Pain

"The processing of nociceptive stimuli requires peripheral sensory receptors, afferent and efferent sensory and motor pathways, and subcortical and cortical neural integration of the related impulse traffic. The development of nociceptive pathways has been extensively reviewed by others and is not the subject of this review. In brief, however, it is generally agreed that an integrated pathway exists by 24–28 weeks of gestation and that"

"The conclusion suggested in the section above is further strengthened by consideration of the increasing body of evidence which shows that there are several suppressors in utero which act to inhibit neural activity in the fetus to a far greater degree than is seen postnatally in the infant. The uterus plays a key role in providing the chemical and physical factors that together help to keep the fetus continuously asleep. We propose that this is achieved, among other things, through the combined"

"Here we consider one final issue: whether nociceptive inputs may have deleterious consequences even if the “endogenously anesthetized” fetus does not consciously perceive pain at the time of stimulation. Can exposure to noxious stimuli initiate a cascade of events that sensitize the nervous system, or can repeated pain exposure in preterm infants contribute to attention, learning, and behavior problems later in life? It is critical to appreciate that not only is most of"

"We have considered whether the fetus, once its nociceptive pathways are complete, can feel pain in utero in a psychological manner akin to adult pain experience, and whether regardless of this the physiological responses to nociceptive input may lead to altered behavior later in life. We conclude that there is currently no strong evidence to suggest that the fetus is ever awake, even transiently; rather, it is actively kept asleep (and unconscious) by a variety of endogenous inhibitory factors."

"Twenty-five years ago, when Kanwaljeet Anand was a medical resident in a neonatal intensive care unit, his tiny patients, many of them preterm infants, were often wheeled out of the ward and into an operating room. He soon learned what to expect on their return. The babies came back in terrible shape: their skin was gray, their breathing shallow, their pulses weak. Anand spent hours stabilizing their vital signs, increasing their oxygen supply and administering insulin to balance their blood sugar. “What’s going on in there to make these babies so stressed?” Anand wondered. Breaking with hospital practice, he wrangled permission to follow his patients into the O.R. “That’s when I discovered that the babies were not getting anesthesia,” he recalled recently. Infants undergoing major surgery were receiving only a paralytic to keep them still. Anand’s encounter with this practice occurred at John Radcliffe Hospital in Oxford, England, but it was common almost everywhere. Doctors were convinced that newborns’ nervous systems were too immature to sense pain, and that the dangers of anesthesia exceeded any potential benefits. Anand resolved to find out if this was true. In a series of clinical trials, he demonstrated that operations performed under minimal or no anesthesia produced a “massive stress response” in newborn babies, releasing a flood of fight-or-flight hormones like adrenaline and cortisol. Potent anesthesia, he found, could significantly reduce this reaction. Babies who were put under during an operation had lower stress-hormone levels, more stable breathing and blood-sugar readings and fewer postoperative complications. Anesthesia even made them more likely to survive. Anand showed that when pain relief was provided during and after heart operations on newborns, the mortality rate dropped from around 25 percent to less than 10 percent. These were extraordinary results, and they helped change the way medicine is practiced. Today, adequate pain relief for even the youngest infants is the standard of care, and the treatment that so concerned Anand two decades ago would now be considered a violation of medical ethics. But Anand was not through with making observations. As NICU technology improved, the preterm infants he cared for grew younger and younger — with gestational ages of 24 weeks, 23, 22 — and he noticed that even the most premature babies grimaced when pricked by a needle. “So I said to myself, Could it be that this pain system is developed and functional before the baby is born?”"

"Whether the fetus feels pain is a question that matters to the doctor wielding the scalpel. And it matters, of course, for the practice of abortion. Over the past four years, anti-abortion groups have turned fetal pain into a new front in their battle to restrict or ban abortion. Anti-abortion politicians have drafted laws requiring doctors to tell patients seeking abortions that a fetus can feel pain and to offer the fetus anesthesia; such legislation has already passed in five states. Anand says he does not oppose abortion in all circumstances but says decisions should be made on a case-by-case basis. Nonetheless, much of the activists’ and lawmakers’ most powerful rhetoric on fetal pain is borrowed from Anand himself."

"Even as some research suggests that fetuses can feel pain as preterm babies do, other evidence indicates that they are anatomically, biochemically and psychologically distinct from babies in ways that make the experience of pain unlikely. The truth about fetal pain can seem as murky as an image on an ultrasound screen, a glimpse of a creature at once recognizably human and uncomfortably strange."

"IF THE NOTION that newborns are incapable of feeling pain was once widespread among doctors, a comparable assumption about fetuses was even more entrenched. Nicholas Fisk is a fetal-medicine specialist and director of the University of Queensland Center for Clinical Research in Australia. For years, he says, “I would be doing a procedure to a fetus, and the mother would ask me, ‘Does my baby feel pain?’ The traditional, knee-jerk reaction was, ‘No, of course not.’” But research in Fisk’s laboratory (then at Imperial College in London) was making him uneasy about that answer. It showed that fetuses as young as 18 weeks react to an invasive procedure with a spike in stress hormones and a shunting of blood flow toward the brain — a strategy, also seen in infants and adults, to protect a vital organ from threat. Then Fisk carried out a study that closely resembled Anand’s pioneering research, using fetuses rather than newborns as his subjects. He selected 45 fetuses that required a potentially painful blood transfusion, giving one-third of them an injection of the potent painkiller fentanyl. As with Anand’s experiments, the results were striking: in fetuses that received the analgesic, the production of stress hormones was halved, and the pattern of blood flow remained normal. Fisk says he believes that his findings provide suggestive evidence of fetal pain — perhaps the best evidence we’ll get. Pain, he notes, is a subjective phenomenon; in adults and older children, doctors measure it by asking patients to describe what they feel. (“On a scale of 0 to 10, how would you rate your current level of pain?”) To be certain that his fetal patients feel pain, Fisk says, “I would need one of them to come up to me at the age of 6 or 7 and say, ‘Excuse me, Doctor, that bloody hurt, what you did to me!’ ” In the absence of such first-person testimony, he concludes, it’s “better to err on the safe side” and assume that the fetus can feel pain starting around 20 to 24 weeks."

