Review article

Fetal pain?

Sampsa Vanhataloa, b,*, Onno van Nieuwenhuizenc

aDepartment of Anatomy, Institute of Biomedicine, University of Helsinki, P.O. Box 9, 00014, Helsinki, FinlandbUnit of Child Neurology, Hospital for the Children and Adolescent, University of Helsinki, Helsinki, Finland

cWilhelmina 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

During the past decade, increasing attention has been paid

to pain perception and its treatment in the neonatal period.

This has led to a wide debate as to whether pain sensation is

possible during fetal life. Pain sensation in the fetus is a

serious and dif®cult issue in public debate [1], especially

in relation to late abortion [2,3], but also because of the

rapidly increasing number of intrauterine operations. This

review will focus on current opinion concerning the devel-

opment of the pain system, on the possibility of a fetus

feeling pain, and on the probable impact of noxious experi-

ences on subsequent development of the individual.

2. Pain as a sensation and its measurement

The International Association for the Study of Pain has

de®ned pain as `an unpleasant sensory and emotional

experience associated with actual or potential tissue

damage', with an emphasis on previous injury-related

experiences [4]. This implies that the biological function

of pain is to help the organism recognize and avoid immi-

nent dangers. Thus, pain consists of two components: (i)

sensation of the stimulus (nociception), and (ii) emotional

reaction, which is the unpleasant feeling due to a noxious

stimulus. These two components occur in the brain in two,

both anatomically and physiologically distinct systems

[5,6].

Sensing pain requires a developed neural pain system,

which includes the peripheral pain receptors, the afferent

neural pathway to the spinal cord, the ascending tract to

the thalamus, and from the thalamus to the cerebral cortex

(Fig. 1). Pain impulses are also processed in a number of

other, subcortical structures, e.g. hypothalamo-pituitary

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-

nomic and hormonal re¯exes. These components of pain

processing do not require cortical level activity, and they

may thus be considered to occur subconsciously.

Being purely subjective, pain is a dif®cult parameter to

measure [8]. While measurements of pain with cooperative

subjects are based on subjective scales of pain intensity,

these methods are not applicable to neonates or premature

babies. Therefore, a number of indirect methods have been

developed to assess clinically their possible painfulness [9±

11]. These methods are based on changes in either behavior

Brain & Development 22 (2000) 145±150

0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.

PII: S0387-7604(00)00089-9

www.elsevier.com/locate/braindev

* Corresponding author. Fax: 1358-9-1918499.

E-mail address: svanhata@helsinki.® (S. Vanhatalo)

(e.g. quality of cry or motor movement patterns) or auto-

nomic parameters (e.g. pulse rate or blood pressure). They

are still being developed; none is yet suitable for assessing

pain in fetuses. Also the question remains: do present pain

treatments only suppress the responses to pain rather than

suppressing the pain itself [12]?

3. Development of the pain systems in the fetus

Pain may be viewed at three different levels, regardless of

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

S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150146

Fig. 1. The neuronal pathways participating in pain: (1) peripheral afferent

nerve transmits the signal to (2) the ascending tract neuron in the spinal

cord dorsal horn, which synapses with (3) the next neuron in the thalamus.

Here the pain impulse is distributed to two systems, which bring the signal

to (4) the somatosensory cortex (pain perception), and (5) the limbic cortex

(affective component). Thus a pain message has to reach the cerebral cortex

to become `a pain'. In addition, there are (6) a number of descending

neuronal pathways to the dorsal horn of the spinal cord, which modulate

the ascending pain impulses.

