Vanhatalo & niewenhuizen on fetal pain

1. Brain & Development 22 (2000) 145±150
www.elsevier.com/locate/braindev
Review article
Fetal pain?
Sampsa Vanhatalo a, b,*, Onno van Nieuwenhuizen c
a
Department of Anatomy, Institute of Biomedicine, University of Helsinki, P.O. Box 9, 00014, Helsinki, Finland
b
Unit of Child Neurology, Hospital for the Children and Adolescent, University of Helsinki, Helsinki, Finland
c
Wilhelmina Children's Hospital, University of Utrecht, Utrecht, The Netherlands
Received 20 May 1999; received in revised form 13 December 1999; accepted 15 December 1999
Abstract
During the last few years a vivid debate, both scienti®cally and emotionally, has risen in the medical literature as to whether a fetus is able
to feel pain during abortion or intrauterine surgery. This debate has mainly been inspired by the demonstration of various hormonal or motor
reactions to noxious stimuli at very early stages of fetal development. The aims of this paper are to review the literature on development of the
pain system in the fetus, and to speculate about the relationship between ``sensing'' as opposed to ``feeling'' pain and the number of reactions
associated with painful stimuli. While a cortical processing of pain theoretically becomes possible after development of the thalamo-cortical
connections in the 26th week of gestation, noxious stimuli may trigger complex re¯ex reactions much earlier. However, more important than
possible painfulness is the fact that the noxious stimuli, by triggering stress responses, most likely affect the development of an individual at
very early stages. Hence, it is not reasonable to speculate on the possible emotional experiences of pain in fetuses or premature babies. A
clinically relevant aim is rather to avoid and/or treat any possibly noxious stimuli, and thereby prevent their potential adverse effects on the
subsequent development. q 2000 Elsevier Science B.V. All rights reserved.
Keywords: Abortion; Fetus; Fetal pain; Intrauterine surgery
1. Introduction nent dangers. Thus, pain consists of two components: (i)
sensation of the stimulus (nociception), and (ii) emotional
During the past decade, increasing attention has been paid reaction, which is the unpleasant feeling due to a noxious
to pain perception and its treatment in the neonatal period. stimulus. These two components occur in the brain in two,
This has led to a wide debate as to whether pain sensation is both anatomically and physiologically distinct systems
possible during fetal life. Pain sensation in the fetus is a [5,6].
serious and dif®cult issue in public debate [1], especially Sensing pain requires a developed neural pain system,
in relation to late abortion [2,3], but also because of the which includes the peripheral pain receptors, the afferent
rapidly increasing number of intrauterine operations. This neural pathway to the spinal cord, the ascending tract to
review will focus on current opinion concerning the devel- the thalamus, and from the thalamus to the cerebral cortex
opment of the pain system, on the possibility of a fetus (Fig. 1). Pain impulses are also processed in a number of
feeling pain, and on the probable impact of noxious experi- other, subcortical structures, e.g. hypothalamo-pituitary
ences on subsequent development of the individual. system, amygdala, basal ganglia [7], and the brain stem
[5,6]. These brain areas account for the subconscious feeling
of painfullness and for the number of pain-triggered auto-
2. Pain as a sensation and its measurement nomic and hormonal re¯exes. These components of pain
processing do not require cortical level activity, and they
The International Association for the Study of Pain has may thus be considered to occur subconsciously.
de®ned pain as `an unpleasant sensory and emotional Being purely subjective, pain is a dif®cult parameter to
experience associated with actual or potential tissue measure [8]. While measurements of pain with cooperative
damage', with an emphasis on previous injury-related subjects are based on subjective scales of pain intensity,
experiences [4]. This implies that the biological function these methods are not applicable to neonates or premature
of pain is to help the organism recognize and avoid immi- babies. Therefore, a number of indirect methods have been
developed to assess clinically their possible painfulness [9±
* Corresponding author. Fax: 1358-9-1918499.
11]. These methods are based on changes in either behavior
E-mail address: svanhata@helsinki.® (S. Vanhatalo)
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
PII: S 0387-760 4(00)00089-9

2. 146 S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150
age: somatosensory functions of pain, pain-induced physio-
logical (autonomic and endocrinological) re¯exes and pain
behavior. In the following, the development of these aspects
in the fetus will be reviewed brie¯y.
