Seminars in Fetal & Neonatal Medicine 17 (2012) 256e260

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Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Fetal neurophysiology according to gestational age

Aida Salihagi

c Kadi

c a, b, Maja Predojevi

c c, *
a
Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia
b
Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia
c
Department of Obstetrics and Gynecology, University Hospital ‘Sveti Duh’, School of Medicine, University of Zagreb, Zagreb, Croatia

s u m m a r y
Keywords: More than 99% of the human neocortex is fashioned during intrauterine life, resulting in the fascinating
Fetal neurophysiology diversity of fetal functions and activities. The objective of this review is to present the most significant
Neuromotor development
neurodevelopmental events, as well as new findings about prenatal motor and sensory development.
Neurosensory development
Ultrasound
Ó 2012 Elsevier Ltd. All rights reserved.

1. Introduction and propagate action potentials as soon as they interconnect.

Furthermore, it has been shown that neurons are able to commu-
During the intrauterine period, the fetus gradually begins to nicate through non-synaptic mechanisms even before the onset of
perform many vital physiologic functions. The repertoire of fetal synapsogenesis.4
functions and activities constantly expands, reflecting the matu- The brain stem, which consists of the medulla oblongata, pons
ration of the fetal central nervous system (CNS). and midbrain, is fashioned around gestational week 7, and the main
parts of the diencephalon and cerebral hemispheres are formed by
the end of gestational week 8.6,7 As the medulla matures ahead of
2. Prenatal neuromotor development
more rostral structures of the brain stem, reflexive movements of
the head, body, extremities, as well as breathing-like movements
The main events in neuromotor development during pregnancy
and alterations in heart rate, come into view prior to other func-
are presented in Table 1. A prerequisite for the establishment of
tions. Facial movements, which are also controlled by cranial nerves
embryonic motility is the development of interneuronal connec-
V and VII, emerge around 10e11 weeks (Table 1).6 From 10 weeks
tions. The first synapses can be detected in the spinal cord shortly
onwards, the number and frequency of fetal movements increase
before the onset of embryonic motility, at 6e7 weeks of gestation.1
and the repertoire of movements begins to expand.4
Consequently, the neural activity leading to the earliest detectable
At 10 weeks of gestation lateralized behavior may be observed,
movements is considered to derive from the spinal motoneurons.2
and the fetus begins to demonstrate the earliest signs of right- or
At the same time, with the inception of spontaneous vermicular
left-handedness. Stimulation of the brain is known to influence
movements at week 7.5 of gestation, the earliest motor reflex
brain organization and it is considered that fetal motor activity may
activity can be observed, representing the existence of the first
eventually stimulate the brain to develop ‘handedness’ and
afferenteefferent circuits in the spinal cord (Table 1).3
subsequent lateralization of function.4 From gestational week 13
The first complex, well-organized movement patterns involve
onwards, a ‘goal orientation’ of hand movements appears and
the head, trunk and limbs. They have been interpreted as the first
a target point can be recognized for each hand movement.8 Finally,
indication of a supraspinal influence on motor activity and can be
at 13e14 weeks, isolated finger movements can be observed.9
seen from 8e9 weeks of gestation onwards (Table 1).4,5 It is
Our longitudinal study, performed by four-dimensional ultra-
necessary to emphasize that even at this early stage of develop-
sound in 100 fetuses from all trimesters of normal pregnancies, has
ment, embryonic and fetal movements emerge in recognizable
shown increasing frequency of general movements, isolated arm
temporal sequences, without any amorphous movement. This
and leg movements, stretching, as well as head movements during
interesting phenomenon can be explained with the intrinsic
the first trimester. Only the startle movement pattern seemed to
properties of neurons. In other words, neural cells begin to generate
occur stagnantly in this period of gestation.10 General movements
were found to be the most frequent movement pattern in the first
trimester of normal pregnancies.11
* Corresponding author. Sveti Duh 64, 10000 Zagreb, Croatia. Tel.: þ385 1
3712317; fax: þ385 1 4590207. In the second trimester the brain stem continues to mature,
E-mail address: [email protected] (M. Predojevi

c). resulting in expansion and complexity of the behavioral patterns.