Table 1

Literature on the anatomical and functional development of the different

parts of the pain systema

Part of the

system

Detail Timing

(weeks)

Nociceptors Nociceptors appear (start around the

mouth and later over the entire body)

7±20

Peripheral

afferents

Synapses appear to the spinal cord 10±30

Spinal cord Stimulation results in motor

movements

7.5

Spinothalamic connections

established

20

Pain pathways myelinize 22

Descending tracts develop Postnatally

Thalamocortical

tracts

First axons appear to the cortical plate 20±22

Functional synapse formation of the

thalamo-cortical connections

26±34

Cerebral cortex Cortical neurons migrate (cortex

develops)

8±20

First EEG bursts may be detected 20

Symmetric and synchronic EEG

activity appears

26

Sleep and wakefulness patterns in the

EEG become distinguishable

30

Evoked potentials become detectable 29

a See Refs. [5,6,13±15,17,42].

may reach the cerebral cortex for the ®rst time during week

26 [13,15]. However, it is not before week 29 that evoked

potentials can be measured from the cortex, suggesting that

a functionally meaningful pathway from the periphery to the

cerebral cortex starts to operate from that time onwards. The

human development of the pain pathways subserving affec-

tive components, i.e. thalamo-limbic connections, is poorly

understood. The thalamo-hippocampal connections prob-

ably develop simultaneously with the other thalamo-cortical

pathways [16]. However, signaling pathways from the

periphery to the deeper brain areas are more likely estab-

lished along with the growth of the spino-thalamic tracts at

20 weeks of age, allowing for subcortical processing of pain

at much earlier ages.

Neurons of the cerebral cortex begin their migration from

the periventricular zone at eight weeks of gestation, by 20

weeks the cortex has acquired its full complement of

neurons, and glial proliferation is active throughout child-

hood [13,17,18]. Organization of the cortical networks

occurs simultaneously with neuronal migration: synapse

formation begins during the 12th week, and peaks during

the last trimester [17,19], as dendritic arborization and

axonal elongation proceed. Thalamo-cortical projections

wait just beneath the cortex (subplate) until the rough orga-

nization of the cortex is completed to allow their ingrowth

[16]. Electroencephalographic activity, which, to some

extent, re¯ects the integrity of the cortex and thalamo-corti-

cal circuitries, appears for the ®rst time at 20 weeks, but

becomes synchronic at 26 weeks, and reveals sleep-wake

cycles only at week 30 [5,13]. Unlike the other senses pain

is essentially a multimodal experience, and thus also

requires a concerted action of multiple cortical areas.

Such a `mature' processing of pain will, in turn, only be

possible long after birth.

Maturation of the pain-modulating, descending pathways

in the spinal cord, are crucial for a proper pain reaction.

These develop very late, and animal experiments on rats

have shown that they are functional only in the second

postnatal week. Such a late functional maturation is prob-

ably due to a late development of both descending noradre-

nergic and serotonergic pathways and spinal cord dorsal

horn interneurons [15]. The strong re¯exes to pain stimuli

seen in fetuses and neonates are probably due to this imma-

turity of the modulatory systems, implying that there is less

control of the entry of the peripheral stimuli into the central

nervous system [15].

As to the fetal physiology of pain, it is notable that the

®rst functional and anatomical pathways may substantially

differ from their mature counterparts [15,20]. For example,

afferent nerves from the touch-sensing receptor in the skin

of a fetus make synapses with the spinal cord ascending

neurons that are specialized for pain impulses in the mature

system [15]. In addition, the skin area innervated by a single

pain-transmitting neuron (receptive ®eld) is much larger

during development than in the mature system. These

fundamental differences in the fetal nervous system (as

compared to the mature system) make it apparently incap-

able of precisely localizing or distinguishing a painful

stimulus from other stimuli. Therefore, various kinds of

stimuli may induce very holistic and unspeci®c reactions,

which in later development become more restricted and

functionally meaningful (see below).

3.2. Behavioral pain reactions during the fetal period

A painful stimulus induces motor movements like with-

drawal re¯exes, body movements or even vocalizations,

which are often regarded as an indication of pain in the

neonate [10,11,20,21]. First motor re¯exes, head tilting

after perioral touch, appear at 7.5 weeks of gestation.