3.1. Development of the somatosensory pain system
The neuroanatomical pathways (Fig. 1) for tactile (e.g.
touch and pain) sensation are amongst the ®rst functional
entities to develop within a long time frame (Table 1). This
suggests that already early in life pain is an important signal
[13]. First nociceptors appear around the mouth as early as
the seventh gestational week; by the 20th week these are
present all over the body. It is only after this that peripheral
afferent nerves make synapses to the spinal cord, during
weeks 10±30 [6], followed by myelination of these path-
ways [14]. A functional spinal re¯ex circuitry develops
almost simultaneously with the ingrowth of the peripheral
afferents towards the spinal cord [6,13].
Far less is known about the development of the higher
parts of pain pathways, spinothalamic and thalamo-cortical
pathways. Spinothalamic connections are established in the
20th gestational week, and their myelinization is completed
by 29 weeks of gestational age [5]. The thalamo-cortical
connections in humans begin to grow into the cortex at
24±26 weeks of gestation, meaning that pain impulses
Table 1
Literature on the anatomical and functional development of the different
parts of the pain system a
Part of the Detail Timing
system (weeks)
Nociceptors Nociceptors appear (start around the 7±20
mouth and later over the entire body)
Peripheral Synapses appear to the spinal cord 10±30
afferents
Fig. 1. The neuronal pathways participating in pain: (1) peripheral afferent
nerve transmits the signal to (2) the ascending tract neuron in the spinal
Spinal cord Stimulation results in motor 7.5
cord dorsal horn, which synapses with (3) the next neuron in the thalamus.
movements
Here the pain impulse is distributed to two systems, which bring the signal
Spinothalamic connections 20
to (4) the somatosensory cortex (pain perception), and (5) the limbic cortex
established
(affective component). Thus a pain message has to reach the cerebral cortex
Pain pathways myelinize 22
to become `a pain'. In addition, there are (6) a number of descending
Descending tracts develop Postnatally
neuronal pathways to the dorsal horn of the spinal cord, which modulate
the ascending pain impulses.
Thalamocortical First axons appear to the cortical plate 20±22
tracts
(e.g. quality of cry or motor movement patterns) or auto- Functional synapse formation of the 26±34
nomic parameters (e.g. pulse rate or blood pressure). They thalamo-cortical connections
are still being developed; none is yet suitable for assessing
Cerebral cortex Cortical neurons migrate (cortex 8±20
pain in fetuses. Also the question remains: do present pain develops)
treatments only suppress the responses to pain rather than First EEG bursts may be detected 20
suppressing the pain itself [12]? Symmetric and synchronic EEG 26
activity appears
Sleep and wakefulness patterns in the 30
EEG become distinguishable
3. Development of the pain systems in the fetus Evoked potentials become detectable 29
a
Pain may be viewed at three different levels, regardless of See Refs. [5,6,13±15,17,42].

3. S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150 147
may reach the cerebral cortex for the ®rst time during week compared to the mature system) make it apparently incap-
26 [13,15]. However, it is not before week 29 that evoked able of precisely localizing or distinguishing a painful
potentials can be measured from the cortex, suggesting that stimulus from other stimuli. Therefore, various kinds of
a functionally meaningful pathway from the periphery to the stimuli may induce very holistic and unspeci®c reactions,
cerebral cortex starts to operate from that time onwards. The which in later development become more restricted and
human development of the pain pathways subserving affec- functionally meaningful (see below).
tive components, i.e. thalamo-limbic connections, is poorly
understood. The thalamo-hippocampal connections prob- 3.2. Behavioral pain reactions during the fetal period
ably develop simultaneously with the other thalamo-cortical
A painful stimulus induces motor movements like with-
pathways [16]. However, signaling pathways from the
drawal re¯exes, body movements or even vocalizations,
periphery to the deeper brain areas are more likely estab-
which are often regarded as an indication of pain in the
lished along with the growth of the spino-thalamic tracts at
neonate [10,11,20,21]. First motor re¯exes, head tilting
20 weeks of age, allowing for subcortical processing of pain
after perioral touch, appear at 7.5 weeks of gestation.
at much earlier ages.