"Mark Rosen was the anesthesiologist at the very first open fetal operation, performed in 1981 at the University of California, San Francisco, Medical Center, and the fetal anesthesia protocols he pioneered are now followed by his peers all over the world. Indeed, Rosen may have done more to prevent fetal pain than anyone else alive — except that he doesn’t believe that fetal pain exists. Research has persuaded him that before a point relatively late in pregnancy, the fetus is unable to perceive pain. Rosen provides anesthesia for a number of other important reasons, he explains, including rendering the pregnant woman unconscious and preventing her uterus from contracting and setting off dangerous bleeding or early labor. Another purpose of anesthesia is to immobilize the fetus during surgery, and indeed, the drugs Rosen supplies to the pregnant woman do cross the placenta to reach the fetus. Relief of fetal pain, however, is not among his objectives. “I have every reason to want to believe that the fetus feels pain, that I’ve been treating pain all these years,” says Rosen, who is intense and a bit prickly. “But if you look at the evidence, it’s hard to conclude that that’s true.”"

"Rosen’s own hard look at the evidence came a few years ago, when he and a handful of other doctors at U.C.S.F. pulled together more than 2,000 articles from medical journals, weighing the accumulated evidence for and against fetal pain. They published the results in The Journal of the American Medical Association in 2005. “Pain perception probably does not function before the third trimester,” concluded Rosen, the review’s senior author. The capacity to feel pain, he proposed, emerges around 29 to 30 weeks gestational age, or about two and a half months before a full-term baby is born. Before that time, he asserted, the fetus’s higher pain pathways are not yet fully developed and functional. What about a fetus that draws back at the touch of a scalpel? Rosen says that, at least early on, this movement is a reflex, like a leg that jerks when tapped by a doctor’s rubber mallet."

"Likewise, the release of stress hormones doesn’t necessarily indicate the experience of pain; stress hormones are also elevated, for example, in the bodies of brain-dead patients during organ harvesting. In order for pain to be felt, he maintains, the pain signal must be able to travel from receptors located all over the body, to the spinal cord, up through the brain’s thalamus and finally into the cerebral cortex. The last leap to the cortex is crucial, because this wrinkly top layer of the brain is believed to be the organ of consciousness, the generator of awareness of ourselves and things not ourselves (like a surgeon’s knife). Before nerve fibers extending from the thalamus have penetrated the cortex — connections that are not made until the beginning of the third trimester — there can be no consciousness and therefore no experience of pain. Sunny Anand reacted strongly, even angrily, to the article’s conclusions. Rosen and his colleagues have “stuck their hands into a hornet’s nest,” Anand said at the time. “This is going to inflame a lot of scientists who are very, very concerned and are far more knowledgeable in this area than the authors appear to be. This is not the last word — definitely not.” Anand acknowledges that the cerebral cortex is not fully developed in the fetus until late in gestation. What is up and running, he points out, is a structure called the subplate zone, which some scientists believe may be capable of processing pain signals. A kind of holding station for developing nerve cells, which eventually melds into the mature brain, the subplate zone becomes operational at about 17 weeks. The fetus’s undeveloped state, in other words, may not preclude it from feeling pain. In fact, its immature physiology may well make it more sensitive to pain, not less: the body’s mechanisms for inhibiting pain and making it more bearable do not become active until after birth."

"Even birth may not inaugurate the ability to feel pain, according to Stuart Derbyshire, a psychologist at the University of Birmingham in Britain. Derbyshire is a prolific commentator on the subject and an energetic provocateur. In milder moods, he has described the notion of fetal pain as a “fallacy”; when goaded by his critics’ “lazy” thinking, he has pronounced it a “moral blunder” and “a shoddy, sentimental argument.” For all his vehemence in print, Derbyshire is affable in conversation, explaining that his laboratory research on the neurological basis of pain in adults led him to the matter of what fetuses feel: “For me, it’s an interesting test case of what we know about pain. It’s a great application of theory, basically.” The theory, in this case, is that the experience of pain has to be learned — and the fetus, lacking language or interactions with caregivers, has no chance of learning it. In place of distinct emotions, it experiences a blur of sensations, a condition Derbyshire has likened to looking at “a vast TV screen with all of the world’s information upon it from a distance of one inch; a great buzzing mass of meaningless information,” he writes."