Hands become touch sensitive at 10.5 weeks, and at 14

weeks of age the lower limbs also begin to participate in

re¯ex movements [15,22,23]. It is important to note,

however, that these reactions are completely re¯exive,

guided by the spinal cord, and it is, therefore, irrelevant to

speculate about sensing or higher perception of pain at this

stage [24].

Due to the immaturity of the pain-modulating systems,

re¯ex threshold is remarkably low and re¯exes are large,

e.g. pinching a toe results in a whole body movement [6,15].

Also, there is no obvious correlation between the intensity

of the noxa and the strength of the re¯ex associated with it.

Therefore the strong, noxa-elicited re¯exes are more a

re¯ection of the immaturity of the modulatory systems

than a reliable indicator of painfulness.

Unlike other motor re¯exes facial expressions may speci-

®cally re¯ect the emotions of pain [10,11]. This idea has

been supported by the observations that premature babies

born as early as the 26th week of gestation may possess

facial expressions that are speci®c for pain. The facial

expressions may even allow for objective analysis of sub-

components, which appear to be similar to those found in

adults during a period of pain [10,21]. A detailed analysis by

Humphrey [22] of the re¯exes triggered by trigeminal nerve

stimulation showed that a rich variety of facial re¯exes to

various somatic stimuli may be observed at very early stages

of development, suggesting an early development of these

motor circuits. Such motor movements are most likely coor-

dinated by subcortical systems, tentatively called an

emotional motor system (for review, see Holstege [25]),

and thus probably re¯ect the development of these lower

brain circuitries.

3.3. Development of the autonomic and endocrine re¯exes

Fetal pain has been repeatedly studied by demonstrating

the autonomic or neuroendocrinological reactions to

noxious stimuli [9,20]. Interpretation of these re¯exes is,

however, complicated because they are relatively unspeci®c

indicators of subjective painfulness, even in adult patients.

Giannokoulopoulos et al. [26] demonstrated in 23-week-old

fetuses that pricking the innervated hepatic vein with a

needle resulted in an elevation of the cortisol and b-endor-

S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150 147

phin levels in the plasma, while stimulation of the uninner-

vated placental cord had no effect. This study gave rise to

widespread speculation that this would indicate painfulness

already at 23 weeks of age, regardless of the absence of the

thalamocortical connections. These ®ndings do rather indi-

cate that the stimulation was able to activate the hypotha-

lamo-hypophysial axis, thereby bringing about a hormonal

re¯ex to the noxa. The same group later showed that inva-

sive procedures may alter the brain blood ¯ow at the 18th

week [27], supporting an idea that painful stimuli may trig-

ger large scale responses in the central nervous system with-

out reaching the cortex.

While noxious stimuli are associated with remarkable

changes in autonomically regulated parameters (e.g. respira-

tion or pulse frequency), there appears to be no reliable

correlation between the changes in these parameters and

the intensity of the noxa [10,28]. Therefore, a reliable esti-

mation of painfulness from these parameters is as yet not

feasible.

Nevertheless, it is interesting to note that the hormonal,

autonomic and metabolic re¯exes are suppressed by analge-

sics: fentanyl suppressed the hormonal and autonomic reac-

tions to surgical operations at 28 weeks of gestation [28,29],

while the adrenal levels were lowered by morphine at a

gestational age of 27±31 weeks in prematurely born children

in an intensive care unit [30]. Although the mechanisms of

these effects are not well understood, these studies provide

evidence that the stress reactions experienced by the fetuses

or the premature babies may be substantially alleviated by

appropriate medication.

4. Impact of pain experiences on later development

Knowledge of the development of pain pathways

provides us with a theoretical time constraint for the devel-

opment of sensing a noxious stimulus. However, processing

of pain occurs in the brain stem and also in the hypotha-

lamo-limbic systems [5,31]. Thus activation of the somato-

sensory cortex is probably not required for a noxa to

in¯uence an individual's development. Indeed, pain induces

redistribution (reduction) of brain blood ¯ow as early as the

18th week of gestation [27], and preterm babies show habi-

tuation to external stimuli already before thalamo-cortical

connections, during the 25th week of gestation [32]. Experi-

ments on rat pups and human preterm babies have shown

that noxious stimulation may result in permanent spinal cord

level sensitization to pain stimuli [15,33], and this can be

reversed by topical anaesthesia [34]. All these ®ndings

imply that effective and meaningful, subcortical pain

processing occurs in fetuses several weeks before the

noxious stimuli reach the cortex.

