0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Clinical Review | Clinician's Corner

Fetal Pain:  A Systematic Multidisciplinary Review of the Evidence FREE

Susan J. Lee, JD; Henry J. Peter Ralston, MD; Eleanor A. Drey, MD, EdM; John Colin Partridge, MD, MPH; Mark A. Rosen, MD
[+] Author Affiliations

Clinical Review Section Editor: Michael S. Lauer, MD. We encourage authors to submit papers for consideration as a “Clinical Review.” Please contact Michael S. Lauer, MD, at lauerm@ccf.org.

Author Affiliations: School of Medicine (Ms Lee), Department of Anatomy and W. M. Keck Foundation for Integrative Neuroscience (Dr Ralston), and Departments of Obstetrics, Gynecology and Reproductive Sciences (Drs Drey and Rosen), Pediatrics (Dr Partridge), and Anesthesia and Perioperative Care (Dr Rosen), University of California, San Francisco.

More Author Information
JAMA. 2005;294(8):947-954. doi:10.1001/jama.294.8.947.
Text Size: A A A
Published online

Context Proposed federal legislation would require physicians to inform women seeking abortions at 20 or more weeks after fertilization that the fetus feels pain and to offer anesthesia administered directly to the fetus. This article examines whether a fetus feels pain and if so, whether safe and effective techniques exist for providing direct fetal anesthesia or analgesia in the context of therapeutic procedures or abortion.

Evidence Acquisition Systematic search of PubMed for English-language articles focusing on human studies related to fetal pain, anesthesia, and analgesia. Included articles studied fetuses of less than 30 weeks’ gestational age or specifically addressed fetal pain perception or nociception. Articles were reviewed for additional references. The search was performed without date limitations and was current as of June 6, 2005.

Evidence Synthesis Pain perception requires conscious recognition or awareness of a noxious stimulus. Neither withdrawal reflexes nor hormonal stress responses to invasive procedures prove the existence of fetal pain, because they can be elicited by nonpainful stimuli and occur without conscious cortical processing. Fetal awareness of noxious stimuli requires functional thalamocortical connections. Thalamocortical fibers begin appearing between 23 to 30 weeks’ gestational age, while electroencephalography suggests the capacity for functional pain perception in preterm neonates probably does not exist before 29 or 30 weeks. For fetal surgery, women may receive general anesthesia and/or analgesics intended for placental transfer, and parenteral opioids may be administered to the fetus under direct or sonographic visualization. In these circumstances, administration of anesthesia and analgesia serves purposes unrelated to reduction of fetal pain, including inhibition of fetal movement, prevention of fetal hormonal stress responses, and induction of uterine atony.

Conclusions Evidence regarding the capacity for fetal pain is limited but indicates that fetal perception of pain is unlikely before the third trimester. Little or no evidence addresses the effectiveness of direct fetal anesthetic or analgesic techniques. Similarly, limited or no data exist on the safety of such techniques for pregnant women in the context of abortion. Anesthetic techniques currently used during fetal surgery are not directly applicable to abortion procedures.

Figures in this Article

Over the last several years, many states, including California, Kentucky, Minnesota, Montana, New York, Oregon, and Virginia, have considered legislation requiring physicians to inform women seeking abortions that the fetus feels pain and to offer fetal anesthesia. This year, Arkansas and Georgia enacted such statutes.1,2 Currently, Congress is considering legislation requiring physicians to inform women seeking abortions 20 or more weeks after fertilization (ie, 22 weeks’ gestational age) that the fetus has “physical structures necessary to experience pain,” as evidenced by “draw[ing] away from surgical instruments.” The physician must also offer anesthesia or analgesia “administered directly” to the fetus. Physicians who do not comply may be subject to substantial fines, license revocation, and civil suits for punitive damages.3

Although this legislation would not affect most US abortions because only 1.4% are performed at or after 21 weeks’ gestational age,4 this legislation raises important scientific, clinical, ethical, and policy issues. When does a fetus have the functional capacity to feel pain? If that capacity exists, what forms of anesthesia or analgesia are safe and effective for treating fetal pain? As a first step in answering these questions, we reviewed the literature on fetal pain and fetal anesthesia and analgesia.

English-language articles involving human participants were searched using PubMed for (1) fetal pain (16 articles), fetal anesthesia (6 articles), and fetal analgesia (3 articles); (2) fetus and (anesthesia or analgesia) (1239 articles); (3) Medical Subject Headings (MeSH) analgesics/administration and dosage and fetus (44 articles); (4) MeSH anesthesia/administration and dosage and fetus (0 articles); (5) (neurodevelopment or development or anatomy) and (fetus or fetal) and (pain or nociception or noxious) (306 articles); (6) (thalamocortical or thalamus or cortex) and (fetus or fetal) and (pain or nociception or noxious) (13 articles); (7) (electroencephalog*orEEGorevoked potential) and (fetusorfetalorpremature neonateorpremature infantorpreterm neonateorpreterm infant) and (painornociceptionornoxiousorconscious*) (7 articles); (8) fetal and pain and (response or assessment or facial expression) (112 articles); and (9) facial expression and (fetus or fetal) or ([neonate or neonatal or infant] and [premature or preterm]) and (pain or nociception or noxious) (360 articles). The search was performed without date limitations and was current as of June 6, 2005. From these search results, we excluded articles that did not study fetuses of less than 30 weeks’ gestational age or that did not specifically address fetal pain perception or nociception. With a focus on topics addressed by earlier review articles on fetal pain, anesthesia, and analgesia, articles were reviewed for additional references.

What Is Pain?

Quiz Ref IDPain is a subjective sensory and emotional experience that requires the presence of consciousness to permit recognition of a stimulus as unpleasant.57 Although pain is commonly associated with physical noxious stimuli, such as when one suffers a wound, pain is fundamentally a psychological construct that may exist even in the absence of physical stimuli, as seen in phantom limb pain.5,7 The psychological nature of pain also distinguishes it from nociception, which involves physical activation of nociceptive pathways without the subjective emotional experience of pain.5,8 For example, nociception without pain exists below the level of a spinal cord lesion, where reflex withdrawal from a noxious stimulus occurs without conscious perception of pain (Figure, A).5

Figure. Spinal Reflex and Pain Perception Pathways
Graphic Jump Location

A, Reflex responses to noxious stimuli occur early in development, before thalamocortical circuits are functional; noxious stimuli trigger reflex movement without cortical involvement. Activated by a noxious stimulus (1), a peripheral sensory neuron (2) synapses on a dorsal horn interneuron (3) that in turn synapses on a ventral horn motor neuron (4), leading to reflex muscle contraction and limb withdrawal (5). B, Later in development, noxious stimuli (1) activate peripheral sensory neurons (2) that synapse on spinothalamic tract neurons (3), the axons of which extend up the spinal cord as the spinothalamic tract (4) to synapse on neurons of the thalamus (5). From here, thalamocortical axons synapse on cortical neurons, resulting in the conscious perception of pain.

Because pain is a psychological construct with emotional content, the experience of pain is modulated by changing emotional input and may need to be learned through life experience.7,9,10 Regardless of whether the emotional content of pain is acquired, the psychological nature of pain presupposes the presence of functional thalamocortical circuitry required for conscious perception, as discussed below.