"“Before a symbolic system such as language, an individual will not know that something in front of them is large or small, hot or cold, red or green” — or, Derbyshire argues, painful or pleasant. He finds “outrageous” the suggestion that the fetus feels anything like the pain that an older child or an adult experiences. “A fetus is biologically human, of course,” he says. “It isn’t a cow. But it’s not yet psychologically human.” That is a status not bestowed at conception but earned with each connection made and word spoken. Following this logic to its conclusion, Derbyshire has declared that babies cannot feel pain until they are 1 year old. His claim has become notorious in pain-research circles, and even Derbyshire says he thinks he may have overstepped. “I sometimes regret that I pushed it out quite that far,” he concedes. “But really, who knows when the light finally switches on?”"

"IN FACT, “THERE may not be a single moment when consciousness, or the potential to experience pain, is turned on,” Nicholas Fisk wrote with Vivette Glover, a colleague at Imperial College, in a volume on early pain edited by Anand. “It may come on gradually, like a dimmer switch.” It appears that this slow dawning begins in the womb and continues even after birth. So where do we draw the line? When does a release of stress hormones turn into a grimace of genuine pain?"

"Recent research provides a potentially urgent reason to ask this question. It shows that pain may leave a lasting, even lifelong, imprint on the developing nervous system. For adults, pain is usually a passing sensation, to be waited out or medicated away. Infants, and perhaps fetuses, may do something different with pain: some research suggests they take it into their bodies, making it part of their fast-branching neural networks, part of their flesh and blood. Anna Taddio, a pain specialist at the Hospital for Sick Children in Toronto, noticed more than a decade ago that the male infants she treated seemed more sensitive to pain than their female counterparts. This discrepancy, she reasoned, could be due to sex hormones, to anatomical differences — or to a painful event experienced by many boys: circumcision. In a study of 87 baby boys, Taddio found that those who had been circumcised soon after birth reacted more strongly and cried for longer than uncircumcised boys when they received a vaccination shot four to six months later. Among the circumcised boys, those who had received an analgesic cream at the time of the surgery cried less while getting the immunization than those circumcised without pain relief. Taddio concluded that a single painful event could produce effects lasting for months, and perhaps much longer. “When we do something to a baby that is not an expected part of its normal development, especially at a very early stage, we may actually change the way the nervous system is wired,” she says. Early encounters with pain may alter the threshold at which pain is felt later on, making a child hypersensitive to pain — or, alternatively, dangerously indifferent to it. Lasting effects might also include emotional and behavioral problems like anxiety and depression, even learning disabilities (though these findings are far more tentative). Do such long-term effects apply to fetuses? They may well, especially since pain experienced in the womb would be even more anomalous than pain encountered soon after birth. Moreover, the ability to feel pain may not need to be present in order for “noxious stimulation” — like a surgeon’s incision — to do harm to the fetal nervous system. This possibility has led some to venture an early end to the debate over fetal pain. Marc Van de Velde, an anesthesiologist and pain expert at University Hospitals Gasthuisberg in Leuven, Belgium, says: “We know that the fetus experiences a stress reaction, and we know that this stress reaction may have long-term consequences — so we need to treat the reaction as well as we can. Whether or not we call it pain is, to me, irrelevant.”"

"BUT THE QUESTION of fetal pain is not irrelevant when applied to abortion. On April 4, 2004, Sunny Anand took the stand in a courtroom in Lincoln, Neb., to testify as an expert witness in the case of Carhart v. Ashcroft. This was one of three federal trials held to determine the constitutionality of the ban on a procedure called intact dilation and extraction by doctors and partial-birth abortion by anti-abortion groups. Anand was asked whether a fetus would feel pain during such a procedure. “If the fetus is beyond 20 weeks of gestation, I would assume that there will be pain caused to the fetus,” he said. “And I believe it will be severe and excruciating pain.” After listening to Anand’s testimony and that of doctors opposing the law, Judge Richard G. Kopf declared in his opinion that it was impossible for him to decide whether a “fetus suffers pain as humans suffer pain.” He ruled the law unconstitutional on other grounds. But the ban was ultimately upheld by the U.S. Supreme Court, and Anand’s statements, which he repeated at the two other trials, helped clear the way for legislation aimed specifically at fetal pain. The following month, Sam Brownback, Republican of Kansas, presented to the Senate the Unborn Child Pain Awareness Act, requiring doctors to tell women seeking abortions at 20 weeks or later that their fetuses can feel pain and to offer anesthesia “administered directly to the pain-capable unborn child.” The bill did not pass, but Brownback continues to introduce it each year. Anand’s testimony also inspired efforts at the state level. Over the past two years, similar bills have been introduced in 25 states, and in 5 — Arkansas, Georgia, Louisiana, Minnesota and Oklahoma — they have become law. In addition, state-issued abortion-counseling materials in Alaska, South Dakota and Texas now make mention of fetal pain."

"In the push to pass fetal-pain legislation, Anand’s name has been invoked at every turn; he has become a favorite expert of the anti-abortion movement precisely because of his credentials. “This Oxford- and Harvard-trained neonatal pediatrician had some jarring testimony about the subject of fetal pain,” announced the Republican congressman Mike Pence to the House of Representatives in 2004, “and it is truly made more astonishing when one considers the fact that Dr. Anand is not a stereotypical Bible-thumping pro-lifer.” Anand maintains that doctors performing abortions at 20 weeks or later should take steps to prevent or relieve fetal pain. But it is clear that many of the anti-abortion activists who quote him have something more sweeping in mind: changing perceptions of the fetus. In several states, for example, information about fetal pain is provided to all women seeking abortions, including those whose fetuses are so immature that there is no evidence of the existence of even a stress response. “By personifying the fetus, they’re trying to steer the woman’s decision away from abortion,” says Elizabeth Nash, a public-policy associate at the Guttmacher Institute, a reproductive-rights group."

