Fetal origin of neonatal behaviour

The existence of motoric competence in the newborn, even preterm infants raises an

important question about the origins of behavior in prenatal life. In order to find out the

answer to this challenging question Kurjak and co. published the study in which they included

both fetuses and neonates (60). The aim was to investigate whether the same behavioral

patterns were present pre- and postnatally, and whether there were any differences in the

frequency of movements observed in fetal and in early neonatal life. They found that there

were no movements observed in fetal life that were not present in neonatal life, while the

Moro reflex was present only in neonates. Their study proofed that there is continuity from

fetal to neonatal behavior, 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 (60). Fetal motor activities seem to indicate typical features as

regards regulatory behaviors in the first month, and they are the starting point for individual

differences in reactivity and regulation in infancy (61, 62). Fetal condition reflects the stage of

22
growth of the CNS and is a stable individual attribute indicating the postnatal state

organization (63). Fetal movement patterns might reflect the emotional state of the fetus (64).

New scoring system for fetal neurobehavior assessed by three- and four

dimensional sonography

The traditional concept that brain damage is caused during birth or early neonatal

period has been challenged and antenatal and unclassifiable factors are now considered as the

most important etiologic factors (65-67). Cerebral palsy is an umbrella term for disorders

of development, movements and posture, resulting in limitations of activity due to non-

progressive impairment of developing brain (68). The diagnosis is retrospective and it is

rarely made before the age of six months when the infant is severely affected (69). The

specificity of the diagnosis improves as the child ages and the nature of the disability evolves

(69). CP does not result from a single event but rather from a sequence of interdependent

adverse events. This time frame of evolving adverse events should be taken into account when

considering the possibility of CP diagnosis in infants (70). Periventricular white-matter injury

is now the most common cause of brain injury in preterm infants and the leading cause of

chronic neurological morbidity and CP. Standardized methods of clinical neurological

assessment from the neonatal period onwards were developed in order to identify three grades

of neurological impairment: severe, moderate and mild. The clinical identification of severely

affected patients is less problematic than the identification of moderately and mildly affected

infants. Cranial ultrasound, magnetic resonance imaging, magnetic resonance spectroscopy

and diffusion weighted imaging are helpful in very low birth weight premature and in term

infants with encephalopathy (68).

From the pediatric experience it is well known that one should wait until the age of 6

months postnatally to be able to diagnose a severe CP, 12 months for a moderate CP and 24

23
months for a minor non-disabling CP. This delay for the full clinical expression of functional

consequences of a brain damage depends on brain maturation. DiPietro was right in saying

that a consensus recognizing the fact that fetal neurobehavior reflects the developing nervous

system is emerging (62, 63). The purposes of early diagnosis of CP could be important from

the point of view of the infant, the mother, the family, and the gynecologist, who is often

accused for clinical negligence. Although randomized studies confirming that the early

intervention as an effective strategy for treatment of CP is not available, it should be

considered as feasible. Because the etiology of CP is mostly shifted towards the prenatal

period, attempts were made to diagnose neurological impairment in the prenatal period (68,

71). Development of Prechtls general movements (GM) for postnatal neurological

evaluation, encouraged obstetricians to implement this technique for fetal neurological

evaluation using two-dimensional ultrasound (14, 15). Development of computer and

ultrasound technology enabled evaluation of fetal GM in three dimensions and in real time

(39, 45, 60). Although the results of fetal GMs in the last 25 years were encouraging, they did

not shift the diagnosis of neurological impairment to the prenatal period.

In the recent study the Zagreb group attempted to produce a new scoring system for

fetal neurobehavior based on prenatal assessment by 3D/4D sonography (82). That scoring

system is a combination of some parameters from fetal GM assessment and parameters from

postnatal Amiel-Tison neurologic assessment for the term neonate (ATNAT) which can be

prenatally easily visualized by 4D US (73, 74). The parameters were chosen basing on

developmental approach to the neurological assessment and on the theory of central pattern

generators of GM emergence. They were the product of multicentric studies conducted during

several years which resulted with the most significant parameters for the assessment of fetal

neurological development (38, 39, 52) (Table 2). The authors developed a three-point scale for

isolated head anteflexion, isolated hand, leg, hand to face and finger movements, while for the

assessment of cranial sutures, isolated eye blinking, facial alterations and mouth opening two-

24
point scale was applied. The distinction between scores 0 and 2 is evident, whereas uncertainty

may exist with regards to the assignation of a score of 1, the latter indicating an abnormal result of

moderate degree. The precise description of the moderate abnormal performance is included for

each item in the record form (Table 3). Interpretation of total score is given in Table 3.

