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J. Perinat. Med. 39 (2011) 171–177 • Copyright
by Walter de Gruyter • Berlin • New York. DOI 10.1515/JPM.2011.004
Original article – Fetus
Neurobehavioral continuity from fetus to neonate
Milan Stanojevic1,*, Asim Kurjak1,3, Aida
Salihagić-Kadić2, Oliver Vasilj1, Berivoj Miskovic1,
Afaf Naim Shaddad3, Badreldeen Ahmed3 and
Sanja Tomasović4
1
Department of Obstetrics and Gynecology, Medical
School University of Zagreb, Sveti Duh Cinical Hospital,
Zagreb, Croatia
2
Institute of Physiology, Medical School University of
Zagreb, Croatia
3
Department of Obstetrics and Gynecology, Women’s
Hospital, Hamad Medical Corporation, Doha, Qatar
4
Department of Neurology Medical School University of
Osijek, Sveti Duh Cinical Hospital, Zagreb, Croatia
Abstract
Neurobehavior represents development of the central nervous
system (CNS). Fetuses and newborns exhibit a large number
of endogenously generated motor patterns, among which
general movements are often investigated pre- and post-
natally. Spontaneous activity is probably a more sensitive
indicator of brain dysfunction than reactivity to sensory stim-
uli while testing reflexes. Nutritional stress at critical times
during fetal development can have persistent and potentially
irreversible effects particularly on brain growth and function.
Unfavorable intrauterine environment can affect adversely
brain growth. All endogenously generated movement pat-
terns from un-stimulated CNS might be observed as early as
from the seven to eight weeks’ gestation, with a rich reper-
toire of movements within the next two or three weeks, con-
tinuing for five to six months postnatally. It is still uncertain
whether a new scoring system for prenatal neurological
assessment will be adequate for the distinction between nor-
mal and abnormal fetuses in low-risk pregnancies. The con-
tinuity of behavioral patterns from prenatal to postnatal life
might answer these intriguing questions.
*Corresponding author:
Milan Stanojevic, MD, PhD
Department of Obstetrics and Gynecology
Medical School University of Zagreb
Clinical Hospital ‘‘Sv. Duh’’ Zagreb
Sv. Duh 64
10000 Zagreb
Croatia
Tel.: q385 1 3712316
E-mail: milan.stanojevic@optinet.hr
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Keywords: Development of central nervous system; fetal
neurobehavior; four-dimensional ultrasound; general move-
ments; neonatal neurobehavior.
Introduction
Neurobehavior is the expression of the development of the
central nervous system (CNS), in particular the brain, and is
a complex process throughout gestation and after birth w26,
27, 39, 40x. It is important to understand how the CNS pro-
duces different kinds of movements and which of them are
indicating disturbed development w28x. Concerning the com-
plexity, voluntary control and stereotypy, there are several
groups of movements such reflexes, fixed action patterns,
rhythmic motor patterns, and directed movements w28, 39x.
Reflexes (i.e., tendon, pupillary) are the simplest involuntary,
stereotyped and graded responses to sensory input, and have
no threshold except that the stimulus must be strong enough
to activate the relevant sensory input pathway w28x. Fixed
action patterns (i.e., sneezing, orgasm) are involuntary and
stereotyped, but typically have a stimulus threshold that must
be reached before they are triggered, and are less graded and
more complex than reflexes w28x. Rhythmic motor patterns
(i.e., walking, breathing) are stereotyped and complex, but
are subject to continuous voluntary control w28, 39x. Directed
movements (i.e., reaching) are voluntary and complex, but
are generally neither stereotyped nor repetitive w28x. Rhyth-
mic motor patterns are complex (unlike reflexes) yet stereo-
typed (unlike directed movements) and, by definition, repet-
itive (unlike fixed action patterns) w28x. It is presumed that
the basic rhythmicity and patterning of rhythmic motor pat-
terns are produced by neural networks termed the central
pattern generators w28x. Fetuses and newborns exhibit a large
number of endogenously generated motor patterns, which are
presumably produced by central pattern generators located
in different parts of the brain w16x. Moreover, substantial
indications suggest that spontaneous activity is a more sen-
sitive sign of brain dysfunction than reactivity to sensory
stimuli in reflex testing w16x. It has been demonstrated that
in newborn infants affected by different brain lesions, spon-
taneous motility does not change in quantity, but it loses its
elegance, fluency, and complexity w1, 13, 16x. As the devel-
opment of the brain is unique and continuing process
throughout gestation and after birth, it is expected that there
is also continuity of fetal to neonatal movements which are
functional indicators of brain development w1, 26, 27, 40,
45x.