Fetal Capacity for Pain

Neuroanatomy and Development.Quiz Ref IDNociception may be characterized by reflex movement in response to a noxious stimulus, without cortical involvement or conscious pain perception. Nociception involves peripheral sensory receptors whose afferent fibers synapse in the spinal cord on interneurons, which synapse on motor neurons that also reside in the spinal cord. These motor neurons trigger muscle contraction, causing limb flexion away from a stimulus (Figure, A).11

In contrast, pain perception requires cortical recognition of the stimulus as unpleasant. Peripheral sensory receptor afferents synapse on spinal cord neurons, the axons of which project to the thalamus, which sends afferents to the cerebral cortex (Figure, B),11 activating any number of cortical regions.12 Sensory receptors and spinal cord synapses required for nociception develop earlier than the thalamocortical pathways required for conscious perception of pain (Table).

Table Graphic Jump LocationTable. Anatomical and Functional Development of Nociception and Pain Perception Pathways

No human studies have directly examined the development of thalamocortical circuits associated with pain perception. The developmental age at which thalamic pain fibers reach the cortex has been inferred from studies of other thalamocortical circuits, which may or may not develop at the same time as thalamic fibers mediating cortical perception of pain.

These histological neurodevelopment studies typically describe fetal maturity in terms of developmental age, representing the number of weeks postovulation or postfertilization. Clinicians regularly use gestational age, representing weeks from the first day of the woman’s last menstrual period. When referring to a fetus at the same point in development, the gestational age is approximately 2 weeks greater than the developmental age.

A histological study of the visual pathway in 8 human fetuses, each at a different developmental age, concluded that thalamic projections reach the visual cortex at 21 to 25 weeks’ developmental age (approximately 23-27 weeks’ gestational age), based on results from a fetus of 24 weeks’ developmental age (26 weeks’ gestational age).18 A similar 7-fetus study found thalamic afferents reached the auditory cortical plate at 24 to 26 weeks’ developmental age, with 1 specimen showing initial cortical plate penetration at 22 weeks’ developmental age (24 weeks’ gestational age).24

In a study of 8 human fetuses, mediodorsal thalamic afferents were first observed in the cortical plate at 22 weeks’ developmental age (24 weeks’ gestational age).19 While connections between mediodorsal afferents and the anterior cingulate cortex25 may be relevant to pain perception,12,26 this study examined mediodorsal afferents to unspecified regions of the frontal cortex,19 which serves numerous functions unrelated to pain perception.19,27

Another histological study of 12 specimens found that afferents from unspecified thalamic regions reached the developing prefrontal cortex in 1 preterm neonate of 27 weeks’ developmental age, concluding that thalamic fibers begin entering the cortex between 26 and 28 weeks’ developmental age (28 and 30 weeks’ gestational age).28 A different study found that thalamic afferents had not reached the somatosensory cortical plate by 22 weeks’ developmental age (24 weeks’ gestational age). By 24 weeks’ developmental age (26 weeks’ gestational age), the density of cortical plate synapses increased, although these were not necessarily from thalamic afferents.16 Based on these studies, direct thalamocortical fibers that are not specific for pain begin to emerge between 21 and 28 weeks’ developmental age (23 and 30 weeks’ gestational age).

However, others have proposed that thalamocortical connections could also be established indirectly if thalamic afferents were to synapse on subplate neurons, which could synapse on cortical plate neurons.29 The subplate is a transient fetal structure 1 layer deep to the cortical plate and serves as a “waiting compartment” for various afferents, including thalamic afferents, en route to the cortical plate.16,29,30 The subplate recedes after 30 weeks’ developmental age,16,29 while the cortical plate matures into the 6 layers of the cerebral cortex.28 In contrast to direct thalamocortical fibers, which are not visible until almost the third trimester, thalamic afferents begin to reach the somatosensory subplate at 18 weeks’ developmental age (20 weeks’ gestational age)16 and the visual subplate at 20 to 22 weeks’ gestational age.17 These afferents appear morphologically mature enough to synapse with subplate neurons,31 although no human study has shown that functional synapses exist between thalamic afferents and subplate neurons. Subplate neurons may synapse with cortical plate neurons and direct the growth of thalamic afferents to their final synaptic targets in the cortical plate.29 Despite this developmental role, no human study has shown that synapses between subplate and cortical plate neurons convey information about pain perception from the thalamus to the developing cortex.

Electroencephalography. The histological presence of thalamocortical fibers is insufficient to establish capacity for pain perception. These anatomical structures must also be functional. Although no electroencephalographic “pain pattern” exists, electroencephalography may be one way of assessing general cortical function because electroencephalograms (EEGs) measure summated synaptic potentials from cortical neurons. However, EEG activity alone does not prove functionality, because neonates with anencephaly who lack functional neural tissue above the brainstem may still have EEG activity.32

Normal EEG patterns have been characterized for neonates as young as 24 weeks’ postconceptional age (PCA) (ie, the gestational age plus number of weeks postpartum).22 Electroencephalographic activity is normally asynchronous between the hemispheres and mostly discontinuous at less than 27 weeks’ PCA,23,33,34 becoming mostly continuous around 34 weeks’ PCA.23,34 Interhemispheric synchrony increases around 29 to 30 weeks’ PCA, then declines, then increases again, reaching almost complete synchrony by term.22,33 Given these baseline differences between neonatal and adult EEGs, patterns associated with impaired consciousness in adults33,35 are inapplicable to the analysis of neonatal EEGs.

Quiz Ref IDSome investigators contend that EEG patterns denoting wakefulness indicate when consciousness is first possible.5,36 Wakefulness is a state of arousal mediated by the brainstem and thalamus in communication with the cortex.5,22 In preterm neonates, the earliest EEG pattern representing wakefulness appears around 30 weeks’ PCA.22,23 However, wakefulness alone is insufficient to establish consciousness, as unconscious patients in a persistent vegetative state may also have wakeful EEGs.5,36

Somatosensory evoked potentials (SEPs) may also provide evidence of pain processing in the somatosensory cortex, although they are not used clinically to test pain pathways. SEPs test the dorsal column tract of the spinal cord, which transmits visceral pain sensation to the somatosensory cortex via the thalamus.12 SEPs with distinct and constant N1 components of normal peak latency are present at 29 weeks’ PCA, indicating that thalamic connections with the somatosensory cortex are functional at that time.20,21

Behavioral Studies. Although widely used to assess pain in neonates, withdrawal reflexes and facial movements do not necessarily represent conscious perception of pain. Full-term neonates exhibit a “cutaneous withdrawal reflex” that is activated at a threshold much lower than that which would produce discomfort in a child or adult.37 This threshold increases with PCA, suggesting that the capacity of the neonate to distinguish between noxious and nonnoxious stimuli is maturing.37 Furthermore, flexion withdrawal from tactile stimuli is a noncortical spinal reflex exhibited by infants with anencephaly38 and by individuals in a persistent vegetative state39 who lack cortical function.

