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 Childrens Hospital, University of Utrecht, Utrecht, The Netherlands Received 20 May 1999; received in revised form 13 December 1999; accepted 15 December 1999Abstract 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 ableto feel pain during abortion or intrauterine surgery. This debate has mainly been inspired by the demonstration of various hormonal or motorreactions to noxious stimuli at very early stages of fetal development. The aims of this paper are to review the literature on development of thepain system in the fetus, and to speculate about the relationship between ``sensing as opposed to ``feeling pain and the number of reactionsassociated with painful stimuli. While a cortical processing of pain theoretically becomes possible after development of the thalamo-corticalconnections in the 26th week of gestation, noxious stimuli may trigger complex re¯ex reactions much earlier. However, more important thanpossible painfulness is the fact that the noxious stimuli, by triggering stress responses, most likely affect the development of an individual atvery early stages. Hence, it is not reasonable to speculate on the possible emotional experiences of pain in fetuses or premature babies. Aclinically relevant aim is rather to avoid and/or treat any possibly noxious stimuli, and thereby prevent their potential adverse effects on thesubsequent development. q 2000 Elsevier Science B.V. All rights reserved.Keywords: Abortion; Fetus; Fetal pain; Intrauterine surgery1. 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 noxiousto 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 systemspossible during fetal life. Pain sensation in the fetus is a [5,6].serious and dif®cult issue in public debate , 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 afferentrapidly increasing number of intrauterine operations. This neural pathway to the spinal cord, the ascending tract toreview will focus on current opinion concerning the devel- the thalamus, and from the thalamus to the cerebral cortexopment of the pain system, on the possibility of a fetus (Fig. 1). Pain impulses are also processed in a number offeeling pain, and on the probable impact of noxious experi- other, subcortical structures, e.g. hypothalamo-pituitaryences on subsequent development of the individual. system, amygdala, basal ganglia , 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 toexperience associated with actual or potential tissue measure . While measurements of pain with cooperativedamage, with an emphasis on previous injury-related subjects are based on subjective scales of pain intensity,experiences . This implies that the biological function these methods are not applicable to neonates or prematureof 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
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 . 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 , followed by myelination of these path- ways . 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 . 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 afferentsFig. 1. The neuronal pathways participating in pain: (1) peripheral afferentnerve transmits the signal to (2) the ascending tract neuron in the spinal Spinal cord Stimulation results in motor 7.5cord dorsal horn, which synapses with (3) the next neuron in the thalamus. movementsHere the pain impulse is distributed to two systems, which bring the signal Spinothalamic connections 20to (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 22to become `a pain. In addition, there are (6) a number of descending Descending tracts develop Postnatallyneuronal pathways to the dorsal horn of the spinal cord, which modulatethe 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±34nomic parameters (e.g. pulse rate or blood pressure). They thalamo-cortical connectionsare still being developed; none is yet suitable for assessing Cerebral cortex Cortical neurons migrate (cortex 8±20pain 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 20suppressing the pain itself ? Symmetric and synchronic EEG 26 activity appears Sleep and wakefulness patterns in the 30 EEG become distinguishable3. 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].
S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150 147may 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 painfulpotentials can be measured from the cortex, suggesting that stimulus from other stimuli. Therefore, various kinds ofa 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 andhuman development of the pain pathways subserving affec- functionally meaningful (see below).tive components, i.e. thalamo-limbic connections, is poorlyunderstood. The thalamo-hippocampal connections prob- 3.2. Behavioral pain reactions during the fetal periodably develop simultaneously with the other thalamo-cortical A painful stimulus induces motor movements like with-pathways . 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 thelished along with the growth of the spino-thalamic tracts at neonate [10,11,20,21]. First motor re¯exes, head tilting20 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 inthe 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 tohood [13,17,18]. Organization of the cortical networks speculate about sensing or higher perception of pain at thisoccurs simultaneously with neuronal migration: synapse stage .