We present possible factors which may influence the con-
tinuity of neurobehavior from prenatal to postnatal life.
2010/020
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172 Stanojevic et al., Neurobehavioral continuity
Prenatal and postnatal growth and brain
development
The beginning of human life is not simple and unequivocal
w32x. Prenatal and postnatal potential for growth of the
human being is different, with the tendency of slowing down
after birth w17x. It could be speculated that development of
morphology and function should be in equilibrium during
different developmental stages, however it is known that pre-
natal and postnatal growth potential of the human heart, liver,
kidneys and lungs is different compared to the brain w12x.
According to the recent data, it is estimated that mature
human brain has 86 billion neurons in total and 85 billion
non-neuron cells w22x. The size of the cerebral cortex is 82%
of the brain mass with 16 billion neourons which is 19% of
total brain neurons w22x. Among primates, humans enjoy the
largest number of neurons w22x. The neocortex has a similar
layered architecture in species over a wide range of brain
sizes w49x. Larger brains require longer fibers to communi-
cate between distant cortical areas; the volume of the white
matter (WM) that contains long axons increases dispropor-
tionally faster than the volume of the gray matter that con-
tains cell bodies, dendrites, and axons for local information
processing w49x.
Cortical growth is achieved predominantly by an increase
in surface area rather than thickness, and during late fetal
human development a rapid increase in brain size occurs
with considerable development of cortical surface area rela-
tive to cerebral volume, manifested in development of cor-
tical convolutions w25, 39x.
Effect of intrauterine conditions on fetal growth
Nutritional stress at critical periods during fetal development
can have persistent and potentially irreversible effects on
organ function w23x. Unfavorable intrauterine environment
can adversely affect fetal growth w36x. Spontaneous preterm
labor carries significant health consequences of neonatal
morbidity and mortality as it is responsible for about 45%
of preterm births, which are 5–12% of pregnancies in devel-
oped countries w36x. There are at least three reasons why
neonates born at term after an episode of preterm labor are
more likely to be small relative to their peers w36x. Firstly, it
is possible that the ‘‘preterm labor event’’ itself constitutes
an insult to fetal growth, altering the subsequent fetal growth
rate and trajectory w36x. Secondly, it is possible that an
altered fetal growth pattern contributes to and eventually cul-
minates in the phenotype of preterm labor w36x. Thirdly, it is
possible that one of the underlying causes of preterm labor
provokes both the event and the subsequent growth insult
w36x. Analysis identified that a greater proportion of fetuses
delivered at term after an episode of preterm labor experi-
enced downward centile crossing during the third trimester
compared to those from uncomplicated pregnancies w36x.
Fetuses from pregnancies complicated by preterm labor were
43% less likely to experience upward centile crossing than
their peers from uncomplicated pregnancies w36x.
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In very low birth weight (VLBW) infants, the course of
postnatal growth rather than the appropriateness of birth
weight for gestational age determines later neurodevelop-
mental outcome w37x. The most striking result of that study
was postnatal catch-down growth in a group of appropriate
for gestational age (AGA) VLBW infants resulting in weight
below the 10th percentile at age of two years w37x.
In the human, intrauterine growth retardation (IUGR) can
result in persistent postnatal growth failure, which may be
attributable, in part, to abnormal growth hormone (GH)
secretion w23x. It is unknown whether putative alterations in
GH secretion are the result of abnormalities intrinsic to the
pituitary or reflect changes in the production of GH-releasing
hormone or somatostatin w23, 39x. The hypothesis was tested
that growth failure associated with IUGR or early postnatal
food restriction is caused by a central defect in hypothalamic
somatostatin gene expression w23x. These observations sug-
gest that nutritional stress during a critical developmental
window either pre- or postnatally produces a persistent and
potentially irreversible alteration in the activity of the hypo-
thalamic-pituitary axis w23x.