To produce the new scoring test the Zagreb group identified severely brain damaged

infants and those with optimal neurological findings by comparing fetal with neonatal

findings. In the group of 100 low-risk pregnancies they retrospectively applied new scoring

system. After delivery, postnatal neurological assessment (ATNAT) was performed (72), and

all neonates assessed as normal reached a score between 14 and 20, which was assumed to be

a score of optimal neurological development (Table 4). New scoring system was applied in

the group of 120 high risk pregnancies in which, based on postnatal neurological findings,

three subgroups of newborns were found: normal, mildly or moderately abnormal and

abnormal. Based on this, a neurological scoring system has been proposed. All normal fetuses

reached a score in the range from 14 to 20. Ten fetuses who were postnatally described as

mildly or moderately abnormal achieved prenatal score of 5 to 13 prenatally, while another

ten fetuses postnatally assigned as neurologically abnormal had a prenatal score from 05.

Among this group four had alobar holoprosencephally, one had severe hypertensive

hydrocephaly, one had tanatophoric dysplasia and four fetuses had multiple malformations.

Assessment of GMs is based on the concept of ontogenetic adaptation corresponding

to the development of human organism, which is during each developmental stage adapted to

the internal and external requirements. Prechtl stated that spontaneous motility, as the

expression of spontaneous neural activity, is a marker of brain proper or disturbed function

(14, 15). The observation of the unstimulated fetus or infant which is the result of spontaneous

behavior without sensory stimulation is the best method to assess its central nervous system

capacity. All endogenously generated movement patterns from an un-stimulated central

25
nervous system could be observed as early as from the 7-8 weeks of postmenstrual age, with a

reach repertoire of movements developing within the next two or three weeks, continuing to

be present for 5 to 6 months postnatally.

The identification of "CNS depression" during fetal life is based on pre-competences

(opening of the eyes, variety of facial expressions), primary reflexes (rhythmical bursts in the

sucking pattern) and quality of GMs (73, 74). The addition of cranial signs (such as

insufficient head growth and overlapping sutures) to neurological signs could be a valuable

complement (73, 74). Moreover, the identification of dynamic and static patterns of the

symptoms may be as helpful to date the insult as it is postnatally: the more stable the signs,

the more precise is the timing of the insult. In the presence of neurological signs in fetuses,

the next step is to proceed to the clinical synthesis. In order to do so all examinees should be

followed till the age of two years, when their categorization to disabling or non- disabling CP

can be possible, based on clinical neurological findings and presence or absence of the ability

to walk (73).

Based on several years of research that group of authors has proposed a new test for

antenatal application. There is a similarity between neonatal optimality test of Amiel-Tison,

and that new scoring system for the assessment of neurological status in fetuses, which is a

combination of postnatal ATNAT and GM assessment (73). One of the differences was that

the analytical criteria of typical passive and active tone in the neonate cannot be elicited in the

fetus: head anteflexion versus retroflexion, ventral versus dorsal incurvations in the axis, both

being of the utmost importance postnatally to confirm CNS optimality. However, the status of

the fetus should be reflected in the typical GMs.

That was a preliminary study that will continue in several collaborative centres. It is

hoped that the future database formed using this new score for fetal neurological assessment

will help in distinguishing fetal brain and neurodevelopmental alternations due to the early

26
brain impairment occurring in utero. Study of a large population will hopefully validate the

value of the new test as a predictive marker for fetal neurodevelopmental outcome in both

low-risk and high-risk populations.

Conclusion

The 4D study of fetal behavior provided us with a great possibility of understanding

the hidden function of the developmental pathway of the fetal CNS and the potentialities of

originating a neurological investigation in utero. Now, by four-dimensional technology, we

might be able to visualize an intrauterine neurological condition that would enable us to

identify which fetus is at risk and which fetus is not. Existence of motoric competence in the

newborn, even preterm infants is assumed to have its origins in prenatal life. Behavioral

perinatology assessed by 4D sonography should be an interdisciplinary area of research

involving concepts and conducting studies of the dynamic interplay between behavioral

processes in fetal, neonatal, and infant life. After standardization of valid reference ranges of

movements appropriate for the gestational age, attempts have been made to produce a new

scoring system for fetal neurobehavior based on prenatal assessment by 3D/4D sonography.

That preliminary work may help in detecting fetal brain and neurodevelopmental alterations

due to in utero brain impairment that is inaccessible by any other method.

27
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of fetal facial expression. J Obstet Gynaecol Res. 2005;3:337-40.
76. Salihagic-Kadic A, Kurjak A, Medi M, Andonotopo W, Azumendi G. New data about embryonic
and fetal neurodevelopment and behavior obtained by 3D and 4D sonography. J Perinat Med.
2005;33:478-90.