Hands become touch sensitive at 10.5 weeks, and at 14
Neurons of the cerebral cortex begin their migration from
weeks of age the lower limbs also begin to participate in
the periventricular zone at eight weeks of gestation, by 20
re¯ex movements [15,22,23]. It is important to note,
weeks the cortex has acquired its full complement of
however, that these reactions are completely re¯exive,
neurons, and glial proliferation is active throughout child-
guided by the spinal cord, and it is, therefore, irrelevant to
hood [13,17,18]. Organization of the cortical networks
speculate about sensing or higher perception of pain at this
occurs simultaneously with neuronal migration: synapse
stage [24].
formation begins during the 12th week, and peaks during
Due to the immaturity of the pain-modulating systems,
the last trimester [17,19], as dendritic arborization and
re¯ex threshold is remarkably low and re¯exes are large,
axonal elongation proceed. Thalamo-cortical projections
e.g. pinching a toe results in a whole body movement [6,15].
wait just beneath the cortex (subplate) until the rough orga-
Also, there is no obvious correlation between the intensity
nization of the cortex is completed to allow their ingrowth
of the noxa and the strength of the re¯ex associated with it.
[16]. Electroencephalographic activity, which, to some
Therefore the strong, noxa-elicited re¯exes are more a
extent, re¯ects the integrity of the cortex and thalamo-corti-
re¯ection of the immaturity of the modulatory systems
cal circuitries, appears for the ®rst time at 20 weeks, but
than a reliable indicator of painfulness.
becomes synchronic at 26 weeks, and reveals sleep-wake
Unlike other motor re¯exes facial expressions may speci-
cycles only at week 30 [5,13]. Unlike the other senses pain
®cally re¯ect the emotions of pain [10,11]. This idea has
is essentially a multimodal experience, and thus also
been supported by the observations that premature babies
requires a concerted action of multiple cortical areas.
born as early as the 26th week of gestation may possess
Such a `mature' processing of pain will, in turn, only be
facial expressions that are speci®c for pain. The facial
possible long after birth.
expressions may even allow for objective analysis of sub-
Maturation of the pain-modulating, descending pathways
components, which appear to be similar to those found in
in the spinal cord, are crucial for a proper pain reaction.
adults during a period of pain [10,21]. A detailed analysis by
These develop very late, and animal experiments on rats
Humphrey [22] of the re¯exes triggered by trigeminal nerve
have shown that they are functional only in the second
stimulation showed that a rich variety of facial re¯exes to
postnatal week. Such a late functional maturation is prob-
various somatic stimuli may be observed at very early stages
ably due to a late development of both descending noradre-
of development, suggesting an early development of these
nergic and serotonergic pathways and spinal cord dorsal
motor circuits. Such motor movements are most likely coor-
horn interneurons [15]. The strong re¯exes to pain stimuli
dinated by subcortical systems, tentatively called an
seen in fetuses and neonates are probably due to this imma-
emotional motor system (for review, see Holstege [25]),
turity of the modulatory systems, implying that there is less
and thus probably re¯ect the development of these lower
control of the entry of the peripheral stimuli into the central
brain circuitries.
nervous system [15].
As to the fetal physiology of pain, it is notable that the 3.3. Development of the autonomic and endocrine re¯exes
®rst functional and anatomical pathways may substantially
differ from their mature counterparts [15,20]. For example, Fetal pain has been repeatedly studied by demonstrating
afferent nerves from the touch-sensing receptor in the skin the autonomic or neuroendocrinological reactions to
of a fetus make synapses with the spinal cord ascending noxious stimuli [9,20]. Interpretation of these re¯exes is,
neurons that are specialized for pain impulses in the mature however, complicated because they are relatively unspeci®c
system [15]. In addition, the skin area innervated by a single indicators of subjective painfulness, even in adult patients.
pain-transmitting neuron (receptive ®eld) is much larger Giannokoulopoulos et al. [26] demonstrated in 23-week-old
during development than in the mature system. These fetuses that pricking the innervated hepatic vein with a
fundamental differences in the fetal nervous system (as needle resulted in an elevation of the cortisol and b-endor-

4. 148 S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150
phin levels in the plasma, while stimulation of the uninner- of the brain circuitries relies predominantly on guidance
vated placental cord had no effect. This study gave rise to from external input, which makes the brain sensitive to
widespread speculation that this would indicate painfulness strong experiences, especially during early maturation.