1744-165X/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2012.05.007
 A. Salihagi
c Kadi
c, M. Predojevi
c / Seminars in Fetal & Neonatal Medicine 17 (2012) 256e260 257

Table 1 Between 26 and 28 weeks, evoked potentials can be registered

Chronology of prenatal neuromotor development (adapted from Salihagi

c Kadi

c from the cortex, indicating that the functional connection between
et al.4).
periphery and cortex operates from that time onwards.13 The upper
Development of the fetal Fetal motility motor control system, consisting of the cerebral hemispheres and
nervous system basal ganglia, matures later than the lower system, and clinically
Early first trimester emerges at 34 weeks of gestation.12 Approximately between 24 and
Spinal cord e earliest synapses: Vermicular movements: 7e7.5, slow
34 weeks, cortical area differentiation begins and continues until
6e7 weeks. flexion/extension of fetal trunk.
Brain stem: 7 weeks. First motor reflexes: 7.5 weeks. the end of gestation.14 Neuronal differentiation and the laminar
Basic structures of the diencephalon General movements (head, trunk and distribution of the thalamocortical axons lead to the appearance of
and cerebral hemispheres: end limb movements): 8e9 weeks six-layered lamination throughout the neocortex after 32 weeks of
of week 8 gestation.15 However, it is important to point out that the cerebral
Late first trimester
Maturation of brain stem structures, Isolated limb movements: 9 weeks.
cortex is still very immature, and that until delivery, subunits of the
primarily of the medulla oblongata: Breathing-like movements: 10 weeks. brain stem remain the main regulators of all fetal behavioral
VIIIeXII cranial nerves. Head flexion and rotation: 10 weeks. patterns.6 The complexity of general movements increases and
Pons: VeVIII cranial nerves. Facial movements e jaw opening, their number decreases, particularly during the last 10 weeks of
Midbrain: maturation delayed. yawning: 10e11 weeks.
pregnancy, as a result of maturation processes in the brain stem.
Synapses in the cerebral cortex: Handedness: 10 weeks.
end of week 10 Goal orientation: 13 weeks Sleep-wakefulness patterns become distinguishable in electroen-
Second trimester cephalogram at 30 weeks, as a result of the pontine maturation. The
Maturation of the brain stem continues. High fetal activity: 14e19 weeks; complexity of eye movements increases as a result of the midbrain
Medulla oblongata e almost completely quiescence periods only 5e6 min. maturation. These movements become integrated with other
mature by the end of this period. Eye movements: 16e18 weeks.
Formation of the subplate zone: Organization of fetal motor patterns:
parameters of fetal activity, such as heart rate and fetal movements,
15e17 weeks of gestation. resteactivity cycles: 20 weeks. into organized behavioral states during the last weeks of
Synaptogenesis e most intensively: Facial movement patterns (except eye pregnancy.4,16,17
15e20 weeks. blinking) e peak frequency: end of Contrary to the declining trend of head movement and hand
First electrocortical activity: 19 weeks. the 2nd trimester
movement patterns from the beginning of the second trimester to
Spinothalamic tract: 20 weeks.
Thalamocortical connections: the end of the third trimester, our longitudinal analysis revealed
24e26 weeks that a variety of facial movement patterns, for instance, mouthing,
Third trimester yawning, swallowing, or grimacing, displayed a peak frequency at
Maturation of the midbrain and pons Eye-blinking pattern e peak the end of the second trimester (Table 1). During the third
continues. frequency: 28 weeks.
Myelinization of the spinothalamic Facial expression patterns e
trimester, decreasing or stagnant incidence of these motor patterns
tract: 29 weeks. decreasing or stagnant incidence. has been noted.10 This developmental trend provides yet another
