Developing consciousness fetal anesthesia and analgesia

1. Seminars in Anesthesia, Perioperative Medicine and Pain (2006) 25, 189-195
Developing consciousness: fetal anesthesia and analgesia
Roland Brusseau, MD, and Laura Myers, MD
From the Department of Anesthesia, Perioperative and Pain Medicine, Children’s Hospital Boston, Harvard Medical
School, Boston, Massachusetts
KEYWORDS: Fetal anatomic study demonstrates that, by 20 weeks gestation, the requisite cytoarchitecture believed
Fetal consciousness; to be necessary for consciousness (eg, the thalamus and associated subcortical structures) and its proper
Fetal connections are in place and accompanied by a coordinating electroencephalogram (EEG) rhythm.
neurodevelopment; Given the structural and functional integrity of these portions of the brain, it is reasonable to conclude
Fetal anesthesia; that consciousness is at least possible from this point in fetal development. If a more stringent threshold
Fetal analgesia for continuous EEG activity is required, then it would appear that by 30 weeks gestation, consciousness
is possible. If we are to accept that consciousness is possible by 20 weeks (or, more conservatively, 30
weeks), then it also would appear possible that fetuses could experience something approximating
“pain.” The mere possibility of consciousness and an experience of pain (however rudimentary) would
appear to mandate the provision of appropriate anesthesia and analgesia to fetuses undergoing surgical
intervention.
© 2006 Elsevier Inc. All rights reserved.
When published in 1954, Penfield and Jasper’s “Epilepsy certain generalized seizures—not by cortical stimulation but
and the Functional Anatomy of the Human Brain” could rather by experimental stimulation of the midline thalamus,
hardly have been considered a landmark work in the field of producing a change from the usual adult EEG to the familiar
fetal consciousness.1 Questions of fetal consciousness were spike and wave pattern of the absence seizure.1 Jasper’s
strictly the domain of philosophy and theology, if possessed demonstration that consciousness might be mediated by
by any domain at all. Penfield, a neurosurgeon, and Jasper, thalamic, and not cortical, stimulation furthered the notion
a psychologist, demonstrated that the consciousness (as of consciousness growing out of such subcortical integra-
traditionally understood) of some 750 patients undergoing tion.
radical cortical excisions, including hemispherectomies, re- What can these observations tell us? The work of Pen-
mained continuous and unimpaired both during and after the field and Jasper suggests that the critical structures for
procedures. Certain discrete cortical functions might be lost organizing and producing consciousness may well be the
or impaired, but consciousness remained. This led to a subcortical system and not solely the cortical structures as
critical insight: that the highest integrative functions of the previously understood. These subcortical structures them-
brain are not organized at the cortical level, but rather within selves are informed by still other structures in an ascending
a divergent system of subcortical structures that process fashion as well as descending cortical inputs. Further, Jas-
cortical and subcortical inputs. Subsequently, Jasper found per’s investigations of seizure neurophysiology suggest that
that consciousness might be disrupted in a manner typical of there is an inherent electrical rhythm (or rhythms) involved
in the conscious state, and that such rhythms may be dis-
rupted in a similar way by both experimental thalamic
Address reprint requests and correspondence: Roland Brusseau, MD,
Department of Anesthesia, Perioperative and Pain Medicine, Children’s
manipulation and by generalized absence seizure, thus in-
Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. dicating that some form of concordant EEG rhythm appears
E-mail address: roland.brusseau@childrens.harvard.edu. necessary to support the conscious state.