Behavioral studies have also identified a distinct set of neonatal facial movements present during invasive procedures such as heel lancing but absent during noninvasive procedures.4046 These facial movements, which are similar to those of adults experiencing pain,47,48 were evident in neonates at 28 to 30 weeks’ PCA but not at 25 to 27 weeks’ PCA.40 Facial movements may not necessarily be cortically controlled.49 One study found no difference in facial activity during heel lancing of neonates with and without significant cortical injury, suggesting that facial activity even around 32 weeks’ PCA may not represent conscious perception of pain.50

Stress Responses. Hemodynamic and neuroendocrine changes in fetuses undergoing stressful procedures have also been used to infer pain perception.51 As early as 16 weeks’ gestational age, fetal cerebral blood flow increases during venipuncture and transfusions that access the fetal hepatic vein through the innervated fetal abdominal wall but not during venipuncture and transfusions involving the noninnervated umbilical cord.52 Increased cerebral blood flow is not necessarily indicative of pain, as this response is thought to constitute a “brain sparing” mechanism associated with hypoxia53 and intrauterine growth restriction.54

Other investigators measured increases in fetal plasma concentrations of cortisol, β-endorphin, and noradrenaline associated with intrauterine needling procedures, finding that increases during blood sampling from the hepatic vein were greater than those during sampling from the umbilical cord.55,56 However, these neuroendocrine responses do not constitute evidence of fetal pain, because the autonomic nervous system and hypothalamic-pituitary-adrenal axis mediate them without conscious cortical processing.57 Additionally, these responses are not specific for painful stimuli. Plasma noradrenaline concentrations may increase after umbilical cord transfusion,56 and plasma β-endorphin concentrations may increase after repeated cordocenteses.58 Plasma cortisol and β-endorphin concentrations increase during innocuous activities such as exercise.59 Moreover, in adults, neuroendocrine stress responses may persist despite well-controlled postoperative pain.60

Quiz Ref IDVital signs also have been used to assess neonatal pain.42,43,45,51,61 However, heart rate, respiratory rate, and transcutaneous oxygen and carbon dioxide levels do not necessarily differ significantly between alcohol-swabbing and lancing the heels of preterm neonates.40 Another group found that a similar proportion of neonates became hypoxic during tracheal suction, as well as during nonnoxious routine care such as washing and weighing.62

Fetal Anesthesia and Analgesia

Anesthetics and analgesics are commonly used to alleviate pain and discomfort. Despite ongoing debate regarding fetal capacity for pain, fetal anesthesia and analgesia are still warranted for surgical procedures undertaken to promote fetal health. When long-term fetal well-being is a central consideration, evidence of fetal pain is unnecessary to justify fetal anesthesia and analgesia because they serve other purposes unrelated to pain reduction, including (1) inhibiting fetal movement during a procedure6365; (2) achieving uterine atony to improve surgical access to the fetus and to prevent contractions and placental separation6670; (3) preventing hormonal stress responses associated with poor surgical outcomes in neonates71,72; and (4) preventing possible adverse effects on long-term neurodevelopment and behavioral responses to pain.7375

These objectives are not applicable to abortions. Instead, beneficence toward the fetus represents the chief justification for using fetal anesthesia or analgesia during abortion—to relieve suffering if fetal pain exists. As with any clinical decision, thorough safety and risk-benefit analyses should be undertaken before performing an intervention. Because the principle of beneficence also requires the woman’s physician to act in her best interests, potential fetal benefit must be weighed against real risks to the woman’s health. The safety and effectiveness of proposed fetal anesthesia and analgesia techniques are discussed below.

General Anesthesia for Fetal Surgery. Fetal surgery involving laparotomy, hysterotomy, or both requires general or regional anesthesia.68,76 Regional anesthesia, such as epidural anesthesia, does not anesthetize the fetus.76 General anesthesia is more commonly used because it induces uterine atony and fetal immobilization.65,77 Studies of inhalational agents in pregnant ewes determined that a dose capable of anesthetizing the ewe also anesthetized the fetus.78 Administering fentanyl, pancuronium, or vecuronium to the fetus intramuscularly may supplement analgesia or immobilization.64,65,77,79

Quiz Ref IDFor pregnant women, general anesthesia is associated with increased morbidity and mortality, particularly because of airway-related complications8082 and increased risk of hemorrhage from uterine atony.70 Historically, general anesthesia was used in abortions, even in the first trimester, until studies found that general anesthesia was a leading cause of abortion-related mortality.8385 In addition to safety concerns, general anesthesia increases the cost of abortion, making it prohibitively expensive for the majority of patients who pay out of pocket.86

Anesthesia and Analgesia in Minimally Invasive Fetal Procedures. In contrast to fetal surgery requiring regional or general anesthesia, minimally invasive fetal procedures do not involve maternal laparotomy or hysterotomy and instead use needles or endoscopy to access the fetus. For the sake of reducing pain, the increased risks of general anesthesia are unjustified for these procedures; adults typically undergo similar procedures with no analgesia or only local analgesia.67 No established fetal analgesia protocol exists for these procedures, although 3 techniques have been proposed, namely, direct delivery of medications to the fetus, delivery of medications to the fetus via maternal intravenous infusion, and intra-amniotic delivery of medications.

Direct Delivery. One group has examined the effects of analgesics delivered directly to human fetuses during minimally invasive procedures.87 Twenty-eight fetuses that received intravenous fentanyl before hepatic vein blood transfusions had diminished changes in plasma β-endorphin concentration and cerebral blood flow, compared with fetuses not receiving fentanyl. The cortisol response was not significantly decreased with fentanyl. The investigators did not examine risks for the woman, such as infection or uncontrolled bleeding.76 Furthermore, reducing the stress response is distinct from reducing pain. For example, plasma glucose and cortisol concentrations may not differ significantly between adults with and without postoperative pain.60

Delivery via Maternal Intravenous Infusion. To achieve presumably effective fetal plasma concentrations of fentanyl by placental transfer, potentially unsafe doses would need to be administered to the woman.88 Although standard doses of fentanyl are generally safe for maternal analgesia during labor,89 fentanyl can pose serious risks such as hypoventilation if maternal doses are significantly increased to achieve more extensive placental transfer.67,68 Severe maternal hypoventilation may require endotracheal intubation, which increases risks and costs for the woman, as described above.

No data exist on the dosing or efficacy of using medications such as diazepam and morphine for fetal analgesia via maternal intravenous infusion, although studies have characterized the placental transfer of these medications.9092 Two related studies found that low-dose remifentanil via maternal intravenous infusion achieved fetal immobilization during laser coagulation of placental vessels.93,94 However, immobilization is not the equivalent of pain reduction, and these procedures did not involve surgery on the fetus.

Intra-amniotic Delivery. Intra-amniotic injection would be technically simpler than direct fetal injection, although the drug must be absorbed through fetal membranes and skin. Intra-amniotic sufentanil injection in 10 pregnant ewes resulted in fetal plasma concentrations that would control postoperative pain in human adults.95,96 Sufentanil concentrations in the ewes also reached adult human therapeutic concentrations without causing significant hemodynamic changes.96 However, the study did not evaluate fetal response to noxious stimuli, and no data exist regarding safety or effectiveness in humans.

Pain is an emotional and psychological experience that requires conscious recognition of a noxious stimulus. Consequently, the capacity for conscious perception of pain can arise only after thalamocortical pathways begin to function, which may occur in the third trimester around 29 to 30 weeks’ gestational age, based on the limited data available. Small-scale histological studies of human fetuses have found that thalamocortical fibers begin to form between 23 and 30 weeks’ gestational age, but these studies did not specifically examine thalamocortical pathways active in pain perception.

While the presence of thalamocortical fibers is necessary for pain perception, their mere presence is insufficient—this pathway must also be functional. It has been proposed that transient, functional thalamocortical circuits may form via subplate neurons around midgestation, but no human study has demonstrated this early functionality. Instead, constant SEPs appear at 29 weeks’ PCA, and EEG patterns denoting wakefulness appear around 30 weeks’ PCA. Both of these tests of cortical function suggest that conscious perception of pain does not begin before the third trimester. Cutaneous withdrawal reflexes and hormonal stress responses present earlier in development are not explicit or sufficient evidence of pain perception because they are not specific to noxious stimuli and are not cortically mediated.

A variety of anesthetic and analgesic techniques have been used for fetal surgery, including maternal general anesthesia, regional anesthesia, and administration of medications for placental transfer to the fetus. However, these techniques are not necessarily applicable to abortions. Surgical procedures undertaken for fetal benefit use anesthesia to achieve objectives unrelated to pain control, such as uterine relaxation, fetal immobilization, and possible prevention of neuroendocrine stress responses associated with poor surgical outcomes. Thus, fetal anesthesia may be medically indicated for fetal surgery regardless of whether fetal pain exists.

