DTD 5
ARTICLE IN PRESS
BRESR-100324; No. of pages: 17; 4C: 7
Brain Research Reviews xx (2005) xxx – xxx
www.elsevier.com/locate/brainresrev
Review
The importance of dawarenessT for understanding fetal pain
David J. Mellora,T, Tamara J. Diescha, Alistair J. Gunnb, Laura Bennetb
a
Riddet Centre and Institute of Food, Nutrition and Human Health, College of Sciences, Massey University, Palmerston North, New Zealand
b
Department of Physiology, University of Auckland, Private Bag 92019, Auckland, New Zealand
Accepted 12 January 2005
Abstract
Our understanding of when the fetus can experience pain has been largely shaped by neuroanatomy. However, completion of the cortical
nociceptive connections just after mid-gestation is only one part of the story. In addition to critically reviewing evidence for whether the fetus
is ever awake or aware, and thus able to truly experience pain, we examine the role of endogenous neuroinhibitors, such as adenosine and
pregnanolone, produced within the feto-placental unit that contribute to fetal sleep states, and thus mediate suppression of fetal awareness.
The uncritical view that the nature of presumed fetal pain perception can be assessed by reference to the prematurely born infant is
challenged. Rigorously controlled studies of invasive procedures and analgesia in the fetus are required to clarify the impact of fetal
nociception on postnatal pain sensitivity and neural development, and the potential benefits or harm of using analgesia in this unique setting.
D 2005 Elsevier B.V. All rights reserved.
Theme: Disorders of the nervous system
Topic: Pain
Keywords: Fetus; Nociception
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Fetal responses to nociceptive stimuli . . . . . . . . . . . . .
2.1. Neuroanatomical maturation . . . . . . . . . . . . . . . .
2.2. The question of cortical awareness . . . . . . . . . . . .
2.3. Is the fetus ever awake? . . . . . . . . . . . . . . . . . .
2.3.1. Characterization of wakefulness . . . . . . . . . .
2.3.2. Sleep-like states in the fetus . . . . . . . . . . . .
2.3.3. Fetal arousal or sleep state transitions? . . . . . . .
2.3.4. Evidence that the fetus remains asleep . . . . . . .
2.4. Sleep transitions—an indeterminate state of sleep . . . . .
2.5. Can the fetus be woken up? . . . . . . . . . . . . . . . .
2.6. Can the fetus dream? . . . . . . . . . . . . . . . . . . .
2.7. Summary of bfetal wakefulnessQ. . . . . . . . . . . . . .
3. Suppressors of fetal behavior and cortical activity . . . . . . .
3.1. Adenosine and oxygen status . . . . . . . . . . . . . . .
3.2. Neuroactive steroids—allopregnanolone and pregnanolone
T Corresponding author.
E-mail address: D.J.Mellor@massey.ac.nz (D.J. Mellor).
0165-0173/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainresrev.2005.01.006
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ARTICLE IN PRESS
2
D.J. Mellor et al. / Brain Research Reviews xx (2005) xxx–xxx
3.3. Prostaglandin D2 . . . . . . . . . . . . . .
3.4. Placental peptide inhibitor and other factors
3.5. Thermal status—warmth . . . . . . . . . .
3.6. Tactile stimulation. . . . . . . . . . . . . .
3.7. Summary of endogenous inhibition . . . . .
4. Long-term sequelae . . . . . . . . . . . . . . .
5. Summary and conclusions . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
Whether the fetus can truly experience pain, at least in
some way analogous to how adults emotionally understand
pain, has been debated extensively over recent years and is
of importance given continuing advances in fetal surgical
and diagnostic procedures [43]. This question has considerable implications for the management of invasive fetal
procedures [16,78,94], particularly as fetal analgesic and
anaesthetic treatment is complex [195] and not without risk
for the fetus [171]. Prevention and treatment of pain are
basic human rights, regardless of age, and if fetal interventions are to progress, then a greater understanding of
nociception and stress responses is required [236].
The timing of the neuroanatomical maturation of the
nociceptive system is now well understood, and the final
critical cortico-thalamic connections appear to be present by
24–28 weeks of gestation [25,40,56,78,136,236]. This
suggests that the fetus could potentially be able to feel pain
by the third trimester, at least in a rudimentary fashion. This
concept is said to be supported by studies which show that
nociceptive stimuli elicit physiological stress-like responses
in the human fetus in utero [210].
However, physiological processing of a nociceptive
stimulus and perceiving a nociceptive stimulus as painful
are not the same. There are both a physiological and an
emotional or cognitive aspect to pain perception, and
indeed a significant element of learning [56]. Certainly,
processing can be independent of perception, as is
demonstrated during surgery under general anesthesia,
for example, where nociceptive stimuli can still elicit
subcortically mediated physiological stress responses
despite unconsciousness [57,85,140]. Thus, to emotionally
experience pain, we must be cognitively aware of the
stimulus (a cortical process), and this in turn requires that
we must be conscious [25,40,56].
The key question then is not about the anatomic completion or functionality of nociceptive pathways in utero, but
whether the fetus is ever conscious and thus aware. In
general, discussion of fetal pain perception tends to treat the
fetus as an unborn newborn; i.e., that responses of the newborn represent an adequate surrogate for the fetus. The
assumption is thus made that if the newborn (including the
preterm newborn) can experience wakefulness (and there-
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fore consciousness), and apparently feels pain, then so too
must the age-equivalent fetus. Furthermore, evidence for
fetal wakefulness (and again therefore consciousness) has
been based on how certain fetal responses bresembleQ newborn sleep–wake behaviors, rather than a true determination of fetal wakefulness per se. Given the complexities of
studying the fetus, extrapolation from or to the newborn
state is understandable. Systematic studies of fetal neurological function suggest, however, that there are major differences in the in utero environment and fetal neural state
that make it likely that this assumption is substantially incorrect. This has important implications for our understanding of fetal pain perception.
The current review critically evaluates the hypothesis that
unlike the newborn, the fetus is actively maintained asleep
(and unconscious) throughout gestation and cannot be
woken by nociceptive stimuli. The evidence is examined
with reference to fetal sleep–wake states, the role of corticothalamic gating in cortical arousal during sleep, and the
unique contribution that certain inhibitory neuromodulators
make in utero to cortical suppression. Finally, we briefly
discuss the validity of the hypothesis that suggests that the
nociceptive input may have long-lasting deleterious effects
regardless of whether the fetus is asleep or not.
