We can only be said to be alive in those moments when our hearts are conscious of our treasures.
Instead of going back as far as 1980 (the most recent on your link was 1996), let's look at more recent findings.
For example, in 2005
There is no such thing as 'fetal pain'Pain specialist Dr Stuart Derbyshire argues that the misguided discussion of fetal pain will have serious negative consequences for the treatment of pregnant women and for scientific practiceIn June a group of anti-abortion parliamentarians published a tract asserting that fetuses experience pain from the tenth week of gestation. Such a debate seems a strange preoccupation for politicians who cannot be expected to know one end of a nerve cell from another, but it has since been the subject of questions to ministers and parliamentary debates. The issue will be re-raised when MPs and peers return from their summer recess and a self-appointed 'pro-life' committee of inquiry reports. The agenda of those who have raised the issue of fetal pain is clear. If they can establish that fetuses feel pain it is bound to generate public unease about abortion procedures. Already the anti-abortion lobby is talking in terms of 'the pre-born' writhing in agony as they are ripped limb from limb--not a pretty thought, however pro-choice you might be.
The discussion also helps to encourage the assumption that there are no qualitative differences between fetuses and babies. It fosters the notion that fetuses are just 'pre-born' babies with the same capacities--and so are worthy of the same care and treatment. The consequence of this would be to reduce the status of the woman to that of a 'walking womb', with no right to decide what happens to her pregnancy. But then her rights tend routinely to be ignored as all eyes focus on the fetus.
It is not surprising that the anti-abortion lobby has raised this issue. But it is surprising that its views have struck a chord with the medical establishment and with 'pro-choice campaigners'. Everybody seems to agree that this is a 'difficult' issue which needs careful consideration. Even the most strongly pro-choice voices appear to concede that fetal pain experiences might be possible after 26 weeks of pregnancy. More equivocal voices suggest that the pro-choice argument should evade the issue by arguing for easier access to abortion before 10 weeks.
What needs to be said is simply this. Fetuses do not and cannot feel pain--not at 10 weeks, 26 weeks or 30 weeks--because pain-experience depends on consciousness and fetuses are not conscious.
The question of fetal pain became an issue for some of the medical profession in the mid-1980s, as a consequence of research which indicated that a fetus is capable of a behavioural response to sensory stimulation. Advances in fetal surgery, which now include placing valves into the heart and injecting red blood cells into the liver to prevent anaemia, meant that neonatal surgeons and experts in embryology were becoming increasingly concerned about the potential consequences of invasive practice, including the concern that the fetus may feel pain. This concern was given a major boost by research from Dr Anand, then a research fellow at the John Radcliffe Hospital, Oxford, which demonstrated that neonates--new-born babies--undergoing surgery had a much improved clinical outcome if they received anaesthetics of a kind usually reserved for controlling pain during adult surgery.
It may come as a shock to hear that, until very recently, it was not considered necessary to use anaesthesia with new-born babies. But the reasons are entirely rational. The use of anaesthetic is not without risk. Even in adults there is a small risk of respiratory depression which can be fatal; for a new-born baby with underdeveloped lungs this risk is heightened, becoming greater if the baby is premature. In addition, it was widely assumed that the new born lacks the biological sophistication necessary for pain-experience. Anand's work overturned these assumptions.
The work of Anand is complemented by that of Professor Maria Fitzgerald from the Department of Anatomy at University College London. For over a decade, Fitzgerald has investigated the nervous system of the rat fetus and the human fetus, with special regard to the developmental neurobiology of pain. She concludes that several basic mechanisms must be connected up in the human being in order for pain to be experienced. The peripheral nerve fibres (that is, the nerves in your outer skin and inner organs) have to be connected to your spinal cord, which in turn needs to be connected to your brain. There are then several circuits within the brain which have to be operational and connected before the biological pain system is operational. According to Fitzgerald's studies, the final link in the pain system (between a cluster of grey nuclei in the brain stem, the thalamus, and the outer rim of the brain, the cortex) is completed at approximately 26 weeks' gestation.
The suggestion that the biological system for pain is operational after 26 weeks is bolstered by studies of invasive procedures. Touching the fetus prior to 26 weeks often results in a generalised response. Repeated skin stimulation, for example, results in hyper-excitability and a generalised movement of all limbs of the body. Such behaviours are characteristic of a purely reflex response. Observations of the fetus after 26 weeks, however, indicate localised movement and avoidance responses to invasive needling. Behavioural studies with very premature babies have demonstrated that the response to noxious stimulation becomes more focused and organised, and can be better discriminated from other distress responses after 26 weeks.
It is now also clear that the fetus of post-26 weeks' gestation launches a stress response to invasive needling, entirely analogous to the response shown by Anand in new-born babies. In 1994 a team at Queen Charlotte's Hospital in London successfully demonstrated that intrauterine needling to obtain a blood sample from fetuses of 20-34 weeks' gestation resulted in a hormonal stress response, as indicated by increased cortisol and ß-endorphin concentrations in fetal plasma.
As a consequence of this research, the previous objections to the use of anaesthetics in the new born and the fetus, on the grounds of danger and minimal biological development, are now untenable. After 26 weeks, the human fetus has the necessary biological apparatus for pain, shows a localised behavioural response to stimulation, and launches a hormonal stress response to needling. But is this sufficient evidence to conclude that the fetus can experience pain?
Whether or not the fetus feels what we understand as pain hinges not on its biological development, but on its conscious development. Unless it can be reasonably demonstrated that the fetus has a conscious appreciation of pain after 26 weeks' gestation, then its responses to noxious stimulation are still essentially reflex responses, exactly as those prior to 26 weeks. This is appreciated in varying degrees by the experts.
Xenophon Giannakoulopoulos and his colleagues at Queen Charlotte's admitted that 'a hormonal response cannot be equated with the perception of pain'. In a paper written for the Department of Health, Fitzgerald even went so far as to say that 'true pain-experience postnatally along with memory, anxiety and other cognitive brain functions' ('Fetal pain: an update of current scientific knowledge', May 1995). In other words, to claim that a fetus feels pain makes as little sense as suggesting that it has kept a mental diary of its time in the womb.
As Fitzgerald has pointed out, pain-experience is now widely seen as a consequence of an amalgam of cognition, sensation and affective processes, described under the rubric of the 'biopsychosocial' model. Pain has been understood as a multi-dimensional phenomenon for some time, and this understanding is reflected in the current International Association for the Study of Pain (IASP) definition of pain as 'an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage' (H Merskey, 'The definition of pain', European Journal of Psychiatry, Vol6, 1991).
If this 'multi-dimensionality' is the basis of conscious pain-experience, it makes no sense to attribute this experience to the neonate or fetus which is naive as to all the cognitive, affective and evaluative experiences necessary for pain-awareness. This is accepted in the current IASP definition of pain, which is further extended to state that 'pain is always subjective, each individual learns the application of the word through experiences related to injury in early life'. Pain does not somehow spring forth 'from the depths of the person's mind' prior to any experience. That would be an essentially metaphysical view of pain, which logically suggests that all the higher mental functions should be present at, or before, birth.
In other words, the experience of pain is a consequence of developmental processes through which the fetus and new-born baby have yet to pass. According to one developmental model of pain, stimulus information is eventually organised and elaborated in the central nervous system with respect to three hierarchical mechanisms. The first two mechanisms in the hierarchy are perceptual-motor processing followed by schematic processing. Both these mechanisms are considered pre-conscious. Perceptual-motor processing involves the activation of innate motor reactions to stimulation. Schematic processing involves the automatic encoding in memory of these stimuli and associated reactions to produce a categorical structure representing the general informational and sensory aspects of aversive stimuli. In addition, it is suggested that a set of conscious abstract rules about emotional episodes and associated voluntary responses arise only over time, as a consequence of self-observation and conscious efforts to cope with aversive situations.
While far from ideal, this model does outline how the pressure of interacting with others gradually forces the subordination of our instinctive, unconscious biology to our developing conscious will. The model shifts us away from a static interpretation of pain towards one in which the reflexive responses to stimulation are developed, and subordinated, according to the dynamics of developing awareness. Pain can then logically be understood as a conscious, developed response which a fetus could never be capable of experiencing.
The failure of the medical and scientific community to tackle the issue has allowed the idea that a fetus can feel pain to gain momentum, strengthening the anti-abortionists' hand. The emotive notion of fetal pain has gone largely unchallenged in the medical journals, the newspapers and in the House of Commons. Last year, anti-abortion crusader David Alton MP introduced an adjournment debate in which he insisted that information on fetal pain should be issued to women considering abortion (Hansard, 136, 1995). This debate was followed by an early day motion calling on the Department of Health to disseminate information 'to medical staff and mothers' and to 'come forward with proposals for avoiding pain in pre-term surgery and abortion' (Hansard, 140, 1995).
It has also been proposed that the Abortion Act and the Criminal Justice Act be amended to make it a crime to inflict pain on the fetus. The Rawlinson committee (a noted anti-choice organisation set up in 1993 to examine the implications of the 1967 Abortion Act) was recently resurrected to examine the question of fetal pain. Although, in the interests of balance, I was invited to give evidence to the committee, it seems likely that it will eventually come out in support of the existence of 'fetal pain' and recommend further restrictions on access to abortion.
The attempt to undermine public confidence in the provision of abortion is only one negative consequence of the misguided discussion around fetal pain. The discussion is also encouraging researchers to take an anti-scientific stance, which denies the possibility of answering the question 'do fetuses feel pain?' and undermines the current, well-supported model of pain.
The emotional hype around fetal pain is also likely to have a detrimental impact upon medical research and practice beyond the cry for restricting abortion. Earlier this year, the Daily Express ran a headline suggesting that babies may feel pain during childbirth. This view was based on the research from Queen Charlotte's Hospital and was endorsed by one of its principal researchers. It seems unlikely, however, that a process which the overwhelming majority of people has passed through--being born--is having long-term detrimental consequences, and there is some evidence to suggest that the increased hormonal release around birth is important in stimulating growth and regulating development. Such work is likely to be overlooked if fetal pain becomes an accepted view. Acceptance of fetal pain will mean that anaesthetic practice may be introduced when there is no clear rationale for its use and where it is likely to be at least uncomfortable, if not dangerous, for the mother-to-be. How long will it be before someone calls for an increase in Caesarian sections to avoid fetal/neonatal 'pain'?
Good clinical research into the effects of anaesthesia on the fetus and the new-born baby is clearly required. But misguided sentimentality about the possibility of fetal pain can only have negative consequences--including undermining the very basis of the clinical research itself.
1. IntroductionThe recent ability to diagnose and treat the fetus in utero resulted from developments in invasive procedures, in understanding of fetal pathophysiology, and in technical advances in imaging. These procedures, ranging from ultrasound-guided needle aspiration through to open fetal surgery, are invasive, leading to the obvious question: does the fetus feel pain? The concept that the fetus is a patient in its own right has led to increasing interest in the subject of fetal pain. A justification for providing fetal analgesia and anaesthesia has arisen not only because of a moral obligation to prevent suffering, but also because pain and stress may affect survival and have long-term neurodevelopmental sequelae.
However, the evidence base for this is limited, largely because research in human fetuses is hampered by ethical constraints, but also due to problems defining satisfactory outcome measures.
2. Fetal painThere is no objective measurement of `pain'; it is a subjective experience. The fetus is unable to tell us if it feels pain, so other evidence must be used to decide at what gestation it is likely that the fetus starts to feel pain. Sensory innervation of the skin and neuronal connections between the periphery and spinal cord have begun by 8 weeks, with C fibres growing into the spine at about 10 weeks. The cerebral cortex starts to form at this stage, with differentiation into neurones, fibres, glia and blood vessels starting at about 17 weeks, and continuing long after birth. Pain fibres pass through the thalamus en route to the cortex. The timing of these thalamo-cortical connections is crucial in deciding when the fetus first becomes capable of feeling pain; this is an area of considerable controversy. Rapid Golgi-staining techniques have shown the ingrowth of afferent fibres into the cortical plate between 26 and 34 weeks of gestation , which has led some to conclude the fetus is incapable of feeling pain prior to 26 weeks . However, between 20 and 26 weeks the subplate zone of the cortex contains an abundant mixture of cholinergic, thalamo-cortical and corticocortical waiting neurones, and there are transient fetal synaptic circuits between the subplate and cortical plate neurones . Awareness of pain is considered to require connections between the cortex and periphery, although, this presumption would render animals lacking a cortex such as reptiles incapable of perceiving pain. It is not known at what point in the maturation from transient, possibly single, connections to permanent multiple connections the fetus may become capable of feeling pain, and it may be a gradual rather than sudden transition. In summary, prior to 22 weeks the fetus does not have the neuroanatomical pathways in place to feel pain, between 22 and 26 weeks thalamo-cortical connections are forming, and after 26 weeks the fetus has the necessary connections to feel pain. 3. Neonatal experienceUntil the last decade, the neonate was treated as if it were incapable of feeling pain. However, studies showed that neonates, even when preterm, mounted a sizeable stress response to cardiac surgery , with rises in adrenaline, noradrenaline, and cortisol. Some of these changes were reduced by opioid analgesia . In one randomised study, opioid anaesthesia was associated with a reduction in peri-operative mortality . Since then, use of analgesia during neonatal surgery has become the standard of care. Neonates also have behavioural responses to pain, for example, by facial expression or by crying. The response to heel lancing by facial action varies depending on the sleep/wake state of the neonate, suggesting that the behavioural context of pain affects behavioural expression, even before the opportunity for learned response occurs .
4. Fetal stressBecause of the obvious difficulties in studying fetal behaviour, activation of the hypothalamo-pituitary-adrenal axis (a `stress response') has been proposed as a surrogate indicator of fetal pain. This has limitations: stress responses do not necessarily imply pain (for example, during exercise), and stress responses do not involve the cortex. However, the converse is the null hypothesis, i.e. in the absence of a stress response the fetus is unlikely to experience pain. Also, one could argue that the stress response is more relevant in terms of immediate and long-term sequelae, whether or not associated with pain in the fetus. Studies in humans are limited by the need for an ethically-acceptable model, namely those fetuses undergoing clinically-indicated procedures for diagnostic or therapeutic reasons. We have studied fetuses undergoing intravascular blood transfusion, which allows collection of serial blood samples at the beginning and end of the procedure. Procedures at the placental cord insertion (PCI), which is not innervated, can be compared with transfusions at the intrahepatic vein (IHV), which involves transgressing the fetal trunk (Fig. 1). In our unit, the site of approach is based on technical access dependent on fetal and placental position, with each site used approximately 50% of the time. While the IHV approach may have a lesser risk of complication due to cord tamponade and arterial spasm, the PCI approach is technically easier.
4.1. Hormonal responseActivation of the fetal hypothalamo-pituitary-adrenal axis can be assessed by measuring stress hormones such as noradrenaline, cortisol, and -endorphin. Studying samples obtained at fetal blood transfusion allows comparison of levels of these hormones before transfusion (immediately after access to the fetal circulation is established), with levels at the end of transfusion (just before the needle is removed). After transfusion at the PCI there is little change in fetal noradrenaline, cortisol, or -endorphin . However, as illustrated in Fig. 2, piercing the fetal abdomen to access the IHV for transfusion is associated with substantial rises in these hormones from as early as 18 weeks gestation. The median increase in -endorphin levels was 590%, in cortisol levels was 183%, and in noradrenaline levels was 196% . Shorter procedures such as blood sampling without transfusion were not associated with rises in cortisol and -endorphin, but there was a variable rise in the more rapid noradrenaline response.