In the context of abortion, fetal analgesia would be used solely for beneficence toward the fetus, assuming fetal pain exists. This interest must be considered in concert with maternal safety and fetal effectiveness of any proposed anesthetic or analgesic technique. For instance, general anesthesia increases abortion morbidity and mortality for women and substantially increases the cost of abortion. Although placental transfer of many opioids and sedative-hypnotics has been determined, the maternal dose required for fetal analgesia is unknown, as is the safety for women at such doses. Furthermore, no established protocols exist for administering anesthesia or analgesia directly to the fetus for minimally invasive fetal procedures or abortions. Experimental techniques, such as administration of fentanyl directly to the fetus and intra-amniotic injection of sufentanil in pregnant ewes, have not been shown to decrease fetal pain and are of unknown safety in humans.

Because pain perception probably does not function before the third trimester, discussions of fetal pain for abortions performed before the end of the second trimester should be noncompulsory. Fetal anesthesia or analgesia should not be recommended or routinely offered for abortion because current experimental techniques provide unknown fetal benefit and may increase risks for the woman. Instead, further research should focus on when pain-related thalamocortical pathways become functional in humans. If the fetus can feel pain, additional research may lead to effective fetal anesthesia or analgesia techniques that are also safe for women.

Corresponding Author: Mark A. Rosen, MD, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 513 Parnassus Ave, San Francisco, CA 94143-0648 (rosenm@anesthesia.ucsf.edu).

Financial Disclosures: None reported.