0277-0326/$ -see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1053/j.sane.2006.09.002

2. 190 Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 25, No 4, December 2006
These very subcortical and cortical structures that Pen- This has come to be known as “cognitive binding” and thus,
field and Jasper suggest as involved in the generation of the anesthetized state may produce a sort of “cognitive
conscious states, as well as their inherent electrical rhythms, unbinding.”2
are known to be present in the term neonate, and their If we are to understand consciousness as a subcortical
development during fetal life is well documented. Is the integration of diverse subcortical and cortical sub-process-
fetus, then, capable of consciousness at any point prior to ing entities, we should be able to establish watersheds in
delivery? Is the preterm neonate, in fact, conscious? And if fetal development when consciousness becomes as least
the fetus and preterm neonate are in fact capable of con- structurally and functionally possible. As currently we have
sciousness, can they experience pain? not any direct way to measure consciousness (though the
These are some of the questions we hope to address in Bispectral Index monitor has been suggested as a tool for
this essay. Although a general theory of consciousness is the measurement of anesthetic-induced cognitive unbind-
well beyond the scope of this essay (or likely this volume, ing), we may have to conclude that consciousness is at least
for that matter), it may be argued that fetal neuroanatomic possible when the necessary structures are in place and
development recapitulates the formation of an integrative proper functional modalities (ie, EEG rhythms) are largely
subcortical mechanism for consciousness, and as such, anal- continuous. With this structural and functional view of
ysis of the development of these structures may serve as a consciousness thus presented, we turn to fetal neuroana-
proxy for the development of consciousness itself. Moving tomic development and, in turn, the possible quickening
from a consideration of fetal neuroanatomical development, moments of fetal consciousness.
we will go on to consider the possibility of fetal pain as a
surrogate for fetal consciousness and discuss the rationale
for the provision of fetal anesthesia and analgesia for fetal Fetal neuroanatomic development
surgical intervention.
The development of the brain and spinal cord begins as
early as the third postconceptual week, when the neural tube
forms from neuroectoderm. Neural crest cells migrate out
Consciousness as subcortical integration laterally to form peripheral nerves from 4 weeks, with the
first synapses between them forming a week later.7,8 Syn-
Penfield and Jasper’s intriguing supposition of a subcortical apses within the spinal cord begin to develop at 8 weeks
organization of consciousness has, in recent times, gained gestation, suggesting the first spinal reflexes may be present
support from a growing body of work in the area of anes- from roughly 8 weeks forward. Between 8 and 18 weeks
thesia and consciousness.2,3 Whereas anesthetics have long gestation is the time of maximal neuronal development. The
been acknowledged as reversible suppressors of consciousness first neurons develop in the ventricular zone (an epithelial
(as well as memory and movement), to date the mechanisms layer) along with glia. These glial cells adopt a radial ar-
of such suppression have been poorly described. Whether rangement, along which the newly formed neurons migrate
anesthetics act locally (by suppressing certain signals) or out in waves to form the neocortex. Neurons are first laid
globally (by depressing the entirety of neural function) has out in the deeper layers and then in the superficial layers.
been the subject of ongoing debate. However, recent evi- After neural proliferation, synaptogenesis occurs, first in
dence suggests that the anesthetized brain is anything but peripheral structures and then more centrally. From around
silent. Indeed, the notion that anesthetics globally suppress 20 weeks, this process is at least partly dependent on sen-
brain function appears wholly incorrect—recent studies of sory stimulation.9
isoflurane have demonstrated a loss of pattern recognition The development of the nociceptive apparatus proceeds
(an integrating function) but not component recognition in in parallel with basic CNS development. The first essential
certain cortical areas.4 Similarly, multiple agents have been requirement for nociception is the presence of sensory re-
demonstrated to uncouple rostrocaudal and intrahemi- ceptors, which develop first in the perioral area at around 7
spheric brain regions as well as caudorostral visual infor- weeks gestation. From here, they develop in the rest of the
mation transfer while not suppressing activity within those face and in the palmar surfaces of the hands and soles of the
regions.2,5,6 The dissociative anesthesia of ketamine serves feet from 11 weeks. By 20 weeks, they are present through-
as a particularly illuminating example of this uncoupling out all of the skin and mucosal surfaces.10 The nociceptive
phenomenon. Such work suggests that regional information apparatus are initially involved in local reflex movements at
processing may persist in the anesthetized state, while the the spinal cord level without supra-spinal integration. As
representation (or integration) of such information that is these reflex responses become more complex, they, in turn,
believed to be rendered by subcortical structures is inhib- involve the brainstem, through which other responses, such
ited. This loss of integration appears to be at the root of as increases in heart rate and blood pressure, are mediated.