2. Fetal responses to nociceptive stimuli
2.1. Neuroanatomical maturation
The processing of nociceptive stimuli requires peripheral
sensory receptors, afferent and efferent sensory and motor
pathways, and subcortical and cortical neural integration of
the related impulse traffic [8]. The development of nociceptive pathways has been extensively reviewed by others
and is not the subject of this review [13,15,56,64,66,
118,174,230,236]. In brief, however, it is generally agreed
that an integrated pathway exists by 24–28 weeks of gestation and that it includes the critical cortico-thalamic connections deemed to be essential for the experience of pain
[78,136]. The thalamus is an obligatory station through
which nearly all sensory information must pass before
reaching the cerebral cortex. One major function of the
thalamus is the selective control of the flow of sensory-
ARTICLE IN PRESS
D.J. Mellor et al. / Brain Research Reviews xx (2005) xxx–xxx
motor information to the cerebral cortex during different
states of the sleep–wake cycle and arousal, modulated by
inputs from the brainstem, hypothalamus, and cerebral cortex [146].
Several commentaries suggest that once the nociceptive pathway is complete the fetus may experience pain and
that various behavioral and physiological responses may
reveal fetal awareness or subjective consciousness of pain
[25,78,210]. For instance, the human fetus responds to
intrahepatic needling (versus umbilical cord sampling) by
moving away and with an increase in the levels of circulating stress hormones such as cortisol, corticotropin releasing hormone (CRH), catecholamines, and beta-endorphins
[71,72,74,75]. These responses are independent of maternal
responses [72,74]. Moreover, fetal intrahepatic sampling
leads to a redistribution of the combined ventricular output away from peripheral organs such as the gut and kidneys towards central organs such as the heart and brain
[211,224], and scalp sampling increases heart rate in some
fetuses [215].
2.2. The question of cortical awareness
It is noteworthy, however, that these responses are
elicited at the subcortical and brainstem level and do not
require cortical input [78,136,243]. Thus, they cannot be
said to represent evidence for cortical awareness. For example, very similar cardiovascular redistribution responses
are seen during severe experimental fetal hypoxemia as part
of a coordinated fetal defense, and occur even when neural
activity is essentially isoelectric; i.e., when fetal brain activity is profoundly suppressed [30,76,107,112,115]. Consistent with this, stress hormones are significantly elevated
during surgical procedures carried out under general anesthesia [57,85,140] and in brain dead patients during organ
harvesting [68,137]. Indeed, even an anencephalic fetus
responds to somatic stimulation by withdrawal, demonstrating that these reflexes are mediated entirely at a subcortical
level [233].
Similarly, patients in vegetative states are thought to be
incapable of conscious experience themselves, even though
they are able to be aroused [242], and in such patients flexor
withdrawal and other reflexes, which are mediated through
the thalamus, are preserved [179]. In the condition of sleepwalking, motor arousal can clearly occur, but while sleep
is disturbed it is not to the extent of full awakening [5].
Similarly, in the neonate, arousal-eliciting stimuli can also
cause respiratory and motor responses without necessarily
leading to cortical arousal [149]. Likewise, moderate pain
can elicit physiological and behavioral responses during
sleep in adults without the subject arousing or waking [69].
These variable cortical states demonstrate that hormonal and
arousal responses to noxious stimuli can be elicited independent of cortical awareness. This, however, does not
mean that fetal awareness does not occur. The question is
then, is the fetus ever conscious?
3
2.3. Is the fetus ever awake?
2.3.1. Characterization of wakefulness
The existence of consciousness is, of course, difficult
to establish in the fetus, but wakefulness might be used as a
provisional index, provided it is borne in mind that wakefulness and consciousness or awareness are quite different
states [63,243]. Wakefulness is a state of brainstem and
thalamic activity; a state of non-sleep-arousal, whereas consciousness requires cortical processing [63,243]. In order for
consciousness to occur, all the incoming information from
the internal and external environment must be available to
all parts of the cortex at the same time [63]. Moreover, sleep
is an arousable state of unconsciousness [243]. Thus, it is
possible to be awake and not conscious (as in some persistent vegetative states and in conditions of blindsight
[242]) and to be awake and conscious, but it is not possible
to be asleep and conscious. It follows that if the fetus was
shown never to be awake, it would always be unconscious.
Whereas if wakefulness was evident, even transiently, it
would indicate the possibility that the fetus may achieve
states of consciousness, but such wakefulness would not
represent unequivocal evidence for consciousness.
2.3.2. Sleep-like states in the fetus
The development of sleep-like states and behavior in the
fetus has been well defined, both clinically and experimentally [17,50,110,143,168,170,186,219]. Of brief note
regarding experimental models, the experimental preparation most often used to systematically study the developing
fetus is that of the chronically instrumented sheep fetus.
This approach permits the physiological and neurological
monitoring of the fetus in utero well after surgical manipulation and without the confounding effects of anesthesia.
Further, physiological responses in the fetal sheep are consistent with those observed in the human.
From mid-gestation, the fetal electroencephalogram
(EEG) begins to evolve from the discontinuous patterns of
tracé alternant, which is associated with the constant simultaneous expression of numerous fetal behaviors (Fig. 1),
into coherent, discrete states which are suggestive of sleep
and are referred to as sleep states [50,170,183]. By late
gestation, as is seen postnatally, there are two well-defined
sleep states, that of rapid-eye-movement (REM) or active
sleep, characterized by low-voltage high-frequency EEG
activity, and non-rapid-eye-movement (NREM) or quiet
sleep, characterized by high-voltage low-frequency EEG
activity (Fig. 2) [188]. In late gestation, these states account
for 95% of fetal EEG activity, they are episodic and during
each state the fetus tends to exhibit specific behaviors.
Generally breathing, swallowing, licking, and eye movements, and atonia occur in REM sleep, whereas apnea, absence of eye movements, and tonic muscle activity occur in
NREM sleep [50,188,219].