Growth impairment and neurodevelopmental
outcome
Weight, length, and head circumference (HC) at birth were
not significantly associated with neurodevelopmental out-
come at age of two years irrespective of whether they were
born as small for gestational age (SGA) or AGA VLBW
infants w37, 47x. However, weight and length at age of two
years correlated with the psychomotor developmental index
(PDI) in SGA and AGA children w37x. Findings from some
studies indicated an association between postnatal growth
and neurodevelopmental outcome w37, 47x.
Different postnatal growth patterns were significantly
associated with neurodevelopmental outcome w37x. SGA
children who showed substantial catch-up growth with
weight above the 10th percentile at age of two years had
neurodevelopmental outcomes comparable to AGA children
whose weight remained appropriate for age; whereas SGA
children who remained below the 10th percentile by age of
two years were impaired in their motor development w37x.
Poor catch-up growth was more frequently associated with
motor, but less so with mental delay w37x. Their mental and
motor functioning was significantly poorer than for AGA
children with weight above the 10th percentile at age of two
years, and even worse than for SGA children with insuffi-
cient catch-up growth w37x. Thus, AGA children with catch-
down growth had the highest risk for mental retardation,
motor delay, and cerebral palsy (CP) among all VLBW chil-
dren w37x. These findings were mostly independent of the
diagnosis of CP w37x.
Impaired intrauterine growth and development may ante-
cede insufficient postnatal growth. Thus, it may be a marker
of impaired CNS integrity because of adverse intrauterine
conditions w1, 37x. Children who were AGA at birth, but
became underweight at age of two years may have already
 Article in press - uncorrected proof
been on a catch-down curve before birth w37x and their post-
natal growth course could be the continuation of insufficient
intrauterine growth. If pregnancy would have continued until
term, those infants may have been born SGA w37x. Insuffi-
cient postnatal growth likely reflects impaired intrauterine
development. In the future, this hypothesis could be substan-
tiated by repeated intrauterine ultrasonographic measure-
ments demonstrating relative catch-down of growth variables
that persist into postnatal life w37x.
Brain development appears to be affected by premature
termination of the intrauterine environment following pre-
term birth w27, 46x. It is estimated that half of all surviving
infants born at F25 weeks show neurodevelopmental
impairment at 30 months of age w12, 27, 46x. At age six
years, about 40% have cognitive impairment compared to
their classroom peers, and impairments are more severe in
boys than in girls w27x. Even among less immature infants
over one third developed neurocognitive and behavioral pro-
blems w12, 27x. This neurocognitive impairment is more
severe with earlier gestation and longer exposure to the pre-
mature extrauterine environment, suggesting that there is a
dose- and gender-dependent effect of prematurity on brain
development w10, 27, 46x.
Poor postnatal growth in preterm infants, especially of the
head, is associated with increased levels of motor and cog-
nitive impairment at seven years of age w1, 10x. This growth
restriction appears to occur largely in the postnatal rather
than antenatal period and may be amenable to intervention
and subsequent improvement in outcome w1, 10x.
Volumetric studies of the brain
In comparison to term-born infants, the premature infants
demonstrated prominent reductions in cerebral cortical gray
matter volume, in deep nuclear gray matter volume, and an
increase in cerebrospinal fluid (CSF) volume w24x. The major
predictors of altered cerebral volumes were gestational age
at birth and the presence of cerebral WM injury w24x.
In a large prospective longitudinal cohort study of 202
preterm and 36 term infants, magnetic resonance (MR) scans
at term equivalent were undertaken for volumetric estimates
of cortical and deep nuclear grey matter, unmyelinated and
myelinated WM and CSF within eight parcellated regions
for each hemisphere of the brain w48x. Perinatal correlates
analyzed in relation to regional brain structure included gen-
der, gestational age, intrauterine growth restriction, broncho-
pulmonary dysplasia, WM injury and intraventricular
hemorrhage w48x. Results revealed region-specific reductions
in brain volumes in preterm infants compared with term con-
trols in the parieto-occipital, sensorimotor, orbitofrontal and
premotor regions w48x. Within the sensorimotor and orbito-
frontal regions cortical grey matter and unmyelinated WM
were most clearly reduced in preterm infants, whereas deep
nuclear gray matter was reduced mainly within the parieto-
occipital and subgenual regions w48x. CSF (ventricular and
extra-cerebral) was doubled in volume within the superior
regions in preterm infants compared with term controls w48x.