already at 23 weeks of age, regardless of the absence of the Although the causal links between the external stimuli and
thalamocortical connections. These ®ndings do rather indi- different developmental features are virtually impossible to
cate that the stimulation was able to activate the hypotha- prove unambiguously in humans, a number of indirect
lamo-hypophysial axis, thereby bringing about a hormonal studies have provided evidence for correlations of the
re¯ex to the noxa. The same group later showed that inva- early pain experiences to later behavioral variables or to
sive procedures may alter the brain blood ¯ow at the 18th later developmental outcomes (for review, see Anand [20]).
week [27], supporting an idea that painful stimuli may trig- The most important common denominator of the devel-
ger large scale responses in the central nervous system with- opmental pain effects is probably the robust and long-lasting
out reaching the cortex. stress response, which has been associated with increased
While noxious stimuli are associated with remarkable mortality at later stage [20,29,35]. Neurodevelopmentally,
changes in autonomically regulated parameters (e.g. respira- the most important stress responses are probably the marked
tion or pulse frequency), there appears to be no reliable ¯uctuations in blood pressure and cerebral blood ¯ow, and
correlation between the changes in these parameters and the hypoxaemia [20,36], which may even predispose to or
the intensity of the noxa [10,28]. Therefore, a reliable esti- accentuate an intracerebral hemorrhage [20]. These changes
mation of painfulness from these parameters is as yet not in oxygenation or circulation may be prevented by adequate
feasible. pain treatment [20,36]. A study on human subjects demon-
Nevertheless, it is interesting to note that the hormonal, strated increased salivatory cortisol responses 6 months
autonomic and metabolic re¯exes are suppressed by analge- after stressful birth conditions [37], and a number of animal
sics: fentanyl suppressed the hormonal and autonomic reac- experiments have provided evidence for permanent changes
tions to surgical operations at 28 weeks of gestation [28,29], in endocrine and/or immune systems or brain hormone
while the adrenal levels were lowered by morphine at a receptor expression patterns after pain or other stressful
gestational age of 27±31 weeks in prematurely born children stimuli (for review see Anand [20]).
in an intensive care unit [30]. Although the mechanisms of Infants treated in neonatal intensive care units (ICU) for 4
these effects are not well understood, these studies provide weeks manifested decreased behavioral and increased cardi-
evidence that the stress reactions experienced by the fetuses ovascular responses to the pain of heel prick, and these
or the premature babies may be substantially alleviated by alterations correlated with the number of invasive proce-
appropriate medication. dures experienced since birth [38]. Furthermore,
unanaesthetized circumcision is associated with long-term
alterations in pain-related behavioral response at 4 and 6
4. Impact of pain experiences on later development months of age [20,39]. In older children an objectively
measurable change in their pain-related behavior, even 4
Knowledge of the development of pain pathways months post-operatively, was shown to depend on the type
provides us with a theoretical time constraint for the devel- of pain treatment during surgical procedures [40]. Long
opment of sensing a noxious stimulus. However, processing term follow-up studies on children exposed to neonatal
of pain occurs in the brain stem and also in the hypotha- pain/stress have repeatedly shown correlations between
lamo-limbic systems [5,31]. Thus activation of the somato- the stay in the ICU and the later neuropsychological
sensory cortex is probably not required for a noxa to complex of altered pain thresholds and/or abnormal pain-
in¯uence an individual's development. Indeed, pain induces related behaviors [20,41].
redistribution (reduction) of brain blood ¯ow as early as the All these data suggest that a repetitive, or sometimes even
18th week of gestation [27], and preterm babies show habi- strong acute pain experience is associated with long-term
tuation to external stimuli already before thalamo-cortical changes in a large number of pain-related physiological
connections, during the 25th week of gestation [32]. Experi- functions, and pain or its concomitant stress increase the
ments on rat pups and human preterm babies have shown incidence of later complications in neurological and/or
that noxious stimulation may result in permanent spinal cord psychological development. Of utmost clinical importance
level sensitization to pain stimuli [15,33], and this can be are the ®ndings that adequate pain treatment may prevent
reversed by topical anaesthesia [34]. All these ®ndings these later sequelae [15,20,29,36].
imply that effective and meaningful, subcortical pain
processing occurs in fetuses several weeks before the
noxious stimuli reach the cortex. 5. Conclusions
Development and subsequent organization of the nervous
system occurs by a primary overproduction of neurons and A fetus reacts to painful stimuli by various motor, auto-
connections, followed by a rivalry and a survival of the nomic, hormonal and metabolic changes at relatively early
functional parts of the circuitry only [17]. Final organization stages of gestation. Due to the immaturity of the modulatory

5. S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150 149
systems, the ®rst reactions are purely re¯exive and they are genesis, ®bre connection, synaptogenesis and myelination in the
often unrelated to the type of stimulus. While the fetal spinal cord. In: Prechtl HFR, editor. Continuity of neural functions
from prenatal to postnatal life. Philadelphia, PA: Lippincott, 1984. pp.
nervous system is capable of mounting such protective 31±45.
re¯exes against potentially harmful noxa, there is no [15] Fitzgerald M. Foetal pain: an update of current scienti®c knowledge,
evidence to support a feeling of pain at the earliest stages. London: Department of Health, 1995.