anesthetic-induced loss of consciousness. Consciousness, However, such reflex responses to noxious stimuli have not
therefore, may be understood (from an anesthetic stand- been shown to involve the cortex and, thus, traditionally
point, at least) as the coordinated integration of inputs from have not been thought to be available to conscious percep-
diverse brain regions, mediated by subcortical structures. tion.8

3. Brusseau and Myers Fetal Anesthesia and Analgesia 191
Consciousness and the cortex arguably, it cannot be until the thalamocortical connections
are formed and functional that the fetus may first attain
This raises an interesting question, however. Is a cortex something approaching Hameroff’s rudimentary conscious-
required for consciousness? If we adopt the view of Hamer- ness. The thalamus is first identified in a primitive form at
off2 that consciousness, in its most basic form, may be day 22 or 23 post-conception. Its connections grow out in
considered equivalent to “minimal awareness” without a phases, initially only as far as the intermediate zone of the
requirement for memory, cognition, or organizational so- cerebral wall, collecting below the cortical plate. The neu-
phistication, perhaps only subcortical structures are neces- rons then advance further into the cerebral hemispheres,
sary and sufficient for such a basic consciousness. Reflec- eventually becoming localized into their specific functional
tive self-consciousness and the higher-order thought that is fields. The final thalamocortical connections are thought to
typically associated with mature cortical function would be, be in place by around 26 weeks, although estimates differ.12
in such a view, a more complex form of consciousness, still In fact, there are thought to be transient cholinergic neurons
mediated through the same subcortical structures, but now with functioning synapses connecting the thalamus and cor-
with higher-order inputs. (This higher-order consciousness tical plate from approximately 20 weeks.13 This time point
may, in fact, be that which separates human consciousness could be taken as the absolute earliest time in gestation
from that of primates and other species, if we are to concede when a fetus could be aware of nociceptive stimuli, or to
that consciousness may not be a uniquely human attribute.) “feel pain.”
As Penfield and Jasper suggested, “the highest cortical func- The link between consciousness and electrical activity
tions of the brain are not completed at the cortical level, but within the brain can be measured and patterns defined using
in a system of highly convergent subcortical structures sup- the electroencephalogram (EEG). The presence of EEG
plying the key mechanism of consciousness.”1 Anand, tak- activity would suggest a degree of functional maturity, in
ing a more extreme view, points to children with hydranen- addition to structural maturity. Although sporadic electrical
cephaly, born with little or no cortical tissue, as evidence for activity has been detected in the fetal brain as early as 43
this supposition.11 Despite a near complete lack of cortical days gestation,14 more coordinated electrical activity (in the
tissue, these children may demonstrate a rudimentary dis- form of intermittent bursts) has been shown to be present in
criminative awareness, including the ability to distinguish the brainstem from 12 weeks, and the cerebral hemispheres
familiar and unfamiliar people and environments, musical at 20 weeks.8 Before 25 weeks, the electrical activity on
preferences, associative learning, and appropriate affective EEG recordings is discontinuous, with periods of inactivity
responses. Indeed, there is evidence that hydranencephalic lasting up to 8 minutes and bursts of activity of only 20
children respond to painful and pleasurable stimuli in a seconds (accounting for only 2% of the total time). From 25
coordinated manner similar to other children.11 It would to 29 weeks, the periods of activity increase, such that by 30
appear, then, that these children meet Hameroff’s minimal weeks, although EEG activity is still not continuous (in-
criteria of consciousness. deed, in some infants, it does not become continuous during
Nevertheless, Penfield and Jasper appear to suggest that quiet sleep until several weeks after term), distinct patterns
cortical structures are at least in some way required: a of wakefulness and sleep can be recognized as the precur-
subcortical system, comprised of the basal ganglia, medial sors of adult patterns.8 At first, these are not necessarily
thalamus, ventrolateral thalamus, substantia nigra, ventral concordant with behavioral state. However, over the next
tegmental area, superior colliculus, median raphe, and the few weeks, the degree of concordance improves.15 By 34
midbrain and pontine reticular formation, does not function weeks, electrical activity is seen 80% of the time. From 34
“by itself alone, independent of the cortex,” but “by means to 37 weeks, sleep/wake cycles become more defined.8
of employment of various cortical areas.”1 As such, if we It is arguable when electrical activity in the fetal brain
posit either subcortical or cortical integration of ascending first becomes indicative of a state of consciousness or at