 Unborn Child Pain Awareness and Prevention Act of 2005. To be codified at Ark Code Ann §§20-16-1101 to 1111.
 Woman’s Right to Know Act. To be codified at Ga Code Ann §31-9A-4.
 Unborn Child Pain Awareness Act, S51, 109th Cong (2005)
Strauss LT, Herndon J, Chang J.  et al.  Abortion surveillance—United States, 2001.  MMWR Surveill Summ. 2004;53:1-32
PubMed
Benatar D, Benatar M. A pain in the fetus: toward ending confusion about fetal pain.  Bioethics. 2001;15:57-76
PubMed   |  Link to Article
Glover V, Fisk NM. Fetal pain: implications for research and practice.  Br J Obstet Gynaecol. 1999;106:881-886
PubMed   |  Link to Article
International Association for the Study of Pain.  IASP Pain Terminology. 2004. Available at: http://www.iasp-pain.org/terms-p.html. Accessed May 2, 2005
Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus.  N Engl J Med. 1987;317:1321-1329
PubMed   |  Link to Article
Derbyshire SW. Locating the beginnings of pain.  Bioethics. 1999;13:1-31
PubMed   |  Link to Article
Derbyshire SW. Fetal pain: an infantile debate.  Bioethics. 2001;15:77-84
PubMed   |  Link to Article
Fitzgerald M, Howard RF. The neurobiologic basis of pediatric pain. In: Schechter NL, Berde CB, Yaster M, eds. Pain in Infants, Children, and Adolescents. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:19-42
Strigo IA, Duncan GH, Boivin M, Bushnell MC. Differentiation of visceral and cutaneous pain in the human brain.  J Neurophysiol. 2003;89:3294-3303
PubMed   |  Link to Article
Humphrey T. Some correlations between the appearance of fetal reflexes and the development of the nervous system.  Prog Brain Res. 1964;4:93-135
Okado N, Kojima T. Ontogeny of the central nervous system: neurogenesis, fibre connection, synaptogenesis and myelination in the spinal cord. In: Prechtl HFR, ed. Clinics in Developmental Medicine: Continuity of Neural Functions From Prenatal to Postnatal Life. Vol 94. Philadelphia, Pa: JB Lippincott Co; 1984:31-45
Konstantinidou AD, Silos-Santiago I, Flaris N, Snider WD. Development of the primary afferent projection in human spinal cord.  J Comp Neurol. 1995;354:11-12
PubMed   |  Link to Article
Kostovic I, Rakic P. Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain.  J Comp Neurol. 1990;297:441-470
PubMed   |  Link to Article
Hevner RF. Development of connections in the human visual system during fetal mid-gestation: a DiI-tracing study.  J Neuropathol Exp Neurol. 2000;59:385-392
PubMed
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
PubMed
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;219:431-447
PubMed   |  Link to Article
Klimach VJ, Cooke RW. Maturation of the neonatal somatosensory evoked response in preterm infants.  Dev Med Child Neurol. 1988;30:208-214
PubMed   |  Link to Article
Hrbek A, Karlberg P, Olsson T. Development of visual and somatosensory evoked responses in pre-term newborn infants.  Electroencephalogr Clin Neurophysiol. 1973;34:225-232
PubMed   |  Link to Article
Clancy RR, Bergqvist AGC, Dlugos DJ. Neonatal electroencephalography. In: Ebersole JS, Pedley TA, eds. Current Practice of Clinical Electroencephalography. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:160-234
Torres F, Anderson C. The normal EEG of the human newborn.  J Clin Neurophysiol. 1985;2:89-103
PubMed   |  Link to Article
Krmpotic-Nemanic J, Kostovic I, Kelovic Z, Nemanic D, Mrzljak L. Development of the human fetal auditory cortex: growth of afferent fibres.  Acta Anat (Basel). 1983;116:69-73
PubMed   |  Link to Article
Vogt BA, Rosene DL, Pandya DN. Thalamic and cortical afferents differentiate anterior from posterior cingulate cortex in the monkey.  Science. 1979;204:205-207
PubMed   |  Link to Article
Schnitzler A, Ploner M. Neurophysiology and functional neuroanatomy of pain perception.  J Clin Neurophysiol. 2000;17:592-603
PubMed   |  Link to Article
Barbas H. Connections underlying the synthesis of cognition, memory, and emotion in primate prefrontal cortices.  Brain Res Bull. 2000;52:319-330
PubMed   |  Link to Article
Mrzljak L, Uylings HB, Kostovic I, Van Eden CG. Prenatal development of neurons in the human prefrontal cortex, I: a qualitative Golgi study.  J Comp Neurol. 1988;271:355-386
PubMed   |  Link to Article
Kostovic I, Judas M. Correlation between the sequential ingrowth of afferents and transient patterns of cortical lamination in preterm infants.  Anat Rec. 2002;267:1-6
PubMed   |  Link to Article
Ulfig N, Neudorfer F, Bohl J. Transient structures of the human fetal brain: subplate, thalamic reticular complex, ganglionic eminence.  Histol Histopathol. 2000;15:771-790
PubMed
Kostovic I, Judas M, Petanjek Z, Simic G. Ontogenesis of goal-directed behavior: anatomo-functional considerations.  Int J Psychophysiol. 1995;19:85-102
PubMed   |  Link to Article
Schenk VW, De Vlieger M, Hamersma K, De Weerdt J. Two rhombencephalic anencephalics: a clinico-pathological and electroencephalographic study.  Brain. 1968;91:497-506
PubMed   |  Link to Article
Fisch BJ, Spehlmann R. Fisch and Spehlmann's EEG Primer: Basic Principles of Digital and Analog EEG3rd ed. New York, NY: Elsevier; 1999
Scher MS. Electroencephalography of the newborn: normal and abnormal features. In: Niedermeyer E, Lopes da Silva FH, eds. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:896-946
Sharbrough FW. Nonspecific abnormal EEG patterns. In: Niedermeyer E, Lopes da Silva FH, eds. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:215-234
Burgess JA, Tawia SA. When did you first begin to feel it?—locating the beginning of human consciousness.  Bioethics. 1996;10:1-26
PubMed   |  Link to Article
Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation.  Pain. 1994;56:95-101
PubMed   |  Link to Article
Ashwal S, Peabody JL, Schneider S, Tomasi LG, Emery JR, Peckham N. Anencephaly: clinical determination of brain death and neuropathologic studies.  Pediatr Neurol. 1990;6:233-239
PubMed   |  Link to Article
Pilon M, Sullivan SJ. Motor profile of patients in minimally responsive and persistent vegetative states.  Brain Inj. 1996;10:421-437
PubMed   |  Link to Article
Craig KD, Whitfield MF, Grunau RV, Linton J, Hadjistavropoulos HD. Pain in the preterm neonate: behavioural and physiological indices.  Pain. 1993;52:287-299
PubMed   |  Link to Article
Johnston CC, Stevens BJ, Yang F, Horton L. Differential response to pain by very premature neonates.  Pain. 1995;61:471-479
PubMed   |  Link to Article
Johnston CC, Stevens B, Yang F, Horton L. Developmental changes in response to heelstick in preterm infants: a prospective cohort study.  Dev Med Child Neurol. 1996;38:438-445
PubMed   |  Link to Article
Lindh V, Wiklund U, Sandman PO, Hakansson S. Assessment of acute pain in preterm infants by evaluation of facial expression and frequency domain analysis of heart rate variability.  Early Hum Dev. 1997;48:131-142
PubMed   |  Link to Article
Hadjistavropoulos HD, Craig KD, Grunau RE, Whitfield MF. Judging pain in infants: behavioural, contextual, and developmental determinants.  Pain. 1997;73:319-324
PubMed   |  Link to Article
Goubet N, Clifton RK, Shah B. Learning about pain in preterm newborns.  J Dev Behav Pediatr. 2001;22:418-424
PubMed   |  Link to Article
Xia C, Yang L, Zhao P, Zhang X. Response to pain by different gestational age neonates.  J Huazhong Univ Sci Technolog Med Sci. 2002;22:84-86
PubMed   |  Link to Article
Craig KD, Prkachin KM, Grunau RE. Facial expression of pain. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2nd ed. New York, NY: Guilford Press; 2001:153-169
Craig KD, Hadjistavropoulos HD, Grunau RV, Whitfield MF. A comparison of two measures of facial activity during pain in the newborn child.  J Pediatr Psychol. 1994;19:305-318
PubMed   |  Link to Article
Waxman SG. Clinical observations on the emotional motor system.  Prog Brain Res. 1996;107:595-604