Development and subsequent organization of the nervous

system occurs by a primary overproduction of neurons and

connections, followed by a rivalry and a survival of the

functional parts of the circuitry only [17]. Final organization

of the brain circuitries relies predominantly on guidance

from external input, which makes the brain sensitive to

strong experiences, especially during early maturation.

Although the causal links between the external stimuli and

different developmental features are virtually impossible to

prove unambiguously in humans, a number of indirect

studies have provided evidence for correlations of the

early pain experiences to later behavioral variables or to

later developmental outcomes (for review, see Anand [20]).

The most important common denominator of the devel-

opmental pain effects is probably the robust and long-lasting

stress response, which has been associated with increased

mortality at later stage [20,29,35]. Neurodevelopmentally,

the most important stress responses are probably the marked

¯uctuations in blood pressure and cerebral blood ¯ow, and

the hypoxaemia [20,36], which may even predispose to or

accentuate an intracerebral hemorrhage [20]. These changes

in oxygenation or circulation may be prevented by adequate

pain treatment [20,36]. A study on human subjects demon-

strated increased salivatory cortisol responses 6 months

after stressful birth conditions [37], and a number of animal

experiments have provided evidence for permanent changes

in endocrine and/or immune systems or brain hormone

receptor expression patterns after pain or other stressful

stimuli (for review see Anand [20]).

Infants treated in neonatal intensive care units (ICU) for 4

weeks manifested decreased behavioral and increased cardi-

ovascular responses to the pain of heel prick, and these

alterations correlated with the number of invasive proce-

dures experienced since birth [38]. Furthermore,

unanaesthetized circumcision is associated with long-term

alterations in pain-related behavioral response at 4 and 6

months of age [20,39]. In older children an objectively

measurable change in their pain-related behavior, even 4

months post-operatively, was shown to depend on the type

of pain treatment during surgical procedures [40]. Long

term follow-up studies on children exposed to neonatal

pain/stress have repeatedly shown correlations between

the stay in the ICU and the later neuropsychological

complex of altered pain thresholds and/or abnormal pain-

related behaviors [20,41].

All these data suggest that a repetitive, or sometimes even

strong acute pain experience is associated with long-term

changes in a large number of pain-related physiological

functions, and pain or its concomitant stress increase the

incidence of later complications in neurological and/or

psychological development. Of utmost clinical importance

are the ®ndings that adequate pain treatment may prevent

these later sequelae [15,20,29,36].

5. Conclusions

A fetus reacts to painful stimuli by various motor, auto-

nomic, hormonal and metabolic changes at relatively early

stages of gestation. Due to the immaturity of the modulatory

S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150148

systems, the ®rst reactions are purely re¯exive and they are

often unrelated to the type of stimulus. While the fetal

nervous system is capable of mounting such protective

re¯exes against potentially harmful noxa, there is no

evidence to support a feeling of pain at the earliest stages.

Cortical processes, and hence, theoretically, the ®rst sensory

experiences, only become possible when the thalamocorti-

cal connections grow during the 26th week of gestation.

It is important to note that, especially in fetuses, noxious

stimuli may have adverse effects on the developing indivi-

dual regardless of the quality or the level of processing in

the brain. In addition to the cerebral cortex, pain also acti-

vates a number of subcortical mechanisms and a large scale

of physiological stress responses, which thus implies that

the growth of the thalamo-cortical connections and subse-

quent cortical activation is not required for the developmen-

tal in¯uences of pain. Hence, after the development of the

spinal cord afferents around the gestational week 10, there

may be no age limit at which one can be sure noxae are

harmless. The clinically relevant question would be: which

sensory experiences are potentially harmful for the devel-

opment of a fetus? While our understanding of the relations

between the noxae and their developmental effects is still

poor, the clinical studies have suggested that the pain-

induced behavioral alterations may be prevented by

adequate pain treatment. There are strong indications that

one should take all reasonable measures to treat potentially

noxious situations, regardless of age.