4.2. Circulatory responseThe fetus in late gestation has a remarkable capacity to redistribute its blood flow in response to stressors to protect its more vital organs, such as brain and myocardium, at the expense of other organs such as gut, kidneys and the extremities . Numerous experimental studies have confirmed such responses to acute hypoxaemia , haemorrhage , and reduced uterine blood flow . Similarly, Doppler studies of human fetuses with intrauterine growth restriction (IUGR) have found decreased resistance indices in cerebral and adrenal blood flow velocity waveforms (FVW) consistent with vasodilatation, and increased indices in FVW from peripheral organ beds such as the renal , femoral and pulmonary arteries consistent with vasoconstriction. Using Doppler ultrasound, our group has shown a fall of 1¯2.5 standard deviations in middle cerebral artery pulsatility index, consistent with this fetal brainsparing response, after procedures involving transgression of the fetal trunk, from as early as 16 weeks. The mechanism for this is not clear, but is compatible with an increase in cerebral flow. There is also an increase in renal and femoral artery resistance indices after procedures involving transgression of the fetal trunk, similarly compatible with fetal brainsparing (manuscript in preparation). These changes are not seen after procedures at the PCI. This redistribution in blood flow may be mediated by the sympathetic system, or by other undetermined mechanisms.
5. Long-term sequelaeThere is increasing evidence that early painful or stressful events can sensitise an individual to later pain or stress. Evidence from animal studies indicates that a stressful perinatal event can have long-term effects on hippocampal development and stress behaviour. In rats, which are born at a stage equivalent in development to the late human fetus, early postnatal handling causes an increase in glucocorticoid receptor density in the hippocampus and a lifelong modification in behavioural stress responses . Rats stressed perinatally secrete more corticosterone and show a slower return to basal levels in stressful situations . The primate model has also been used to study the effects of stress hormones and stress. Administration of dexamethasone to pregnant rhesus monkeys in the latter third of pregnancy at a dose similar to that used in humans is associated with degenerative changes in the fetal hippocampus . Exposure to a 2-week period of exogenous ACTH is associated with impaired motor coordination and muscle tonicity, reduced attention span, and greater irritability . Exposure to stress in the latter third of pregnancy is associated with higher levels of ACTH and cortisol in the neonate when stressed . Exposure to stress in utero, especially during the first third of pregnancy, is also associated with lower scores of attention and neuromotor maturity after birth .
In humans, neonatal circumcision without analgesia has been shown to increase subsequent pain behaviour (measured objectively from videotape by an independent observer) following vaccination 4¯6 months later when compared to uncircumcised controls . This suggests that a single stressful event early in life, when the nervous system is still developing, can influence neurodevelopment and may have a lifelong effect on stress responses. Furthermore, preoperative treatment with local anaesthetic cream attenuated the response to vaccination, suggesting that analgesia can alter the effect of stress on neurodevelopment .
In response to vaccination in infancy, we have found that babies born by instrumental delivery have a greater rise in salivary cortisol and cry for longer than those born normally, while those born by elective Caesarean section have a smaller rise and cry less than the normal group .
Whether pain or stress in utero has long-term implications is not known, and studies are limited by the ethical need to confine invasive procedures to those for which there is a diagnostic or therapeutic indication. Many such fetuses will be abnormal, making it difficult to correct for confounding factors when comparing them to control fetuses not undergoing invasive procedures. Further, the number of invasive procedures continues to decline with the advent of rapid molecular methods of chromosomal analysis, and a fall in the incidence of Rh disease due to antenatal prophylaxis.
6. Fetal analgesiaAwareness of the need for fetal analgesia increased following Anand's work on opiates in neonates . The rationale was that if a premature infant was capable of feeling pain then there is no reason why a fetus of the same gestation should not also feel pain . The case strengthened following the demonstration that human fetuses mount sizeable biochemical and circulatory stress responses to invasive procedures . Potential indications include any procedure from which the fetus could probably experience pain. These can be grouped into `open' fetal surgical procedures via laparotomy, and `closed' percutaneous procedures via endoscopes and needles. Fetal surgery is now being offered in highly selected circumstances where fetal prognosis is otherwise poor . Such circumstances are rare, and include fetal lung lesions (congenital cystic adenomatoid malformation and bronchopulmonary sequestration), congenital diaphragmatic hernia, sacrococcygeal teratoma, and myelomeningocele. As well as IHV fetal blood sampling and transfusion discussed earlier, other `closed' surgical and needling techniques may be used on the fetus. These include vesicoamniotic shunting, fetal cystoscopy, thoraco-amniotic shunting, and fetal tissue biopsy.
Fetal analgesia for open fetal surgery is facilitated by maternal anaesthesia. The potent inhalational agents all cross the placenta, with fetal uptake depending on uterine blood flow, the solubility of the drug in fetal blood, and its distribution in the fetal compartment . Isoflurane is rapidly taken up by the fetus and both maternal and fetal anaesthesia can theoretically be achieved. Work in sheep suggests that the fetus requires a lower concentration of isoflurane to achieve the same level of anaesthesia as the adult , so concentrations, which provide maternal anaesthesia, are likely to provide adequate fetal anaesthesia. Inhalational agents also provide uterine relaxation, which allows handling of the uterus without contractions and the risk of placental separation. High levels of isoflurane may reduce uterine blood flow, although, in contrast work in pregnant ewes has shown that at lower concentrations uterine blood flow increases slightly . Direct fetal administration of fentanyl and pancuronium is reserved for cases where the fetus moves during the procedure .
During `closed' endoscopic or needling procedures, administration of safe and effective analgesia presents difficulties. The risks of maternal (and consequently fetal) general anaesthesia are unlikely to be justified by the degree of pain inflicted on the fetus. Similar procedures in adults involving cutaneous puncture are usually performed using no analgesia or local analgesia, depending on the size of needle. Local anaesthesia is not practical in the fetus: it would be difficult to administer to the fetal skin accurately, and the fetus may move before the needle is advanced into the target organ. Opioids cross the placenta, but fetomaternal ratios are low, only about 0.3:1 for fentanyl . Thus, to provide fetal analgesic levels, the higher maternal levels required would expose the mother to a risk of sedation and respiratory depression. Intra-amniotic opioids have been tried in experimental animal models but not surprisingly result in subtherapeutic fetal levels due to impermeability of the fetal skin . Administering drugs to the fetal IHV or intramuscularly would itself involve fetal puncture and thus potentially pain.
Accessing the PCI to administer analgesia before proceeding to the fetus would increase the procedure-related risks, and cannot be justified at least until analgesia has been shown to be beneficial in closed procedures.
Our group is currently investigating the effects of direct opioid analgesia during closed procedures at the IHV. One problem with this approach is that the fetus is punctured before analgesia is administered. Even if shown efficacious, the optimal drug, dose, and route of administration remain to be determined.
7. ConclusionEvidence in neonates of stress responses to surgical insults and their prevention with analgesia has led to increased awareness of pain and the need for analgesia in newborns. This raises the obvious question if and when the fetus can feel pain. The critical thalamo-cortical connections for nociception form from 20¯26 weeks, while substantial hormonal and circulatory stress responses to invasive procedures are observed by 20 weeks. Although, there is yet no evidence that analgesia works in the human fetus, fetal analgesia warrants investigation, both because of a moral imperative to prevent possible suffering, and because of the increasing evidence in animals and humans suggesting that exposure to perinatal stress has long-term neurodevelopmental sequelae. During open fetal surgery under maternal general anaesthesia, inhalational agents are considered to provide adequate fetal anaesthesia. In contrast, the more common closed needling and shunting procedures are usually performed using only maternal local anaesthesia. Fetal analgesia provides a challenge in such circumstances, due to the desire to avoid both maternal sedation, and the procedure-related risk of accessing the fetal circulation. Research is needed into safe, efficacious methods of administering analgesia to the human fetus in utero.
AcknowledgementsOur work in this area is supported by the Henry Smith Charity, WellBeing, and the Women & Children's Welfare Fund. We acknowledge equipment support from the Children Nationwide Medical Research Fund. References1. L. Mrzljak, H.B. Uylings, I. Kostovic and C.G. Van Eden, Prenatal development of neurons in the human prefrontal cortex. I. A qualitative Golgi study. J. Comp. Neurol.271 (1988), pp. 355¯386. EMBASE 2. RCOG. Fetal Awareness. Report of a working party. London: RCOG Press, 1997.
3. V. Glover and N.M. Fisk, Fetal pain: implications for research and practice. Br. J. Obstet. Gynaecol.106 (1999), pp. 881¯886. Abstract
4. K.J. Anand, W.G. Sippell and A. Aynsley-Green, Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet1 (1987), pp. 62¯66.
5. K.J. Anand and P.R. Hickey, Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery (see comments). N. Engl. J. Med. 326 (1992), pp. 1¯9. EMBASE
6. R.V. Grunau and K.D. Craig, Pain expression in neonates: facial action and cry. Pain 28 (1987), pp. 395¯410. EMBASE
7. X. Giannakoulopoulos, W. Sepulveda, P. Kourtis, V. Glover and N.M. Fisk, Fetal plasma cortisol and beta-endorphin response to intrauterine needling. Lancet 344 (1994), pp. 77¯81. Abstract
8. X. Giannakoulopoulos, J. Teixeira, N. Fisk and V. Glover, Human fetal and maternal noradrenaline responses to invasive procedures. Pediatr. Res. 45 (1999), pp. 494¯499. Abstract
9. D. Giussani, J. Spencer and M. Hanson, Fetal cardiovascular reflex responses to hypoxaemia. Fetal Matern. Med. Rev. 6 (1994), pp. 17¯37. EMBASE
10. A.J. Llanos, R.A. Riquelme, F.A. Moraga, G. Cabello and J.T. Parer, Cardiovascular responses to graded degrees of hypoxaemia in the llama fetus. Rep. Fertil. Dev. 7 (1995), pp. 549¯552.
11. C.A. Gleason, C. Hamm and M.D. Jones, Jr., Effect of acute hypoxemia on brain blood flow and oxygen metabolism in immature fetal sheep. Am. J. Physiol. 258 (1990), pp. H1064¯9.
12. R.L. Meyers, R.P. Paulick, C.D. Rudolph and A.M. Rudolph, Cardiovascular responses to acute, severe haemorrhage in fetal sheep. J. Dev. Physiol. 15 (1991), pp. 189¯197. EMBASE
13. A. Jensen, C. Roman and A.M. Rudolph, Effects of reducing uterine blood flow on fetal blood flow distribution and oxygen delivery. J. Dev. Physiol. 15 (1991), pp. 309¯323. EMBASE
14. J.W. Wladimiroff, J.A. v.d. Wijngaard, S. Degani, M.J. Noordam, J. van Eyck and H.M. Tonge, Cerebral and umbilical arterial blood flow velocity waveforms in normal and growth-retarded pregnancies. Obstet. Gynecol. 69 (1987), pp. 705¯709. EMBASE
15. G. Mari, B. Uerpairojkit, A.Z. Abuhamad and J.A. Copel, Adrenal artery velocity waveforms in the appropriate and small-for-gestational-age fetus. Ultrasound Obstet. Gynecol. 8 (1996), pp. 82¯86.
16. D. Arduini and G. Rizzo, Fetal renal artery velocity waveforms and amniotic fluid volume in growth-retarded and post-term fetuses. Obstet. Gynecol. 77 (1991), pp. 370¯373. EMBASE
17. G. Mari, Arterial blood flow velocity waveforms of the pelvis and lower extremities in normal and growth-retarded fetuses. Am. J. Obstet. Gynecol. 165 (1991), pp. 143¯151. EMBASE
18. G. Rizzo, A. Capponi, R. Chaoui, F. Taddei, D. Arduini and C. Romanini, Blood flow velocity waveforms from peripheral pulmonary arteries in normally grown and growth-retarded fetuses. Ultrasound Obstet. Gynecol. 8 (1996), pp. 87¯92.
19. M.J. Meaney and D.H. Aitken, The effects of early postnatal handling on hippocampal glucocorticoid receptor concentrations: temporal parameters. Brain Res. 354 (1985), pp. 301¯304. EMBASE
20. C. Henry, M. Kabbaj, H. Simom, M. Le Moal and S. Maccari, Prenatal stress increases the hypothalamo-pituitary-adrenal axis response in young and adult rats. J. Neuroendocrinol. 6 (1994), pp. 341¯345. Abstract
21. Uno H, Lohmiller L, Thieme C, et al. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus. Brain Res Dev Brain Res 1990;53:157¯67.
22. M.L. Schneider, C.L. Coe and G.R. Lubach, Endocrine activation mimics the adverse effects of prenatal stress on the neuromotor development of the infant primate. Dev. Psychobiol.25 (1992), pp. 427¯439.
23. A.S. Clarke, D.J. Wittwer, D.H. Abbott and M.L. Schneider, Long-term effects of prenatal stress on HPA axis activity in juvenile rhesus monkeys. Dev. Psychobiol. 27 (1994), pp. 257¯269.
24. M.L. Schneider, E.C. Roughton, A.J. Koehler and G.R. Lubach, Growth and development following prenatal stress exposure in primates: an examination of ontogenetic vulnerability. Child Dev. 70 (1999), pp. 263¯274.
25. A. Taddio, J. Katz, A.L. Ilersich and G. Koren, Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet 349 (1997), pp. 599¯603. SummaryPlus | Article | Journal Format-PDF (83 K)
26. Taylor A, Fisk NM, Glover V. Mode of delivery and subsequent stress response. Lancet 2000;355:120.
27. V. Glover and N. Fisk, Do fetuses feel pain? We don't know better to err on the safe side from mid-gestation. BMJ 313 (1996), p. 796.
28. J.M. Teixeira, V. Glover and N.M. Fisk, Acute cerebal redistribution in response to invasive in the human fetus. Am. J. Obstet. Gynecol. 181 (1999), pp. 1018¯1025. Abstract
29. Y. Kitano, A.W. Flake, T.M. Crombleholme, M.P. Johnson and N.S. Adzick, Open fetal surgery for life-threatening fetal malformations. Semin. Perinatol. 23 (1999), pp. 448¯461. Abstract
30. R.R. Gaiser and C.D. Kurth, Anesthetic considerations for fetal surgery. Semin. Perinatol. 23 (1999), pp. 507¯514. Abstract
31. R. Dwyer, J.P. Fee and J. Moore, Uptake of halothane and isoflurane by mother and baby during caesarean section. Br. J. Anaesth. 74 (1995), pp. 379¯383. Abstract
32. G.A. Gregory, J.G. Wade, D.R. Beihl, B.Y. Ong and D.S. Sitar, Fetal anesthetic requirement (MAC) for halothane. Anaesth. Analg. 62 (1983), pp. 9¯14. EMBASE
33. R.J. Palahniuk and S.M. Shnider, Maternal and fetal cardiovascular and acid¯base changes during halothane and isoflurane anesthesia in the pregnant ewe. Anesthesiology41 (1974), pp. 462¯472. EMBASE
34. J.R. Loftus, H. Hill and S.E. Cohen, Placental transfer and neonatal effects of epidural sufentanil and fentanyl administered with bpivacaine during labor. Anesthesiology83 (1995), pp. 300¯308. Abstract
35. H.H. Szeto, L.I. Mann, A. Bhakthavathsalan, M. Liu and C.E. Inturrisi, Meperidine pharmacokinetics in the maternal¯fetal unit. J. Pharmacol. Exp. Ther.206 (1978), pp. 448¯459. EMBASE
*1 Review for the European Journal of Obstetrics and Gynaecology and Reproductive Biology. Presented at `Invasive Fetal Diagnosis and Therapy in the Third Millennium', a Joint Eurofetus/National Institute of Child Health and Human Development Meeting.