PubMed
Oberlander TF, Grunau RE, Fitzgerald C, Whitfield MF. Does parenchymal brain injury affect biobehavioral pain responses in very low birth weight infants at 32 weeks’ postconceptional age?  Pediatrics. 2002;110:570-576
PubMed   |  Link to Article
Franck LS, Miaskowski C. Measurement of neonatal responses to painful stimuli: a research review.  J Pain Symptom Manage. 1997;14:343-378
PubMed   |  Link to Article
Teixeira JM, Glover V, Fisk NM. Acute cerebral redistribution in response to invasive procedures in the human fetus.  Am J Obstet Gynecol. 1999;181:1018-1025
PubMed   |  Link to Article
Woo JS, Liang ST, Lo RL, Chan FY. Middle cerebral artery Doppler flow velocity waveforms.  Obstet Gynecol. 1987;70:613-616
PubMed
Wladimiroff JW, vd Wijngaard JA, Degani S, Noordam MJ, van Eyck J, Tonge HM. Cerebral and umbilical arterial blood flow velocity waveforms in normal and growth-retarded pregnancies.  Obstet Gynecol. 1987;69:705-709
PubMed
Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma cortisol and beta-endorphin response to intrauterine needling.  Lancet. 1994;344:77-81
PubMed   |  Link to Article
Giannakoulopoulos X, Teixeira J, Fisk N, Glover V. Human fetal and maternal noradrenaline responses to invasive procedures.  Pediatr Res. 1999;45:494-499
PubMed   |  Link to Article
Carrasco GA, Van de Kar LD. Neuroendocrine pharmacology of stress.  Eur J Pharmacol. 2003;463:235-272
PubMed   |  Link to Article
Radunovic N, Lockwood CJ, Ghidini A, Alvarez M, Berkowitz RL. Is fetal blood sampling associated with increased beta-endorphin release into the fetal circulation?  Am J Perinatol. 1993;10:112-114
PubMed   |  Link to Article
Williams RH, Larsen PR. Williams Textbook of Endocrinology10th ed. Philadelphia, Pa: Saunders; 2003
Schulze S, Roikjaer O, Hasselstrom L, Jensen NH, Kehlet H. Epidural bupivacaine and morphine plus systemic indomethacin eliminates pain but not systemic response and convalescence after cholecystectomy.  Surgery. 1988;103:321-327
PubMed
Porter FL, Wolf CM, Miller JP. Procedural pain in newborn infants: the influence of intensity and development.  Pediatrics. 1999;104:e13
PubMed   |  Link to Article
Pokela ML. Pain relief can reduce hypoxemia in distressed neonates during routine treatment procedures.  Pediatrics. 1994;93:379-383
PubMed
Seeds JW, Corke BC, Spielman FJ. Prevention of fetal movement during invasive procedures with pancuronium bromide.  Am J Obstet Gynecol. 1986;155:818-819
PubMed
Rosen MA. Anesthesia for fetal procedures and surgery.  Yonsei Med J. 2001;42:669-680
PubMed
Cauldwell CB. Anesthesia for fetal surgery.  Anesthesiol Clin North America. 2002;20:211-226
PubMed   |  Link to Article
Rosen MA. Anesthesia for procedures involving the fetus.  Semin Perinatol. 1991;15:410-417
PubMed
Smith RP, Gitau R, Glover V, Fisk NM. Pain and stress in the human fetus.  Eur J Obstet Gynecol Reprod Biol. 2000;92:161-165
PubMed   |  Link to Article
White MC, Wolf AR. Pain and stress in the human fetus.  Best Pract Res Clin Anaesthesiol. 2004;18:205-220
PubMed   |  Link to Article
Rosen MA. Anesthesia and tocolysis for fetal intervention. In: Harrison MR, Golbus MS, Filly RA, eds. The Unborn Patient: Prenatal Diagnosis and Treatment. Orlando, Fla: Grune & Stratton; 1984:417-433
Schwarz U, Galinkin JL. Anesthesia for fetal surgery.  Semin Pediatr Surg. 2003;12:196-201
PubMed   |  Link to Article
Anand KJ, 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
PubMed   |  Link to Article
Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response.  Lancet. 1987;1:62-66
PubMed   |  Link to Article
Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response.  Pediatrics. 1996;98:925-930
PubMed
Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination.  Lancet. 1997;349:599-603
PubMed   |  Link to Article
Taylor A, Fisk NM, Glover V. Mode of delivery and subsequent stress response.  Lancet. 2000;355:120
PubMed   |  Link to Article
Myers LB, Bulich LA, Hess P, Miller NM. Fetal endoscopic surgery: indications and anaesthetic management.  Best Pract Res Clin Anaesthesiol. 2004;18:231-258
PubMed   |  Link to Article
Myers LB, Cohen D, Galinkin J, Gaiser R, Kurth CD. Anaesthesia for fetal surgery.  Paediatr Anaesth. 2002;12:569-578
PubMed   |  Link to Article
Gregory GA, Wade JG, Beihl DR, Ong BY, Sitar DS. Fetal anesthetic requirement (MAC) for halothane.  Anesth Analg. 1983;62:9-14
PubMed   |  Link to Article
Gaiser RR, Kurth CD. Anesthetic considerations for fetal surgery.  Semin Perinatol. 1999;23:507-514
PubMed   |  Link to Article
Clyburn PA. Early thoughts on “Why Mothers Die 2000-2002.”  Anaesthesia. 2004;59:1157-1159
PubMed   |  Link to Article
Munnur U, Suresh MS. Airway problems in pregnancy.  Crit Care Clin. 2004;20:617-642
PubMed   |  Link to Article
Royal College of Obstetricians and Gynaecologists.  Confidential Enquiry Into Maternal and Child Health: Why Mothers Die 2000-2002: Report on Confidential Enquiries Into Maternal Deaths in the United KingdomLondon, England: RCOG Press; 2004
Atrash HK, Cheek TG, Hogue CJ. Legal abortion mortality and general anesthesia.  Am J Obstet Gynecol. 1988;158:420-424
PubMed
Atrash HK, MacKay HT, Binkin NJ, Hogue CJ. Legal abortion mortality in the United States: 1972 to 1982.  Am J Obstet Gynecol. 1987;156:605-612
PubMed
Bartlett LA, Berg CJ, Shulman HB.  et al.  Risk factors for legal induced abortion-related mortality in the United States.  Obstet Gynecol. 2004;103:729-737
PubMed   |  Link to Article
Henshaw SK, Finer LB. The accessibility of abortion services in the United States, 2001.  Perspect Sex Reprod Health. 2003;35:16-24
PubMed   |  Link to Article
Fisk NM, Gitau R, Teixeira JM, Giannakoulopoulos X, Cameron AD, Glover VA. Effect of direct fetal opioid analgesia on fetal hormonal and hemodynamic stress response to intrauterine needling.  Anesthesiology. 2001;95:828-835
PubMed   |  Link to Article
Loftus JR, Hill H, Cohen SE. Placental transfer and neonatal effects of epidural sufentanil and fentanyl administered with bupivacaine during labor.  Anesthesiology. 1995;83:300-308
PubMed   |  Link to Article
Rayburn W, Rathke A, Leuschen MP, Chleborad J, Weidner W. Fentanyl citrate analgesia during labor.  Am J Obstet Gynecol. 1989;161:202-206
PubMed   |  Link to Article
Jauniaux E, Jurkovic D, Lees C, Campbell S, Gulbis B. In-vivo study of diazepam transfer across the first trimester human placenta.  Hum Reprod. 1996;11:889-892
PubMed   |  Link to Article
Haram K, Bakke OM. Diazepam as an induction agent for caesarean section: a clinical and pharmacokinetic study of fetal drug exposure.  Br J Obstet Gynaecol. 1980;87:506-512
PubMed   |  Link to Article
Gerdin E, Rane A, Lindberg B. Transplacental transfer of morphine in man.  J Perinat Med. 1990;18:305-312
PubMed   |  Link to Article
Missant C, Van Schoubroeck D, Deprest J, Devlieger R, Teunkens A, Van de Velde M. Remifentanil for foetal immobilisation and maternal sedation during endoscopic treatment of twin-to-twin transfusion syndrome: a preliminary dose-finding study.  Acta Anaesthesiol Belg. 2004;55:239-244
PubMed
Van de Velde M, Van Schoubroeck D, Lewi LE.  et al.  Remifentanil for fetal immobilization and maternal sedation during fetoscopic surgery: a randomized, double blind comparison with diazepam.  Anesth Analg. 2005;101:251-258
Link to Article
Lehmann KA, Gerhard A, Horrichs-Haermeyer G, Grond S, Zech D. Postoperative patient-controlled analgesia with sufentanil: analgesic efficacy and minimum effective concentrations.  Acta Anaesthesiol Scand. 1991;35:221-226
PubMed   |  Link to Article
Strumper D, Durieux ME, Gogarten W, Van Aken H, Hartleb K, Marcus MA. Fetal plasma concentrations after intraamniotic sufentanil in chronically instrumented pregnant sheep.  Anesthesiology. 2003;98:1400-1406
PubMed   |  Link to Article