References

[1] Concar D. Into the mind unborn. New Sci 1996;19:40±45.

[2] Savage W. Do fetuses feel pain? Surgical terminations of pregnancy

take place under general anaesthesia. Br Med J 1997;314:1201.

[3] McCullagh P. Do fetuses feel pain? Can fetal suffering be excluded

beyond reasonable doubt? Br Med J 1997;314:302±303.

[4] Merskey H, Albe-Fessard DG, Bonica JJ. Pain terms: a list with

de®nitions and notes on usage: recommended by the IASP Subcom-

mittee on Taxonomy. Pain 1979;6:249±252.

[5] Anand KJS, Phil D, Carr DB. The neuroanatomy, neurophysiology,

and neurochemistry of pain, stress, and analgesia in newborns and

children. Ped Clin North Am 1989;36:795±822.

[6] Fitzgerald M. Development of pain mechanisms. Br Med Bull

1991;47:667±675.

[7] Wollert HG, Eckel L. Cerebral near-infrared spectroscopy in children

undergoing heart surgery. Ann Neurol 1996;40:818±819.

[8] Larsson BA. The measurement of paediatric pain. Acta Paediatr

1999;88:115±117.

[9] Porter F. Pain in the newborn. Clin Perinatol 1989;16:549±564.

[10] Craig KD, Whit®eld MF, Grunau RV, Linton J, Hadjistavropoulos

HD. Pain in the preterm neonate: behavioural and physiological

indices. Pain 1993;52:287±299.

[11] Johnston CC, Stevens B, Craig KD, Grunau RVE. Developmental

changes in pain expression in premature, full-term, two- and four-

month-old infants. Pain 1993;52:201±208.

[12] Lindahl S. Calming minds or killing pain in newborn infants? Acta

Paediatr 1997;86:787±788.

[13] Anand KJS, Hickey PR. Pain and its effects in the human neonate and

fetus. N Engl J Med 1987;317:1321±1329.

[14] Okado N, Kojima T. Ontogeny of the central nervous system: neuro-

genesis, ®bre connection, synaptogenesis and myelination in the

spinal cord. In: Prechtl HFR, editor. Continuity of neural functions

from prenatal to postnatal life. Philadelphia, PA: Lippincott, 1984. pp.

31±45.

[15] Fitzgerald M. Foetal pain: an update of current scienti®c knowledge,

London: Department of Health, 1995.

[16] SupeÂr H, Soriano E, Uylings HBM. The functions of the preplate in

development and evolution of the neocortex and hippocampus. Brain

Res Rev 1998;27:40±64.

[17] Volpe JJ. Neuronal proliferation, migration, organization and myeli-

nation. In: Neurology of the newborn. Philadelphia, PA: Saunders,

1995. pp. 43±90.

[18] Kuljis RO. Development of the human brain: the emergence of the

neural substrate for pain perception and conscious experience. In:

Beller FK, Weir RF, editors. The beginning of human life. Dortrecht,

The Netherlands: Kluwer Academic, 1994. pp. 49±56.

[19] Sarnat HB, Born DE. Synaptophysin immunocytochemistry with

thermal intensi®cation: a marker of terminal axonal maturation in

the human fetal nervous system. Brain Dev 1999;21:41±50.

[20] Anand KJS. Clinical importance of pain and stress in preterm

neonates. Biol.Neonate 1998;73:1±9.

[21] Hadjistavropoulos HD, Craig KD, Grunau RE, Whit®eld MF. Judging

pain in infants: behavioural, contextual, and developmental determi-

nants. Pain 1997;73:319±324.