"In his speeches about fetal pain, Senator Brownback often asks why a fetus undergoing surgery receives anesthesia but not a fetus “who is undergoing the life-terminating surgery of an abortion.” Mark Rosen rejects the analogy. “Fetal surgery is a different circumstance than abortion,” he says, pointing out that none of the objectives of anesthesia for fetal surgery — relaxing the uterus, for example — apply to the termination of pregnancy. That includes an objective identified just recently: preventing possible long-term damage. For the fetus that is to be aborted, there is no long term. And if there is no pain, as Rosen maintains, then there is no cause to put the woman’s health at risk."

"In their use of pain to make the fetus seem more fully human, anti-abortion forces draw on a deep tradition. Pain has long played a special role in how society determines who is like us or not like us (“us” being those with the power to make and enforce such distinctions). The capacity to feel pain has often been put forth as proof of a common humanity. Think of Shylock’s monologue in “The Merchant of Venice”: Are not Jews “hurt with the same weapons” as Christians, he demands. “If you prick us, do we not bleed?” Likewise, a presumed insensitivity to pain has been used to exclude some from humanity’s privileges and protections. Many 19th-century doctors believed blacks were indifferent to pain and performed surgery on them without even that era’s rudimentary anesthesia. Over time, the charmed circle of those considered alive to pain, and therefore fully human, has widened to include members of other religions and races, the poor, the criminal, the mentally ill — and, thanks to the work of Sunny Anand and others, the very young. Should the circle enlarge once more, to admit those not yet born? Should fetuses be added to what Martin Pernick, a historian of the use of anesthesia, has called “the great chain of feeling”? Anand maintains that they should."

"When it comes to the way adults feel pain, science has borne out the optimistic belief that we are all the same under the skin. As research is now revealing, the same may not be true for fetuses; even Anand calls the fetus “a unique organism.” Exhibiting his flair for the startling but apt expression, Stuart Derbyshire warns against “anthropomorphizing” the fetus, investing it with human qualities it has yet to develop. To do so, he suggests, would subtract some measure of our own humanity. And to concern ourselves only with the welfare of the fetus is to neglect the humanity of the pregnant woman, Mark Rosen notes. When considering whether to provide fetal anesthesia during an abortion, he says, it’s not “erring on the safe side” to endanger a woman’s health in order to prevent fetal pain that may not exist. Indeed, the question remains just how far we would take the notion that the fetus is entitled to protection from pain. Would we be willing, for example, to supply a continuous flow of drugs to a fetus that is found to have a painful medical condition? For that matter, what about the pain of being born? Two years ago, a Swiftian satire of the Unborn Child Pain Awareness Act appeared on the progressive Web site AlterNet.org. Written by Lynn Paltrow, the executive director of the National Advocates for Pregnant Women, it urged the bill’s authors to extend its provisions to those fetuses “subjected to repeated, violent maternal uterine contraction and then forced through the unimaginably narrow vaginal canal.”"

"Following concerns generated by the debate on fetal awareness and, particularly, the controversy around whether the fetus could feel pain, the RCOG published, in October 1997, a working party report.1 A guiding principle in that report was concern that the fetus should be protected from any potentially harmful or painful procedure but, at the same time, the assessment of the capacity to be harmed should be based on established scientific evidence. A major and important conclusion of the report was that the human fetus did not have the necessary structural integration of the nervous system to experience awareness or pain before 26 weeks of gestation. In addition, the report recommended that those carrying out diagnostic or therapeutic procedures on the fetus in utero at or after 24 weeks should consider the need for fetal analgesia."

"[B]ecause of possible risks and difficulties in administration, fetal analgesia should not be employed where the only consideration is concern about fetal awareness or pain. Similarly, there appeared to be no clear benefit in considering the need for fetal analgesia prior to termination of pregnancy, even after 24 weeks, in cases of fetal abnormality. However, this did not obviate the need to consider feticide in these circumstances and, in this respect, further recommendations of relevance are included in the parallel report on Termination of Pregnancy for Fetal Abnormality."