Corresponding author. Tel.: +44-208-383-3190; fax: +44-208-748-6311; email: firstname.lastname@example.org
Do Fetuses Feel Pain During An Abortion?by Stuart Derbyshire Research fellow in neuropsychology, Rheumatic Diseases Centre, University of Manchester This issue was the subject of four articles in the Britsh Medical Journal 27 September 1996
The issue of whether fetuses feel pain has recently been raised repeatedly as a cause of concern by anti-choice parliamentarians (see Abortion Review no 56).
In July, David Alton MP (Lib Dem: Liverpool Mossley Hill) secured an adjournment debate during which he argued that the Department of Health should take action on the matter. `First,' he suggested, `a circular could be issued to health authorities and to doctors, drawing their attention to the conclusions of latest research and recommending action to anaesthetise foetuses before any invasive procedure, such as needling or uterine surgery liable to cause trauma to the fetus. Secondly, in the interest of a fully informed decision, any parents who are considering giving permission for such procedures should be alerted to the possibility that pain will be inflicted on their unborn child.' Failing the introduction of such measures Alton warned that `legislation may be the only way to ensure that the suffering and the pain currently inflicted on the foetus will be alleviated'.
This debate was accompanied by an Early Day Motion, eventually signed by eleven MPs calling on the Department of Health to disseminate information `to medical staff and mothers and come forward with proposals for avoiding pain in pre-term surgery and abortion'.
Alton has suggested that it should be made a criminal offence to inflict pain on the unborn child and has announced his intention to seek legislative amendments and changes in codes of practice to secure this.
Currently the Government does not appear to accept that there is a need for legislation, although in replying to David Alton's motion, Health Minister, the Hon Tom Sackville MP (Con: Bolton W) suggested that there may be a need for more research on abortions after 24 weeks gestation. Nor does the Government appear to accept the anti-choice interpretation of current research. It was notable that Sackville used the opportunity of the adjournment debate to stress that the conclusions of a recent report commissioned by the Department of Health `do not support the view that before 26 weeks, foetuses feel or perceive pain.'
However, this is unlikely to be the final word on the matter. Following this statement a Department of Health spokesperson reportedly told the Catholic Herald that the Government was aware of `considerable diversity of opinion within society and the medical profession. The Government does not have one view on foetal sentience; they listen to a whole range of opinions-personal, medical and scientific.' Newspapers have reported that Alton is determined to make legislation on fetal pain an issue for the next parliamentary term.
The anti-choice concern about fetal sentience or pain is clearly a tactic to undermine public confidence in the current abortion legislation and to exploit understandable concern that the abortion procedure should not cause suffering. It is a rather disingenuous stance, as those who promote it-being opposed to abortion in principle-would not support abortion even if it were clearly established that the fetus were incapable of any awareness.
The anti-choice movement do not primarily oppose abortion on the grounds that the fetus feels pain any more than the pro-choice movement support a woman's right to abortion on the grounds that the fetus does not feel pain. Both perspectives are informed by other concerns.
However, given the claims by those who oppose abortion on principle that science supports their views, it is useful to examine the relevant research closely. Such an examination supports Sackville's assertion that before 26 weeks gestation (and arguably after this time), fetuses do not feel pain.
The research to which Sackville referred in the Adjournment Debate was commissioned by the Department of Health, and presented to them in May 1995 by Maria Fitzgerald, Professor of Developmental Neurobiology in the Department of Anatomy and Developmental Biology at University College London. Fitzgerald had been asked to review the current medical knowledge in this area.
Through an examination of the biological development of the fetus, Fitzgerald first rules out the possibility of fetal pain prior to 26 weeks gestation. Those who argue that a fetus can feel pain early in gestation point to experiments which show that a fetus responds to touching at 7.5 weeks. At this point touching the mouth or the surrounding region results in the fetus bending its head away. Similar responses can be observed with the hands at 10.5 weeks and the rest of the body and lower limbs at approximately 13.5 weeks. Shortly after the development of touch sensitivity repeated skin stimulation results in a generalised movement of all limbs, which gives the impression that the fetus is stressed and is taken by some as experience of pain.
This movement is however, understood to be a reflex response, not dependent on a conscious appreciation of pain. Fitzgerald states that, prior to 26 weeks gestation, `any discussion of "perception" or "conscious" reaction to stimuli is inappropriate'. She writes that: `t is important to emphasise the movements evoked at this stage are of a reflex or spontaneous nature only, even if they involve extensive body regions and therefore inter-segmental and brainstem connections. The cortex is not a functional unit at this stage ... and therefore any discussion of "perception" or "conscious reaction" is inappropriate.'
Summarising her paper she clearly states that `evidence shows that little sensory input reaches the developing cortex before 26 weeks and therefore these reactions to noxious stimuli cannot be interpreted as feeling or perceiving pain.'
This is important as it undermines the broader aim of those who oppose abortion to use this research to challenge the provision of abortion at earlier gestations.
Abortions later than 26 weeks gestation are very uncommon. In 1992 just 60, of more than 150,000 abortions in England and Wales were carried out at gestations later than 24 weeks. Nevertheless, the possible fetal response in these few late terminations warrants attention, particularly as almost all of these abortions are carried out for reasons of fetal handicap and are of wanted pregnancies in circumstances where the putative parents are often very emotionally vulnerable.
Fitzgerald becomes more equivocal regarding the possibility of fetal pain once the fetus passes 26 weeks gestation. This is because the nerve fibres which are believed to be responsible for passing `pain messages' begin to reach the higher brain areas at 26-34 weeks gestation. Fitzgerald's suggestion that responses to noxious stimuli prior to 26 weeks cannot be interpreted as pain because the brain `is not a functional unit' begs the question of whether the biological development of the fetus is so advanced after this time that it may now be able to experience pain. This point remains controversial among those who work in pain research.
It can be argued that the capacity of the fetus to feel pain hinges not on its biological development but on its conscious development, and that unless it can be demonstrated that the fetus has a conscious appreciation of pain post-26 weeks gestation, then the responses to noxious stimulation are still essentially reflex responses, exactly as those prior to 26 weeks. Fitzgerald does not address this point. However, the suggestion that there is a direct relationship between stimulus and pain-even in adults-is hugely controversial.
The idea that pain occurs as a direct consequence of an injury in the same way that a bell rings as a direct result of pulling a bellrope is one that is accepted by many lay-people, but no longer holds much currency with those researching into pain mechanisms. Those working with, or researching into pain have largely rejected the concept of a specific `pain line' associated with a `pain centre'. This `specificity theory' has been rejected because the definition of pain based on a direct relationship between injury and response failed to resolve many issues in pain research. Interpretations of injury based on a direct relationship between stimulus and pain are inadequate because they fail to account for the variable link between stimulus and pain experience. Specificity theory cannot explain, for example, why soldiers wounded in battle rarely ask for analgesia in comparison with civilians wounded in accidents, why patients after amputation complain of pain in their `phantom-limb', or why people can sometimes sustain major injury without experiencing pain. The variable link between pain and injury suggests that pain is a multidimensional experience incorporating emotional and cognitive factors.
Many pain specialists believe that in its later stages of development the fetal brain begins gradually to organise and elaborate stimulus information by encoding the memory of the activation of reflex motor responses. At this point the fetus may begin to show evidence of knowledge as to which things may result in reflex aversive movement. This `knowledge' however, is still unconscious. Conscious sensory experience and associated voluntary response is proposed to arise over time as a result of self-observation and efforts to cope with arousing situations. While some biological development is obviously necessary for this stage to be realised, it is a mistake to say that biological development is sufficient. The capacity to experience pain is part of a developmental process which the fetus is yet to experience. Many specialists believe that the final necessary stages in the experience of pain can only develop after a child has been born and it is mistaken to refer to `fetal pain' at any stage of development. Dr Fitzgerald suggests in her paper that `true pain experience' develops `postnatally along with memory, anxiety, and other cognitive brain functions'.
David Alton obviously disputes this interpretation and anticipated it in his adjournment debate speech claiming that it was `bunkum' and relied on an understanding of pain as a `metaphysical experience' and not as he believes `a physical fact'. It should be noted that in this interpretation he is relying on outdated theories which are at odds with the theories of those who are currently working in this field.
THE NEW ENGLAND JOURNAL OF MEDICINE, Volume 317, Number 21: Pages 1321-1329,19 November 1987.PAIN AND ITS EFFECTS IN THE HUMAN NEONATE AND FETUSK.J.S. ANAND, M.B.B.S., D.PHIL., AND P.R. HICKEY, M.D
From the Department of Anesthesia, Harvard Medical School, and Children's Hospital, Boston. Address reprint requests to Dr. Anand at the Department of Anesthesia, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
THE evaluation of pain in the human fetus and neonate is difficult because pain is generally defined as a subjective phenomenon.1 Early studies of neurologic development concluded that neonatal responses to painful stimuli were decorticate in nature and that perception or localization of pain was not present.2 Furthermore, because neonates may not have memories of painful experiences, they were not thought capable of interpreting pain in a manner similar to that of adults.3-5 On a theoretical basis, it was also argued that a high threshold of painful stimuli may be adaptive in protecting infants from pain during birth.6 These traditional views have led to a widespread belief in the medical community that the human neonate or fetus may not be capable of perceiving pain.7,8
Strictly speaking, nociceptive activity, rather than pain,should be discussed with regard to the neonate, because pain is a sensation with strong emotional associations. The focus on pain perception in neonates and confusion over its differentiation from nociceptive activity and the accompanying physiologic responses have obscured the mounting evidence that nociception is important in the biology of the neonate. This is true regardless of any philosophical view on consciousness and "pain perception" in newborns. In the literature, terms relating to pain and nociception are used interchangeably; in this review, no further distinction between the two will generally be made.
One result of the pervasive view of neonatal pain is that newborns are frequently not given analgesic or anesthetic agents during invasive procedures, including surgery.9-19 Despite recommendations to the contrary in textbooks on pediatric anesthesiology, the clinical practice of inducing minimal or no anesthesia in newborns, particularly if they are premature, is widespread.9-19 Unfortunately, recommendations on neonatal anesthesia are made without reference to recent data about the development of perceptual mechanisms of pain and the physiologic responses to nociceptive activity in preterm and full-term neonates. Even Robinson and Gregory's landmark paper demonstrating the safety of narcotic anesthesia in preterm neonates cites "philosophic objections" rather than any physiologic rationale as a basis for using this technique.20 Although methodologic and other issues related to the study of pain in neonates have been discussed,21-23 the body of scientific evidence regarding the mechanisms and effects of nociceptive activity in newborn infants has not been addressed directly.
ANATOMICAL AND FUNCTIONAL REQUIREMENTS FOR PAIN PERCEPTION The neural pathways for pain may be traced from sensory receptors in the skin to sensory areas in the cerebral cortex of newborn infants. The density of nociceptive nerve endings in the skin of newborns is similar to or greater than that in adult skin.24 Cutaneous sensory receptors appear in the perioral area of the human fetus in the 7th week of gestation; they spread to the rest of the face, the palms of the hands, and the soles of the feet by the 11th week, to the trunk and proximal parts of the arms and legs by the 15th week, and to all cutaneous and mucous surfaces by the 20th week.25,26 The spread of cutaneous receptors is preceded by the development of synapses between sensory fibers and interneurons in the dorsal horn of the spinal cord, which first appear during the sixth week of gestation.27,28 Recent studies using electron microscopy and immunocytochemical methods show that the development of various types of cells in the dorsal horn (along with their laminar arrangement, synaptic interconnections, and specific neurotransmitter vesicles) begins before 13 to 14 weeks of gestation and is completed by 30 weeks.29
Lack of myelination has been proposed as an index of the lack of maturity in the neonatal nervous system30 and is used frequently to support the argument that premature or full-term neonates are not capable of pain perception.9-19 However, even in the peripheral nerves of adults, nociceptive impulses are carried through unmyelinate (C-polymodal) and thinly myelinated (A-delta) fibers.31 Incomplete myelination merely implies a slower conduction velocity in the nerves or central nerve tracts of neonates, which is offset completely by the shorter interneuron and neuromuscular distances traveled by the impulse.32 Moreover, quantitative neuroanatomical data have shown that nociceptive nerve tracts in the spinal cord and central nervous system undergo complete myelination during the second and third trimesters of gestation. Pain pathways to the brain stem and thalamus are completely myelinated by 30 weeks; whereas the thalamocortical pain fibers in the posterior limb of the internal capsule and corona radiata are myelinated by 37 weeks.33
Development of the fetal neocortex begins at 8 weeks gestation, and by 20 weeks each cortex has a full complement of 109 neurons.34 The dendritic processes of the cortical neurons undergo profuse arborizations and develop synaptic targets for the incoming thalamocortical fibers and intracortical connections.35,36 The timing of the thalamocortical connection is of crucial importance for cortical perception, since most sensory pathways to the neocortex have synapses in the thalamus. Studies of primate and human fetuses have shown that afferent neurons in the thalamus produce axons that arrive in the cerebrum before mid-gestation. These fibers then "wait" just below the neocortex until migration and dendritic arborization of cortical neurons are complete and finally establish synaptic connections between 20 and 24 weeks of gestation (Fig. 1).36-38
Functional maturity of the cerebral cortex is suggested by fetal and a neonatal electroencephalographic patterns, studies of cerebral metabolism, and the behavioral development of neonates. First, intermittent electroencephalograpic bursts in both cerebral hemispheres are first seen at 20 weeks gestation; they become sustained at 22 weeks and bilaterally synchronous at 26 to 27 weeks.39 By 30 weeks, the distinction between wakefulness and sleep can be made on the basis of electroencephalo- graphic patterns.39,40 Cortical components of visual and auditory evoked potentials have been recorded in preterm babies (born earlier than 30 weeks of gestation),40,41 whereas olfactory and tactile stimuli may also cause detectable changes in electroencephalograms of neonates.40,42 Second, in vivo measurements of cerebral glucose utilization have shown that maximal metabolic activity in located in sensory areas of the brain in neonates (the sensorimotor cortex, thalamus, and mid brain- brain-stem regions), further suggesting the functional maturity of these regions.43 Third, several forms of behavior imply cortical function during fetal life. Well-defined periods of quiet sleep, active sleep, and wakefulness occur in utero beginning at 28 weeks of gestation.44 In addition to the specific behavioral responses to pain described below, preterm and full-term babies have various cognitive, coordinative, and associative capabilities in response to visual and auditory stimuli, leaving no doubt about the presence of cortical function.45
Several lines of evidence suggest that the complete nervous system is active during prenatal development and that detrimental and developmental changes in any part would affect the entire system.25,26,42,46 In studies in animals, Ralston found that somatosensory neurons of the neocortex respond to peripheral noxious stimuli and proposed that "it does not appear necessary to postulate a subcortical mechanism for appreciation of pain in the fetus or neonate."47 Thus, human newborns do have the anatomical and functional components required for the perception of painful stimuli. Since these stimuli may undergo selective transmission, inhibition, or modulation by various neurotransmitters, the neurochemical mechanisms associated with pain pathways in the fetus and newborn are considered below.