Cortical processes, and hence, theoretically, the ®rst sensory [16] Â
Super H, Soriano E, Uylings HBM. The functions of the preplate in
experiences, only become possible when the thalamocorti- development and evolution of the neocortex and hippocampus. Brain
Res Rev 1998;27:40±64.
cal connections grow during the 26th week of gestation. [17] Volpe JJ. Neuronal proliferation, migration, organization and myeli-
It is important to note that, especially in fetuses, noxious nation. In: Neurology of the newborn. Philadelphia, PA: Saunders,
stimuli may have adverse effects on the developing indivi- 1995. pp. 43±90.
dual regardless of the quality or the level of processing in [18] Kuljis RO. Development of the human brain: the emergence of the
the brain. In addition to the cerebral cortex, pain also acti- neural substrate for pain perception and conscious experience. In:
Beller FK, Weir RF, editors. The beginning of human life. Dortrecht,
vates a number of subcortical mechanisms and a large scale The Netherlands: Kluwer Academic, 1994. pp. 49±56.
of physiological stress responses, which thus implies that [19] Sarnat HB, Born DE. Synaptophysin immunocytochemistry with
the growth of the thalamo-cortical connections and subse- thermal intensi®cation: a marker of terminal axonal maturation in
quent cortical activation is not required for the developmen- the human fetal nervous system. Brain Dev 1999;21:41±50.
tal in¯uences of pain. Hence, after the development of the [20] Anand KJS. Clinical importance of pain and stress in preterm
neonates. Biol.Neonate 1998;73:1±9.
spinal cord afferents around the gestational week 10, there [21] Hadjistavropoulos HD, Craig KD, Grunau RE, Whit®eld MF. Judging
may be no age limit at which one can be sure noxae are pain in infants: behavioural, contextual, and developmental determi-
harmless. The clinically relevant question would be: which nants. Pain 1997;73:319±324.
sensory experiences are potentially harmful for the devel- [22] Humphrey T. Some correlations between the appearance of human
opment of a fetus? While our understanding of the relations fetal re¯exes and the development of the nervous system. Prog Brain
Res 1964;4:93±135.
between the noxae and their developmental effects is still [23] de Vries JIP, Visser GHA, Prechtl HFR. Fetal motility in the ®rst half
poor, the clinical studies have suggested that the pain- of pregnancy. In: Prechtl HFR, editor. Continuity of neural functions
induced behavioral alterations may be prevented by from prenatal to postnatal life. Philadelphia, PA: Lippincott, 1984. pp.
adequate pain treatment. There are strong indications that 46±64.
one should take all reasonable measures to treat potentially [24] Lloyd-Thomas AR, Fitzgerald M. Do fetuses feel pain? Re¯ex
responses do not necessarily signify pain. Br Med J 1996;313:797±
noxious situations, regardless of age. 798.
[25] Holstege G. Descending motor pathways and the spinal motor system:
limbic and non-limbic components. Prog Brain Res 1991;87:307±
References 421.
[26] Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM.
[1] Concar D. Into the mind unborn. New Sci 1996;19:40±45. Fetal plasma cortison and b-endorphin response to intrauterine need-
[2] Savage W. Do fetuses feel pain? Surgical terminations of pregnancy ling. Lancet 1994;344:77±81.
take place under general anaesthesia. Br Med J 1997;314:1201. [27] Teixeira J, Fogliani R, Giannakoulopoulos X, Glover V, Fisk NM.
[3] McCullagh P. Do fetuses feel pain? Can fetal suffering be excluded Fetal haemodynamic stress response to invasive procedures. Lancet
beyond reasonable doubt? Br Med J 1997;314:302±303. 1996;347:624.