These observations demonstrate that sleep, or unconsciousness, is the dominant fetal state for at least 95% of the
ARTICLE IN PRESS
4
D.J. Mellor et al. / Brain Research Reviews xx (2005) xxx–xxx
Fig. 1. Example of a chart recorder tracing from a sheep fetus at 91 days of gestation (0.6 gestation, term = 147 days). This stage of maturity corresponds with
the human brain at around 26–28 weeks of gestation. The trace shows changes in fetal electroencephalogram (EEG), electrooculogram (EOG), nuchal
electromyogram (EMG), and tracheal pressure measurements. Note the lack of clearly defined sleep state and the near-continuous presence of eye, body, and
breathing movements which typify behavior in the immature fetus. The first half of the trace is run at a higher speed to show that a variety of fetal activities
frequently occur coincidentally. Bar A = 10 s, bar B = 10 min.
time. The obvious and critical question is what state lategestation fetuses are in during the 5% of the time that they
are apparently not in REM or NREM sleep? Are the fetuses
awake or merely in transition between the two sleep states,
and how is an awake state defined? Prechtl described
the categorization of state-related behavior as follows: bby
the term state, one tries to describe constellations of certain
functional patterns and physiological variables that may be
relatively stable and that seem to repeat themselvesQ [182].
Postnatally, wakefulness is defined clinically by reference to
opening and moving of the eyes and purposeful movements
of the head; there is high muscle tone superimposed on
general body movements; increased and irregular heart rate
and respiration; and a low-voltage, irregular, mixed pattern
of EEG with frequent movement artefacts [92,157].
2.3.3. Fetal arousal or sleep state transitions?
Using this definition of neonatal wakefulness, two
barousalQ states have been suggested to occur in the human
fetus [54,73,168]. The fetus is said to be actively awake (in
state F4) when vigorous, continual activity, including trunk
rotations, and eye movements are present and its heart rate is
unstable with long accelerations [168]. Fetal bwakefulnessQ
has also been reported in the late-gestation sheep fetus; it
was characterized by REM sleep (which may contain other
intermediate voltages and frequencies) coupled with the
simultaneous appearance of vigorous somatic muscle activity, breathing movements, and the presence of eye activity [48,109,110,165,167,189,193,194,219]. The very
brief and infrequent occurrence of this combination of
behaviors typically only appears to occur as the fetus is
transitioning into, or sometimes out of, NREM sleep, and
this intermediate state appears to increase with gestational age [193,204,219,228] (Fig. 2). Curiously, in the fetal
sheep literature at least, despite the simultaneous and almost
constant occurrence of all of these behaviors earlier in
gestation, at an age where brain maturation is equivalent to a
30-week-old human [148] and thus when nociceptive
pathways may be intact (Fig. 1), fetuses are not referred
to as being awake.
2.3.4. Evidence that the fetus remains asleep
Certainly there is no consensus on whether this constellation of simultaneously occurring bawakeQ behaviors truly
represents a distinct state and, if so, whether it represents
wakefulness; that is, purposeful directed behavior as seen
after birth [110,172,188]. Indeed, surprisingly little work
has been done to explore the physiology of so-called fetal
wakefulness, so that the existence of this state is accepted
only because it is similar to newborn activity. However, an
intriguing study by Rigatto and colleagues, in which the
unanesthetized sheep fetus was observed directly in utero
using a Plexiglas window, showed no evidence of fetal
wakefulness, defined by open eyes and coordinated movements of the head, despite some 5000 h of recording [190].
Instead, fetal behavior alternated between the two basic
behavioral states of REM and NREM sleep. Moreover, they
considered that the polysynaptic reflexes they observed
previously, which they had speculated might reflect wakefulness, were associated with generalized tonic discharge
and rotation of the body and head during transition from
REM to NREM sleep [189].
ARTICLE IN PRESS
D.J. Mellor et al. / Brain Research Reviews xx (2005) xxx–xxx
5
Fig. 2. Example of a chart recorder tracing from a near-term sheep fetus at 124 days of gestation (0.8 gestation, term = 147 days). This stage of maturity
corresponds with the human brain at term. The trace shows changes in fetal electroencephalogram (EEG), electrooculogram (EOG), nuchal electromyogram
(EMG), diaphragm EMG, and tracheal pressure measurements. Note the clear presence of several episodes of a high voltage (low frequency) state, which is
analogous to non-rapid eye movement (NREM) sleep, and a low voltage (high frequency) state, which is analogous to REM sleep. Fetal behavior at this age is
now episodic in nature with fetal breathing movements and ocular activity typically occurring in REM sleep and body movements occurring in NREM sleep.
The two arrows denote brief periods of a third state prior to a transition to NREM sleep, sometimes referred to as evidence of bwakefulnessQ. This state is
characterized by eye, body, and breathing movements during either the end of a phase of REM sleep (first arrow) or during a short period of intermediate EEG
amplitude (second arrow). We propose that this state corresponds with indeterminate or transitional sleep rather than a true state of wakefulness.
The considered conclusion of this review, based on the
analysis outlined below, and Rigatto’s important observations, is that the fetal behavior described by others as
dwakefulnessT in fact represents a transition phase between
sleep states, a state which in the newborn is called indeterminate sleep [65,157,202]. Thus, the increasing occurrence of this bstateQ with increasing fetal age is not because
the fetus is more bawakeQ, but merely reflects the increased
rate of switching between sleep states with advancing gestational age [50,170,220,228].
2.4. Sleep transitions—an indeterminate state of sleep
In both the term and preterm infant, active sleep segments are interrupted by periods of indeterminate or transitional sleep [202]. Indeed, preterm infants spend a
considerable time in indeterminate sleep [133]. Transitional or indeterminate sleep is a state that cannot be definitely classified as active or quiet sleep and is comprised of
mixed EEG activity, increased heart rate, blood pressure,
and respiration, and behavioral changes including startlelike jerking and limb thrashing [82,92,157,202]. Importantly, this transitional sleep state does not represent
wakefulness; it is not, for example, drowsiness [82]. We
hypothesize that so-called wakefulness in utero is likely to
represent transitional sleep in view of the behaviors described, its brief nature and temporal relationship to the
onset or end of NREM sleep (Fig. 2), and its similarity to
post-natal sleep-arousal.