stimuli as the minimum necessary for conscious interpreta- least the possibility thereof, but if we attend to Penfield and
tion of noxious stimuli, then at minimum we must consider Jasper’s contention of some form of cortical involvement in
the structural, functional, and temporal development of the the generation of conscious states, then the lack of cortical
thalamus. electrical activity detected below 20 weeks sets the lowest
possible limit. As periods of electrical activity gradually
lengthen, it would seem likely that no sudden event marks
Development of the thalamus the beginning of consciousness, but that as the gaps between
periods of electrical activity gradually shorten, conscious-
The thalamus is the structure responsible for relaying affer- ness emerges incrementally. If one were to require a greater
ent signals from the spinal cord to various subcortical struc- continuity of EEG activity as a necessary substrate for
tures and the cerebral cortex itself.8 Thus, if integrative conscious experience, then the more mature patterns seen
thalamic function is necessary for nociceptive perception from 30 weeks could well be taken as a pragmatic rational
(ie, “pain”) or any other higher order sensory perception, cutoff.15

4. 192 Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 25, No 4, December 2006
Subcortical integration of the physiologic Motor response
stress response
A motor response can first be seen as a whole-body
If we accept the premise that, given the presence of certain movement away from a stimulus and observed on a sono-
structural elements (eg, the thalamus) and functional integ- gram from as early as 7.5 weeks gestation.8 It is difficult to
rities (EEG activity), consciousness is at least possible, then know if these first movements represent a coordinated and
we may consider whether the fetus has the capacity to subcortically or cortically integrated reaction or simply a
experience pain. “Pain,” in this context, must be distin- spinal reflex response to external stimuli. The perioral area
guished from “nociception.” “Pain,” according to the Inter- is the first part of the body to respond to touch at approxi-
national Association for the Study of Pain (IASP), is an mately 8 weeks, but by 14 weeks, most of the body is
unpleasant sensation which may be associated with actual or responsive to touch. As gestation progresses, fetal move-
potential tissue damage, possibly including physical and ments become increasingly complex, with the fetus showing
emotional components.16 As such, pain is clearly a subjec- limited responses to stimulation, such as isolated limb
tive phenomenon, one that typically accompanies nocicep- movement.18
tion, but can also arise without any nociceptive stimulus, Preterm babies in a neonatal intensive care unit provide
and thus includes the emotional response. Nociception, on a good opportunity to observe facial expressions and behav-
the other hand, is a neurophysiological term and denotes ior in relation to potentially painful procedures. Although
specific activity in nerve pathways. It functions as the artificially ventilated adults are generally provided sedation
transmission mechanism for physiological pain, but does and analgesia, this is not always the case in ventilated
not necessarily subserve or describe psychological pain preterm babies. In a study observing ventilated babies from
states.16 28 to 32 weeks gestation, the use of fentanyl analgesia
Given current knowledge, it is impossible to know ex- significantly reduced pain-related behaviors, such as agita-
actly when the fetus (or preterm or term neonate, as the case tion, inconsolability, and facial expressions consistent with
discomfort.19 Oral sucrose given during heel lancing for
may be) first becomes aware of pain. Even more difficult
neonatal phenylketonuria testing reduced infant crying time
than measuring consciousness in the adult is the challenge
by 31%.20 Similar findings are observed in infant rats, with
afforded by making the same determination of conscious-
the reduction in behavioral distress being reversed by the
ness in the uterine fetus. If we are to take pain as a subset
administration of naltrexone, suggesting that the analgesic
of conscious experience, then the same difficulty applies to
effect from sucrose is mediated by endogenous opioids.21
this question. One school of thought insists that the entire
Unlike the other physiologic responses observed in rela-
cytoarchitecture of nociceptive signal transduction and pro-
tion to pain, these behavioral observations provide some
cessing is necessary to translate noxious inputs into subjec-
indication that the preterm baby is indeed sensate, but
tive instantiations of “pain.”17 Others suggest that, whereas whether this is an integrated, cognitively bound experience
the entire cytoarchitecture (including descending inhibitory that might qualify as conscious perception of pain is un-
pathways) present in adults may not be fully developed in clear. Furthermore, the assumption that the prematurely
the fetus, there are transient structures present during fetal born baby is directly comparable to the fetus, even at the
development that may allow such signal transduction and same gestational age, is not necessarily correct.