"Following concerns generated by the debate on fetal awareness and, particularly, the controversy around whether the fetus could feel pain, the RCOG published, in October 1997, a working party report. A guiding principle in that report was concern that the fetus should be protected from any potentially harmful or painful procedure but, at the same time, the assessment of the capacity to be harmed should be based on established scientific evidence. A major and important conclusion of the report was that the human fetus did not have the necessary structural integration of the nervous system to experience awareness or pain before 26 weeks of gestation. In addition, the report recommended that those carrying out diagnostic or therapeutic procedures on the fetus in utero at or after 24 weeks should consider the need for fetal analgesia. This guidance was welcomed by the clinical and scientific communities, although, in recent years, the report has from time to time come under criticism in some quarters for being out of date and perhaps not having assessed all the known scientific evidence. This criticism has been most evident in discussing the age of viability (at present taken as 24 weeks of gestation in the UK) and the upper gestational limit in the context of induced abortion. The House of Commons Science and Technology Committee, in its report on Scientific Developments Relating to the Abortion Act 1967 (published in October 2007), made a number of important conclusions and recommendations, including some of direct relevance to this issue: ‘We conclude that, while the evidence suggests that foetuses have physiological reactions to noxious stimuli, it does not indicate that pain is consciously felt, especially not below the current upper gestational limit of abortion. We further conclude that these factors may be relevant to clinical practice but do not appear to be relevant to the question of abortion’. A minority report, however, recorded in the minutes of the Committee on 29 October 2007 said, ‘We are deeply concerned that the RCOG failed to give full information to the House of Commons Select Committee...since 1997 the RCOG has consistently denied that foetuses can feel pain earlier than 26 weeks, without acknowledging that amongst experts in this field there is no consensus. Professor Anand is a world authority in the management of neonatal pain and has put forward a cogent argument suggesting that the RCOG position is based on a number of false or uncertain presuppositions’. In the Government response to the House of Commons report (released November 2007) the Minister of State for Health welcomed the report and its conclusions and recommendations but importantly also indicated that ‘we note the Committee’s findings and are in agreement that the consensus of scientific evidence with regard to fetal pain at gestations below 26 weeks and we will be commissioning the College to review their 1997 working party report into fetal pain which will re-examine the latest evidence, much of which has been considered by the Committee, and any new research currently underway’."

"We begin by considering the scientific evidence for the presence of specific anatomical and physiological connections in the brain that are responsible for signalling noxious events to the central nervous system. Noxious stimuli are those that damage the tissues of the body or threaten to do so, such as surgical incision or physical trauma of the skin. In this context, we define pain as ‘the unpleasant sensory or emotional response to such tissue damage’ and trace the development of those responses through fetal development. We follow the path of the signals produced by tissue damage at sensory detectors in the skin and other organs, through to sensory circuits in the spinal cord, brainstem and thalamus and finally to the cerebral cortex, the site of higher level sensory processing. At each stage, we consider the scientific evidence for functional development and how this evidence may be interpreted. This section includes details derived from over 50 papers identified as relevant. Most were published since the last Working Party report1 but this current report also considers the older material included in the previous report. In addition to understanding the anatomical and physiological connections, it is also important to consider the psychological aspects of pain. Broadly accepted definitions of pain refer to pain as a subjective experience involving cognition, sensation and affective processes. These psychological concepts are inevitably harder to address in a fetus but should not be ignored."

"The neural regions and pathways that are responsible for pain experience remain under debate but it is generally accepted that pain from physical trauma requires an intact pathway from the periphery, through the spinal cord, into the thalamus and on to regions of the cerebral cortex including the primary sensory cortex (S1), the insular cortex and the anterior cingulated cortex. Fetal pain is not possible before these necessary neural pathways and structures (figure 1) have developed."

"For the fetus to respond to surgical damage, receptors in the affected tissue, such as skin and muscle, must signal the noxious stimulus or damage to the central nervous system. Nociceptors are sensory nerve terminals found in the skin and internal organs that convert tissue damage into electrical signals. The pattern and strength of these nociceptor signals is the first determining step in generating pain. If nociceptor activity is prevented, such as following local anaesthesia, then pain is blocked. Deep tissue damage, for example, that cuts through nerve bundles causes a brief burst of electrical activity in some of the cut nerve endings known as an injury discharge. The injured tissue, however, is now isolated from the central nervous system and, within a few minutes, the isolated tissue becomes ‘numb’ and pain free. Similarly, rare genetic defects that prevent all nociceptive signals result in a complete inability to sense pain. Anatomical studies of human fetal skin shows the presence of nerve terminals and fibres deep in the skin from 6 weeks of gestational age. These terminals are not nociceptors and are specialised for the processing of non-damaging sensations such as touch, vibration and temperature, rather than pain. From 10 weeks, nerve terminals become more numerous and extend towards the outer surface of the skin. The terminals closer to the surface are likely to be immature nociceptors, necessary for pain experience following tissue damage, but they are not unequivocally present until 17 weeks. In other mammals, newly formed fetal nociceptors are able to signal tissue damage but the intensity of their signals is weaker than in adults. The internal organs develop nerve terminals later than the skin, beginning to appear from 13 weeks and then increasing and spreading with age, so that the pancreas, for example, is innervated by 20 weeks."

"Specialised nerve terminals, nociceptors, are likely to detect surgical tissue damage from early in fetal life (around 10 weeks for the skin and 13 weeks for the internal organs). These nociceptors gradually mature over the next 6–8 weeks and the strength of their signals increases over fetal life. The presence of nociceptors is necessary for perception of acute surgical pain and so pain is clearly not possible before the nociceptors first appear at 10 weeks. The presence of nociceptors alone, however, is not a sufficient condition for pain experience. The electrical activity that is generated at nociceptor terminals by tissue damage must also be conducted along nerve fibres from the skin and into the spinal cord and brain. It is only when the brain receives information about the damage that the fetus can have any potential of awareness of it."