Full arousal from sleep (waking up) is a caudal–rostral
brain process which originates in the ascending reticular
activating system of the brainstem, spreads to the thalamus,
and finally to the cortex. Importantly, however, arousal can
also occur without cortical activation and waking; this is
termed sleep-arousal. In the infant, sleep-arousal without
waking is common [49,150,185]. The cardiorespiratory and
postural changes during arousal do not represent cortical
activation; rather, they are mediated by the brainstem
[150,225]. In part, these periodically occurring reflexes
serve cardiorespiratory homeostatic functions and also provide for several aspects of growth and development [225].
These functions are important, but critically, so too is sleep,
particularly REM sleep, for normal neural maturation both
pre- and postnatally [142,187]. Thus, during sleep-arousal,
the caudal to rostral progression of impulses from the
brainstem to the cortex is retarded by increasing inhibition
which serves to decrease cortical arousal, thereby preserving the integrity of REM and NREM sleep, but at the same
time allowing for essential cardiorespiratory and muscle
activity [225].
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Arousing stimuli, such as obstructive apnea or tactile or
auditory stimulation, can produce changes in cardiorespiratory activity and behavior (e.g., limb withdrawal), even in
the absence of cortical EEG changes and waking [49,149].
These observations are consistent with the general concept
that during sleep there is a blunted capacity to respond to
external stimuli; i.e., stimuli may reach the cortex, but
sensory information is bgatedQ. This is due to activitydependent depression of cortico-thalamic synapses produced by increased thalamic firing during arousal. Because
cortico-thalamic cells are well coupled to inhibitory interneurons, this can result in enhanced cortical inhibition
[41,83]. During indeterminate transitional sleep, corticothalamic responsiveness and thalamic transmission levels
are the lowest of all sleep-waking stages [82]. Feedback
inhibition in gating is mediated by a complex interaction of
neurotransmitters [83], and the putative mechanisms of this
enhanced inhibition in utero are discussed in depth below.
In the newborn where sleep predominates, gating of
sensory stimuli is likely to be a key mechanism helping to
keep infants predominantly asleep [116,142]. As suggested
by Roffwarg’s ontogenetic hypothesis, in the fetus REM
sleep may in a large part substitute for wakefulness in the
development of neural network organization, providing intense sensory input not otherwise available in utero
[104,192]. Studies of fetal cerebral metabolism and activity
during sleep states and altered oxygenation further support
this contention [187]. Moreover, reduced sensory perception, as would be experienced in utero, acts to increase
cortico-thalamic gating [130]. Postnatally, it is suggested
that the decline in REM sleep after birth reflects the capacity
to experience an awake state and the availability of sensory
input to help the brain develop [104].
Collectively, these observations strongly suggest that the
fetal behavior described as wakefulness is in fact that which
is typically associated with changes in sleep states and is
consistent with sleep-arousal. This does not equate with being
awake. Further, it is not clear what purpose wakefulness
would in fact serve for the fetus given the limited duration of
this state and the limited sensory input available within the
bdark and muffled confinesQ of the in utero environment
[104]. However, it is clear that while sleep-arousal does not
usually terminate in waking, full arousal can and does occur
in the newborn, and this is an important part of the newborns
defense against acute threats to its survival during sleep.
Thus, noxious and nociceptive stimuli will awaken the
newborn, but can the same stimuli awaken the fetus?
2.5. Can the fetus be woken up?
If the fetus is essentially always asleep under physiological conditions, then can it be woken up by external
nociceptive stimulation? This question has not been directly
tested. In the newborn, a sufficiently threatening noxious
stimulus (e.g., hypoxia or hypercapnia) will lead to full
arousal, even in the preterm individual [135,150,173,225].
However, fetal responses to such stimuli are significantly
different. The fetal response to hypoxia and severe asphyxia, for example, is characterized by apnea, cessation of
fetal body movements, a shift to hypometabolic EEG states,
and redistribution of combined ventricular output away
from peripheral organs to key central organs such as the
heart and brain [31,187,188,201]. Anatomically, some of
these responses, such as the apneic response to hypoxia,
are facilitated by unique inhibitory pathways within the fetal
brain [53,79] and, as discussed below, cerebral metabolic
changes are in a large part mediated by adenosine [107,120].
Similarly, while elevated CO2 tensions can elicit an increase
in stimulated breathing movements if started in REM sleep,
this response is inhibited when the fetus transitions into
NREM sleep [191], and this is in part due to the inhibitory
effect of temperature in utero [126].
These data demonstrate that stimuli which induce arousal
to waking postnatally do the opposite in utero; they further
suppress fetal arousal, and for that reason, promote survival
of the fetus during adverse conditions. This inhibitory set
of responses is a key defense strategy to conserve energy
[31,187]. These responses to hypoxia also exist in very
young fetuses [31,70,115], although the greater anaerobic
reserves of the younger fetus appear to permit a brief period
of intense movements at the onset of a severe asphyxial
insult which may help the fetus extricate itself from harm
[70]. However, these movements occur despite the cortical
EEG switching to an isoelectric state, i.e., a state of profound suppression [30]. Thus, they are likely to be subcortically/brainstem mediated and do not reflect arousal to
an awake state. This is despite the life-threatening severity
of the insult and the greater quantities of cerebral energy
reserves in the preterm fetus which could potentially be
utilized to transition to an awake state [51,206], if such a
state was important for survival. These observations are
important because they demonstrate that the in utero environment is not the same as that in which the newborn
lives, and this necessitates different responses from the
fetus, mediated in part by unique wiring of the fetal brain.
Unlike the situation postnatally, arousal costs the fetus critically limited energy resources and for little advantage.
Further evidence that fetal arousal in response to noxious
stimuli is suppressed is suggested by studies of the intense
and potentially bpainful or distressingQ stimuli used in vibroacoustic stimulation (VAS). The purpose of VAS is to
evaluate the integrity of the fetal central nervous system by
eliciting distinct fetal movements or fetal heart rate changes
[1]. It is accompanied by variable changes in EEG activity,
depending on the fetal dsleep stateT during stimulation [2,23,
131,234]. Recent detailed analysis of the EEG, however,
shows similar dynamics to those seen during spontaneous
sleep state transitions rather than arousal to an awake state
[204]. These data suggest the effects of VAS are mediated
by actions of the brainstem structures and activation of the
afferent reticular arousal system [204]. These findings are
consistent with the observations that in the newborn cortical
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arousal can occur in response to stimuli, without wakefulness occurring [149,225].