processing on an intermittent basis.13 At present, it is not
known whether either of these suggestions is correct, and Fetal endocrine response to stress
therefore we cannot be assured that there is, or is not, a
subjective experience of pain available to the fetus. Instead, Although discussions of fetal consciousness and pain are
one must rely on other fetal physiologic responses that complicated and controversial, there is little disagreement
could serve as indicators of aversion to a stimulus. Different about the capacity for a fetal physiochemical stress response
studies have used various indicators of fetal response; all are from early gestation. Human fetal endocrine responses to
physiologic responses seen in times of stress in older chil- stress have been demonstrated from as early as 18 weeks
dren and adults. Observed responses fall under three main gestation. Giannakoulopoulos and colleagues first demon-
categories: motor responses, endocrine responses, and cir- strated increases in fetal plasma concentrations of cortisol
culatory redistribution. What all these responses have in and -endorphin in response to prolonged needling of the
common, however, is that they all imply coordinated func- intrahepatic vein (IHV) for intrauterine transfusion.22 The
tion of the very subcortical structures believed to be in- median increase was 590% for cortisol and 183% for -en-
volved in the generation of conscious states. Therefore, by dorphin. Fetuses receiving the same procedure of transfu-
examining at what points in development these various sion, but via the non-innervated placental cord insertion,
responses become active, we again may be able to set failed to show these hormonal responses. IHV needling
certain thresholds as to when consciousness, and the sub- studies have shown a rise in -endorphin and norepineph-
jective experience of nociception as “pain,” is at least pos- rine during intrahepatic transfusion from 18 weeks gesta-
sible. tion, which was seen throughout pregnancy independent of

5. Brusseau and Myers Fetal Anesthesia and Analgesia 193
both gestation and the maternal response. A fetal cortisol the neural processing architecture that might support con-
response, again independent of the mother’s, was observed sciousness is in place and functional. The complex physio-
from 20 weeks gestation.23 The level of this response in- logic responses to stress require a neural integration similar
creased throughout gestation. Fetal intravenous administra- to that proposed for conscious states. Further, it would
tion of an opioid ablated the -endorphin response and appear that these motor, endocrine, and circulatory re-
partially ablated the cortisol response to the stress of IHV sponses to stimuli are processed, at least in part, by the same
needling, suggesting an analgesic effect.24 structures thought to be involved in the binding of conscious
A randomized controlled trial of fentanyl analgesia dur- states. If we are to accept that by approximately 20 weeks
ing surgery for patent ductus arteriosus in babies of a mean the requisite cytoarchitecture for consciousness (eg, the
gestation of 28 weeks found that the rise in -endorphin thalamus and associated subcortical structures) and its
seen in controls was prevented in the treatment group.25 proper connections are in place and accompanied by a
Treated babies also had lower levels of lactate and pyruvate coordinating EEG rhythm (even if only intermittently con-
and fewer complications during the postnatal period. Ad- tinuous), what can we say about the beginning moments of
ministration of low-dose morphine by infusion reduced neu- a fetal consciousness? Again, it would seem that we may
rological sequelae in preterm infants requiring ventilatory have to conclude that consciousness is at least possible from
support to 4% compared with a rate of 24% in a placebo this point forward in fetal development. If a more stringent
group in one randomized controlled trial.26 A reduced cor- threshold for continuous EEG activity is required, then it
tisol response after fentanyl administration has been ob- would appear that by 30 weeks gestation, when patterns
served in premature ventilated neonates as young as 28 consistent with wakefulness and sleep may be discrimi-
weeks in neonatal intensive care units.19 nated, consciousness is, again, at least possible.
Thus, from these studies, one can conclude that the This brings us back to the question of the fetal experi-
human fetal hypothalamic–pituitary–adrenal axis is func- ence of “pain.” If we are to accept that consciousness is
tionally mature enough to produce a -endorphin response possible by 20 weeks (or, more conservatively, 30 weeks),
by 18 weeks and to produce cortisol and noradrenaline then it also would appear possible that fetuses could expe-
responses from 20 weeks gestation and that these may be
rience something approximating “pain.” Surely the complex
modulated by receptor agonism. Although this does not
behavioral responses seen in ventilated neonates have the
indicate that the fetus is aware of pain at these gestational
external appearance of “pain,” but as we yet have no metric
ages, the mechanisms for physiologic endocrine reactions to
with which to make such a determination, we cannot know
noxious stimuli are certainly in place.