Evoked potentials from the cerebral General movements e decrease in example of the maturation of the medulla oblongata, pons, and
cortex: 26e28 weeks. number, increase in complexity. midbrain, or possibly even the establishment of control of more
Beginning of cortical area Eye movements e increase in
cranial structures. Even in the embryonic period the same inductive
differentiation: 24e34 weeks. complexity: 33e38 weeks.
Lamination of the neocortex: 32 Establishment of behavioral states: forces cause the growth and reshaping of the neural tube, influ-
weeks onwards 36e38 weeks encing the development of facial structures, and many genetic
disorders affecting the CNS are also characterized by dysmorphol-
ogy and dysfunction of facial structures; these facts highlight the
significance of structural and functional evaluation of the fetal
Early in the second trimester, at week 15, 16 different types of face.7,18
movement can be observed. The first eye movements appear as Our studies have also demonstrated that there were no move-
sporadic movements with a limited frequency, at 16e18 weeks of ments observed in fetal life that were not present in neonatal life.
gestation. The delayed onset of eye movements can be explained Furthermore, prenataleneonatal continuity exists even in subtle,
with later onset of midbrain maturation. Its maturation begins in fine movements such as facial mimics.19,20
the second trimester.4 The diverse repertoire of fetal movements raises the question of
One of the important regions in the developing cortex is the their function and significance for normal fetal development. It has
subplate zone, which is a site for transient synapses and neuronal been shown that fetal motor activity is fundamental for the
interactions. The development of the subplate zone, between development of most parts of the nervous system and the muscles.4
weeks 15 and 17 of gestation, is accompanied with an increase in Specialized movement patterns, crucial for the survival of
the number of cortical synapses, which probably form the substrate newborns, such as swallowing and respiratory movements,
for the earliest electrocortical activity at 19 weeks of gestation.4 develop and mature during gestation. Furthermore, these move-
The spinothalamic tract is established at 20 weeks and myeli- ments play an important role during intrauterine life.4
nized by 29 weeks of gestation, and thalamocortical connections Fetal breathing-like movements become visible at 10 weeks of
penetrate the cortical plate at 24e26 weeks.4 The lower motor gestation (Table 1). These brain stem reflexes occur more frequently
control system, consisting of the brain stem and cerebellum, begins as the medulla oblongata matures.6 Moreover, changes in the
maturation at gestational week 24, and becomes accessible to frequency and complexity of breathing-like patterns are conse-
clinical estimation at about 28 weeks.12 quences of the maturation of the fetal lungs as well as the respi-
The second half of pregnancy is characterized by gradual orga- ratory and sleep centers in the CNS. During weeks 38 and 39 of
nization of fetal movement patterns (Table 1). The periods of fetal gestation, the frequency of movements decreases to 41 respirations
quiescence begin to increase, and the resteactivity cycles become per minute and the movements become as regular as in the post-
recognizable.4 natal period.21 Recent data have indicated the role of fetal
According to our results, the most frequent facial movement breathing-like movements in lung organogenesis.22 They are
patterns in the second trimester were isolated eye-blinking important for normal lung development as well as the develop-
patterns (with a peak frequency at 28 weeks of gestation), gri- ment of respiratory muscles, widening of the alveolar spaces, and
macing, sucking, and swallowing (Table 1).10 maintenance of lung liquid volume.4
258 A. Salihagi
c Kadi
c, M. Predojevi
c / Seminars in Fetal & Neonatal Medicine 17 (2012) 256e260