7
typically characterized by greater inhibition. If the fetus is
always asleep, it is not conscious, and therefore cannot
experience nociceptive inputs as pain.
2.6. Can the fetus dream?
We note in passing that these observations bear on the
question of whether the fetus can be said to bdreamQ. Suffice
to say the subject of how and why we dream remains a
complex and hotly debated field of research: for example,
whether it has a role in consolidating conscious experiences
such as learning and memory, or do we dream in order to
forget [216,231]? To ask whether the fetus dreams is an
equally difficult issue to address. The inherent psychoanalytical issues aside, dreams (at least postnatally) are
composed in a large part by memories obtained in the awake
state. Sleep itself, however, is often referred to as an
bamnesiac stateQ: the content of sleep is poorly remembered,
suggesting that the structures responsible for encoding and
storing information are suppressed or absent in sleep [231].
This in turn suggests that new memories, at least declarative
memories (the type of memory commonly referred to by the
terms bmemoryQ or brememberingQ [231]), are not likely to
be obtained during sleep.
From this perspective, due caution should be given to the
hypothesis that fetuses can learn in utero and that memories
based on this learning can be recalled after birth. It may be
argued that neural entrainment to a repeated stimulus (such
as noise) which produces a reflex response to that stimulus,
as has been demonstrated recently in chimpanzee newborns
after repeated exposure in utero to sound [114], is not the
same as cognitive awareness or learning about a stimulus to
produce declarative memory. Whether procedural or implicit
memory (memory formed by unconscious acquisition and
utilization of perceptual and motor skills) truly occurs in
utero, or more importantly is a source for dreams, can only
be speculated upon. On the whole, however, given the
apparent importance for dreaming of memory obtained in
the awake state, the general amnesiac aspect of sleep and
that the fetus appears to be actively maintained asleep, fetal
dreaming seems unlikely.
2.7. Summary of bfetal wakefulnessQ
In summary, this evaluation of the clinical and experimental literature shows that there is no convincing evidence
to suggest that the fetus is ever awake; rather, it supports the
concept that the fetus exists in a continuous sleep-like state.
The evidence suggests, further, that so-called fetal wakefulness, which is said to occur between REM and NREM sleep
states, is more akin to transitional or indeterminate sleep or
to non-waking cortical arousal rather than an awake state.
Although a state of cortical arousal can be elicited by external stimuli, it is a continuation of sleep. Indeed, evidence
suggests that unlike the newborn, noxious or nociceptive
stimuli do not cause cortical arousal to an awake state as a
defense response; rather, the response of the fetus is
3. Suppressors of fetal behavior and cortical activity
The conclusion suggested in the section above is further
strengthened by consideration of the increasing body of
evidence which shows that there are several suppressors in
utero which act to inhibit neural activity in the fetus to a far
greater degree than is seen postnatally in the infant. The
uterus plays a key role in providing the chemical and
physical factors that together help to keep the fetus continuously asleep. We propose that this is achieved, among
other things, through the combined neuroinhibitory actions
of a powerful EEG suppressor and sleep inducing agent
(adenosine), two neurosteroidal anesthetics (allopregnanolone, pregnanolone) and a potent sleep-inducing hormone
(prostaglandin D2), acting together with a putative peptide
inhibitor and other factors produced by the placenta, further
supported by the warmth and cushioned tactile stimulation
of the uterine environment.
When considering this concept, it is important to distinguish between overall neural activity and the maturation
of local gating at the spinal level. For example, there is
evidence from the neonatal rat that descending inhibition is
markedly less than in the adult. This immaturity is suggested
to reflect either delayed maturation of crucial interneurons in the dorsal horn or insufficient local levels of
5-hydroxytryptamine [67], and not overall neural activity.
A proposed schema of the putative inhibitory factors can
be seen in Fig. 3. In this section, we review the fetal EEG
and fetal behavioral evidence for a key role for these
neurosuppressors.
3.1. Adenosine and oxygen status
Adenosine, a purinergic messenger, regulates many physiological processes in excitable tissues, especially the brain,
by inhibiting metabolic activity and/or by modulating the supply of metabolic substrates via vasodilatation [61,169,180].
Adenosine, acting via its A1 receptors, inhibits many neurotransmitters, especially the excitatory glutaminergic systems,
so that the net effect in nearly every region of the brain is to
reduce excitability [61]. This is relevant to sleep and arousal
states, as high circulating and tissue concentrations of
adenosine promote sleep [169,180]. The biological half-life
of adenosine is very short, well under 10 s [34,214], typically
in the range of 0.6–1.5 s [159], so that the plasma and tissue
concentrations of adenosine change very rapidly in response
to changes in adenosine production.
In the sheep and human being, the circulating concentrations of adenosine are 2- to 4-fold higher in the fetus than
the dam [20,153,200,239–241]. Although all tissues may
contribute to circulating adenosine, the placenta and to a
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gen status and adenosine concentrations [20,21,153,196,
200,238,239]. Similarly, adenosine concentrations rise during hypoxia–ischaemia in the perinatal brain before the
onset of anoxic depolarization [176].
These findings indicate that the relatively high levels of
adenosine in the fetus, compared with those postnatally, are
derived primarily from the placenta. They indicate further
that variations due to changes in fetal oxygen tensions are
superimposed on these high levels, such that fetal hypoxemia further elevates and hyperoxemia reduces adenosine
levels. Finally, they show that the high adenosine levels,
augmented at times by hypoxemia, contribute to maintaining the fetus in sleep.
3.2. Neuroactive steroids—allopregnanolone and
pregnanolone
Fig. 3. Flow diagram illustrating the production of inhibitory neurotransmitters both within the brain and in the placenta that help to suppress
fetal awareness. The physical characteristics of the fetal environment such
as its relative warmth and low absolute oxygen tensions also contribute to
this state, at least in part by augmenting fetal adenosine levels, and
potentially other inhibitory factors as well.
lesser extent probably the fetal liver are the major sources
[20,21,138,200,209]. Fetal plasma adenosine concentrations
increase further during hypoxemia or anemia in human
fetuses [196,238,239,240] and in fetal sheep [120,123] and
decrease during marked hyperoxemia in fetal sheep [20,21,
153,200]. The increase in local adenosine during severe
hypoxia suppresses cerebral metabolism and helps limit
neural injury [107].