NEUROCHEMICAL SYSTEMS ASSOCIATED WITH PAIN PERCEPTIONThe Tachykinin System
Various putative neurotransmitters called the tachykinins (substance P, neurokinin A, neuromedin K, and so forth) have been identified in the central nervous system, but only substance P has been investigated thoroughly and shown to have a role in the transmission and control of pain impulses.48-56 Neural elements containing substance P and its receptors appear in the dorsal-root ganglia and dorsal horns of the spinal cord at 12 to 16 weeks of gestation.57 A high density of substance P fibers and cells have been observed in multiple areas of the fetal bran stem associated with pathways for pain perception and control and visceral reactions to pain.58-63 Substance P fibers and cells have also been found in the hypothalamus, mamillary bodies, thalamus, and cerebral cortex of human fetuses early in the development.58 Many studies have found higher densities of substance P and it receptors in neonates than in adults of the same species, although the importance of this finding is unclear.61,64-68
The Endogenous Opioid System
With the demonstration of the existence of stereospecific opiate receptors69,70 and their endogenous ligands,71 the control of pain was suggested as a primary role for the endogenous opioid system.72 Both the enkephalinergic and the endorphinergic systems may modulate pain transmission at spinal and supraspinal levels.56,73 In the human fetus, however, there are no data on the ontogeny and distribution of specific cells, fibers, and receptors (mu-, delta-, and kappa opiate receptors) that are thought to mediate the antinociceptive effects of exogenous and endogenous opioids.74 However, functionally mature endorphinergic cells in fetal pituitary glands have been observed at 15 weeks of gestation and possibly earlier.75,76 Beta-endorphin and beta-lipotropin were found to be secreted from fetal pituitary cells at 20 weeks in response to in vitro stimulation by corticotropin- releasing factor.77 In addition, more production of beta-endorphin may occur in fetal and neonatal pituitary glands than in adult glands.78-79
Endogenous opioids are released in the human fetus at birth and in response to fetal and neonatal distress.80 Umbilical-cord plasma levels of beta-endorphin and beta-lipotropin from healthy full-term neonates delivered vaginally or by cesarean section have been shown to be three to five times higher than plasma levels in resting adults.78,81 Neonates delivered vaginally by breech presentation or vacuum extraction had further increases in beta-endorphin levels, indication beta-endorphin secretion in response to stress at birth.82 Plasma beta-endorphin concentrations correlated negatively with umbilical-artery pH and partial pressure of oxygen and positively with base deficit and partial pressure of carbon dioxide, suggesting that birth asphyxia may be a potent stimulus to the release of endogenous opioids.81,83-87 Cerebrospinal fluid levels of beta-endorphin were also increased markedly in newborns with apnea of prematurity,88-90 infections, or hypoxemia.83,91,92 These elevated values may have been caused by the "stress" of illness,93 the pain associated with these clinical conditions, or the invasive procedures required for their treatment. However, these high levels of beta-endorphin are unlikely to decrease anesthetic or analgesic requirements,94 because the cerebrospinal fluid levels of beta-endorphin required to produce analgesia in human adults have been found to be 10,000 times higher than the highest recorded levels in neonates.95
The high levels of beta-endorphin and beta-lipotropin in cord plasma decreased substantially by 24 hours after birth87,96 and reached adult levels by five days, whereas the levels in the cerebrospinal fluid fell to adult values in 24 hours.87,97,98 In newborn infants of women addicted to narcotics, massive increases in plasma concentrations of beta-endorphin, beta-lipotropin, and metenkephalin occurred within 24 hours, with some values reaching 1000 times those in resting adults. Markedly increased levels persisted for up to 40 days after birth.87 However, these neonates were considered to be clinically normal, and no behavioral effects were observed (probably because of the development of prenatal opiate tolerance).
PHYSIOLOGIC CHANGES ASSOCIATED WITH PAINCardiorespiratory Changes
Changes in cardiovascular variables, transcutaneous partial pressure of oxygen, and palmar sweating have been observed in neonates undergoing painful clinical procedures. In preterm and full-term neonates undergoing circumcision99,100 or heel lancing,101-103 marked increases in the heart rate and blood pressure occurred during and after the procedure. The magnitude of changes in the heart rate was related to the intensity and duration of the stimulus104 and to the individual temperaments of the babies.105 The administration of local anesthesia to full-term neonates undergoing circumcision prevented the changes in heart rate and blood pressure,99,100,106 whereas giving a "pacifier" to preterm neonates during heel-stick procedures did not alter their cardiovascular or respiratory responses to pain.101 Further studies in newborn and older infants showed that noxious stimuli were associated with an increase in heart rate, whereas non-noxious stimuli (which elicited the attention or orientation of infants) caused a decrease in heart rate.22,107,108
Large fluctuations in transcutaneous partial pressure of oxygen above and below an arbitrary "safe" range of 50 to 100 mm Hg have been observed during various surgical procedures in neonates.109-111 Marked decreases in transcutaneous partial pressure of oxygen also occurred during circumcision,106,112 but such changes were prevented in neonates given local analgesic agents.100,106,112 Tracheal intubation in awake preterm and full-term neonates caused a significant decrease in transcutaneous partial pressure of oxygen, together with increases in arterial blood pressure113-115 and intracranial pressure.116 The increases in intracranial pressure with intubation were abolished in preterm neonates who were anesthetized.117 In addition, infants' cardiovascular responses to tracheal suctioning were abolished by opiate-induced analgesia.118
Palmar sweating has also been validated as a physiologic measure of the emotional state in full-term babies and has been closely related to their state of arousal and crying activity. Substantial changes in palmar sweating were observed in neonates undergoing heel-sticks for blood sampling, and subsequently, a mechanical method of heel lancing proved to be less painful than manual methods, on the basis of the amount of palmar sweating.120
Hormonal and Metabolic Changes
Hormonal and metabolic changes have been measured primarily in neonates undergoing surgery, although there are limited data on the neonatal responses to venipuncture and other minor procedures. Plasma renin activity increased significantly 5 minutes after venipuncture in full-term neonates and returned to basal levels 60 minutes thereafter; no changes occurred in the plasma levels of cortisol, epinephrine, or norepinephrine after venipuncture.121 In preterm neonates receiving ventilation therapy, chest physiotherapy and endotracheal suctioning produced significant increases in plasma epinephrine and norepinephrine; this response was decreased in sedated infants.122 In neonates undergoing circumcision without anesthesia, plasma cortisol levels increased markedly during and after the procedure.123,124 Similar changes in cortisol levels were not inhibited in a small number of neonates given a local anesthetic,125 but the efficacy of the nerve block was questionable in these cases.
Further detailed hormonal studies126 in preterm and full-term neonates who underwent surgery under minimal anesthesia documented a marked release of catecho- lamines,127 growth hormone,128 glucagon,127 cortisol, aldosterone, and other corticosteroids,129,130 as well as suppression of insulin secretion.131 These responses resulted in the breakdown of carbohydrate and fat stores,127,132,133 leading to severe and prolonged hyperglycemia and marked increases in blood lactate, pyruvate, total ketone bodies, and nonesterified fatty acids. Increased protein breakdown was documented during and after surgery by changes in plasma amino acids, elevated nitrogen excretion, and increased 3-methyl- histidine:creatinine ratios in the urine (Anand KJS, Aynsley-Green A: unpublished data). Marked differences also occurred between the stress responses of premature and full-term neonates (Anand KJS, Aynsley-Green A: unpublished data) and between the responses of neonates undergoing different degrees of surgical stress.134 Possibly because of the lack of deep anesthesia, neonatal stress responses were found to be three to five times greater than those in adults, although the duration was shorter.126 These stress responses could be inhibited by potent anesthetics, as demonstrated by randomized, controlled trials of halothane and fentanyl. These trials showed that endocrine and metabolic stress responses were decreased by halothane anesthesia in full-term neonates 35 and abolished by low-dose fentanyl anesthesia in preterm neonates.136 The stress responses of neonates undergoing cardiac surgery were also decreased in randomized trials of high-dose fentanyl and sufentanil anesthesia.126,137,138 These results indicated that the nociceptive stimuli during surgery performed with minimal anesthesia were responsible for the massive stress responses of neonates. Neonates who were given potent anesthetics in these randomized trials were more clinically stable during surgery and had fewer postoperative complications as compared with neonates under minimal anesthesia.126,129 There is preliminary evidence that the pathologic stress responses of neonates under light anesthesia during major cardiac surgery may be associated with an increased postoperative morbidity and mortality (Anand KJS, Hickey PR: unpublished data). Changes in plasma stress hormones (e.g., cortisol) can also be correlated with the behavioral states of newborn infants,124,139,140 which are important in the postulation of overt subjective distress in neonates responding to pain.
BEHAVIORAL CHANGES ASSOCIATED WITH PAIN PERCEPTIONSimple Motor Responses
Early studies of the motor responses of newborn infants to pinpricks reported that the babies responded with a "diffuse body movement" rather than a purposeful withdrawal of the limb,2 whereas other studies found reflex withdrawal to be the most common response.141-143 More recently, the motor responses of 24 healthy full-term neonates to a pinprick in the leg were reported to be flexion and adduction of the upper and lower limbs associated with grimacing, crying, or both, and these responses were subsequently quantified.144,145 Similar responses have also been documented in very premature neonates, and in a recent study, Fitzgerald et al. found that premature neonates (<30 weeks) not only had lower thresholds for a flexor response but also had increased sensitization after repeated stimulation.146
Distinct facial expressions are associated with pleasure, pain, sadness, and surprise in infants.147 These expressions, especially those associated with pain, have been objectively classified and validated in a study of infants being immunized.102,148 With use of another method of objectively classifying facial expressions of neonates, different responses were observed with different techniques of heel lancing and with different behavioral states149 (and Grunau RVE, Craig KD: unpublished data). These findings suggest that the neonatal response to pain is complex and may be altered by the behavioral state and other factors at the time of the stimulus.150
Crying is the primary method of communication in newborn infants and is also elicited by stimuli other than pain.151 Several studies have classified infant crying according to the type of distress indicated and its spectrographic properties.152-154 These studies have shown that cries due to pain, hunger, or fear can be distinguished reliably by the subjective evaluation of trained observers and by spectrographic analysis.155-160 This has allowed the cry response to be used as a measure of pain in numerous recent studies. 22,99,100,102,106,152
The pain cry has specific behavioral characteristics and spectrographic properties in healthy full-term neonates.161-164 Pain cries of preterm neonates and neonates with neurologic impairment, hyperbilirubinemia, or meningitis are considerably different, thereby indicating altered cortical function in these babies.165-168 Changes in the patterns of neonatal cries have been correlated with the intensity of pain experienced during circumcision and were accurately differentiated by adult listeners.169 In other studies of the painful procedures, neonates were found to he more sensitive to pain than older infants (those 3 to 12 months old) but had similar latency periods between exposure to a painful stimulus and crying or another motor response.99-101,103,152,170 This supports the contention that slower conduction speed in the nerves of neonates is offset by the smaller inter-neuron distances traveled by the impulse.
Complex Behavioral Responses
Alterations in complex behavior and sleep-wake cycles have been studied mainly in newborn infants undergoing circumcision without anesthesia. Emde and coworkers observed that painful procedures were followed by prolonged periods of non-rapid-eye-movement sleep in newborns and confirmed these observations in a controlled study of neonates undergoing circumcision without anesthesia.171 Similar observations have been made in adults with prolonged stress. Other subsequent studies have found increased wakefulness and irritability for an hour after circumcision, an altered arousal level in circumcised male infants as compared with female and uncircumcised male infants, and an altered sleep-wake state in neonates undergoing heel-stick procedures.103,172,173 In a double-blind, randomized controlled study using the Brazelton Neonatal Behavioral Assessment Scale, 90 percent of neonates had changed behavioral states for more than 22 hours after circumcision, whereas only 16 percent of the uncircumcised infants did.174 It was therefore proposed that such painful procedures may have prolonged effects on the neurologic and psychosocial development of neonates.175 A similar randomized study showed the absence of these behavioral changes in neonates given local anesthetics for circumcision.176 For two days after circumcision, neonates who had received anesthetics were more attentive to various stimuli and had greater orientation, better motor responses, decreased irritability, and a greater ability to quiet themselves when disturbed. A recent controlled study showed that intervention designed to decrease the amount of sensory input and the intensity of stressful stimuli during intensive care of preterm neonates was associated with improved clinical and developmental outcomes.177 Because of their social validity and communicational specificity, the behavioral responses observed suggest that the neonatal response to pain is not just a reflex response.178-180
MEMORY OF PAIN IN NEONATES The persistence of specific behavioral changes after circumcision in neonates implies the presence of memory. In the short term, these behavioral changes may disrupt the adaptation of newborn infants to their postnatal environment,174-176 the development of parent-infant bonding, and feeding schedules.182,183 In the long term, painful experiences in neonates could possibly lead to psychological sequelae,22 since several workers have shown that newborns may have a much greater capacity for memory than was previously thought.183-186
Pain itself cannot be remembered, even by adults187; only the experiences associated with pain can be recalled. However, the question of memory is important, since it has been argued that memory traces are necessary for the "maturation" of pain perception,3 and a painful experience may not be deemed important if it is not remembered. Long-term memory requires the functional integrity of the limbic system and diencephalon (specifically, the hippocampus, amygdala, anterior and mediodorsal thalamic nuclei, and mamillary nuclei)188; these structures are well developed and functioning during the newborn period.42 Furthermore, the cellular, synaptic, and molecular changes required for memory and learning depend on brain plasticity, which is known to be highest during the late prenatal and neonatal periods.189,190 Apart from excellent studies in animals demonstrating the long-term effects of sensory experiences in the neonatal period,191 evidence for memories of pain in human infants must, by necessity, be anecdotal.178,192,193 Early painful experiences may be stored in the phylogenically old "procedural memory," which is not accessible to conscious recall.182,183,194 Although Janov195 and Holden196 have collected clinical data that they claim indicate that adult neuroses or psychosomatic illnesses may have their origins in painful memories acquired during infancy or even neonatal life, their findings have not been substantiated or widely accepted by other workers.