[4] Merskey H, Albe-Fessard DG, Bonica JJ. Pain terms: a list with [28] Anand KJS, Sippell WG, Aynsley-Green A. Randomised trial of
de®nitions and notes on usage: recommended by the IASP Subcom- fentanyl anaesthesia in preterm babies undergoing surgery: effects
mittee on Taxonomy. Pain 1979;6:249±252. on the stress response. Lancet 1987;1:62±66.
[5] Anand KJS, Phil D, Carr DB. The neuroanatomy, neurophysiology, [29] Guinsburg R, Kopelman BI, Anand KJS, de Almeida MF, Peres C,
and neurochemistry of pain, stress, and analgesia in newborns and deA. Miyoshi MH. Physiological, hormonal, and behavioural
children. Ped Clin North Am 1989;36:795±822. responses to a single fentanyl dose in intubated and ventilated preterm
[6] Fitzgerald M. Development of pain mechanisms. Br Med Bull neonates. J Pediatr 1998;132:954±959.
1991;47:667±675. [30] Quinn MW, Wild J, Dean HG, Hartley R, Rushforth JA, Puntis JW, et al.
[7] Wollert HG, Eckel L. Cerebral near-infrared spectroscopy in children Randomised double blind controlled trial of effect of morphine on cate-
undergoing heart surgery. Ann Neurol 1996;40:818±819. cholamine concetrations in ventilated babies. Lancet 1993;342:324±
[8] Larsson BA. The measurement of paediatric pain. Acta Paediatr 327.
1999;88:115±117. [31] Chudler EH, Dong WK. The role of the basal ganglia in nociception
[9] Porter F. Pain in the newborn. Clin Perinatol 1989;16:549±564. and pain. Pain 1995;60:3±38.
[10] Craig KD, Whit®eld MF, Grunau RV, Linton J, Hadjistavropoulos [32] Leader LR, Baillie P, Martin B, Molteno C, Wynchank S. Fetal
HD. Pain in the preterm neonate: behavioural and physiological responses to vibrotactile stimulation: a possible predictor of fetal
indices. Pain 1993;52:287±299. and neonatal outcome. Aust NZ J Obstet Gynaecol 1984;24:251±
[11] Johnston CC, Stevens B, Craig KD, Grunau RVE. Developmental 256.
changes in pain expression in premature, full-term, two- and four- [33] Andrews K, Fitzgerald M. The cutaneous withdrawal re¯ex in human
month-old infants. Pain 1993;52:201±208. neonates sensitization, receptive ®elds, and the effects of contralateral
[12] Lindahl S. Calming minds or killing pain in newborn infants? Acta stimulation. Pain 1994;56:95±101.
Paediatr 1997;86:787±788. [34] Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity
[13] Anand KJS, Hickey PR. Pain and its effects in the human neonate and following peripheral tissue damage in newborn infants and its reversal
fetus. N Engl J Med 1987;317:1321±1329. with topical anaesthesia. Pain 1989;39:31±36.
[14] Okado N, Kojima T. Ontogeny of the central nervous system: neuro- [35] Anand KJS, Phil D, Hansen DD, Hickey PR. Hormonal-metabolic

6. 150 S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150
stress responses in neonates undergoing cardiac surgery. Anesthesiol- [40] Kotiniemi LH, Ryhanen PT, Moilanen IK. Behavioural changes in
ogy 1990;73:661±670. children following day-case surgery: a 4-week follow-up of 551 chil-
[36] Pokela ML. Pain relief can reduce hypoxemia in distressed neonates dren. Anaesthesia 1997;52:970±976.
during routine treatment procedures. Pediatrics 1994;93:379±383. [41] Grunau RVE, Whit®eld MF, Petrie JH, Fryer EL. Early pain experi-
[37] Ramsay DS, Lewis M. The effects of birth condition on infants' ence, child and family factors, as precursors of somatization: a
cortisol response to stress. Pediatrics 1995;95:546±549. prospective study of extremely premature and fullterm children.
[38] Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit Pain 1994;56:353±359.
affects pain response. Pediatrics 1996;98:925±930. [42] Minkowski A, Larroche JC, Vignaud J, Dreyfus-Brisac C, Dargassies
[39] Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumci- SSA. Development of the nervous system in early life. In: Falkner F,
sion on pain response during subsequent routine vaccination. Lancet editor. Human development. London: W.B. Saunders, 1966. pp. 254±
1997;349:599±603. 276.