Fetal swallowing activity was observed as early as 11 weeks of onwards (Table 2).13 Furthermore, SEPs may provide evidence of
gestation,23 with daily swallowing rates near term of pain processing in the somatosensory cortex.25 The earliest reac-
500e1000 mL.24 Fetal swallowing and ingestive behavior tions to painful stimuli e motor reflexes e can be detected at 7.5
contribute significantly to the regulation of the amniotic fluid weeks of gestation (Table 2). As early as 16e18 weeks, fetal cerebral
volume and the development and maturation of the fetal gastro- blood flow increases during invasive procedures.26,27 An elevation
intestinal tract. They also contribute to the fetal somatic growth.4 of noradrenaline, cortisol, and beta-endorphin plasma levels, in
response to needle pricking of the innervated hepatic vein for
3. Prenatal neurosensory development intrauterine transfusion, was registered in a 23-week-old fetus
(Table 2). Pricking of the non-innervated placental cord insertion
The main events in neurosensory development during preg- for the same purpose had no effect.28,29 Painful stimuli trigger
nancy are presented in Table 2. a wide spectrum of reactions, such as activation of the
Tactile sensations, such as touch and pain, are among the first to hypothalamo-hypophysial axis or autonomic nervous system,
be developed during intrauterine life (Table 2). Twin pregnancies without reaching the cortex. In premature neonates born after
allow us to observe the first reactions to touch in utero. Peri-oral gestational week 28, the most promising pain indicators are
region, hands, and lower limbs become touch sensitive at 7.5, 10.5 changes in facial activity, shifts in infant sleep/wake state, and
and 14 weeks of gestation, respectively (Table 2). Thalamocortical physiological changes of heart rate and blood oxygen satura-
pathways, important for the perception of sensory impulses, reach tion.30,31 One of the most important effects of a painful experience
the somatosensory cortex around week 23 (Table 2). Maturation of is the prolonged stress response.32 This includes marked fluctua-
the primary somatosensory cortex continues in the postnatal tions in blood pressure, cerebral blood flow and hypoxemia, which
period.4 may predispose to intracranial hemorrhage.27 Moreover, prenatal
The first nociceptors appear at 7 weeks of gestation, and by and/or neonatal exposure to pain can lead to altered pain thresh-
week 20 these are present all over the body (Table 2). Sensing pain olds as well as abnormal pain-related behavior later in life.32
requires a developed neural pain system and after 26 weeks the The intrauterine environment is not completely deprived of
fetus has the necessary connections to sense pain. Somatosensory light. According to some experimental results, the development of
evoked potentials (SEPs) can be registered from the cortex at 29 visual and auditory organs could not be possible without any light
weeks, indicating that a functionally meaningful pathway from the or auditory stimulation.33 Human visual connections between
periphery to the cerebral cortex starts to operate from that time retina, lateral geniculate nucleus, and visual cortex are partially
established by mid-gestation and undergo further development
during and after this period.34 In the primary visual cortex syn-
Table 2 aptogenesis persists between 24 weeks of gestation and 8 months
Chronology of prenatal neurosensory development. after delivery (Table 2). Maturation of the visual cortex is charac-
Development of the nervous system Fetal reaction terized by the appearance of surface-positive evoked potentials,
First trimester which occurs between weeks 36 and 40 and continues after birth
Tactile sensation (the touch and pain) Peri-oral region, hands, lower limbs (Table 2).4 A flash stimulus over the maternal abdomen can cause
emerging first: 7 weeks. become touch sensitive at 7.5, 10.5 the visual evoked brain activity in the human fetus, recorded by
Development of nociceptors: and 14 weeks of gestation. magnetoencephalography. Fetal eye motility plays a role in retinal
from 7 weeks Motor reflexes as first fetal response
to painful stimuli: 7.5 weeks
(neuronal) cell differentiation, as well as eye functional
Development of taste buds: maturation.4
from 7 weeks Cochlear function develops between 22 and 25 weeks of
Second trimester gestation, and its maturation continues during the first 6 months
Secretion of neuropeptide Y and Possible regulation of appetite and
after delivery (Table 2). Fetal reactions to very loud sounds have
leptin: 16e18 weeks ingestive behavior
Nociceptors present all over the Alterations in cerebral blood flow in been detected from 26 weeks onwards. Delayed selective response
body: 20 weeks. response to painful stimuli: to sounds can be explained by the prolonged pontine maturation.
Thalamocortical pathways: around 16e18 weeks. During the last weeks of pregnancy (from week 36 onward), the
week 23. Elevation of cortisol and beta- fetus responds to external noise, even to the sound of mother’s
endorphin levels in response to
painful stimuli: 23 weeks
voice, with reflexive body movements, head-turning and heart rate
Visual connections between retina, acceleration. But an even more astonishing finding is that the fetus
lateral geniculate nucleus, and at this age is able not only to perceive the sounds, but also to
visual cortex: mid-gestation. discriminate between different sounds (Table 2). Furthermore, the
Synaptogenesis in the primary visual
fetus displays the selective preference for the mother’s voice or
cortex: from 24 weeks.
Cochlear function: 22e25 weeks other familiar voices. These findings are explained by the tonotopic
Third trimester organization of the cochlear nuclei and by the maturation of the
Somatosensory evoked potentials (pain Sense of pain: after 26 weeks. brain stem during the last weeks of pregnancy (Table 2).6 The brain
processing in the somatosensory Response to pain as changes in stem displays learning-related activity. Fetuses at <37 weeks of
cortex): 29 weeks facial activity, shifts in infant
sleep/wake state, and physiological
gestation of mothers who smoke throughout pregnancy have
changes of heart rate and blood a delayed onset of response to the maternal voice.35 If the mother
oxygen saturation: after 28 weeks does not speak, a newborn may be 2 months delayed in develop-
Surface-positive evoked potentials in the ment of the tonotopic column and less able to discern intensity,
visual and auditory cortex: from
rhythm, and shape of each sound.36 Growth restriction could also
36e40 weeks
Pons maturation. Fetal reactions to very loud sounds: affect the development of auditory perception in human fetuses.37
Tonotopic organization of the cochlear from 26 weeks. The chemical senses, such as the sense of taste, also develop
nuclei, maturation of the brain stem: Fetal response to external noise, during intrauterine life. Human embryos demonstrate taste buds
last weeks of pregnancy discrimination between different by week 7 of gestation (Table 2).38 It has been shown that sweet
sounds, selective preference for
mother’s voice: from 36 weeks
taste stimulates swallowing in the human fetus, whereas bitter and
sour tastes decrease fetal swallowing. Flavors from the mother’s
 A. Salihagi
c Kadi
c, M. Predojevi
c / Seminars in Fetal & Neonatal Medicine 17 (2012) 256e260 259