CONCLUSIONS Numerous lines of evidence suggest that even in the human fetus, pain pathways as well as cortical and subcortical centers necessary for pain perception are well developed late in gestation, and the neurochemical systems now known to be associated with pain transmission and modulation are intact and functional. Physiologic responses to painful stimuli have been well documented in neonates of various gestational ages and are reflected in hormonal, metabolic, and cardiorespiratory changes similar to but greater than those observed in adult subjects. Other responses in newborn infants are suggestive of integrated emotional and behavioral responses to pain and are retained in memory long enough to modify subsequent behavior patterns.
None of the data cited herein tell us whether neonatal nociceptive activity and associated responses are experienced subjectively by the neonate as pain similar to that experienced by older children and adults. However, the evidence does show that marked nociceptive activity clearly constitutes a physiologic and perhaps even a psychological form of stress in premature or full-term neonates. Attenuation of the deleterious effects of pathologic neonatal stress responses by the use of various anesthetic techniques has now been demonstrated. Recent editorials addressing these issues have promulgated a wide range of opinions, without reviewing all the available evidence.197-201 The evidence summarized in this paper provides a physiologic rationale for evaluating the risks of sedation, analgesia, local anesthesia, or general anesthesia during invasive procedures in neonates and young infants. Like persons caring for patients of other ages, those caring for neonates must evaluate the risks and benefits of using analgesic and anesthetic techniques in individual patients. However, in decisions about the use of these techniques, current knowledge suggests that humane considerations should apply as forcefully to the care of neonates and young, nonverbal infants as they do to children and adults in similar painful and stressful situations.
REFERENCESMenskey H, Albe-Fessard DG, Bonica JJ, et al. Pain terms: a list with definitions and notes on usage: recommended by the IASP Subcommittee on Taxonomy. Pain 1979; 6:249-52. McGraw MD. The neuromuscular maturation of the human infant. New York: Columbia University Press, 1943. Merskey H. On the development of pain. Headache 1970; 10:116-23. Levy DM. The infant's earliest memory of inoculation: a contribution to public health procedures. J Gen Psychol 1960; 96:3-46. Harris FC, Lahey BB. A method for combining occurrence and nonoccurrence interobserver agreement scores. J Appl Behav Anal 1978; 11: 523-7. Bondy AS. Infancy. In: Gabel S, Erickson MT, eds. Child development and developmental disabilities. Boston: Little, Brown, 1980:3-19. Eland JM, Anderson JE. The experience of pain in children. In: Jacox AK, ed. Pain: a source book for nurses and other health professionals . Boston: Little, Brown, 1977:453-73. Wallerstein E. Circumcision: the uniquely American medical enigma. Urol Clin N Am 1985; 12:123- 32. Anand KJS, Aynsley-Green A. Metabolic and endocrine effects of surgical ligation of patent ductus arteriosus in the human preterm neonate: Are there implications for further improvement of postoperative outcome? Mod Probl Paediatr 1985; 23:143-57. Lippmann N, Nelson RJ, Emmanouilides GC, Diskin J, Thibeault DW. Ligation of patent ductus arteriosus in premature infants. Br J Anaesth 1976; 48:365-9. Shaw EA. Neonatal anaesthesia. Hosp Update 1982;8:423-34. Katz J. The question of circumcision. Int Surg 1977; 62:490-2. Swafford LI, Allan D. Pain relief in the pediatric patient. Med Clin North Am 1968; 52:131-6. Rees GJ. Anesthesia in the newborn. Br Med J 1950; 2:1419-22. Betts EK, Downes JJ. Anesthetic considerations in newborn surgery. Semin Anesth 1984; 3:59-74. Inkster JS. Paediatric anaesthesia and intensive care. Int Anesthesiol Clin 1978; 16:58-91. Norman EA. Pulse oximetry during repair of congenital diaphragmatic hernia. Br J Anaesth 1986; 58:934-5. Hatch DJ. Analgesia in the neonate. Br Med J 1987; 294:920. Shearer MH. Surgery on the paralysed, unanesthetized newborn. Birth 1986; 13:79. Robinson S, Gregory GA. Fentanyl-air-oxygen anesthesia for ligation of patent ductus arteriosus in preterm infants. Anesth Analg 1981; 60:331-4. Weiss C. Does circumcision of the newborn require an anesthetic? Clin Pediatr (Phila) 1968; 7:128-9. Owens ME. Pain in infancy: conceptual and methodological issues.Pain 1984; 20:213-30. Richards T. Can a fetus feel pain? Br Med J 1985; 291:1220-1. Gleiss J, Stuttgen G. Morphologic and functional development of the skin. In: Stave U, ed. Physiology of the perinatal period . Vol. 2. New York: Appleton-Century Crofts, 1970:889-906. Humphrey T. Some correlations between the appearance of human fetal reflexes and the development of the nervous system. Prog Brain Res 1964; 4:93-135. Valnaan HB, Pearson JF. What the fetus feels. Br Med J 1980; 280:233-4. Okado N. Onset of synapse formation in the human spinal cord. J Comp Neurol 1981; 201:211-9. Wozniak W, O'Rahilly R, Olszewska B. The fine structure of the spinal cord in human embryos and early fetuses. J Hirnforsch 1980; 21:101-24. Rievi T, Wadhwa S, Bijlani V. Development of spinal substrate for nociception. Pain Suppl 1987; 4:195. Tilney F, Rosett J. The value of brain lipoids as an index of brain development. Bull Neurol Inst NY 1931; 1:28-71. Schulte FJ. Neurophysiological aspects of brain development. Mead Johnson Symp Perinat Dev Med 1975; 6:38-47. Idem. Gestation, wachsturn und hirnentwicklung. In: Linneweh F, ed. Fortscritte der Paedologie. Vol. 2. Berlin: Springer-Verlag, 1968:46-64. Gilles FJ, Shankle W, Dooling EC. Myelinated tracts: growth patterns. In: Gilles FH, Leviton A, Dooling EC, eds. The developing human brain: growth and epidemiologic neuropathology. Boston: John Wright, 1983: 117-83. Marin-Padilla M. Structural organization of the human cerebral cortex prior to the appearance of the cortical plate. Anat Embryol (Berl) 1983; 168:21-40. Molliver ME, Kostovic I, Van der Loos H. The development of synapses in cerebral cortex of the human fetus. Brain Res 1973; 50:403-7. Rakic P, Goldman-Rakic PS. Development and modifiability of the cerebral cortex: early developmental effects: cell lineages, acquisition of neuronal positions, and areal and larninar development. Neurosci Res Prog Bull 1982; 20:433-51. Kostovic I, Rakic P. Development of prestriate visual projections in the monkey and human fetal cerebrum revealed by transient cholinesterase staining. J Neurosci 1984; 4:25-42. Kostovic I, Goldman-Rakic PS. Transient cholinesterase staining in the mediodorsal nucleus of the thalamus and its connections in the developing human and monkey brain. J Comp Neurol 1983; 219:431-47. Spehlmann R. In: EEG primer. New York: Elsevier/North-Holland, 1981:159-65. Torres F, Anderson C. The normal EEG of the human Newborn. J Clin Neurophysiol 1985; 2:89-103. Henderson-Smart DJ, Pettigrew AG, Campbell DJ. Clinical apnea and brain-stem neural function in preterm infants. N Engl J Med 1983; 308:353-7. Prechtl HFR, ed. Continuity of neural functions from prenatal to postnatal life. Oxford: Blackwell, 1984. Chugani HT, Phelps ME. Maturational changes in cerebral function in infants determined by 18FDG positron emission tomography. Science 1986; 231:840-3. Arduini D, Rizzo G, Giorlandino C, Valensise H, Dell'acqua S, Romanini C. The development of fetal behavioural states: A longitudinal study. Prenat Diagn 1986; 6:117-24. Sammons WAH. Premature behavior and the neonatal intensive care unit environment. In: Cloherty JP, Stark AR, eds. Manual of neonatal care. Boston: Little, Brown, 1980:359-63. Flower MJ. Neuromaturation of the human fetus. J Med Philos 1985; 10:237-51. Ralston HJ. Synaptic organization of spinothalamic projections to the thalamus, with special reference to pain. Adv Pain Res Ther 1984; 6:183-95. Nawa H, Hirose T, Takashima H, Inayama S, Nakanishi S. Nucleotide sequences of cloned cDNAs for two types of bovine brain substance P precursor. Nature 1983; 306:32-6. Watson SP, Sandberg BEB, Hanley MR, Iversen LL. Tissue selectivity of substance P alkyl esters: suggesting multiple receptors. Eur J Pharmacol 1983; 87:77-84. Mantyh PW, Maggio JE, Hunt SP. The autoradiographic distribution of kassinin and substance K binding sites is different from the distribution of substance P binding sites in rat brain. Eur J Pharmacol 1984;102:361-4. Valentino KL, Tatemoto K, Hunter J, Barchas JD. Distribution of neuropeptide K-immunoreactivity in the rat central nervous system. Peptides 1986: 7:1043-59. Pernow B. Substance P. Pharmacol Rev 1983; 35:85-141. Otsuka M, Konishi S. Substance P - the first peptide neurotransmitter? Trends Neurosci 1983; :317-20. Henry JL. Relation of substance P to pain transmission: neurophysiological evidence. In: Porter R, O'Connor M, eds. Substance P in the nervous system, Ciba Foundation Symposium 91. London: Pitman, 1982:206-24. Pearson J, Brandeis L, Cuello AC. Depletion of substance P-containing axons in substantia gelatinosa of patients with diminished pain sensitivity. Nature 1982; 295:61-3. Jessel T, Iversen LL. Opiate analgesics inhibit substance P release from rat trigeminal nucleus. Nature1977; 268:549-51. Chamay Y, Paulin C, Chayvialle J-A, Dubois PM. Distribution of substance P-like immunoreactivity in the spinal cord and dorsal root ganglia of the human foetus and infant. Neuroscience 1983; 10:41-55. Paulin C, Chamay Y, Dubois PM, Chayvialle J-A. Localisation de substance P dans le systeme nerveux du foetus humain: resultats preliminaires. C R Acad Sci Paris Series D 1980; 291:257-60. Pickel VM, Sumal KK, Reis DJ, Miller RI, Hervonen A. Immunocytochemical localization ofenkephalin and substance Pin the dorsal tegmental nuclei in the human fetal brain. J Comp Neurol 1980; 193:805-14. Roizen MF, Newfield P, Eger El II, Hosobuchi Y, Adams JE, Lamb S. Reduced anesthetic requirement after electrical stimulation of periaqueductal gray matter. Anesthesiology 1985; 62:120-3. Del Fiacco M, Dessi ML, Leranti MC. Topographical localization of sub-stance P in the human post-mortem brainstem: an immunohistochemical study in the newborn and adult tissue. Neuroscience 1984; 12:591-611. Nomura H, Shiosaka S, Inagaki S, et al. Distribution of substance P-like immunoreactivity in the lower brainstem of the human fetus: an immunohistochemical study. Brain Res 1982; 252:315-25. Helke CA, Charlton CG, Keeler JR. Bulbospinal substance P and sympathetic regulation of the cardiovascular system: a review. Peptides 1985; 6:Suppl 2:69-74. Inagaki S, Sakanaka M, Shiosaka S, et al. Ontogeny of substance P-containing neuron system of the rat: immunohistochemical analysis. Neuroscience 1982; 7:251-77, 1097-126. Quirion R, Dam T-V. Ontogeny of substance Preceptor binding sites in rat brain. J Neurosci 1986; 6:2187-99. Jonsson G, Hallman H. Substance P counteracts neurotoxin damage on norepinephrine neurons in rat brain during ontogeny. Science 1982; 215:75-7. Idem. Effect of substance P on neonatally axotomized noradrenaline neurons in rat brain. Med Biol 1983; 61:179-85. Narumi S, Fujita T. Stimulatory effects of substance P and nerve growth factor (NGF) on neurite outgrowth in embryonic chick dorsal root ganglia. Neuro-pharmacology 1978; 17:73-6. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973; 179:1011-4. Terenius L. Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex. Aeta Pharmacol Toxicol (Copenh) 1973; 32:317-20. Hughes J. Isolation of an endogenous compound from the brain with pharmacological properties similar to morphine. Brain Res 1975; 88:295-308. Jacob JJC, Ramabadran K. Role of opiate receptors and endogenous ligands in nociception. In: Williams NE, Wilson H, eds. Pain and its management. Oxford: Pergamon Press, 1983:13-32. Hosobuehi Y, Li CH. The analgesic activity of human beta-endorphin in man.Commun Psychopharmacol 1978; 2:33-7. Paterson DJ, Robson LE, Kosterlitz MW. Classification of opioid receptors. Br Med Bull 1983; 39:31-6. Bigeot M, Dubois MP, Dubois PM. Immunologic localization of a- and B-endorphins and B-lipotropin in corticotropic cells of the normal and an-encephalic fetal pituitaries. Cell Tissue Res 1978; 193:413-22. Li JY, Dubois MP, Dubois PM. Ultrastructural localization of immunoreactive corticotropin, B-lipotropin, a- and B-endorphin in cells of the human fetal anterior pituitary. Cell Tissue Res1979; 204:37-51. Gibbs DM, Stewart RD, Liu JH, Vale W, Rivier J, Yen SSC. Effects of synthetic corticotropin-releasing factor and dopamine on the release of immunoreactive B-endorphin/B-lipotropin and a-melanocyte-stimulating hormone from human fetal pituitaries in vitro. J Clin Endocrinol Metab 1982; 55:1149-52. Csontos K, Rust M, Hollt V, Mahr W, Kromer W, Teschemacher HJ. Elevated plasma B-endorphin levels in pregnant women and their neonates. Life Sci 1979; 25:835-44. Vuolteenaho 0, Leppaluoto J, Hoyhtya M, Hirvonen J. B-endorphin-like peptides in autopsy pituitaries from adults, neonates and foetuses. Acta Endocrinol (Copenh) 1983; 102:27-34. Gautray JP, Jolivet A, Vielh JP, Guillemin R. Presence of immunoassayable B-endorphin in human amniotic fluid: elevation in cases of fetal distress. Am J Obstet Gynecol 1977; 129:211-2. Wardlaw SL, Stark RI, Baxi L, Frantz AG. Plasma B-endorphin and B-lipotropin in the human fetus at delivery: correlation with arterial pM and pO2. J Clin Endocrinol Metab 1979; 49:888-91. Puolakisa J, Kauppila A, Leppaluoto J, Vuolteenaho 0. Elevated betaendorphin immunoreactivity in umbilical cord blood after complicated delivery. Acta Obstet Gynecol Scand 1982; 61:513-4. Shaaban MM, Hung TT, Hoffman Dl, Lobo RA, Goebelsmann U. B-endorphin and B-lipotropin concentrations in umbilical cord blood. Am J Obstet Gynecol 1982; 144:560-9. Browning AJF, Butt WR, Lynch SS, Shakespear RA, Crawford JS. Maternal and cord plasma concentrations of B-lipotropin, B-endorphin and y-lipotropin at delivery: effect of analgesia. Br J Obstet Gynecol 1983; 90:1152-6. Pohjavuori M, Rovamo L. Laatikainen T. Plasma immunoreactive B-endorphin and cortisol in the newborn infant after elective caesarean section and after spontaneous labour. Eur J Obstet Gynecol Reprod Biol 1985; 19:67-74. Pohjavuori M, Rovamo L, Laatikainen T, Kariniemi V, Pettersson J. Stress of delivery and plasma endorphins and catecholamines in the newborn infant. Biol Res Pregnancy Perinatol 1986; 7:1-5. Paneral AE, Martini A, Di Giulio AM, et al. Plasma B-endorphin, B-slipotropin, and met-enkephalin concentrations during pregnancy in normal and drug-addicted women and their newborn. J Clin Endocrinol Metab 1983; 57:537-43. MacDonald MG, Moss IR, Kefale GG, Ginzburg HM, Fink RI, Chin L. Effect of naltrexone on apnea of prematurity and on plasma beta-endorphin-like immunoreactivity. Dev Pharmacol Ther 1986; 9:301-9. Orlowski JP. Cerebrospinal fluid endorphins and the infant apnea syndrome. Pediatrics 1986; 78:233-7. Sankaran K, Hindmarsh KW, Watson VG. Plasma beta-endorphin Concentration in infants with apneic