As in the adult, fetal adenosine levels affect sleep state
and arousal as reflected in REM-related and NREM-related
EEG activity, muscular activity, and breathing movements.
Infusion of adenosine reduces the incidence of rapid eye
movements and fetal breathing during the first hour [120–
122], but these effects are not sustained during 9-h infusions
[121]. The metabolically stable adenosine analogue, 1phenylisopropyl-adenosine, reduces the incidence of REMrelated and increases the incidence of NREM-related EEG
activity in a dose-dependent manner, and abolishes fetal
breathing and muscular activity [221]. Conversely, infusions
of theophylline, a non-specific adenosine receptor antagonist, increase fetal breathing and the incidence of REM
sleep [18], and abolish the suppressive effects of adenosine
infusion [121].
These data demonstrate that the higher concentrations of
adenosine in fetal than in maternal plasma contribute to the
predominance of sleep-like EEG activity seen before birth in
the human and sheep fetus [32,44,52,93,226]. Moreover, the
effects of short-term and long-term hypoxemia [37,38] and
of hyperoxemia [19,95] on EEG activity, rapid eye movement, breathing, and body movements in fetal sheep seem to
primarily reflect the inverse relationship between fetal oxy-
Pregnane metabolites of progesterone which contain a
3a-hydroxyl group include allopregnanolone (5a-pregnane3a-ol-20-one) and pregnanolone (5h-pregnane-3a-ol-20one), and have potent sedative/hypnotic and anaesthetic
effects [139,156,175]. They enhance g-amino-butyric-acid
(GABAA) receptor binding [47], thereby increasing the activity of GABA inhibitory pathways in the central nervous
system (CNS) [139]. These pregnane metabolites are primarily synthesized within the CNS from cholesterol, via
progesterone, by 5a-reductase-mediated conversion [178],
but may also be synthesized from progesterone produced
elsewhere, and circulating pregnanes synthesized in other
tissues readily cross the blood–brain barrier [24,47,134].
Given their demonstrated CNS-suppressive effects, 3ahydroxyl pregnanes are strongly implicated as inhibitory
modulators of fetal EEG activity and behavioral state.
Similar to adenosine, the placenta produces large quantities
of progesterone [22] and possibly pregnanes throughout at
least the last half of pregnancy [163]. Thus, plasma concentrations and brain concentrations of progesterone and the
pregnanes fall markedly after birth [59,111,163,178,205].
GABAA receptors are present in the brain of fetal sheep
from at least 56 days of gestation [232]. During the last 20–
30 days of pregnancy, injections of progesterone or its 3ahydroxyl metabolites into the fetal circulation or cerebral
ventricles reduce fetal EEG activity and eye, breathing, and
body movements, and conversely, inhibition of placental production of progesterone or its metabolites enhances
these activities [48,102,164–167]. Similarly, inhibition of
GABAA by picrotoxin increases fetal EEG, breathing, and
behavioral activity [113,166].
Consistent with data from the sheep fetus, 3a-hydroxyl
pregnanes, produced from progesterone in fetal CNS and
other tissues, can act on GABAA receptors in the human
fetal brain [134]. The placenta produces large quantities
of progesterone throughout the last half of human
pregnancy (and likely earlier) [60,99]. Progesterone and
its 3a-hydroxyl metabolites have been detected in human
fetal plasma [36,101,119,155] and 5a-reductase is present
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from at least 17 weeks of gestation in the human fetal
CNS, skin, liver, kidneys, lungs, and small intestines
[197]. Moreover, allopregnanolone and pregnanolone are
present at significant concentrations in umbilical blood at
birth in the human infant [36,101]. In stress situations
such as hypoxia, allopregnanolone levels are actively
maintained in the brain and are increased in circulating
plasma [163].
3.3. Prostaglandin D2
Prostaglandin D2 (PGD2) is a potent sleep-inducing paracrine hormone which is formed in the adult mammalian
CNS from prostaglandin H2 under the action of the enzyme
prostaglandin D synthase (PGDS) [96]. Sleep induced by
intracerebroventricular (icv) infusion of PGD2 is indistinguishable from natural sleep as judged by its normal REM
and NREM characteristics and by several other electrophysiological and behavioral criteria [96]. PGD2 infused
into the subarachnoid space promotes sleep by increasing
the firing rate of sleep-active neurons in the ventrolateral
preoptic area, adjacent to the anterior hypothalamus, and not
elsewhere in the brain [96]. The mechanisms of action of
PGD2 involve paracrine stimulation of adenosine release
which leads to GABAergic inhibition of wake-promoting
neurons in the posterior hypothalamus [97].
PGDS is present in the cerebrospinal fluid of fetal sheep
at 125 and 135 days of gestation, but not at 90 days [132].
Inhibition of PGDS action by icv infusion of SeCl4 increases fetal behavioral activity as indicated by increased
nuchal muscle, electroocular, and breathing activity, and icv
infusion of PGD2 reverses these SeCl4-induced effects
[132]. These observations suggest that PGD2 has a basal
role in inducing sleep in fetal sheep from at least 125 days of
gestational, when discrete REM and NREM sleep states are
established [52,193,194].
3.4. Placental peptide inhibitor and other factors
A key role for the placenta in maintaining fetal sleep
states is shown by studies of bbirth in uteroQ, in which
the fetus is ventilated to achieve normal oxygenation.
Under these conditions, when the umbilical cord is
occluded, continuous behavioral activity and continuous
breathing develop in the fetal lamb [9–11]. This paradigm
mimics the effects of separation from the placenta at
birth, and thus removal of its inhibitory effects. Placental
adenosine and pregnanes are likely important mediators
of this effect, but there is some evidence for an
additional placental inhibitory factor. Infusion of a
placental extract but not extracts of other fetal tissues
suppresses fetal activity and respiration within 2 min [9–
11]. This putative factor has not been fully characterized,
but is probably a peptide with a molecular mass between
2.5 and 4.5 kDa. However, not all studies support the
existence of such a placental mediator [125].