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Stanojevic et al., Neurobehavioral continuity 173
Severe regional disruptions to cerebral development were
found in preterm infants by term equivalent, which vary in
relation to perinatal exposures. WM injury has the most sig-
nificant impact together with IUGR, influencing more pos-
terior cerebral structures w48x.
The rates of brain growth are highest in the last part of
gestation and the first one-year of life w18, 39x. There is
evidence that impaired brain growth in utero and in infancy
may lead to poorer cognitive function in childhood w18x. The
brain volume a child achieves by the age of one-year helps
determine later intelligence w18x. Growth in brain volume
after infancy may not compensate for poorer earlier growth
w18x. However, it is unclear whether these associations reflect
the cumulative effect of brain growth achieved until infancy
or are they influenced by critical periods of growth earlier
in life w18x. Extremely immature (-26 weeks) infants
showed a marked drop in weight in the neonatal period, and
continued to decline up to three months corrected age w15x.
After three months’ corrected age, their weight began to
increase and continued to do so, reaching the mean of the
reference at 11 years of age w15x. The mean difference in
weight between the extremely immature and control partic-
ipants was significant at all ages with decreasing tendency
towards the 11th year of life w15x. The proportion of extreme-
ly immature infants with subnormal weight increased from
7% at birth to 60% at three months corrected age, after which
there was a reduction in this proportion w15x. At expected
date of delivery, the mean HCs in extremely immature infants
were significantly lower than in controls w15x. These
remained significantly lower than in controls and in the ref-
erence mean at all ages w15x. A significantly higher propor-
tion of the extremely immature cohort compared with
controls had subnormal HC at 11 years of age w15x. More-
over, there were significant differences between extremely
immature and control children by gender at 11 years of age:
the mean HC of extremely immature boys was 2 cm lower,
and it was 1.2 cm lower in extremely immature girls than in
controls w15x. In contrast to weight and height, extremely
immature infants did not show catch-up growth in HC after
the first six months of life w15x. It means that extremely
immature infants have growth failure in early extrauterine
life in comparison with those of normal intrauterine growth
during the third trimester w15x.
Assessment of general movements (GMs) from
prenatal to postnatal life
Prechtl’s work enabled that spontaneous motility during
human development has been brought into focus of interest
of many perinatologists prenatally and developmental neu-
rologists postnatally w1, 13, 38x. According to the research
preceding Prechtl’s idea, the functional repertoire of the
developing neural structure must meet the requirements of
the organism and its environment during the development of
the individual w13x. This concept of ontogenetic adaptation
fits excellently to the development of human organism,
which is adapted during each developmental stage to the
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174 Stanojevic et al., Neurobehavioral continuity
internal and external requirements w13x. Prechtl stated that
spontaneous motility, as the expression of spontaneous neural
activity, is a marker of brain proper or disturbed function
w13, 20x. The observation of unstimulated fetus or infant
which is the result of spontaneous behavior without sensory
stimulation is the best method to assess its CNS capacity
w13x. All endogenously generated movement patterns from
unstimulated CNS could be observed as early as from the
seven to eight weeks of postmenstrual age, with developing
a reach repertoire of movements within the next two or three
weeks, continuing to be present for five to six months post-
natally w1, 13x. This remarkable continuity of endogenously
generated activity from prenatal to postnatal life is a great
opportunity to indentify high-risk fetuses and infants in
whom development of neurological impairment is emerging.