31
Figure 1. Fetal face assessed by three-dimensional (3D) ultrasound

32
Figure 2. Fetal hand to mouth movement assessed by three-dimensional (3D) ultrasound

33
34
Figure 3. Fetal yawning assessed by three-dimensional (3D) ultrasound

35
Figure 4. 3D surface rendering mode of the fetus in the first trimester

36
Figure 5. Scatter plot and multiple regression analysis of the first trimester frequency of: a)
general movements, b) startle, c) stretch, d) isolated arm movement, e) isolated leg
movement, f) head retroflexion, g) head rotation, h) head anteflexion

a) b)

c) d)

e) f)

g) h)

37
Figure 6. Scatter plot and multiple regression analysis of the 2nd to 3rd trimesters
frequency of: a) isolated eye blinking, b) mouthing, c) jawning, d) tongue expulsion, e)
grimacing, f) swallowing, g) head retroflexion, h) head rotation, i) head anteflexion, j) hand to
head, k) hand to mouth, l) hand to eye, m) hand to face, n) hand to ear.

a) b)

c)

d)

38
e)

f)

g)

h)

39
i)

j)

k)

l)

40
m)

n)

41
Figure 7. 3D surface rendering mode of the different fetal facial expressions in the third
trimester

42
Figure 8. 2D and 3D surface rendering mode of a third trimester 4D sequence of anencephalic
fetus

43
Table 1. Additional findings of fetal behavior by 4DUS in published reports.
___________________________________________________________________________
Author Year Main findings__________________________________
35
Kuno et al. 2001 Provided a novel means for evaluation of fetal behavior
in the early second trimester of pregnancy.

Kurjak et al.4 2002 Improved visualization of details of the dynamics of

small anatomical structures, body and limb movements
can be visualized a week earlier than with conventional
2D US.

Kurjak et al.37 2003 Enhanced determination of exact direction of the fetal

hand and improved assessment of complex fetal facial
activity and expression.

Andonotopo et al.22 2004 Better assessment of general movements.

Kurjak et al.60 2004 Enhanced assessment of fetal behavior, and proved

continuation from fetal to neonatal behavior.

Hata et al.75 2005 Provided novel means for evaluation of fetal

movement, particularly fetal facial expression, in the
second and third trimesters.

Andonotopo et al.21 2005 Allowed early diagnosis of a functionally affected

anencephalic fetus.

Kurjak et al.46 2005 Enhanced depiction of different facial expressions and

movements, which might represent fetal awareness.

Andonotopo et al.31 2005 Both 2D and 4D methods are required for the
assessment of early fetal motor development and motor
behavior.

Kurjak et al.7 2005 Reviewed antenatal development of fetal behavioral

patterns.

Ahmed et al.52 2005 Provided more information of specific movement

patterns and quality of movement in the high risk
fetuses.

Kurjak et al.27 2005 Both structural and functional early human development
are illustrated.

Pooh et al.32 2005 Enhanced assessment on details of fetal hand or finger

positioning and movement in early pregnancy in vivo.

44
Salihagic et al.76 2005 Reviewed a significant advance in studying fetal
behavioral patterns and understanding structural and
functional development of fetal CNS.

Kurjak et al.39 2006 First paper on longitudinal assessment of normal

neurobehavioral development by 4DUS.

Yigiter et al33 2006 Prospective randomized study on fetal facial

expressions and fetal movement patterns in all three
trimesters.

Yan et al47 2006 4D analysis of fetal facial expression early in the third
Trimester.

Morokuma et al59 2007 First simplified ultrasound screening for fetal brain
function based on behavioral pattern.

Kurjak et al.72 2007 New scoring system for fetal neurobehavior assessd by
3D and 4D US.

45
Table 2. Neurological scoring test for fetus

Sign Score Sign Score

1 2 3
Isolated head Abrupt Small range Variable in full range,
anteflexion (0 3 times of many alternation (> 3
movements) times of movements)

Cranial sutures and Overlapping of cranial Normal cranial Normal cranial

head circumference suttures sutures with sutures with normal
measurement of measurement of HC
HC below the normal according to GA
limit (-2
SD) according to
GA
Isolated eye blinking Not fluent Fluency
(0 5 times of (> 5 times of blinking)
blinking)

Facial alteration Not fluent Fluency

(grimace or tongue (0 5 times of (> 5 times of
expulsion) alteration) alteration)

Mouth opening Not fluent Fluency

(yawning or mouthing) (0 3 times of (> 3 times of
alteration) alteration)

Isolated hand Cramped Poor repertoire Variable and complex

movement

Isolated leg movement Cramped Poor repertoire Variable and complex

Hand to face Abrupt Small range Variable in full range,

movements (0 5 times of many alternation (> 6
movement) times of movements)

Fingers movements Unilateral Cramped invariable Smooth and complex,

or bilateral clenched finger movements variable finger
fist, (neurological movements
thumb)

Gestalt perception of Definitely abnormal Borderline Normal

GMs

Total score

46
47
Table 3. Interpretation of total score

TOTAL SCORE INTERPRETATION

0-5 Abnormal

6-13 Borderline

14-20 Normal

Table 4. Comparison of prenatal scoring and neonatal findings

Group investigated Total prenatal score Subtotal Neonatal

14-20 6-13 0-5 findings

Low risk group 0 0 0 0 Abnormal

N=100* 2 8 0 10 Mildly
abnormal

74 1 0 75 Optimal
Subtotal 76 9 0 85
High risk group 0 0 10 10 Abnormal
N=120**
0 10 0 10 Mildly
abnormal

77 0 0 77 Optimal
Subtotal 77 10 10 97

48