9
Other inhibitors are also likely to contribute, for example,
neuropeptide Y (NPY), somatostatin, enkephalins, and corticotropin releasing hormone (CRH) [100,213]. Postnatally,
NPY is known to have sleep promoting and sedative actions
and to reduce pain [161,235]. The levels of NPY are
relatively high in the fetal brain and decline after birth [100],
and during fetal life are known to play a role in fetal
responses to asphyxia [199]. Other peptides, such as substance P, which is a primary sensory transmitter mediating
pain sensations via the thin C-fibers, markedly increase
expression and function after birth [33,184]. While CRH is
well known to be produced during stress and mediates many
of its effects, it is less well appreciated that it also has
analgesic effects at all levels of the neuraxis [129], which
may augment the overall protective role of this system
during stress. Likewise, placental CRH in human beings is
speculated to play a role in mediating the rapid attenuation
of fetal responses to repeated stimuli [198], and needling
procedures appear to stimulate CRH release from placental
not fetal sources [75]. In the late-gestation sheep fetus CRH
is known to play a critical role in modulating the episodic
nature of fetal behavior [29]. Also, endogenous activity in
the kappa opioid system may be functional in modulating
responses to the sensory environment; in particular, it may
regulate the rapid fetal habituation to sensory input [213].
Finally, growth hormone (GH) levels are high in fetal
life, but unlike the situation postnatally, GH does not significantly contribute to fetal growth [108]. There is a positive relationship, however, between GH and sleep [227],
and sleep-related GH secretion is probably caused by an
increased production of hypothalamic growth hormonereleasing hormone acting on the pituitary [227]. Speculatively, the high levels of GH seen during fetal life may
reflect an important role for growth hormone in keeping the
fetus asleep. A similar role may be postulated for ghrelin, an
endogenous ligand for the growth hormone secretagogue
receptor, which may be secreted both by the fetus and the
placenta [117,229].
3.5. Thermal status—warmth
Sleep-wakefulness and body temperature are known to
influence each other. Postnatally, we know that warmth can
make us drowsy; sleep is effectively promoted by a hot bath,
for example [105]. There is evidence that fetal thermal status
affects the level of behavioral activity in utero, i.e., that
warmth suppresses it. The work by Kuipers and colleagues
suggests that temperature modulates the state-related fetal
respiratory response to elevated CO2 tensions [126].
Human, sheep, and other fetuses are slightly hyperthermic
in relation to their mothers because the heat they generate
can only be dissipated down a thermal gradient across the
placenta [3,80,181]. Cooling mature well-oxygenated fetal
sheep in utero, such that their cutaneous thermoreceptors are
exposed to cold via cooling coils in amniotic fluid, elicits
behavioral activity, shivering, and increased respiration, and
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rewarming such fetuses reverses these effects [80,88–
90,181]. In utero cooling of the fetal skin using amniotic
fluid cooling coils apparently induces EEG changes indicative of arousal [203]. Immersing aroused, physically
active, and conscious newborn lambs in water at maternal
body temperature induces a sleep-like, non-aroused, unconscious state, and cooling the water restores their prior
aroused, conscious, and physically active state [62].
The translation of thermal information from the skin to
induction of sleep may occur via temperature-sensitive
neurons within the hypothalamus [147,154]. Various regions
of the hypothalamus (e.g., the hypothalamic preoptic area
and prefrontal areas of the lateral hypothalamus) are
involved in both the regulation of sleep-wakefulness and
body temperature [147,154]. Activation of sleep-related
warm sensitive neurons and the deactivation of wake-related
cold-sensitive neurons appear to play a role in the onset and
regulation of NREM sleep [6]. Further, warmth inhibits
neuronal discharge in arousal-related brain structures, including regions which promote wakefulness such as the
dorsal raphe nucleus [6,91,147]. These responses may be
mediated by multiple inhibitors such as adenosine, GABA,
prostaglandins, and growth hormone [7,98,145,218,244]. In
this way, the constant moderate ambient warmth experienced by the fetus may facilitate a constant state of sleep.
3.6. Tactile stimulation
Tactile sensory input is minimized in utero by amniotic
fluid which buffers the embryo/fetus against mechanical
stimulation and presumably also reduces sensations associated with gravity. In contrast, intense tactile stimulation
during labor and after delivery is considered to contribute to
the usually rapid onset of behavioral activity and consciousness in newborn human infants [127,128] and other newborn animals, including lambs [151].
4. Long-term sequelae
Here we consider one final issue: whether nociceptive
inputs may have deleterious consequences even if the
bendogenously anesthetizedQ fetus does not consciously
perceive pain at the time of stimulation. Can exposure to
noxious stimuli initiate a cascade of events that sensitize the
nervous system [84], or can repeated pain exposure in preterm infants contribute to attention, learning, and behavior
problems later in life [35,87,237]? It is critical to appreciate
that not only is most of the available information based on
studies in preterm infants, and not the fetus, but also there
are no direct studies which have robustly tested these
speculations, even in the preterm newborn, and thus no
empirical data to demonstrate a causal relationship.
It is striking that where bstressQ or treatment with steroids
has been found to affect the fetus [45,46,55,86,162], the
bstressQ has been chronic, often extending over a third or
more of gestation, whereas brief treatment seems to affect
development only when given very early in gestation [58].
Moreover, the fetus is likely to be naturally exposed to
elevations in bstressQ hormones, for example, during periods
of hypoxia or other stresses [77]. Such exposure may occur
frequently throughout development, particularly during
early to mid-gestation [27,70], and circulating cortisol concentrations increase markedly in late-gestation, staying
elevated until several weeks after birth [144]. Thus, it is
likely that a brief period of fetal hypothalamic–pituitary–
adrenal (HPA) activation in mid- to late gestation in response to short duration surgery-induced nociceptor input
would have limited importance.
In summary, considerably more work is required to evaluate the long-term consequences of nociceptor activation in
the fetus and indeed the premature newborn. Until then, we,
like Grunau, advise against overinterpreting correlational
studies and limited data [87].