spells. Am J Perinatol 1984; 1:331-4. Hindmarsh KW, Sankaran K, Watson VG. Plasma beta-endorphin Concentrations in neonates associated with acute stress. Dev Pharinacol Ther 1984; 7:198-204. Sankaran K, Hindmarsh KW, Watson VG. Hypoxic-ischemic encephalopathy and plasma B-endorphin. Dev Pharmacol Ther 1984; 7:377-83, Hindmarsh KW, Sankaran K. Endorphins and the neonate. Can Med Assoc J 1985; 132:331-4. Lerman J, Robinson S, Willis MM, Gregory GA. Anesthetic requirements for halothane in young children 0-1 month and 1-6 months of age. Anesthesiology 1983; 59:421-4. Foley KM, Kourides IA1 Inturrisi CE, et al. B-endorphin: analgesic and hormonal effects in humans. Proc Natl Acad Sci USA 1979; 76:5377-81. Facchinetti F, Bagnoli F, Bracci R, Genazzani AR. Plasma opioids in the first hours of life. Pediatr Res 1982; 16:95-8. Moss IR, Conner H, Yee WFH, Iorio P, Scarpelli EM. Human B-endorphin-like immunoreactivity in the perinatal/neonatal period. J Pediatr 1982; 101:443-6. Burnard ED, Todd DA, John E, Hindmarsh KW. Beta-endorphin levels in newborn Cerebrospinal fluid. Aust Paediatr J 1982; 18:258-63. Williamson PS, Williamson ML. Physiologic stress reduction by a local anesthetic during newborn circumcision. Pediatrics 1983; 71:36-40. Holve RL, Bromberger BJ, Groverman HD, Klauber MR, Dixon SD, Snyder JM. Regional anesthesia during newborn circumcision: effect on infant pain response. Clin Pediatr (Phila) 1983; 22:813-8. Owens ME, Todt EH. Pain in infancy: neonatal reaction to a heel lance. Pain 1984; 20:77-86. Johnson CC, Strada ME. Acute pain response in infants: a multidimensional description. Pain 1986; 24:373-82. Field T, Goldson E. Pacifying effects of nonnutritive sucking on term and preterm neonates during heelstick procedures. Pediatrics 1984; 74:1012-5. Clifton RK, Graham FK, Hatton HM. Newborn heart-rate response and response habituation as a function of stimulus duration. J Exp Child Psychol 1968; 6:265-78. Kagan J. Heart rate and heart rate variability as signs of a temperamental dimension in infants. In: Izard CE, ed. Measuring emotions in infants and children. Cambridge: Cambridge University Press, 1982:38-66. Maxwell LG, Yaster M, Wetzel RC. Penile nerve block reduces the physiologic stress of newborn circumcision, Anesthesiology 1986; 65:A432. abstract. Berg KM Berg WK, Graham FK. Infant heart rate response as a function of stimulus and state. Psychophysiology 1971; 8:30-44. Campos JJ. Heart rate: a sensitive tool for the study of emotional develop-ment in the infant. In: Lipsitt LD, ed. Developmental psychobiology. Hillsdale, N.J.: Lawrence Erlbaum Associates, 1976:1-31. Weile P, Hayden W, Miller T. Continuous measurement of transcutaneous oxygen tension of neonates under general anesthesia. J Pediatr Surg 1980); 15:257-60. Venus B, Patel KC, Pratap KS, Konchigeri H, Vidyasagar D. Transcutaneous PO2 monitoring during pediatric surgery. Crit Care Med 1981; 9:714-6. Messner JT, Loux PC, Grossman LB. Intraoperative transcutaneous pO2 monitoring in infants. Anesthesiology 1979; 51:S319. abstract. Rawlings DJ, Miller PA, Engel RR. The effect of circumcision on transcutaneous PO2 in term infants. Am J Dis Child 1980; 134:676-8. Kelly MA, Finer NN. Nasotracheal intubation in the neonate: physiologic responses and effects of atropine and pancuronium. J Pediatr 1984; 105:303-9. Marshall TA, Deeder R, Pai S, Berkowitz GP, Austin TL. Physiologic changes associated with endotracheal intubation in preterm infants. Crit Care Med 1984; 12:501-3. Gibbons PA, Swedlow DB. Changes in oxygen saturation during elective tracheal intubation in infants. Anesth Analg 1986; 65:S58. abstract. Raju TNK, Vidyasagar D, Torres C, Grundy D, Bennett EJ. Intracranial pressure during intubation and anesthesia in infants. J Pediatr 1980; 96:860-2. Friesen RH, Honda AT, Thieme RE. Changes in anterior fontanel pressure in preterm neonates during tracheal intubation. Anesth Analg 1987; 66:874-8. Hickey PR, Hansen DD, Wessel DL, Lang P, Jonas RA, Elixson EM. Blunting of stress responses in the pulmonary circulation of infants by fentanyl. Anesth Analg 1985; 64:1137-42. Harpin VA, Rutter N. Development of emotional sweating in the newborn infant. Arch Dis Child 1982; 57:691-5. Idem. Making heel pricks less painful. Arch Dis Child 1983; 58:226-8. Fiselier T, Monnens L, Moerman E, Van Munster P, Jansen M, Peer P. Influence of the stress of venepuncture on basal levels of plasma renin activity in infants and children. Int J Pediatr Nephrol 1983; 4:181-5. Oreisen G, Frederiksen PS, Hertel J, Christensen NJ. Catecholamine response to chest physiotherapy and endotracheal suctioning in preterm infants. Acta Paediatr Scad 1985; 74:525-9. Talbert LM, Kraybill EN, Potter HD. Adrenal cortical response to circumcision in the neonate. Obstet Gynecol 1976; 48:208-10. Gunnar MR, Fisch RO, Korsvik S, Donhowe JM. The effects of circumcision on serum cortisol and behavior. Psychoneuroendocrinology 1981; 6:269-75. Williamson PS, Evans ND. Neonatal cortisol response to circumcision with anesthesia. Clin Pediatr (Phila) 1986; 25:412-5. Anand KJS. Hormonal and metabolic functions of neonates and infants undergoing surgery. Curr Opin Cardiol 1986; 1:681-9. Anand KJS, Brown MJ, Bloom SR, Aynsley-Green A. Studies on the hormonal regulation of fuel metabolism in the human newborn infant undergoing anaesthesia and surgery. Horm Res 1985; 22:115-28. Milne EMG, Elliott MJ, Pearson DT, Holden MP, Orskov H, Alberti KGMM. The effect on intermediary metabolism of open-heart surgery with deep hypothermia and circulatory arrest in infants of less than 10 kilograms body weight. Perfusion 1986; 1:29-40. Obara H, Sugiyama D, Maekawa N, et al. Plasma cortisol levels in paediatric anaesthesia. Can Anaesth Soc J 1984; 31:24-7. Srinivasan 0, Jain R, Pildes RS, Kannan CR. Glucose homeostasis during anesthesia and surgery in infants. J Pediatr Surg 1986; 21:718-21. Anand KJS, Brown MJ, Causon RC, Christofides ND, Bloom SR, Aynsley-green A. Can the human neonate mount an endocrine and metabolic response to surgery? J Pediatr Surg 1985; 20:41-8. Pintir A. The metabolic effects of anaesthesia and surgery in the newborn infant: changes in the blood levels of glucose, plasma free fatty acid amino-nitrogen, plasma amino-acid ratio and lactate in the neonat. Z Kinderchir 1973; 12:149-62. Elphick MC, Wilkinson AW. The effects of starvation and surgical injury on the plasma levels of glucose, free fatty acids, and neutral lipids in newborn babies suffering from various congenital anomalies. Pediatr Res 1981; 15.313-8. Anand KJS, Aynsley-Green A. Measuring the severity of surgical stress in newborn infants. J Pediatr Surg (in press). Idem. Does the newborn infant require anesthesia during surgery? Answers from a randomised trial of halothane anesthesia. Pain Res Clin Manage(in press). Anand KJS, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm neonates undergoing surgery: effects on the stress response. Lancet 1987; 1:243-8. Anand KJS, Carr DB, Hickey PR. Randomized trial of high-dose sufentanil anesthesia in neonates undergoing cardiac surgery: hormonal and hemodynamic stress responses. Anesthesiology 1987; 67:A50 abstract. Anand KJS, Hickey PR. Randomized trial of high-dose sufentanil anesthesia in neonates undergoing cardiac surgery: effects on the metabolic stress response. Anesthesiology 1987; 67: A502. abstract. Anders TF, Sachar EJ, Kream J, Roffwarg HP, Hellman L. Behavioral state and plasma cortisol response in the human newborn. Pediatrics 1970; 46:532-7. Tennes K, Carter D. Plasma cortisol levels and behavioral states in early infancy. Psychosom Med 1973; 35:121-8. Lipsitt LP, Levy N. Electrotactual threshold in the neonate. Child Dev 1959; 30:547-54. Dockeray FC, Rice C. Responses of newborn infants to pain stimulation. Ohio State Univ Stud Contrib Psychol 1934; 12:82-93. Sherman M, Sherman IC. Sensori-motor responses in infants. J Comp Psychol 1925; 5:53-68. Rich EC, Marshall RE, Volpe JJ. The normal neonatal response to pinprick. Dev Med Child Neurol 1974; 16:432-4. Franck LS. A new method to quantitatively describe pain behavior in infants. Nurs Res 1986; 35:28-31. Fitzgerald M, Shaw A, MacIntosh N. The postnatal development of the cutaneous flexor reflex: a comparative study in premature infants and newborn rat pups. Dev Med Child Neurol (in press). Ekman P, Oster H. Facial expressions of emotion. Annu Rev Psychol 1979; 30:527-54. Izard CE, Huebner RR, Risser D, McGinnes GC, Dougherty LM. The young infant's ability to produce discrete emotional expressions. Dev Psychol 1980; 16:132-40. Grunau RVE, Craig KD. Pain expression in neonates: facial action amd cry. Pain 1987; 28:395-410. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965 150:971-9. Lester BM. A biosocial model of infant crying. In: Lipsill L, ed. Advances in infancy research. New York: Ablex, 1984:167-212. Levine JD, Gordon NC. Pain in prelingual children and its evaluation pain-induced vocalisation. Pain 1982; 14:85-93. Wasz-Hockert 0, Lind J, Vuorenkoski V. The infant cry: a spectrographic and auditory analysis. Clin Dev Med 1968; 2:9-42. Michelsson K, Raes J, Thoden C-J, Wasz-Hockert 0. Sound spectrographic cry analysis in neonatal diagnostics: an evaluative study. J Phonetics 1982; 10:79-88. Zeskind PL, Sale J, Majo ML, Huntington L, Weisemari JR. Adult perceptions of pain and hunger cries: a synchrony of arousal. Child Dev 1985: 56:549-54. Boukydis CFZ. Perception of infant crying as an interpersonal event. In: Lester, BM, Boukydis CFZ, eds. Infant crying: theoretical and research perspectives. New York: Plenum Press, 1985:187-215. Muny T, Amundson P, Hollien H. Acoustical characteristics of infant cries fundamental frequency. J Child Lang 1977; 3:321-8. Wasz-Hockert 0, Partanen T, Vourenkoski V, Valanne E, Michelsson K. Effect of training on ability to identify preverbal vocalizations. Dev Med Child Neurol 1964; 6:393-6. Gladding ST. Effects of training Versus non-training in identification of cry-signals: a longitudinal study. Percept Mot Skills 1979; 48:752-4. Johnston CC, O'Shaugnessy D. Acoustical attributes of infant pain cries: discriminating features. Pain 1987; Suppl 4:233. Wolff PH. The natural history of crying and other vocalizations in early infancy. In: Foss BM, ed. Determinants of infant behaviour. Vol. 4. London: Methuen, 1969:88-295. Wasz-Hockert 0, Michelsson K, Lind J. Twenty-five years of Scandinavian cry research. In: Lester BM, Boukydis CFZ, eds. Infant crying: theoretical and research perspectives. New York: Plenum Press, 1985:83-104. Michelsson K, Jarvenpaa A-L, Rinne A. Sound spectrographic analysis of pain cry in preterm infants. Early Hum Dev 1983; 8:141-9. Friedman SL, Zahn-Waxler C, Radke-Yarrow M. Perceptions of cries of full-term and preterm infants. Infant Behav Dev 1982; 5:161-73. Michelsson K, Sirvio P, Wasz-Hockert 0. Pain cry in full-term asphyxiated newborn infants correlated with late findings. Acta Paediatr Scand 1977; 66:611-6. Fisichelli VR, Coxe M, Rosenfeld L, Haber A, Davis J, Karelitz S. The phonetic content of the cries; of normal infants and those with brain damage. J Psychol 1966; 64:119-26. Wasz-Hockert 0, Koivisto M, Vuorenkoski V, Partanen Ti, Lind J. Spectrographic analysis of pain cry in hyperbilirubinemia. Biol Neonate 1971; 17:260-71. Michelsson K, Sirvio P, Wasz-Hockert 0. Sound spectrographic cry analyses of infants with bacterial meningitis. Dev Med Child Neurol 1977; 19:309-15. Porter FL Miller RH, Marshall RE. Neonatal pain cries: effect of circumcision on acoustic features and perceived urgency. Child Dev 1986; 57:790-802. Fisichelli VR, Karelitz S, Fisichelli RM, Cooper J. The course of induced crying activity in the first year of life. Pediatr Res 1974; 8:921-8. Emde RN, Harmon RJ, Metcalf D, Koenig KL, Wagonfeld S. Stress and neonatal sleep. Psychosom Med 1971; 33:491-7. Anders TF, Chalemian RJ. The effects of circumcision on sleep-wake states in human neonates. Psychosom Med 1974; 36:174-9. Brackbill Y. Continuous stimulation and arousal level in infancy: effects of stimulus intensity and stress. Child Dev 1975; 46:364-9. Marshall RE, Stratton WC, Moore JA, Boxerman SB. Circumcision I: Effects upon newborn behaviour. Infant Behav Dev 1980; 3;1-14. Richards MPM, Bernal JF, Brackbill Y. Early behavioral differences: gender or circumcision? Dev Psychobiol 1976; 9:89-95. Dixon S, Snyder J, Holve R, Bromberger P. Behavioural effects of circumcision with and without anesthesia. J Dev Behav Pediatr 1984; 5:246-50. Als H, Lawhon G, Brown E, et al. Individualized behavioral and environmental care for the very low birth weight preterm infant at high risk for bronchopulmonary dysplasia: neonatal intensive care unit and developmental outcome. Pediatrics 1986; 78: 1123-32. Darwin C. The expression of the emotions in man and animals. London: John Murray, 1872:65-7. Kazdin AE. Assessing the clinical or applied importance of behavior change through social validation. Behav Modif 1977; 1:427-52. D'Apolito K. The neonate's response to pain. Am J Matern Child Nurs 1984; 9:256-8. Marshall RE, Porter FL, Rogers AU, Moore JA, Anderson B, Boxerman SB. Circumcision. II. Effects upon mother-infant interaction. Early Hum Dev 1982; 7:367-74. Osofsky JD. Neonatal characteristics and mother-infant interaction in two observational situations. Child Dev 1976; 47:1138-47. Lipsitt LP. The study of sensory and learning processes of the newborn. Clin Perinatol 1977; 4:163-86. Stone LJ, Smith H, Murphy LB, eds. The competent infant: research and commentary. New York: Basic Books, 1973. Moscovitch M. Infant memory; its relation to normal and pathological memory in humans and other animals. New York: Plenum Press, 1984. Kolata G. Early signs of school age IQ. Science 1987; 236:774-5. Jones E. Pain. Int J Psychoanal 1957; 38:255. Squire LR. Mechanisms of memory. Science 1986; 232:1612-9. Will B, Schmitt P, Dalrymple-Alford J. Brain plasticity, learning and memory: historical background and conceptiial perspectives. Adv.Behav Biol 1985; 28:1-11. Bischof H-J. Influence of developmental factors on imprinting. Behav Biol 1985; 28:51-9. Fillion TJ, Blass EM. Infantile experience with suckling odors determines adult sexual behavior in male rats. Science 1986; 231:729-31. Wachter-Shikora NL. Pain theories and their relevance to the pediatric population. Issues Compr Pediatr Nurs 1981; 5:321-6. Dale JC. A multidimensional study of infants' responses to painful stimuli. Pediatr Nurs 1986; 12:27-31. Reynolds 0E, Hutchins HC. Reduction of central hyper-irritability following block anesthesia of peripheral nerve. Am J Physiol 1948; 152:658-62. Janov A. The anatomy of mental illness. New York: Putnam's Sons, 1971. Holden EM. Primal pathophysiology. J Psychosom Res 1977; 21:341-50. abstract. Hatch DJ. Analgesia in the neonate. Br Med J 1987; 294:920. Berry FA, Gregory GA. Do premature infants require anesthesia for surgery? Anesthesiology 1987; 67:291-3. Booker PD. Postoperative analgesia for neonates? Anaesthesia 1987; 42:343-4. Pain, anaesthesia and babies. Lancet 1987; 2:543-5. Yaster M. Analgesia and anesthesia in neonates. J Pediatr 1987; 111:394-6.