The most important among those movements are the so-
called general movements (GMs) involving the whole body
in a variable sequence of arm, leg, neck and trunk move-
ments, with gradual beginning and end w11, 13, 20, 38x. They
wax and wane in intensity, force and speed being fluent and
elegant with the impression of complexity and variability
w11, 13, 20, 38x. GMs are called fetal or preterm from 28 to
36 to 38 weeks’ postmenstrual age, while after that there are
at least two types of movements: writhing present to
46–52 weeks of postmenstrual age and fidgety movements
present till 54–58 weeks’ postmenstrual age w11, 13, 20, 38x.
Lack of fluency and existence of considerable variation and
complexity are the main characteristics of mildly abnormal
GMs w21x. When complexity, variation and fluency are
absent GMs are definitely abnormal w21x. The quality of each
individual movement includes speed, amplitude and force
combined in one complex perception w7, 11, 13, 20, 21, 38x.
Some facts are important in the assessment of GMs. The
first is that evaluation of GMs should be based on the video
recorded movements either pre- or postnatally (so called
‘‘off-line’’ analysis). The second fact is that when assessing
GMs one should use the so-called ‘‘Gestalt perception’’,
which could be described as overall impression of GMs with
a standardized procedure w13x. During the perception one
should recognize the movement patterns of GMs, than assess
their complexity, variability and fluency w13, 20x. According
to Hadders-Algra, GMs could be classified as normal-opti-
mal, normal-suboptimal, mildly abnormal and definitely
abnormal w20x.
It seems that postnatal assessment of the quality of GM is
a window for early detection of children at high risk for
developmental disorders w20x. An abnormal assessment of
GMs at 2–4 months post-term, at the so-called fidgety GM
age, has the highest predictive value for later development
of CP w13, 20x.
Assessment of GMs in high-risk newborns has signifi-
cantly higher predictive value for later development than
neurological examination w13, 38, 43x. Kurjak and coworkers
conducted a study by 4D ultrasound and confirmed earlier
findings made by 2D ultrasonography, that a behavioral pat-
tern continuity exists from prenatal to postnatal life, although
the conditions for the infant postnatally are quite different,
because of gravity, which is absent prenatally w1, 31, 45x.
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Assessment of neonatal behavior is a better method for early
detection of CP than neurological examination alone w9, 13,
21x. In our work we observed that all movements observed
in the fetuses were present in neonates, except for the Moro
reflex w34, 44, 45x. The most frequent were hand to mouth
and hand to face fetal and neonatal movements. Hand to
mouth and hand to face movements were more frequent in
fetuses than in neonates, whereas all other hand movements
were less frequent in neonates than in fetuses (Figure 1) w34,
44, 45x.
In our study of fetal behavior by 4D sonography we were
able to observe different expressions and movements of fetal
face, but the question was if they were indicating fetal aware-
ness w6, 29, 35x. Is it the facial expression of the fetus that
can help in understanding what does the fetus like to com-
municate? As our recent investigation showed, there is a
behavioral continuity from fetal to neonatal life, which prob-
ably includes facial expression w6, 34, 35, 44, 45x. Possibil-
ities of 4D sonography are demonstrating the prenatal onset
of a brain damage, based on morphological and functional
signs. In the authors’ opinion, this observation will be help-
ful, even though that prenatally observed signs are not yet
highly predictive due to brain immaturity. Their identifica-
tion however will be at least recognized as a retrospective
marker for a prenatal insult w1–4x. It is still not clear whether
we are approaching the era when a neurological test for the
fetus and assessment will be applied. Even postnatally, sev-
eral neurological methods of evaluation exist, whereas in ute-
ro there is a more complicated situation and a less mature
brain w33x. It is also still unclear and should be investigated
w33x if neonatal assessment of neurologically impaired fetus-
es would bring new insights into their prenatal neurological
status. New scoring system for neurological assessment of
the fetus proposed by Kurjak et al. might give some new
possibilities to detect fetuses at high neurological risk,
although it is obvious that dynamic and complicated process
of functional CNS development is not easy to investigate
w33x.