3.7. Summary of endogenous inhibition
5. Summary and conclusions
This analysis suggests that the suppression of fetal
wakefulness-related CNS activity and behavior described
in the first part of this review is achieved to a significant
extent by the combined effects of multiple neurotransmitters, peptides, and endocrine factors coupled with warmth,
buoyancy, and cushioned tactile stimulation (Fig. 3). During
stress situations, CNS suppressor effects are often significantly increased, and this leads to an even deeper
inhibition of the fetus, providing, we argue, a greater degree
of bendogenous anesthesiaQ. Clearly much more work is
required to dissect the relative importance of each of these
systems and to understand fully how the systems interact.
Nevertheless, the existing data strongly suggest that the
fetal response to noxious and nociceptive stimuli is significantly different from that seen after birth and is in large
part due to its unique environment, with the placenta playing a key role.
We have considered whether the fetus, once its nociceptive pathways are complete, can feel pain in utero in a
psychological manner akin to adult pain experience, and
whether regardless of this the physiological responses to
nociceptive input may lead to altered behavior later in life.
We conclude that there is currently no strong evidence to
suggest that the fetus is ever awake, even transiently; rather,
it is actively kept asleep (and unconscious) by a variety of
endogenous inhibitory factors. Thus, despite the presence of
intact nociceptive pathways from around mid-gestation, the
critical aspect of cortical awareness in the process of pain
perception is missing. Furthermore, there is currently no
direct evidence to suggest that subcortical effects of
nociceptor input in the fetus can alone alter neural development and cause long-term adverse outcomes. Rather, the
inference that this may occur is derived from studies of
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chronic maternal bstressQ or administration of synthetic
glucocorticoids, or speculation about the potential vulnerability of immature neurons.
It is of concern that such hypotheses about the impact of
nociceptive stimuli are readily accepted as fact and that this
perception in turn instructs our clinical understanding about
the management of presumed pain in utero. The influence of
the postnatal environment and of cognition and learning on
modulating these effects is clearly quite considerable; an
influence that has not been considered in most studies and
reviews. Furthermore, key questions have typically not been
addressed when considering the potential impact of presumed pain in utero. For example, what is the interrelationship between the relatively diffuse immature pain
pathways [136], and the overall inhibition from endogenously-produced analgesic neurotransmitters during noxious
stimuli? Another example is that the stress response to
noxious stimuli includes release of CRH which has analgesic effects in its own right in the fetus but not postnatally
[39,160]. The fetal response to nociceptive input is clearly
more complex than we currently appreciate, and as highlighted above appears to be dengineeredT to further anesthetize the fetus during exposure to noxious stimuli. It may
be strongly argued that these factors interact to significantly ameliorate, if not eliminate, the deleterious impact
of nociceptive input in the fetus compared to the effects
postnatally.
Surprisingly, despite advocacy for analgesic use during
fetal surgery, the impact of analgesics and anesthetics on
brain and other organ development has not been extensively
studied. Yet there is good evidence to show that such agents
affect the fetus quite differently and may cause fetal compromise. In fetal sheep, morphine, for example, is not a
cardiorespiratory depressant; rather, it induces continuous
fetal breathing movements (FBMs) which increase metabolic demand [28,42]; it also stimulates the fetal HPA axis
[223] and alters fetal glucose handling [222]. In utero,
opiates do not necessarily have analgesic properties and
may increase fetal compromise during stress situations
[124,141,212]. Importantly, there is now evidence to show
that exposure of the fetus to opiates may cause significant
neuronal and white matter cell loss [81,106,207,217].
Non-narcotic analgesic agents have also not been evaluated extensively [177], but may have similar consequences.
For example, indomethacin also significantly increases
FBMs [4] and may alter the fetal responses to hypoxia
[103]. In newborn immature rats, at least indomethacin
administration is associated with subsequent impaired neural
development [26]. For all agents, given the diffuse nature of
pain receptivity and the limited fetal capacity to metabolize
many agents, it is difficult to judge dosage and the required
duration of treatment, and it is difficult to find a safe route
which can be used repeatedly or chronically.
In the adult, some experimental studies have indicated
that pre-emptive analgesia which blocks the intense afferent
barrage of impulses received by the subcortex and brainstem
11
during surgery significantly modifies post-surgical pain
[152]. These findings are, however, not supported by a
recent major meta-analysis of clinical trials, mainly in
adults, which found no evidence that pre-operative analgesia
can substantially reduce post-injury pain hypersensitivity
[158]. Although there are few large studies in preterm
newborns, a randomized controlled trial of pre-emptive
analgesia with morphine was associated with worse outcomes [14], no appreciable change in pain scores [208], and
no reduction in adverse neurological outcome [14,208].
Indeed, there is some evidence that prolonged exposure to
analgesic drugs may detrimentally alter neuronal and synaptic organization permanently [12].
What we hope is apparent from this review is that this
important issue is clouded by inappropriate extrapolation
from the postnatal state to the fetal condition. The assumption that the newborn can act as a surrogate for the
fetus is wrong, for it denies that the environment in which
the fetus lives is unique, and that the fetus itself responds
quite differently to many challenges. Greater scientific rigor
is required to directly address the concept of fetal awareness
in utero as part of understanding presumed fetal pain perception, and of the potential impact of nociceptor input on
neural development and subsequent behavior. It is not
enough to say, bIf in doubt treatQ, for treatment may produce
greater adverse outcomes than the effects of relatively
transient nociceptor input. Certainly, it is the conclusion of
this review that in order to better understand the nature of
presumed fetal pain, we must first evaluate the fetus and its
unique in utero environment from the viewpoint of the fetus;
not as a newborn not yet born or as an adult who is simply
waiting to grow up.
Acknowledgments
The authors gratefully acknowledge several organizations which provided funding that directly or indirectly
supported the completion of this review: the Auckland Medical Research Council, the Health Research Council of
New Zealand, the National Institutes of Health (RO1 HD32752), the Institute of Food, Nutrition and Human Health
and the Riddet Centre (Massey University), and the Ministry
of Agriculture and Forestry. We also wish to thank Drs.
Craig Johnson (Massey University, New Zealand) and
David Walker (Monash University, Australia) for helpful
advice and comments.
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