diet during pregnancy are transmitted to amniotic fluid and swal- Progression in behavioral complexity begins with spontaneous
lowed by the fetus. Consequently, the type of food eaten by the fetal movements and culminates with presumed preferences for
mother during pregnancy is experienced by infants before their the sound of mother’s voice, reflecting maturational events that
first exposure to solid food.39 It has also been suggested that take place in the brain stem, followed by forebrain structures.
preference for a certain food is acquired during intrauterine Furthermore, the fetus is able to learn and remember familiar
development.40 auditory stimuli. This finding could be interpreted as evidence for
It is generally believed that thirst, satiety and appetite mecha- fetal rudimentary, learning-related cognitive-like activity.
nisms develop prenatally in all precocious species. Experiments in
fetal lambs have indicated that dipsogenic mechanisms begin to
regulate swallowing during intrauterine life. Swallowing and
arginineevasopressin (AVP) secretion increase following the Research directions
central administration of hypertonic saline solution and angio-
tensin II. According to some studies, an altered intrauterine osmotic  The investigations of fetal neuromotor and neurosen-
environment may modulate not only fetal swallowing activity, but sory development according to gestational age are of
great importance, because more and more indicators of
also the development of adult sensitivities for thirst, AVP secretion,
normal functional brain development in different
and AVP responsiveness.24,41,42 Mothers, consuming excessive periods of gestation have been made available.
amounts of salt and water during pregnancy, increase salt prefer-  Deviations from normal fetal neuromotor and neuro-
ence in adult offspring which may lead to hypertension.43 sensory development, indicating delayed or abnormal
The main feeding regulatory factors, neuropeptide Y (NPY) and brain development, still need to be explored.
leptin, are secreted in the human fetus as early as 16 and 18 weeks,  Further investigations, supported by the new imaging
respectively (Table 2).44e46 NPY is the most powerful known techniques, should open a new perspective for the
inducer of food intake and a leptin is a main satiety factor. Contrary development of prenatal diagnostic strategies to detect
to its function in adults, leptin does not suppress fetal ingestive and/or prevent severe neurological disorders as well as
minimal cerebral dysfunctions.
behavior.41 Fetal swallowing was significantly increased following
the injection of leptin.47 Therefore, some investigators have
postulated that the lack of leptin-inhibitory responses might
potentiate feeding and facilitate weight gain in newborns, despite Conflict of interest statement
high body fat levels.48
Further, it has been discussed that the mechanisms by which None declared.
environmental factors modulate the physiologic systems control-
ling body weight may begin their development before birth.49 An
adverse intrauterine environment, with altered fetal orexic factors, Funding source
could change the normal set-points of appetitive behavior and
potentially lead to programming of childhood or/and adulthood This work was supported by a grant from the Ministry of
hyperphagia and obesity. Prenatal exposure to over- or undernu- Science, Education and Sport of the Republic of Croatia.
trition, rapid growth in early infancy, early adiposity rebound in
childhood, and early pubertal development have all been impli- References
cated in the development of obesity.50
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