"Before any information about a noxious or tissue damaging stimulus can reach the brain, it has to be transmitted through the spinal cord (for the body) or the brainstem (for the head and neck). This transmission requires the growth of nerve fibres from the skin to the spinal cord or brainstem and then further growth of nerve fibres along the spinal cord or brainstem and into the brain. Staining of postmortem tissue reveals that nerve fibres grow into the fetal spinal cord from 8 weeks. These fibres, however, are specialised for the control of movement and some aspects of touching or prodding the body or positioning a limb. The growth of nerve fibres connecting nociceptive terminals to the spinal cord lags behind that of other sensory inputs in non-human mammals. Similar connections in the human are also likely to lag but the specific timings remain unknown. Preliminary studies have failed to demonstrate nerve fibres from nociceptive terminals in the fetal post-mortem spinal cord before 19 weeks."

"The exact timing of the first nociceptive reflex responses to more traumatic mechanical stimulation is not known but they are unlikely to occur before the second trimester, somewhat later than responses to touch. It is known that the fetus withdraws from a needle from about 18 weeks and also launches a stress response following needle puncture. This stress response includes the release of hormones and neurotransmitters dependent on activity in areas of the midbrain. These findings confirm that signals about tissue damage are transmitted from the spinal cord and brainstem to the midbrain from at least 18 weeks."

"The word ‘pain’ is used in different ways. The most frequent use, especially with respect to subjects that cannot communicate verbally, is in describing the behavioural response to noxious stimulation. However, if we accept this use, we are presented with the difficulty of distinguishing between the responses of simple versus complex organisms. Fruit fly larvae, for example, have been demonstrated to bend and roll away when approached with a naked flame but most people would agree that larvae do not feel pain in the way that we do. Ruling out the responses of larvae and similarly simple organisms as indicating pain is possible if we suggest that responses must include more than mere reflex responses to be labelled as a pain response. When someone reaches out and accidentally touches something very hot, there is an immediate tendency to drop the object. That reaction is entirely regulated by a simple loop of sensory neurons speaking to motor neurons in the spinal cord. Typically, the person will drop the object before there is any conscious appreciation of pain. The action of dropping the object indicates the presence of something noxious but does not necessarily indicate the presence of pain."

"Most pain researchers adopt a definition of pain that emphasises the sensory, cognitive and affective response to a noxious event. This understanding of pain is supported by the International Association of Pain (IASP) which defines pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage,or described in terms of such damage...pain is always subjective. Each individual learns the application of the word through experiences related to injury in early life’.1 By this definition, pain does not have primacy over subjectivity, existing before and in addition to subjectivity, but is experienced through subjectivity. It suggests that pain is a part of knowledge and requires the existence of a conceptual apparatus that can marshal all its dimensions into a coherent experience. Although there is considerable merit in the IASP definition of pain, it does tend towards a view of pain as being a constituent part of higher cognitive function. There is disquiet in denying a rawer, more primitive, form of pain or suffering that the fetus, neonate and many animals might experience.2–4 One possible solution is to recognise that the newborn infant might be said to feel pain, whereas only the older infant can experience that they are in pain and explicitly share their condition with others as an acknowledged fact of being.5 Currently there is no immediately obvious way of resolving these arguments empirically. It is possible, however, to argue that even a raw sense of pain involves more than reflex activity and will, therefore, require the higher regions of the cortex to be connected and functional. The age when this minimum requirement is fulfilled is explored in the rest of this chapter."

"A connection from the skin to the spinal cord and brain is a basic requirement for the fetus to feel or be aware of pain. Again, it is important to emphasise that, while such input to the spinal cord and brain is necessary for perception of acute surgical pain, it is not sufficient. Activity in the spinal cord, brainstem and subcortical midbrain structures are sufficient to generate reflexive behaviours and hormonal responses but are not sufficient to support pain awareness."

"Hormonal responses to needling show that there are functional brainstem and midbrain mediated reactions to noxious events but they, too, do not require higher brain processing to take place and can occur independently of sensory awareness. The specific relationship between pain and the release of hormones and neurotransmitters is unclear. In a prospective crossover study on 50 extremely low gestational age infants (less than 28 weeks of gestation), no difference in hormonal response was observed after heel lance15 and, in adult mice, it is difficult to distinguish changes in levels of naturally occurring opioids due to stressful handling from those due to tissue damage."

"At 8 weeks, the fetal brain is profoundly immature and its surface layer, the cerebral cortex, is smooth, with no indication of the folds (sulci and gyri) that are so prominent later. There is also no internal cellular organisation in either the thalamus, which is the main source of sensory input to the cortex, or the cortex itself. The limbic system, an evolutionary older part of the brain, consisting of interconnected deep brain structures involved in various fundamental drives and regulatory functions, is already discernable and has began to form interconnections. The external surface of the brain is about 1 mm thick and consists of an inner and outer layer with no cortical plate, the structure that will gradually develop into the layers of the cortex proper."

"[T]he relocation of neurons from the subplate to the cortical plate also begins around 24 weeks, thus coinciding with the invasion of thalamic afferents. This relocation is extremely rapid from about 34 weeks, leading to the dissolution of the subplate as the extracellular matrix and other growth-related and guidance molecules disappear.21 The subplate has been observed to thin in the insula and in areas where cortical folding occurs rather earlier than the rest of the cortex, from at least 20 weeks. It is currently uncertain whether this thinning is due to earlier maturation and potentially earlier synaptic activity in these regions, some of which are key areas in the experience of pain in adults, 3 or attributable to incidental morphological changes."