Figures

Figure. Spinal Reflex and Pain Perception Pathways
Graphic Jump Location

A, Reflex responses to noxious stimuli occur early in development, before thalamocortical circuits are functional; noxious stimuli trigger reflex movement without cortical involvement. Activated by a noxious stimulus (1), a peripheral sensory neuron (2) synapses on a dorsal horn interneuron (3) that in turn synapses on a ventral horn motor neuron (4), leading to reflex muscle contraction and limb withdrawal (5). B, Later in development, noxious stimuli (1) activate peripheral sensory neurons (2) that synapse on spinothalamic tract neurons (3), the axons of which extend up the spinal cord as the spinothalamic tract (4) to synapse on neurons of the thalamus (5). From here, thalamocortical axons synapse on cortical neurons, resulting in the conscious perception of pain.

Tables

Table Graphic Jump LocationTable. Anatomical and Functional Development of Nociception and Pain Perception Pathways

References

 Unborn Child Pain Awareness and Prevention Act of 2005. To be codified at Ark Code Ann §§20-16-1101 to 1111.
 Woman’s Right to Know Act. To be codified at Ga Code Ann §31-9A-4.
 Unborn Child Pain Awareness Act, S51, 109th Cong (2005)
Strauss LT, Herndon J, Chang J.  et al.  Abortion surveillance—United States, 2001.  MMWR Surveill Summ. 2004;53:1-32
PubMed
Benatar D, Benatar M. A pain in the fetus: toward ending confusion about fetal pain.  Bioethics. 2001;15:57-76
PubMed   |  Link to Article
Glover V, Fisk NM. Fetal pain: implications for research and practice.  Br J Obstet Gynaecol. 1999;106:881-886
PubMed   |  Link to Article
International Association for the Study of Pain.  IASP Pain Terminology. 2004. Available at: http://www.iasp-pain.org/terms-p.html. Accessed May 2, 2005
Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus.  N Engl J Med. 1987;317:1321-1329
PubMed   |  Link to Article
Derbyshire SW. Locating the beginnings of pain.  Bioethics. 1999;13:1-31
PubMed   |  Link to Article
Derbyshire SW. Fetal pain: an infantile debate.  Bioethics. 2001;15:77-84
PubMed   |  Link to Article
Fitzgerald M, Howard RF. The neurobiologic basis of pediatric pain. In: Schechter NL, Berde CB, Yaster M, eds. Pain in Infants, Children, and Adolescents. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:19-42
Strigo IA, Duncan GH, Boivin M, Bushnell MC. Differentiation of visceral and cutaneous pain in the human brain.  J Neurophysiol. 2003;89:3294-3303
PubMed   |  Link to Article
Humphrey T. Some correlations between the appearance of fetal reflexes and the development of the nervous system.  Prog Brain Res. 1964;4:93-135
Okado N, Kojima T. Ontogeny of the central nervous system: neurogenesis, fibre connection, synaptogenesis and myelination in the spinal cord. In: Prechtl HFR, ed. Clinics in Developmental Medicine: Continuity of Neural Functions From Prenatal to Postnatal Life. Vol 94. Philadelphia, Pa: JB Lippincott Co; 1984:31-45
Konstantinidou AD, Silos-Santiago I, Flaris N, Snider WD. Development of the primary afferent projection in human spinal cord.  J Comp Neurol. 1995;354:11-12
PubMed   |  Link to Article
Kostovic I, Rakic P. Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain.  J Comp Neurol. 1990;297:441-470
PubMed   |  Link to Article
Hevner RF. Development of connections in the human visual system during fetal mid-gestation: a DiI-tracing study.  J Neuropathol Exp Neurol. 2000;59:385-392
PubMed
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
PubMed
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;219:431-447
PubMed   |  Link to Article
Klimach VJ, Cooke RW. Maturation of the neonatal somatosensory evoked response in preterm infants.  Dev Med Child Neurol. 1988;30:208-214
PubMed   |  Link to Article
Hrbek A, Karlberg P, Olsson T. Development of visual and somatosensory evoked responses in pre-term newborn infants.  Electroencephalogr Clin Neurophysiol. 1973;34:225-232
PubMed   |  Link to Article
Clancy RR, Bergqvist AGC, Dlugos DJ. Neonatal electroencephalography. In: Ebersole JS, Pedley TA, eds. Current Practice of Clinical Electroencephalography. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:160-234
Torres F, Anderson C. The normal EEG of the human newborn.  J Clin Neurophysiol. 1985;2:89-103
PubMed   |  Link to Article
Krmpotic-Nemanic J, Kostovic I, Kelovic Z, Nemanic D, Mrzljak L. Development of the human fetal auditory cortex: growth of afferent fibres.  Acta Anat (Basel). 1983;116:69-73
PubMed   |  Link to Article
Vogt BA, Rosene DL, Pandya DN. Thalamic and cortical afferents differentiate anterior from posterior cingulate cortex in the monkey.  Science. 1979;204:205-207
PubMed   |  Link to Article
Schnitzler A, Ploner M. Neurophysiology and functional neuroanatomy of pain perception.  J Clin Neurophysiol. 2000;17:592-603
PubMed   |  Link to Article
Barbas H. Connections underlying the synthesis of cognition, memory, and emotion in primate prefrontal cortices.  Brain Res Bull. 2000;52:319-330
PubMed   |  Link to Article
Mrzljak L, Uylings HB, Kostovic I, Van Eden CG. Prenatal development of neurons in the human prefrontal cortex, I: a qualitative Golgi study.  J Comp Neurol. 1988;271:355-386
PubMed   |  Link to Article
Kostovic I, Judas M. Correlation between the sequential ingrowth of afferents and transient patterns of cortical lamination in preterm infants.  Anat Rec. 2002;267:1-6
PubMed   |  Link to Article
Ulfig N, Neudorfer F, Bohl J. Transient structures of the human fetal brain: subplate, thalamic reticular complex, ganglionic eminence.  Histol Histopathol. 2000;15:771-790
PubMed
Kostovic I, Judas M, Petanjek Z, Simic G. Ontogenesis of goal-directed behavior: anatomo-functional considerations.  Int J Psychophysiol. 1995;19:85-102
PubMed   |  Link to Article
Schenk VW, De Vlieger M, Hamersma K, De Weerdt J. Two rhombencephalic anencephalics: a clinico-pathological and electroencephalographic study.  Brain. 1968;91:497-506
PubMed   |  Link to Article
Fisch BJ, Spehlmann R. Fisch and Spehlmann's EEG Primer: Basic Principles of Digital and Analog EEG3rd ed. New York, NY: Elsevier; 1999
Scher MS. Electroencephalography of the newborn: normal and abnormal features. In: Niedermeyer E, Lopes da Silva FH, eds. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:896-946
Sharbrough FW. Nonspecific abnormal EEG patterns. In: Niedermeyer E, Lopes da Silva FH, eds. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:215-234
Burgess JA, Tawia SA. When did you first begin to feel it?—locating the beginning of human consciousness.  Bioethics. 1996;10:1-26
PubMed   |  Link to Article
Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation.  Pain. 1994;56:95-101
PubMed   |  Link to Article
Ashwal S, Peabody JL, Schneider S, Tomasi LG, Emery JR, Peckham N. Anencephaly: clinical determination of brain death and neuropathologic studies.  Pediatr Neurol. 1990;6:233-239
PubMed   |  Link to Article
Pilon M, Sullivan SJ. Motor profile of patients in minimally responsive and persistent vegetative states.  Brain Inj. 1996;10:421-437
PubMed   |  Link to Article
Craig KD, Whitfield MF, Grunau RV, Linton J, Hadjistavropoulos HD. Pain in the preterm neonate: behavioural and physiological indices.  Pain. 1993;52:287-299
PubMed   |  Link to Article
Johnston CC, Stevens BJ, Yang F, Horton L. Differential response to pain by very premature neonates.  Pain. 1995;61:471-479
PubMed   |  Link to Article
Johnston CC, Stevens B, Yang F, Horton L. Developmental changes in response to heelstick in preterm infants: a prospective cohort study.  Dev Med Child Neurol. 1996;38:438-445
PubMed   |  Link to Article
Lindh V, Wiklund U, Sandman PO, Hakansson S. Assessment of acute pain in preterm infants by evaluation of facial expression and frequency domain analysis of heart rate variability.  Early Hum Dev. 1997;48:131-142
PubMed   |  Link to Article
Hadjistavropoulos HD, Craig KD, Grunau RE, Whitfield MF. Judging pain in infants: behavioural, contextual, and developmental determinants.  Pain. 1997;73:319-324
PubMed   |  Link to Article
Goubet N, Clifton RK, Shah B. Learning about pain in preterm newborns.  J Dev Behav Pediatr. 2001;22:418-424
PubMed   |  Link to Article
Xia C, Yang L, Zhao P, Zhang X. Response to pain by different gestational age neonates.  J Huazhong Univ Sci Technolog Med Sci. 2002;22:84-86
PubMed   |  Link to Article