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 intensitynization of the cortex is completed to allow their ingrowth of the noxa and the strength of the re¯ex associated with it.. Electroencephalographic activity, which, to some Therefore the strong, noxa-elicited re¯exes are more aextent, re¯ects the integrity of the cortex and thalamo-corti- re¯ection of the immaturity of the modulatory systemscal 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 hasis essentially a multimodal experience, and thus also been supported by the observations that premature babiesrequires a concerted action of multiple cortical areas. born as early as the 26th week of gestation may possessSuch a `mature processing of pain will, in turn, only be facial expressions that are speci®c for pain. The facialpossible 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 inin the spinal cord, are crucial for a proper pain reaction. adults during a period of pain [10,21]. A detailed analysis byThese develop very late, and animal experiments on rats Humphrey  of the re¯exes triggered by trigeminal nervehave shown that they are functional only in the second stimulation showed that a rich variety of facial re¯exes topostnatal week. Such a late functional maturation is prob- various somatic stimuli may be observed at very early stagesably due to a late development of both descending noradre- of development, suggesting an early development of thesenergic and serotonergic pathways and spinal cord dorsal motor circuits. Such motor movements are most likely coor-horn interneurons . The strong re¯exes to pain stimuli dinated by subcortical systems, tentatively called anseen in fetuses and neonates are probably due to this imma- emotional motor system (for review, see Holstege ),turity of the modulatory systems, implying that there is less and thus probably re¯ect the development of these lowercontrol of the entry of the peripheral stimuli into the central brain circuitries.nervous system . 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 substantiallydiffer from their mature counterparts [15,20]. For example, Fetal pain has been repeatedly studied by demonstratingafferent nerves from the touch-sensing receptor in the skin the autonomic or neuroendocrinological reactions toof 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®csystem . 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.  demonstrated in 23-week-oldduring development than in the mature system. These fetuses that pricking the innervated hepatic vein with afundamental differences in the fetal nervous system (as needle resulted in an elevation of the cortisol and b-endor-
148 S. Vanhatalo, O. van Nieuwenhuizen / Brain & Development 22 (2000) 145±150phin levels in the plasma, while stimulation of the uninner- of the brain circuitries relies predominantly on guidancevated placental cord had no effect. This study gave rise to from external input, which makes the brain sensitive towidespread 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 andthalamocortical connections. These ®ndings do rather indi- different developmental features are virtually impossible tocate that the stimulation was able to activate the hypotha- prove unambiguously in humans, a number of indirectlamo-hypophysial axis, thereby bringing about a hormonal studies have provided evidence for correlations of there¯ex to the noxa. The same group later showed that inva- early pain experiences to later behavioral variables or tosive procedures may alter the brain blood ¯ow at the 18th later developmental outcomes (for review, see Anand ).week , 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-lastingout 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 markedtion or pulse frequency), there appears to be no reliable ¯uctuations in blood pressure and cerebral blood ¯ow, andcorrelation between the changes in these parameters and the hypoxaemia [20,36], which may even predispose to orthe intensity of the noxa [10,28]. Therefore, a reliable esti- accentuate an intracerebral hemorrhage . These changesmation of painfulness from these parameters is as yet not in oxygenation or circulation may be prevented by adequatefeasible. 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 monthsautonomic and metabolic re¯exes are suppressed by analge- after stressful birth conditions , and a number of animalsics: fentanyl suppressed the hormonal and autonomic reac- experiments have provided evidence for permanent changestions to surgical operations at 28 weeks of gestation [28,29], in endocrine and/or immune systems or brain hormonewhile the adrenal levels were lowered by morphine at a receptor expression patterns after pain or other stressfulgestational age of 27±31 weeks in prematurely born children stimuli (for review see Anand ).in an intensive care unit . Although the mechanisms of Infants treated in neonatal intensive care units (ICU) for 4these 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 theseor the premature babies may be substantially alleviated by alterations correlated with the number of invasive proce-appropriate medication. dures experienced since birth . Furthermore, unanaesthetized circumcision is associated with long-term alterations in pain-related behavioral response at 4 and 64. 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 typeprovides us with a theoretical time constraint for the devel- of pain treatment during surgical procedures . Longopment of sensing a noxious stimulus. However, processing term follow-up studies on children exposed to neonatalof pain occurs in the brain stem and also in the hypotha- pain/stress have repeatedly shown correlations betweenlamo-limbic systems [5,31]. Thus activation of the somato- the stay in the ICU and the later neuropsychologicalsensory cortex is probably not required for a noxa to complex of altered pain thresholds and/or abnormal pain-in¯uence an individuals 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 even18th week of gestation , and preterm babies show habi- strong acute pain experience is associated with long-termtuation to external stimuli already before thalamo-cortical changes in a large number of pain-related physiologicalconnections, during the 25th week of gestation . Experi- functions, and pain or its concomitant stress increase thements on rat pups and human preterm babies have shown incidence of later complications in neurological and/orthat noxious stimulation may result in permanent spinal cord psychological development. Of utmost clinical importancelevel sensitization to pain stimuli [15,33], and this can be are the ®ndings that adequate pain treatment may preventreversed by topical anaesthesia . All these ®ndings these later sequelae [15,20,29,36].imply that effective and meaningful, subcortical painprocessing occurs in fetuses several weeks before thenoxious stimuli reach the cortex. 5. Conclusions Development and subsequent organization of the nervoussystem 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 earlyfunctional parts of the circuitry only . Final organization stages of gestation. Due to the immaturity of the modulatory
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