"While the study of anatomical connections between brain regions provides important information about developing pain processes, the existence of a connection is not evidence of its function. Connections viewed under the microscope between the thalamus and the cortical plate at 24 weeks, for example, may or may not transmit information from nociceptors upon tissue damage. Fetal magnetoencephalography has been used to effectively record fetal auditory and visual evoked responses and spontaneous brain activity of cortical origin from 28 weeks and fetal brain activation to sound has been demonstrated using functional magnetic resonance imaging (fMRI) from 33 weeks. It has not been possible to record directly from human fetal cortex to establish when cortical neurons first begin to respond to tissue damaging inputs. Near infrared spectroscopy with preterm infants in intensive care, however, has demonstrated localised somatosensory cortical responses in premature newborn infants (from 24 weeks) following noxious heel lance36 and venepuncture. More recently, EEG has demonstrated a clear, time-locked, nociceptive-evoked potential in preterm infants following heel lance. Thus, there is direct evidence of neural activity in primary sensory cortex following tissue damage in very premature infants equivalent to 24 weeks of gestational age."

"Fetal behavioural responses have also been used as indicators of stress or pain. Shortly after the development of skin sensitivity, around 10 weeks, repeated stimulation results in hyperexcitability and a generalised movement of all limbs. After 26 weeks, this generalized movement gradually gives way to more coordinated behavioural responses that indicate improved organisation within the nervous system. Infants delivered at 26–31 weeks, for example, show coordinated facial expressions in response to heel prick, although these are immature compared to older infants. Four-D images of the fetus have also been reported to show fetuses ‘scratching’, ‘smiling’, ‘crying’ and ‘sucking’ at 26 weeks of gestational age. Although these later behavioural responses are not spinal cord reflexes, the responses are still unlikely to involve higher cortical centres. An anencephalic fetus withdraws from noxious stimulation, demonstrating that this response is mediated at a subcortical level. Similarly, infants with significant neonatal neurological injury due to a parenchymal brain injury respond to noxious stimulation with a pattern of behavioural reactions similar to infants without brain injury."

"The cortex is required for both the discriminative and emotional aspects of the processing of noxious stimuli and both anatomical and functional studies show that cortical neurons begin to receive input about sensory events in the body and the external environment from 24 weeks. Long axonal tracts now course through the brain to the cortex and evoked responses in the primary sensory cortex indicate the presence of a spinothalamic connection and the ability of somatosensory cortical neurons to generate specific activity in response to tissue damaging stimulation. The primary sensory cortex is an important area in pain processing but it is only one of many areas that are active during pain experience. Other important areas include the secondary somatosensory, the anterior cingulate and the insular cortices. Although we may speculate that these regions will also be functionally active from 24 weeks, similar to primary sensory cortex, there is no evidence for this at the moment. It has been suggested that subcortical regions, including the brainstem, and transient brain structures, including the subplate, organise responses to noxious information at each stage of development and provide for a pain experience complete within itself at each stage. There is, however, no evidence or rationale for subcortical and transient brain regions supporting mature function. Although developing brain circuits often display spontaneous neuronal activity this activity is a fundamental developmental process and not evidence of mature function."

"The fact that the cortex can receive and process sensory inputs from 24 weeks is only the beginning of the story and does not necessarily mean that the fetus is aware of pain or knows that it is in pain. It is only after birth, when the development, organisation and reorganisation of the cortex occurs in relation to the action and reaction of the neonate and infant to a world of meaning and symbols, that the cortex can be assumed to have mature features. The cortex is an important step beyond the spinal cord and brainstem because it facilitates pain experience by enabling the higher functions of cognition, emotion and self-awareness that are realized in the postnatal environment. Thus, there is good evidence for claiming that the cortex is necessary for pain experience but not sufficient."

"It has been proposed that arguments around fetal pain can be resolved by the fact that the fetus never enters a state of wakefulness in utero."

"Connections from the periphery to the cortex are not intact before 24 weeks of gestation. Most pain neuroscientists believe that the cortex is necessary for pain perception; cortical activation correlates strongly with pain experience and an absence of cortical activity generally indicates an absence of pain experience. The lack of cortical connections before 24 weeks, therefore, implies that pain is not possible until after 24 weeks. Even after 24 weeks, there is continuing development and elaboration of intracortical networks. Furthermore, there is good evidence that the fetus is sedated by the physical environment of the womb and usually does not awaken before birth."

"Vaginal delivery may be considered a stress-inducing event to which most fetuses are subject. Fetuses born vaginally have higher levels of catecholamines, cortisol and endorphins than those born by elective caesarean section. It is unclear whether this stress response is related to the painful stimulus of head compression or to other factors, such as mild hypoxaemia or maternal stress. In normal labour, this evidence of fetal stress would be considered a normal fetal physiological response and the stress is thought to have benefits for fetal survival. The labour-related surge in steroids and catecholamines is an important factor in activating sodium channels and promoting the clearance of lung fluid. Babies born by caesarean section before the onset of labour have an increased incidence of respiratory complications, such as transient tachypnoea of the newborn. In addition, recent data show that elements of the stress response, perhaps noradrenaline or endorphins, have a short-term analgesic effect, so that babies born vaginally have an attenuated physiological and behavioural response to a painful stimulus compared with those born by elective caesarean section. Evidence of endogenous fetal analgesia during vaginal birth, as well as the role of catecholamines in promoting lung fluid reabsorption and the respiratory depressant actions of fetal opiate exposure, all suggest that the current approach to intrapartum analgesia, centred around maternal, rather than fetal, requirements for pain relief, is the correct one. The evidence that stress responses during normal vaginal delivery have benefits cannot, however, be readily extrapolated to stress responses during pregnancy."