this with any confidence. Again, it would appear we are
forced to assume that given the appropriate cytoarchitec-
Fetal circulatory redistribution
ture, etc., the fetus is capable of experiencing pain. In a
certain sense, whether the fetus actually experiences pain or
Adults respond to extreme cold, hypoxia, or significant
not is a moot point, as the possibility of such experience
hemorrhage by a sympathetically derived redistribution of
should be sufficient to inform fetal management in this
blood flow to maximize blood flow to the body’s more vital
regard. Does the 24-week fetus undergoing an in utero
organs (the brain, heart, and adrenal glands), at the expense
percutaneous aortic valvuloplasty experience pain? Should
of the peripheral circulation. These changes have been dem-
onstrated in the fetus in numerous animal studies, in re- that fetus be provided with appropriate perioperative anes-
sponse to reduced uterine blood flow, hypoxemia, and hem- thesia and analgesia? The mere possibility of consciousness
orrhage.27-30 Compared with the large amount of animal and an experience of pain (however rudimentary) would
literature examining acute cardiovascular redistribution, hu- appear to mandate such a provision of anesthesia and anal-
man studies are limited because they can only observe gesia.
fetuses undergoing clinically indicated procedures as acute Indeed, the fetal experience of pain may be even greater
stressors. Consequently, many of these fetuses studied will than that of the term neonate or young child, owing to the
be abnormal. However, human fetal intrauterine needling immaturity of systems of descending inhibition. Descending
studies that involve perturbation of the fetal trunk have inhibition is the process whereby ascending nociceptive
suggested that blood flow is redistributed to the fetal brain signals in the ascending spinal neurons are dampened via
as early as 16 weeks gestation.31 This was observed as a fall inhibitory descending serotonin neurons of the dorsal horn
in the middle cerebral artery pulsatility index of 10%, com- of the spinal cord.33 These inhibitory tracts develop only
bined with an increase in the pulsatility index in the femoral late in gestation and are still immature at birth. Indeed, in
artery of 22%.32 the rat, descending inhibition has been found to be func-
tionally ineffective until the 10th postnatal day.34 This
makes it possible that the third trimester fetus, far from
The possibility of fetal consciousness being incapable of the sensation of pain, actually perceives
pain as being more severe than in the adult.
Again, although such studies do not by themselves provide Further, when considering the effects of noxious stimuli
direct evidence of fetal consciousness, they do suggest that on the developing fetus and the rationale for fetal anesthesia

6. 194 Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 25, No 4, December 2006
and analgesia, we must consider not just the humanitarian our responsibility to consider and act upon such issues.
need to alleviate the possible distress of pain sensation from Rather, we are compelled to find the answers.
surgery or other interventions but also whether being sub-
jected to surgical stress during early development might
cause permanent alterations in physiology. This concept is References
known as programming, defined by Barker as “the process
whereby a stimulus or insult at a critical, sensitive period of 1. Penfield W, Jasper HH: Epilepsy and the Functional Anatomy of the
Human Brain. Boston, MA, Little, Brown & Co., 1954
development has permanent effects on structure, physiology 2. Mashour GA: Consciousness unbound: toward a paradigm of general
and metabolism.”35 There is now a vast literature document- anesthesia. Anesthesiology 100:428-433, 2004
ing this phenomenon in response to perinatal stress. Studies 3. Hameroff SR: The entwined mysteries of anesthesia and conscious-
in rats and non-human primates have shown permanent ness. Anesthesiology 105:400-412, 2006
4. Pack CC, Berezovskii VK, Born RT: Dynamic properties of neurons in
reductions in the numbers of hippocampal and hypotha- cortical area MT in alert and anesthetized macaque monkeys. Nature
lamic glucocorticoid receptors in the offspring of antena- 94:1058-1065, 2001
tally stressed animals. This attenuates the negative feedback 5. John ER, Prichep LS, Valdes-Sosa P, et al: Invariant reversible QEEG
response, resulting in increased basal and stress-induced effects of anesthetics. Conscious Cogn 10:165-183, 2001
6. John ER: The neurophysics of consciousness. Brain Res Rev 39:1-28,
cortisol or corticosterone levels in the offspring, which can 2002
last into adulthood. Behavioral changes, such as poor cop- 7. Okado N, Kakimi S, Kojima T: Synaptogenesis in the cervical cord of
ing behaviors, have also been observed.8 the human embryo: sequence of synapse formation in a spinal reflex
Data in humans are comparatively sparse. Taddio and pathway. J Comp Neurol 184:491-518, 1979