The Science and Politics of Fetal Pain Commentary by Dr Stuart Derbyshire 4/9/00 The following paper was written in 1996, in response to the debate about whether fetuses feel pain. Comments or questions about it can be sent / e-mailed to the author at the addresses below. Stuart W. G. Derbyshire, Ph.D. Asst. Professor University of Pittsburgh Medical Center, PET Facility, Room B-938 PUH, 200 Lothrop Street, Pittsburgh, PA 15213-2582. Phone: 412-647-0736 Fax: 412-647-0700 email: email@example.com
The Science and Politics of Fetal pain - Doing the Wrong Thing?
In 1987, the Lancet published an article unequivocally demonstrating that neonates receiving fentanyl anaesthesia in preparation for surgery had improved clinical outcome as compared with neonates who only received nitrous oxide and curare (1). This research, and subsequent studies, (2)(3) led to a major reconsideration of analgesic practice with regard to neonates. In 1992, the New England Journal ran an editorial calling on clinicians to 'Do the Right Thing' concluding that 'it is our responsibility to treat pain in neonates and infants as effectively as we do in other patients'(4). Since then it has become common place to assume that neonates feel pain (5)(6). The assumption that neonates feel pain has led inevitably to speculation that the fetus may also experience pain (7). While the discussion about neonatal pain remained largely confined to the pages of medical texts, the discussion around fetal pain has attracted the attention of several major British newspapers and led the British parliament to discuss the curtailing of abortion (8)(9). Given the sensitivity of this issue in the United States (10), it is surely only a matter of time before this issue crosses the Atlantic. This article evaluates the evidence for and against fetal and neonatal pain and considers the implications for current clinical practice, abortion procedure and the contemporary understanding of pain.
The Evidence that the Fetus or Neonate can Feel Pain
Anand's seminal work on the use of fentanyl with neonates undergoing surgery demonstrated that the major hormonal response to invasive practice could be significantly reduced with fentanyl added to the anaesthetic regimen. Specifically it was demonstrated that plasma adrenalin, noradrenaline, glucagon, aldosterone, corticosterone, 11-deoxycorticosterone and 11-deoxycortisol levels were significantly greater in the non-fentanyl group than the fentanyl group up to 24 hours after surgery. The reduction of the 'stress response' to surgery by fentanyl was considered to be responsible for the improved clinical outcome of the fentanyl group who required less post-surgical ventilatory support and had reduced circulatory or metabolic complications. Anand and his colleagues later advanced these important and impressive findings in a report indicating that neonates receiving deep anaesthesia during surgery had improved post-operative morbidity compared with those neonates who received lighter anaesthesia. The reduced hormonal response and improved clinical outcome following invasive surgery in conjunction with anaesthetics used for pain relief in adults led naturally to the conclusion that the neonate could feel pain and that this pain needed to be controlled.
Dovetailing with the work of Anand and his colleagues was that of Fitzgerald. Fitzgerald has examined the developing nervous system of the rat and human fetus with special regard to the developmental neurobiology of pain (11)(12)(13). Fitzgerald has reviewed the biological development of the fetus and examined the possibility of fetal pain at each stage of development. The impression that a fetus experiences sensation is apparent at 7.5 weeks gestation when reflex responses to somatic stimuli begin. At this point touching the peri-oral region results in a contralateral bending of the head. The palms of the hands become sensitive to stroking at 10.5 weeks and the rest of the body and hindlimbs become sensitive at approximately 13.5 weeks. Shortly after the development of sensitivity, repeated skin stimulation results in hyperexcitability and a generalized movement of all limbs. This hyperexcitability has been interpreted as evidence for the presence of a functional pain system, reflecting an immature but intact pain response with early hypersensitivity to stimulation (14). This is not a view which is widely accepted, however, and is rejected by Fitzgerald herself. Prior to 26 weeks the thalamocortical fibres have not yet penetrated the cortical plate (15), and it seems unlikely, therefore, that the cortical structures considered necessary for pain are responding to noxious stimulation. The evidence for cortical involvement post 26 weeks is enhanced by behavioral studies which have demonstrated that the response to noxious stimulation becomes more focused and organized and can be better discriminated from other distress responses after 26 weeks (16). As with the hormonal response to surgery, the behavioral responses can be reduced with the use of appropriate anaesthetic adding support to the suggestion that these responses are related to pain perception (17).
Having established that the necessary neurobiology for pain is in place after 26 weeks and that behavioral responses to noxious stimulation are present in very premature babies of approximately 26 weeks gestation, it is logical to suggest that a fetus of 26 weeks gestation or more will launch a similar hormonal response to invasive practice as that observed in the neonate undergoing surgery. In 1994 Giannakoulopoulos and his colleagues from the Queen Charlottes Hospital in London, England successfully demonstrated that intrauterine needling to obtain a blood sample from fetuses of 20-34 weeks gestation resulted in a hormonal stress response analogous to that seen by Anand et al seven years previously (18). They demonstrated that needling the innervated intra-abdominal portion of the umbilical vein rather than the placental cord, which is not innervated, resulted in increased cortisol and -endorphin concentrations in fetal plasma. If this group can now demonstrate that the hormonal and neural 'stress response' can be prevented with the use of appropriate anesthetics then they will have mirrored the criteria which have led to the widespread acceptance of 'neonatal pain'.
The Evidence Against
The undisputed discovery that the neonate and fetus launch a hormonal and neural response to invasive practice can not be considered definitive proof that there is an experience of pain. An experience implies that sensations have been interpreted in a conscious manner. Even when combined with the observations of behavior and improved clinical outcome when using anesthetics, there is still no proof that there is an experience of pain. Although all of these phenomena are associated with the notion of 'pain', none of them adequately describe or explain the phenomenological experience of 'pain'. These phenomena may exist independently of conscious experience. The relationship between the physiological responses of nociceptors, the hormonal and other responses of the CNS and the behavioral outcome of these changes to the psychological response has yet to be determined (19).
Unless it can be reasonably suggested that the fetus has a conscious appreciation of pain post 26 weeks gestation, then the responses to noxious stimulation post 26 weeks are still essentially just behaviorally complex reflex responses, similar to the responses prior to 26 weeks. Despite the importance of providing evidence for the conscious appreciation of pain, the fetal and neonatal literature largely tries to ignore this issue. Anand, for example, highlighted the clinical findings with neonates as being of greater importance than 'any philosophical view on consciousness and 'pain perception''. Giannakoulopoulos et al distanced themselves from any implied fetal pain experience with the statement 'a hormonal response cannot be equated with the perception of pain'. In a report for the British Department of Health (Foetal pain: an update of current scientific knowledge. A paper for the Department of Health May 1995) Fitzgerald even went so far as to say that 'true pain experience postnatally along with memory, anxiety and other cognitive brain functions' leaving confusion as to what the 'untrue' pain experience of a fetus may be. More recently Lloyd-Thomas and Fitzgerald have suggested that if feeling and pain are properly understood then the fetus cannot be said to feel pain (20).
Such equivocation is perhaps not surprising in view of the general failure of material interpretations, i.e. interpretations which focus specifically upon the biological properties of human beings (21), to deliver a coherent account of human consciousness (22). Nevertheless, if a proper assessment of neonatal and fetal pain is to be undertaken, then we should examine the structure of the psychological experience 'pain', as the biological structures have been examined, and then work backwards to the fetus and neonate to decide whether it is likely or possible that these psychological structures are in place.
As Fitzgerald has identified, pain experience is now widely seen as a consequence of an amalgam of cognition, sensation and affective processes, this amalgam is commonly described under the rubric of the 'biopsychosocial' model of pain (23). Pain is no longer regarded as merely a physical sensation of noxious stimulus and disease, but is seen as a conscious experience which may be modulated by mental, emotional and sensory mechanisms and includes both sensory and emotional components. The whole biopsychosocial concept emphasizes the multidimensional nature of illness, injury and pain rather than emphasizing pain as purely a physical fact of illness or injury. Pain has been described as a multidimensional phenomena for some time (24) and this understanding is reflected in the current IASP (International Association for the Study of Pain) definition of pain as 'an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage' (25).
If this 'multidimensionality' is the basis of conscious pain experience, it seems unlikely that we can attribute this experience to the neonate or unborn fetus, which is naive as to all the cognitive, affective and evaluative experiences necessary for pain awareness. This is accepted in the current definition of pain that is further extended to state: 'pain is always subjective. Each individual learns the application of the word through experiences related to injury in early life.' Pain does not, so to speak, spring forth 'from the depths of the person's mind' prior to any experience, but is gradually formed as a consequence of general conscious development.
A further reason to doubt the viability of fetal pain post 26 weeks gestation is the development of the fetal cortex. Although it is true that the thalamocortical fibres penetrate the cortical plate at approximately 26 weeks gestation, the cortical regions which have been identified as important in processing the suffering components of pain (26)(27) do not become fully responsive until after birth (28). These structures, especially the anterior cingulate cortex (29), have a plasticity which allows for learning and adaptation and therefore retain the capacity to have a more dynamic relationship with conscious awareness. Interestingly, this capacity is not shared by the structures associated with sensory detection, such as the somatosensory cortex, which develop earlier but are less likely to have an involvement in the processes associated with pain experience. The concept of pain as a product of learning and adaptation is pursued in more detail under Implications for Pain Research.
The Implications for Current Clinical Practice
The debate about fetal pain need not affect clinical practice involving the fetus or neonate. Evidence that the stress response, which the fetus and new-born launches in response to physical insult, has known detrimental consequences is acceptable even to those who do not accept that pain is experienced. New borns who have been operated on without analgesia show increased mortality compared with new-borns who receive analgesia. There is also evidence that early physically stressing experiences may produce detrimental changes in later responses to potentially painful experience, such as inoculation (30). Therefore, in the cases of invasive practice where there is a clear clinical rational for the use of anesthetics, which does not rely upon the additional diagnosis of pain, the withholding of analgesia for fetus' and neonates should remain an unethical practice. As exciting advances in fetal surgery are being made continuously, it is imperative that similar clinically orientated research be carried out with the fetus.
Where the clinical advantage of anaesthetic is less clear, however, it is probably wise to avoid potentially dangerous procedures for the fetus or neonate, and probable uncomfortable procedures for the mother. There are those who argue that, while there is no consensus on this issue, clinicians should act according to the precautionary principle of assuming that pain is experienced until it is conclusively proved otherwise. However, as few clinical procedures are entirely risk free it seems more appropriate to reserve any form of intervention for occasions when it is known to be necessary.
A consideration of vaginal childbirth helps to place the discussion about fetal pain into some context. Childbirth is known to give rise to the hormonal and neural stress response which has been used as evidence for fetal and neonatal pain, this has led at least one popular British newspaper to run an article questioning whether babies feel pain during childbirth (31). It seems unlikely, however, that a process which the very vast majority of people have passed through is having long term detrimental consequences, and there is evidence which suggests the contrary to be the case (32)(33). It is still unknown exactly what the consequences of a hormonal stress response may be both for adults (34) and newborns. Under these circumstances an increase in relatively problematic anaesthetic, or even surgical practices such as caesarean section, to avoid fetal/neonatal 'pain' seems unnecessary and irrational (35)(36).
The Implications for Abortion Procedure
Fetal pain is obviously an important issue for those carrying out fetal operations and other invasive practices, but it is also of interest for those involved in abortion procedure and for those motivated to restrict the current abortion legislation. The broadly accepted conclusion that recorded responses to noxious stimulation prior to 26 weeks gestation are reflex responses, not dependent on conscious appreciation, is important as it eliminates much of the generated concern regarding abortion. In 1994 just 94 abortions, out of more than 160,000 carried out in the UK, were later than 24 weeks (37). If it is accepted that consciousness is essential to the pain experience, and that consciousness is contingent upon psychological development, it would follow that even after 24 weeks gestation it would be more appropriate to describe fetal reaction to stimuli as reflex responses than as pain.
Guidelines on the termination of pregnancy for fetal abnormality issued by the UK Royal College of Obstetricians and Gynaecologists (RCOG) draws on the work of Fitzgerald (1995) which suggests strongly that the immaturity of the fetal nervous system prevents conscious awareness of pain before 26 weeks gestation. The document argues that 'it follows that up to this gestation the method of abortion should be selected to minimise the physical and emotional trauma to the woman' (38).