"The fetal response to noxious stimuli, described in detail in section 2, comprises two elements, both of which need to be present for the fetus to feel pain. The first of these involves nociception and a physiological stress response to it, while the second requires cortical processing of the nociceptive stimulus to produce a negative emotional perception. The evidence clearly suggests that the autonomic and endocrine pathways are in place for the fetus to mount a stress response as early as 18 weeks of gestation, with increases in cerebral blood flow, catecholamines and cortisol observed following invasive procedures. These responses can be attenuated by administration of fetal analgesia at the start of the procedure. It is worth noting that the fetal stress response can be elicited by a number of non-painful stimuli; the most extensively described is the response to acute hypoxia, where many of the components, such as increased cerebral blood flow, are part of a coordinated fetal response to minimise damage to organs such as the brain and heart. Increased cerebral blood flow, catecholamines and cortisol cannot therefore be interpreted as evidence that the fetus is feeling pain."

"Data gathered from premature babies on intensive care units suggest that exposure to repeated, strong stimuli can alter cardiovascular responses to a painful stimulus later in infancy and that fetuses born with higher cortisol levels in cord blood, owing to vaginal delivery, have an altered stress response to vaccination. These data suggest that fetal exposure to ‘stress’ in utero can modulate the later function of the hypothalamic pituitary axis. From this, it has been suggested that reducing the magnitude of the initial stress response, for example by using fetal analgesia, will have a beneficial effect. However, the degree to which these effects can be observed following fetal exposure to a painful stimulus remains uncertain, as the majority of studies to date are postnatal and refer to intense, repetitive stimuli that are not normally experienced in utero. The uncertain benefit of attenuating the fetal stress response to a noxious stimulus in utero by administering analgesia needs to be balanced against the practical difficulties to the administration of effective fetal analgesia, as well as the possibility of adverseeffects."

"In contrast to the endocrine and haemodynamic responses to a noxious stimulus, which are easily quantified, it has not been possible to directly measure the cortical response to such a stimulus. Assessments about the gestation at which a fetus could feel pain are therefore made on the basis of the existence of the necessary neural pathways for pain perception, particularly the nature of thalamocortical connections (see section 2), as well as indirect evidence for functionality based on evoked responses and evidence for a sleep–wake cycle of EEG activity. Interpretation of existing data indicates that cortical processing of pain perception, and therefore the ability of the fetus to feel pain, cannot occur before 24 weeks of gestation and that the nature of cortical activity becomes more complex as gestation advances from this point. It is reasonable to infer from this that the fetus does not require analgesia for interventions occurring before 24 weeks of gestation. Furthermore, and importantly, the evidence that analgesia confers any benefit on the fetus at any gestation is lacking."

"[A]s current evidence indicates the inability of the fetus to experience pain, certainly before the end of the second trimester, it should not be necessary to consider the need for fetal analgesia."

"The implications for clinical practice of the neurobiological evidence presented in section 2 have been considered. Interpretation of existing data suggests that cortical processing and therefore fetal perception of pain cannot occur before 24 weeks of gestation. It is reasonable to infer from this that the fetus does not require analgesia for interventions occurring before 24 weeks of gestation. Diagnostic or therapeutic procedures that involve the fetus directly are very uncommon but do occur and can be associated with a stress response. However, this does not indicate that the fetus is aware or can feel pain. The case for administering analgesia before an invasive procedure (in addition to maternal general anaesthesia) after 24 weeks when the neuroanatomical connections are in place, needs to be considered together with the practicalities and risks of administration of fetal analgesia in continuing pregnancies and the uncertainties over long-term effects. Evidence that analgesia confers any benefit on the fetus at any gestation is lacking but should be a focus of future research that will need to include medium and longer-term as well as immediate outcomes."

"Will the fetus/baby feel pain? No, the fetus does not experience pain. Pain relates to an unpleasant sensory or emotional response to tissue damage. To be aware of something or have pain, the body has to have developed special sensory structures and a joined-up nerve system between the brain and the rest of the body to communicate such a feeling. Although the framework for the nervous system in the growing fetus occurs early, it actually develops very slowly. Current research shows that the sensory structures are not developed or specialised enough to experience pain in a fetus less than 24 weeks. After 24 weeks, it is difficult to say that the fetus experiences pain because this, like all other experiences, develops postnatally along with memory and other learned behaviours. In addition, increasing evidence suggests that the fetus never enters a state of wakefulness inside the womb. The placenta produces chemicals that suppress nervous system activity and awareness."

"Will the process hurt the baby? No. To be hurt, you need to feel pain. Current research shows that the sensory structures are not developed or specialised enough for a fetus to experience pain less than 24 weeks. Pain experience after 24 weeks depends upon a psychological development that is restricted before birth. See the question ‘Will the fetus/baby feel pain?’"

"Does an anaesthetic or the pain relief I receive affect the baby? If you are given a general anaesthetic for a diagnostic procedure, the substances used in this will cross the placenta to the baby. The effect will happen more slowly to the baby and will not cause any harm to the baby. If you are given other forms of pain relief, there is evidence that they will cross the placenta to the baby, but the doses are not large enough to cause any harm."