8. Myers LB, Bulich LA: Anesthesia for Fetal Intervention and Surgery.
colleagues demonstrated that boys circumcised in the first 4
Hamilton, BC Decker, Inc., 2005
to 5 days of the neonatal period had higher behavioral 9. Rabinowicz T, de Courten-Myers GM, Petetot JM, et al: Human cortex
scores and cried longer in response to their vaccination development: estimates of neuronal numbers indicate major loss late
injection at 4 to 6 months of age than boys who were not during gestation. J Neuropathol Exp Neurol 55:320-328, 1996
10. Smith S: Commission of Inquiry into Fetal Sentience. London, CARE,
circumcised. This response was partially attenuated with the
1996
use of local anesthetic cream at the time of circumci- 11. Anand KJS: A scientific appraisal of fetal pain and conscious sensory
sion.36-38 Notably, other investigators have found that there perception. Written testimony offered to the Constitution Subcommit-
is an increased cortisol response to vaccination at 4 and 6 tee of the U.S. House of Representatives, U.S. House Committee on
the Judiciary, 109th United States Congress on October 1, 2005.
months in infants stressed at delivery.39
Available at: http://judiciary.house.gov/media/pdfs/anand110105.pdf.
Jacobson and Bygdeman suggested that the long-term Last accessed August 31, 2006
effects of birth stress might last well into adulthood. Albeit 12. Royal College of Obstetricians and Gynecologists: Fetal Awareness:
in a retrospective study, they found the risk of suicide by Report of a Working Party. London, RCOG Press, 1997
13. Kostovic I, Rakic P: Developmental history of the transient subplate
violent means to be more than fourfold higher in those men
zone in the visual and somatosensory cortex of the macaque monkey
who had had a traumatic birth. However, if opiate analgesia and human brain. J Comp Neurol 297:441-470, 1990
had been administered at birth, minimizing discomfort to 14. Holzman RS, Hickey PR: The development of pain perception and the
both mother and baby, this reduced the relative risk mark- stress response, in Bailin MT (ed): Pediatric Anesthesia (chapter 2,
edly.40 Conversely, other studies have found links between section 8), in Harvard Electronic Anesthesia Library. New York, NY,
Lippincott Williams and Wilkins, 2001
the use of maternal opiate analgesia in labor and opiate 15. Clancy R: Electroencephalography in the premature and fullterm in-
addiction of the offspring in later life.41 These studies raise fant, in Poilin RA, Fox WW (eds): Fetal and Neonatal Physiology
the possibility of long-term sequelae from obstetric inter- (ed 2). Philadelphia, PA, WB Saunders, 1998, pp 2147-2165
ventions, including drugs administered during pregnancy 16. International Association for the Study of Pain. IASP pain terminol-
ogy: a sample list of frequently used terms, in Merskey H, Bogduk
and labor. Paradoxically, it appears that while measures (eds): Classification of Chronic Pain (ed 2). Seattle, WA, IASP Press,
employed to limit antenatal and peripartum nociceptive in- 1994, pp 209-214 (Also available at: http://www.iasp-pain.org/terms-
puts have the capacity to alter conscious function in later p.html)
life (insofar as they limit suicidal thinking and behavior), 17. Lee SJ, Ralston HJP, Drey EA, et al: Fetal pain: a systematic review
of the evidence. JAMA 294:947-954, 2005
these same analgesic measures applied to counteract such 18. Hepper P, Shahidullah S: The beginnings of mind: evidence from the
nociceptive programming effects can significantly alter behaviour of the fetus. J Reprod Infant Psychol 12:143-154, 1994
an individual’s neurochemistry and produce their own 19. Guinsburg R, Kopelman BI, Anand KJ, et al: Physiological, hormonal,
derogatory effects upon consciousness. Robust studies and behavioral responses to a single fentanyl dose in intubated and
ventilated preterm neonates. J Pediatr 132:954-959, 1998