[22] Humphrey T. Some correlations between the appearance of human

fetal re¯exes and the development of the nervous system. Prog Brain

Res 1964;4:93±135.

[23] de Vries JIP, Visser GHA, Prechtl HFR. Fetal motility in the ®rst half

of pregnancy. In: Prechtl HFR, editor. Continuity of neural functions

from prenatal to postnatal life. Philadelphia, PA: Lippincott, 1984. pp.

46±64.

[24] Lloyd-Thomas AR, Fitzgerald M. Do fetuses feel pain? Re¯ex

responses do not necessarily signify pain. Br Med J 1996;313:797±

798.

[25] Holstege G. Descending motor pathways and the spinal motor system:

limbic and non-limbic components. Prog Brain Res 1991;87:307±

421.

[26] Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM.

Fetal plasma cortison and b-endorphin response to intrauterine need-

ling. Lancet 1994;344:77±81.

[27] Teixeira J, Fogliani R, Giannakoulopoulos X, Glover V, Fisk NM.

Fetal haemodynamic stress response to invasive procedures. Lancet

1996;347:624.

[28] Anand KJS, Sippell WG, Aynsley-Green A. Randomised trial of

fentanyl anaesthesia in preterm babies undergoing surgery: effects

on the stress response. Lancet 1987;1:62±66.

[29] Guinsburg R, Kopelman BI, Anand KJS, de Almeida MF, Peres C,

deA. Miyoshi MH. Physiological, hormonal, and behavioural

responses to a single fentanyl dose in intubated and ventilated preterm

neonates. J Pediatr 1998;132:954±959.

[30] Quinn MW,Wild J, Dean HG, HartleyR, Rushforth JA, Puntis JW, et al.

Randomised double blind controlled trial of effect of morphine on cate-

cholamine concetrations in ventilated babies. Lancet 1993;342:324±

327.

[31] Chudler EH, Dong WK. The role of the basal ganglia in nociception

and pain. Pain 1995;60:3±38.

[32] Leader LR, Baillie P, Martin B, Molteno C, Wynchank S. Fetal

responses to vibrotactile stimulation: a possible predictor of fetal

and neonatal outcome. Aust NZ J Obstet Gynaecol 1984;24:251±

256.

[33] Andrews K, Fitzgerald M. The cutaneous withdrawal re¯ex in human

neonates sensitization, receptive ®elds, and the effects of contralateral

stimulation. Pain 1994;56:95±101.

[34] Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity

following peripheral tissue damage in newborn infants and its reversal

with topical anaesthesia. Pain 1989;39:31±36.

[35] Anand KJS, Phil D, Hansen DD, Hickey PR. Hormonal-metabolic

S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150 149

stress responses in neonates undergoing cardiac surgery. Anesthesiol-

ogy 1990;73:661±670.

[36] Pokela ML. Pain relief can reduce hypoxemia in distressed neonates

during routine treatment procedures. Pediatrics 1994;93:379±383.

[37] Ramsay DS, Lewis M. The effects of birth condition on infants'

cortisol response to stress. Pediatrics 1995;95:546±549.

[38] Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit

affects pain response. Pediatrics 1996;98:925±930.

[39] Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumci-

sion on pain response during subsequent routine vaccination. Lancet

1997;349:599±603.

[40] Kotiniemi LH, Ryhanen PT, Moilanen IK. Behavioural changes in

children following day-case surgery: a 4-week follow-up of 551 chil-

dren. Anaesthesia 1997;52:970±976.

[41] Grunau RVE, Whit®eld MF, Petrie JH, Fryer EL. Early pain experi-

ence, child and family factors, as precursors of somatization: a

prospective study of extremely premature and fullterm children.

Pain 1994;56:353±359.

[42] Minkowski A, Larroche JC, Vignaud J, Dreyfus-Brisac C, Dargassies

SSA. Development of the nervous system in early life. In: Falkner F,

editor. Human development. London: W.B. Saunders, 1966. pp. 254±

276.

S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150150