In a recent paper on fetal behavior in high risk pregnan-
cies, it was observed that some of the prenatal conditions are
probably temporarily affecting fetal neurological status (ven-
triculomegaly, intramniotic infection, thrombocytopenia,
thrombophilia, polyhydramnios, pre-eclampsia, IUGR,
achondroplasia), having a tendency for improvement in neu-
rological status after birth w30x. On the basis of our prelim-
inary results, we speculate why this happens after delivery
w30x. It is known that birth is affecting neonates neurologi-
cally, but it seems that some fetuses are liberated after birth
from numerous intrauterine constrains, but are exposed to the
gravity w1, 30x. Our study showed that the new test might be
useful in standardization of neurobehavioral assessment w30x.
Furthermore, there is a potential for antenatal detection of
serious neurological problems w30x.
Preterm birth and/or VLBW affect on health related qual-
ity of life at various ages w19, 46x. The impact of low birth
weight and gestational age is greatest during the younger
years, but the influence also extends into adolescence and
adulthood w19, 46x. From a practical perspective, we may
improve the neurological outcome and the quality of life of
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Stanojevic et al., Neurobehavioral continuity 175

Figure 1 Comparison of hand movement frequency between fetuses in the third trimester of pregnancy and in neonates w34, 44, 45x.
WhiskersMin–max, h25–75%, —median value.

preterm and/or VLBW preschool- and school-aged children
by early referral to rehabilitation professionals w19x. It is yet
to be determined if such a follow-up of neurobehavior from
prenatal to postnatal life might be helpful.
Influence of the gravity on fetal and neonatal
motor development
Data concerning the influence of the gravity on fetal motor
development are contradictory. The concept that the fetus
floats in a state of weightlessness cannot be applied to the
whole pregnancy, and after the fetus is confined by the uter-
us, it is exposed to the force of gravity w8x. The fetus is not
in significant contact with the walls of the amniotic sac until
the very end of pregnancy, and sensory input arising from
antigravity activity is absent, which is similar to the condi-
tions of microgravity w14x. Certain level of mechanical stress
is necessary for the physiological development of the fetus.
Along with muscle activity, gravitational loading also causes
this mechanical stress w14x. Buoyant forces apparently
decrease fetal weight and in this way they reduce the effect
of gravitation on the musculoskeletal system w14x. It was
clearly visible that until 21st week of gestation the fetus is
in a condition similar to neutral buoyancy with apparent
weight around 5% w41x. After the 26th week the fetus is, to
a significant extent, exposed to mechanical stress that occurs
due to gravitation forces and has 60–80% apparent weight
w41x. If fetal movements cause deformation of the amniotic
sac and the uterus then the force required to overcome elastic
tension of the walls additionally contributes to the total
mechanical stress to which the fetus is exposed w41x. Total
force of mechanical stress affecting the fetus in microgravity
would, for this reason, be less than in a 1G environment w41x.
The development of antigravity muscular control is critical
to normal motor development during the first year of life.
After birth the newborn is exposed to the 1G environment.
Movement against gravity begins during the first month of
life, and by four months of age increased flexion control
balances the strong extensor muscle patterns w42x. Adequate
development of trunk flexion and extension is a prerequisite
to the development of anterior and posterior pelvic tilting,
lateral trunk flexion, and trunk elongation w5, 42x. These
components enable the child to develop weight shifting,
which in turn stimulates righting and equilibrium responses
w5, 42x.
Conclusions
Although the development of the CNS is complex, there is
a continuation from prenatal to postnatal life w1, 34, 44, 45x.
The expressions of CNS function are in different types of
movements, emerging from different parts of the brain. Envi-
ronmental conditions influence the movement expression
pre- and postnatally. The intrauterine environment with
microgravity is probably pleasant and suitable for fetuses,
whereas the extrauterine environment requires adaptation and
development of antigravity muscular control w1, 5x. In some
cases the impaired growth of fetal brain can adversely affect
fetal neurobehavior, cognition, and other developmental
functions. After birth, the fetus is the same person but in
different environments, with the possibility to keep the con-
tinuity of all vital processes from prenatal to postnatal life.
Continuity of neurobehavior is to be further investigated in
order to better understand development and function of the
CNS.

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176 Stanojevic et al., Neurobehavioral continuity
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The authors stated that there are no conflicts of interest regarding
the publication of this article.
Received January 29, 2010. Revised July 28, 2010. Accepted Sep-
tember 24, 2010. Previously published online February 10, 2011.

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