are now needed to determine possible long-term effects 20. Blass EM, Hoffmeyer LB: Sucrose as an analgesic for newborn in-
of both. fants. Pediatrics 87:215-218, 1991
It would appear, then, that the question of what to do 21. Kehoe P, Blass EM: Behaviorally functional opioid systems in infant
about the possibility of fetal consciousness and pain is just rats. II. Evidence for pharmacological, physiological, and psycholog-
ical mediation of pain and stress. Behav Neurosci 100:624-630, 1986
as murky and confusing as the possibility of fetal conscious- 22. Giannakoulopoulos X, Sepulveda W, Kourtis P, et al: Fetal plasma
ness and pain itself. It is important to note, however, that cortisol and beta-endorphin response to intrauterine needling. Lancet
even in the face of this uncertainty we are not discharged of 344:77-81, 1994

7. Brusseau and Myers Fetal Anesthesia and Analgesia 195
23. Gitau R, Fisk NM, Teixeira JM, et al: Fetal hypothalamic-pituitary- 32. Smith RP, Glover V, Fisk NM: Acute increase in femoral resistance in
adrenal stress responses to invasive procedures are independent of response to direct physical stimuli in the human fetus. Br J Obstet
maternal responses. J Clin Endocrinol Metab 86:104-109, 2001 Gynaecol 110:916-921, 2003
24. Fisk NM, Gitau R, Teixeira JM, et al: Effect of direct fetal opioid 33. Fitzgerald M: Development of pain pathways and mechanisms, in
analgesia on fetal hormonal and hemodynamic stress response to Anand KJS (ed): Pain Research and Clinical Management. Amster-
intrauterine needling. Anesthesiology 95:828-835, 2001 dam, Elsevier, 1993, pp 19-38
25. Anand KJ, Sippell WG, Aynsley-Green A: Randomised trial of fent- 34. Fitzgerald M, Koltzenburg M: The functional development of de-
anyl anaesthesia in preterm babies undergoing surgery: effects on the scending inhibitory pathways in the dorsolateral funiculus of the new-
stress response. Lancet 1:62-66, 1987 born rat spinal cord. Brain Res 389:261-270, 1986
26. Anand KJ, Barton BA, McIntosh N, et al: Analgesia and sedation in 35. Barker DJ: In utero programming of cardiovascular disease. Therio-
preterm neonates who require ventilatory support: results from the genology 53:555-574, 2000
NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neo-
36. Taddio A, Katz J, Ilersich AL, et al: Effect of neonatal circumcision on
nates. Arch Pediatr Adolesc Med 153:331-338, 1999
pain response during subsequent routine vaccination. Lancet 349:599-
27. Jensen A, Roman C, Rudolph AM: Effects of reducing uterine blood
603, 1997
flow on fetal blood flow distribution and oxygen delivery. J Dev
37. Taddio A, Goldbach M, Ipp M, et al: Effect of neonatal circumcision
Physiol 15:309-323, 1991
on pain responses during vaccination in boys. Lancet 345:291-292,
28. Gleason CA, Hamm C, Jones MD Jr: Effect of acute hypoxemia on
brain blood flow and oxygen metabolism in immature fetal sheep. 1995
Am J Physiol 258:H1064-H1069, 1990 38. Taddio A, Stevens B, Craig K, et al: Efficacy and safety of lidocaine-
29. Llanos AJ, Riquelme RA, Moraga FA, et al: Cardiovascular responses prilocaine cream for pain during circumcision. N Engl J Med 336:
to graded degrees of hypoxaemia in the llama fetus. Reprod Fertil Dev 1197-1201, 1997
7:549-552, 1995 39. Ramsay DS, Lewis M: The effects of birth condition on infants’
30. Meyers RL, Paulick RP, Rudolph CD, et al: Cardiovascular responses cortisol response to stress. Pediatrics 95:546-549, 1995
to acute, severe haemorrhage in fetal sheep. J Dev Physiol 15:189-197, 40. Jacobson B, Bygdeman M: Obstetric care and proneness of offspring
1991 to suicide as adults: case-control study. BMJ 317:1346-1349, 1998
31. Teixeira JM, Glover V, Fisk NM: Acute cerebral redistribution in 41. Jacobson B, Nyberg K, Gronbladh L, et al: Opiate addiction in adult
response to invasive procedures in the human fetus. Am J Obstet offspring through possible imprinting after obstetric treatment. BMJ
Gynecol 181:1018-1025, 1999 301:1067-1070, 1990