Regardless of one's own views on whether late term induced abortions may cause pain to the fetus, the issue warrants special attention because almost all late terminations are of wanted pregnancies where the putative parents may be emotionally vulnerable. Often, during counselling, they express concern about what the fetus may 'feel' during an abortion. In these circumstances it is common for the putative parents to think of the fetus as a 'baby' and to attribute to it the qualities that they anticipated their child would have were it to be born. In such cases good sympathetic clinical practice would require steps to be taken to reduce the concerns of the woman.
In the UK, the RCOG recommends that measures to stop the fetal heart should be taken in all terminations after 21 weeks gestation. This is to ensure that there is no possibility of the abortion resulting in a live birth. After 26 weeks the guidelines suggest that it is not possible to know the extent to which the fetus is aware and so after this gestation it is suggested that 'methods used during abortion to stop the fetal heart should be swift and involve a minimum of injury to fetal tissue.' Even if the fetus is not aware, as we suggest, these guidelines would be appropriate to avoid unnecessary distress to the woman.
The paramount interests of the woman in abortion procedures is an important principle. Arguments that with viability the fetus becomes a patient and the doctors' responsibilities towards the woman need to be balanced against those of the fetal patient remain controversial (39)(40). The view that the pregnant woman is the patient while the fetus is cared for on behalf of the woman endures among many clinicians and is in my view the ethical stance (41)(42).
Concern about fetal suffering is raised by those who oppose abortion in principle as a reason to restrict some methods of abortion. In both the US and the UK legislative changes have been proposed which would outlaw a late abortion procedure known by gynaecologists as intact dilation and evacuation and by opponents of abortion as 'partial-birth abortion'. In both countries the method was defended by the medical establishment on the grounds that there may be circumstances when such practice was in the interests of the woman. It was for this reason that President Clinton exercised his right of presidential veto in respect of the Partial Birth Abortion Ban Bill of 1995 (H.R. 1833/S 939) which had been approved by Congress. Clinton correctly stated that: 'By refusing to permit women in reliance on their doctors' best medical judgement, to use this procedure when their lives are threatened or when their health is put in serious jeopardy, Congress has fashioned a Bill that is neither consistent with the Constitution nor with sound public policy' (43).
The Implications for Pain Research
The implications of accepting the notion of neonatal and fetal pain for pain research are profound. The consequence of such a view is to undermine the current theoretical outlook of most pain researchers, namely the 'biopsychosocial' model of pain, the undermining of the current definition of pain (44)(45), and the return of ideas more closely resembling the discredited ideas of 'specificity' theory(46).
In the absence of any conceptual framework to account for a fetal/neonatal experience of pain, the fetal literature is drawn inexorably towards the discredited ideas of 'specificity' and 'pain centers'. Within the discussion of fetal pain, pain fibres (or peptides or neurotransmitters) are proposed to be stimulated and relay information to suggested pain centers somewhere in the brain. As for specificity, a painful stimulus therefore becomes that which activates the pain center, and pain becomes activity in the pain center. Specificity theory, however, has long been rejected because the definition of pain based on a direct relationship between stimulus and response has failed to resolve many of the major issues in pain research. Interpretations of injury based on a direct relationship between stimulus and pain cannot account for the variable link between stimulus and pain experience. This variable link is well documented (47)(48)(49)(50), and is a consequence of the fact that pain experience is a multidimensional phenomena contingent upon processes involved in general conscious awareness, namely evaluative, emotional and cognitive processing. The biopsychosocial model of pain has also encouraged a less 'specificity biased' view of central pain neurology which has long been dogged by specificity theorists searching for pain centers (51). Classical neurology has viewed the central projection to the somatosensory cortex as essentially a pain center, a region necessary and sufficient for the experience of pain (52). The information about noxious stimuli that travels via the spinothalamic tract to excite the lateral group of thalamic nuclei interconnected with somatosensory cortex, undergoes few alterations between the spinal cord and cortex (53). Excitatory responses in monkey somatosensory cortex are generally restricted to both innocuous and noxious mechanical and thermal stimuli. Somatosensory neurons have receptive fields that are small or at least confined to one limb and always contralateral (54). Such a system is ideal for providing detailed information about the location and characteristics of particular noxious stimuli but is not well suited for processes associated with affective and cognitive responses to noxious stimuli. The conscious appreciation of pain cannot be explained within this system, instead a 'neuromatrix' (55) of regions, incorporating anterior cingulate, prefrontal and insula cortices which show a plasticity with learning and development, is proposed as necessary for the experience of pain. Functional imaging studies have now demonstrated that a number of cortical regions are activated in response to pain which conform to the concept of a neuromatrix (56)(57).
While the neuromatrix is an important step away from specificity, a step which is threatened by the concept of neonatal and fetal pain, so long as the neuromatrix is seen as sufficient for pain experience it will fall foul of the same problems that the materialist accounts of consciousness face and can ultimately be reconciled with neonatal and fetal pain. The only way to avoid the failings of materialism, avoiding the view that the higher mental functions are fixed a priori or that consciousness is a product of metaphysical forces (58), is to see consciousness, and within it the experience of pain, as a consequence of developmental processes which the fetus and newborn baby are yet to pass through. According to one developmental model of pain, stimulus information is eventually organized and elaborated in the central nervous system with respect to three hierarchical mechanisms (59). The first two mechanisms in the hierarchy are perceptual-motor processing followed by schematic processing. Both these mechanisms are considered preconscious. Perceptual-motor processing involves the activation of an innate set of expressive motor reactions to environmental stimuli. Schematic processing involves the automatic encoding in memory of the experience to produce a categorical structure representing the general informational and sensory aspects of pain experiences. A set of conscious abstract rules about emotional episodes and associated voluntary responses is proposed to arise over time as a consequence of self observation and conscious efforts to cope with aversive situations. While rather mechanistic and far from ideal, this model outlines how the pressure of interacting with others gradually forces the subordination of our instinctual, unconscious, biology to our developing conscious will.
The response of fetuses and neonates to invasive practice is a valuable research area that should lead to better clinical practice in the future. Basing this research upon the assumption that there is pain experience, however, could lead to the hasty introduction of unnecessary and possibly detrimental anaesthetic procedures as well as increasing the distress faced by those women who seek abortion. In addition, the focus on fetal pain is likely to result in a considerable challenge on the current understanding of pain - a challenge which will push back the past 30 years of pain research and undermine the contemporary conceptual framework for understanding pain. Such changes do not appear to be advantageous and may even be damaging to the pain field in general and to the treatment and understanding of nociceptive responses in the fetus and newborn baby.
(1) Anand KJS, Sippel WG, Aynsley-Green A. Randomised trial of fentanyl anasthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987; 1: 243-248.
(2) Anand KJS, Hickey PR. Halothane-morphine compared with high dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992; 326: 1-9.
(3) Fitzgerald M. Pain and analgesia in neonates. Trends Neurosci 1987; 10: 344-346.
(4) Rogers MC. Do the right thing: Pain relief in infants and children. N Engl J Med 1992; 326: 55-56.
(5) Fitzgerald M. Developmental biology of inflammatory pain. Br J Anaesth 1995; 75: 177-185.
(6) Anand KJS, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987; 317: 1321-1329.
(7) Richards T. Can a fetus feel pain? BMJ 1985; 291:1220-1221
(8) Hansard 1995; 236 (136): 906-914
(9) Derbyshire SWG. Comment: Do fetuses feel pain during abortion? Abortion Review 1995; 57: 1-2.
(10) Annas GJ, Caplan A, Elias S. Sounding Board: The politics of human-embryo research - avoiding ethical gridlock. N Engl J Med 1996; 334: 1329-1332.
(11) Fitzgerald M. Spontaneous and evoked activity of foetal primary afferents in vivo. Nature 1987; 326: 603-605.
(12) Fitzgerald M. The prenatal growth of fine diameter afferents into the rat spinal cord - a transganglionic study. J Comp Neurol 1987; 261: 98-104.
(13) Fitzgerald M. Neurobiology of fetal and neonatal pain. In Wall P, Melzack R, eds. Textbook of Pain. Churchill Livingstone, 1994: 153-163.
(14) Barr RG. Pain experience in Children. In Wall P, Melzack R, eds Textbook of Pain. Churchill Livingstone, 1994: 739-765.
(15) Mrzljak L, Uylings HBM, Kostovic I, van Eden CG. Prenatal development of neurons in prefrontal cortex: a qualitative Golgi study. J Comp Neurol 1988; 271: 355-386.
(16) Craig KD, Whitfield MF, Grunau RVE, Linton J, Hadjistavropoulos HD. Pain in the preterm neonate: behavioural and physiological indices. Pain 1993; 52: 287-299.
(17) Fitzgerald M, Millard M, McIntosh N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia. Pain 1989; 39: 31-36.
(18) Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma cortisol and ?-endorphin response to intrauterine needling. Lancet 1994; 344: 77-81.
(19) Wall PD, McMahon SB. The relationship of perceived pain to afferent nerve impulses. Trends Neurosci 1986; 9: 254-255.
(20) Lloyd-Thomas AR, Fitzgerald M. Reflex responses do not necessarily signify pain. BMJ 1996.
(21) Crick F. The Astonishing Hypothesis: The Scientific Search for the Soul. Simon & Schuster, 1994.
(22) Chalmers DJ. Facing up to the problem of consciousness. JCS 1994; 1: 1-16.
(23) Waddell G. A new clinical model for the treatment of low-back pain. Spine 1987; 12: 632-644.
(24) Melzack R, Casey KL. Sensory, motivational and central control determinants of pain. In Kenshalo D, ed. The Skin Senses. Springfield Ill: Thomas 1968: 423-443.
(25) Merskey H. The definition of pain. Eur J Psychiatry 1991; 6: 153-159.
(26) Jones APK, Brown WD, Friston KJ, Qi LY, Frackowiak RSJ. Cortical and subcortical localization of response to pain in man using positron emission tomography. Proc R Soc Lond 1991; 244: 39-44.
(27) Derbyshire SWG, Jones AKP, Devani P et al. Cerebral responses to pain in patients with atypical facial pain measured by positron emission tomography. J Neurol Neurosurg Psychiatry 1994; 57: 1166-1173.
(28) Chugani HT, Phelps ME. Maturational changes in cerebral function in infants determined by 18FDG positron emission tomography. Science 1986; 231: 840-843.
(29) Gabriel M. Functions of anterior and posterior cingulate cortex during avoidance learning in rabbits. In Uylings H, Van Eden C, De Bruin J, Corner M, Feenstra M eds. Progress in Brain Research. NY: Academic press 1990; 85: 467-483.
(30) Taddio A, Goldbach M, Ipp M, Stevens B, Koren G. Effect of neonatal circumcision on pain responses during vaccination in boys. Lancet 1995; 344: 291-292.
(31) Feger H. Babies feel the pain of childbirth, say doctors. Sunday Express 1996; Jan 28: 17.
(32) Sangild PT, Hilsted L, Nexo E, Fowden AL, Silver M. Secretion of acid, gastrin, and cobalmin-binding proteins by the fetal pig stomach: developmental regulation by cortisol. Exp Physiol 1994; 79: 135-146.
(33) Wenderlein JM, Ritz-Schafer R. Is moderate labor stress for newborn infants an advantage? Pilot study of postpartum weight gain of 791 newborn infants. Geburtshilfe Frauenheilkd 1994; 54: 65-68.
(34) Salmon P. Anxiety and stress in surgical patients. Br J Hosp Med 1992; 48: 531-532.
(35) Glasser M. Cesarean section: science or ritual surgery? Med Hypotheses 1991; 34: 73-80.
(36) Francome C, Savage W. Caesarean section in Britain and the United States 12% or 24%: is either the right rate? Soc Sci Med 1993; 37: 1199-1218.
(37) Abortion Statistics Series AB 1995; 19 (HMSO).
(38) Royal College of Obstetricians and Gynaecologists, Termination of Pregnancy for Fetal Abnormality in England, Wales and Scotland. 1996; pp. 12.
(39) McCullough LB, Chervenak FA. Ethics in Obstetrics and Gynaecology. Oxford University Press, New York 1994.
(40) Chervenak FA, McCullough LB, Campbell S. Is third trimester abortion justified? Br J Obstet Gynaecol 1995; 103: 187-189.
(41) Sirisena J. Correspondence. Is third trimester abortion justified? Br J Obstet Gynaecol 1996; 103: 187-189.
(42) Derbyshire, SWG. Locating the beginnings of pain. Bioethics 1999; 13: 1-31.
(43) Furedi A. Clinton vetoes ban on abortion methods. Abortion Review 1996; 59: 7.
(44) Anand KJS, Craig KD. New perspectives on the definition of pain. Pain 1996.
(45) Derbyshire SWG. A response to Anand and Craig on new perspectives on the definition of pain. Pain 1996.
(46) Wall PD. Why the definition of pain is crucial. In Wall P, Melzack R, eds. Textbook of Pain. Churchill Livingstone 1989: 1-18.
(47) Beecher HK. Measurement of Subjective Responses. Oxford University Press, New York 1959.
(48) Kosambi DD. Living prehistory in India. Sci Ameri 1967; 216: 105-114.
(49) Carlen PL, Wall PD, Nadvorna H, Steinbach T. Phantom limbs and related phenomena in recent traumatic amputations. Neurology 1978; 28: 211-217.
(50) Melzack R, Wall PD, Ty TC. Acute pain in an emergency clinic: Latency of onset and descriptor patterns. Pain 1982; 14: 33-43.
(51) Jones AKP. Do 'pain centres' exist? Br J Rheum 1994; 31, 290-292.
(52) Albe-Fassard D, Berkley KJ, Kruger L, Ralston HJ, Willis WD. Diencephalic mechanisms of pain sensation. Brain Res Rev 1985; 9: 217-296.
(53) Vogt BA, Sikes RW, Vogt LJ. Anterior cingulate cortex and the medial pain system. In Vogt BA, Gabriel M eds. Neurobiology of cingulate cortex and limbic thalamus: A comprehensive treatise. Birkhauser, Boston 1993: 330-360.
(54) Kenshalo DR, Isensee O. Responses of primate S1 cortical neurons to noxious stimuli. J Neurophysiol 1983; 50: 1479-1496.
(55) Melzack R. Phantom limbs, the self and the brain: The D.O. Hebb memorial lecture. Can Psychol 1989; 30: 1-16.
(56) Hsieh JC, Belfrage M, Stone-Elander S, Hansson P, Ingvar M. Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain 1995; 63: 225-236.
(57) Vogt BA, Derbyshire SWG, Jones AKP. Pain processing in four regions of human cingulate cortex localized with coregistered PET and MR imaging. Eur J Neurosci 1996; 8: 1461-1473
(58) Eccles JC. How the Self Controls its Brain. Springer Verlag, 1994.
(59) Leventhal H. A perceptual-motor theory of emotion. Adv Exp Psychology 1984; 17: 117-175.
So what you're saying is you're going to trust objective research over biased propaganda?
Me, too :)
The fact of the matter is that we will never really know if and when a "baby" feels pain inside the womb.