Craig KD, Prkachin KM, Grunau RE. Facial expression of pain. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2nd ed. New York, NY: Guilford Press; 2001:153-169
Craig KD, Hadjistavropoulos HD, Grunau RV, Whitfield MF. A comparison of two measures of facial activity during pain in the newborn child.  J Pediatr Psychol. 1994;19:305-318
PubMed   |  Link to Article
Waxman SG. Clinical observations on the emotional motor system.  Prog Brain Res. 1996;107:595-604
PubMed
Oberlander TF, Grunau RE, Fitzgerald C, Whitfield MF. Does parenchymal brain injury affect biobehavioral pain responses in very low birth weight infants at 32 weeks’ postconceptional age?  Pediatrics. 2002;110:570-576
PubMed   |  Link to Article
Franck LS, Miaskowski C. Measurement of neonatal responses to painful stimuli: a research review.  J Pain Symptom Manage. 1997;14:343-378
PubMed   |  Link to Article
Teixeira JM, Glover V, Fisk NM. Acute cerebral redistribution in response to invasive procedures in the human fetus.  Am J Obstet Gynecol. 1999;181:1018-1025
PubMed   |  Link to Article
Woo JS, Liang ST, Lo RL, Chan FY. Middle cerebral artery Doppler flow velocity waveforms.  Obstet Gynecol. 1987;70:613-616
PubMed
Wladimiroff JW, vd Wijngaard JA, Degani S, Noordam MJ, van Eyck J, Tonge HM. Cerebral and umbilical arterial blood flow velocity waveforms in normal and growth-retarded pregnancies.  Obstet Gynecol. 1987;69:705-709
PubMed
Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma cortisol and beta-endorphin response to intrauterine needling.  Lancet. 1994;344:77-81
PubMed   |  Link to Article
Giannakoulopoulos X, Teixeira J, Fisk N, Glover V. Human fetal and maternal noradrenaline responses to invasive procedures.  Pediatr Res. 1999;45:494-499
PubMed   |  Link to Article
Carrasco GA, Van de Kar LD. Neuroendocrine pharmacology of stress.  Eur J Pharmacol. 2003;463:235-272
PubMed   |  Link to Article
Radunovic N, Lockwood CJ, Ghidini A, Alvarez M, Berkowitz RL. Is fetal blood sampling associated with increased beta-endorphin release into the fetal circulation?  Am J Perinatol. 1993;10:112-114
PubMed   |  Link to Article
Williams RH, Larsen PR. Williams Textbook of Endocrinology10th ed. Philadelphia, Pa: Saunders; 2003
Schulze S, Roikjaer O, Hasselstrom L, Jensen NH, Kehlet H. Epidural bupivacaine and morphine plus systemic indomethacin eliminates pain but not systemic response and convalescence after cholecystectomy.  Surgery. 1988;103:321-327
PubMed
Porter FL, Wolf CM, Miller JP. Procedural pain in newborn infants: the influence of intensity and development.  Pediatrics. 1999;104:e13
PubMed   |  Link to Article
Pokela ML. Pain relief can reduce hypoxemia in distressed neonates during routine treatment procedures.  Pediatrics. 1994;93:379-383
PubMed
Seeds JW, Corke BC, Spielman FJ. Prevention of fetal movement during invasive procedures with pancuronium bromide.  Am J Obstet Gynecol. 1986;155:818-819
PubMed
Rosen MA. Anesthesia for fetal procedures and surgery.  Yonsei Med J. 2001;42:669-680
PubMed
Cauldwell CB. Anesthesia for fetal surgery.  Anesthesiol Clin North America. 2002;20:211-226
PubMed   |  Link to Article
Rosen MA. Anesthesia for procedures involving the fetus.  Semin Perinatol. 1991;15:410-417
PubMed
Smith RP, Gitau R, Glover V, Fisk NM. Pain and stress in the human fetus.  Eur J Obstet Gynecol Reprod Biol. 2000;92:161-165
PubMed   |  Link to Article
White MC, Wolf AR. Pain and stress in the human fetus.  Best Pract Res Clin Anaesthesiol. 2004;18:205-220
PubMed   |  Link to Article
Rosen MA. Anesthesia and tocolysis for fetal intervention. In: Harrison MR, Golbus MS, Filly RA, eds. The Unborn Patient: Prenatal Diagnosis and Treatment. Orlando, Fla: Grune & Stratton; 1984:417-433
Schwarz U, Galinkin JL. Anesthesia for fetal surgery.  Semin Pediatr Surg. 2003;12:196-201
PubMed   |  Link to Article
Anand KJ, 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
PubMed   |  Link to Article
Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response.  Lancet. 1987;1:62-66
PubMed   |  Link to Article
Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response.  Pediatrics. 1996;98:925-930
PubMed
Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination.  Lancet. 1997;349:599-603
PubMed   |  Link to Article
Taylor A, Fisk NM, Glover V. Mode of delivery and subsequent stress response.  Lancet. 2000;355:120
PubMed   |  Link to Article
Myers LB, Bulich LA, Hess P, Miller NM. Fetal endoscopic surgery: indications and anaesthetic management.  Best Pract Res Clin Anaesthesiol. 2004;18:231-258
PubMed   |  Link to Article
Myers LB, Cohen D, Galinkin J, Gaiser R, Kurth CD. Anaesthesia for fetal surgery.  Paediatr Anaesth. 2002;12:569-578
PubMed   |  Link to Article
Gregory GA, Wade JG, Beihl DR, Ong BY, Sitar DS. Fetal anesthetic requirement (MAC) for halothane.  Anesth Analg. 1983;62:9-14
PubMed   |  Link to Article
Gaiser RR, Kurth CD. Anesthetic considerations for fetal surgery.  Semin Perinatol. 1999;23:507-514
PubMed   |  Link to Article
Clyburn PA. Early thoughts on “Why Mothers Die 2000-2002.”  Anaesthesia. 2004;59:1157-1159
PubMed   |  Link to Article
Munnur U, Suresh MS. Airway problems in pregnancy.  Crit Care Clin. 2004;20:617-642
PubMed   |  Link to Article
Royal College of Obstetricians and Gynaecologists.  Confidential Enquiry Into Maternal and Child Health: Why Mothers Die 2000-2002: Report on Confidential Enquiries Into Maternal Deaths in the United KingdomLondon, England: RCOG Press; 2004
Atrash HK, Cheek TG, Hogue CJ. Legal abortion mortality and general anesthesia.  Am J Obstet Gynecol. 1988;158:420-424
PubMed
Atrash HK, MacKay HT, Binkin NJ, Hogue CJ. Legal abortion mortality in the United States: 1972 to 1982.  Am J Obstet Gynecol. 1987;156:605-612
PubMed
Bartlett LA, Berg CJ, Shulman HB.  et al.  Risk factors for legal induced abortion-related mortality in the United States.  Obstet Gynecol. 2004;103:729-737
PubMed   |  Link to Article
Henshaw SK, Finer LB. The accessibility of abortion services in the United States, 2001.  Perspect Sex Reprod Health. 2003;35:16-24
PubMed   |  Link to Article
Fisk NM, Gitau R, Teixeira JM, Giannakoulopoulos X, Cameron AD, Glover VA. Effect of direct fetal opioid analgesia on fetal hormonal and hemodynamic stress response to intrauterine needling.  Anesthesiology. 2001;95:828-835
PubMed   |  Link to Article
Loftus JR, Hill H, Cohen SE. Placental transfer and neonatal effects of epidural sufentanil and fentanyl administered with bupivacaine during labor.  Anesthesiology. 1995;83:300-308
PubMed   |  Link to Article
Rayburn W, Rathke A, Leuschen MP, Chleborad J, Weidner W. Fentanyl citrate analgesia during labor.  Am J Obstet Gynecol. 1989;161:202-206
PubMed   |  Link to Article
Jauniaux E, Jurkovic D, Lees C, Campbell S, Gulbis B. In-vivo study of diazepam transfer across the first trimester human placenta.  Hum Reprod. 1996;11:889-892
PubMed   |  Link to Article
Haram K, Bakke OM. Diazepam as an induction agent for caesarean section: a clinical and pharmacokinetic study of fetal drug exposure.  Br J Obstet Gynaecol. 1980;87:506-512
PubMed   |  Link to Article
Gerdin E, Rane A, Lindberg B. Transplacental transfer of morphine in man.  J Perinat Med. 1990;18:305-312
PubMed   |  Link to Article
Missant C, Van Schoubroeck D, Deprest J, Devlieger R, Teunkens A, Van de Velde M. Remifentanil for foetal immobilisation and maternal sedation during endoscopic treatment of twin-to-twin transfusion syndrome: a preliminary dose-finding study.  Acta Anaesthesiol Belg. 2004;55:239-244
PubMed
Van de Velde M, Van Schoubroeck D, Lewi LE.  et al.  Remifentanil for fetal immobilization and maternal sedation during fetoscopic surgery: a randomized, double blind comparison with diazepam.  Anesth Analg. 2005;101:251-258
Link to Article
Lehmann KA, Gerhard A, Horrichs-Haermeyer G, Grond S, Zech D. Postoperative patient-controlled analgesia with sufentanil: analgesic efficacy and minimum effective concentrations.  Acta Anaesthesiol Scand. 1991;35:221-226
PubMed   |  Link to Article
Strumper D, Durieux ME, Gogarten W, Van Aken H, Hartleb K, Marcus MA. Fetal plasma concentrations after intraamniotic sufentanil in chronically instrumented pregnant sheep.  Anesthesiology. 2003;98:1400-1406
PubMed   |  Link to Article
CME


You need to register in order to view this quiz.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 104

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles