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1.
 Unborn Child Pain Awareness and Prevention Act of 2005. To be codified at Ark Code Ann §§20-16-1101 to 1111.
2.
 Woman’s Right to Know Act. To be codified at Ga Code Ann §31-9A-4.
3.
 Unborn Child Pain Awareness Act, S51, 109th Cong (2005)
4.
Strauss LT, Herndon J, Chang J.  et al.  Abortion surveillance—United States, 2001.  MMWR Surveill Summ. 2004;53:1-3215562258Google Scholar
5.
Benatar D, Benatar M. A pain in the fetus: toward ending confusion about fetal pain.  Bioethics. 2001;15:57-7611699550Google ScholarCrossref
6.
Glover V, Fisk NM. Fetal pain: implications for research and practice.  Br J Obstet Gynaecol. 1999;106:881-88610492096Google ScholarCrossref
7.
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
8.
Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus.  N Engl J Med. 1987;317:1321-13293317037Google ScholarCrossref
9.
Derbyshire SW. Locating the beginnings of pain.  Bioethics. 1999;13:1-3111657057Google ScholarCrossref
10.
Derbyshire SW. Fetal pain: an infantile debate.  Bioethics. 2001;15:77-8411699551Google ScholarCrossref
11.
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
12.
Strigo IA, Duncan GH, Boivin M, Bushnell MC. Differentiation of visceral and cutaneous pain in the human brain.  J Neurophysiol. 2003;89:3294-330312611986Google ScholarCrossref
13.
Humphrey T. Some correlations between the appearance of fetal reflexes and the development of the nervous system.  Prog Brain Res. 1964;4:93-135Google Scholar
14.
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
15.
Konstantinidou AD, Silos-Santiago I, Flaris N, Snider WD. Development of the primary afferent projection in human spinal cord.  J Comp Neurol. 1995;354:11-127615870Google ScholarCrossref
16.
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;297:441-4702398142Google ScholarCrossref
17.
Hevner RF. Development of connections in the human visual system during fetal mid-gestation: a DiI-tracing study.  J Neuropathol Exp Neurol. 2000;59:385-39210888368Google Scholar
18.
Kostovic I, Rakic P. Development of prestriate visual projections in the monkey and human fetal cerebrum revealed by transient cholinesterase staining.  J Neurosci. 1984;4:25-426693940Google Scholar
19.
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;219:431-4476196382Google ScholarCrossref
20.
Klimach VJ, Cooke RW. Maturation of the neonatal somatosensory evoked response in preterm infants.  Dev Med Child Neurol. 1988;30:208-2143384200Google ScholarCrossref
21.
Hrbek A, Karlberg P, Olsson T. Development of visual and somatosensory evoked responses in pre-term newborn infants.  Electroencephalogr Clin Neurophysiol. 1973;34:225-2324129609Google ScholarCrossref
22.
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
23.
Torres F, Anderson C. The normal EEG of the human newborn.  J Clin Neurophysiol. 1985;2:89-1033916842Google ScholarCrossref
24.
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;116:69-736858605Google ScholarCrossref
25.
Vogt BA, Rosene DL, Pandya DN. Thalamic and cortical afferents differentiate anterior from posterior cingulate cortex in the monkey.  Science. 1979;204:205-207107587Google ScholarCrossref
26.
Schnitzler A, Ploner M. Neurophysiology and functional neuroanatomy of pain perception.  J Clin Neurophysiol. 2000;17:592-60311151977Google ScholarCrossref
27.
Barbas H. Connections underlying the synthesis of cognition, memory, and emotion in primate prefrontal cortices.  Brain Res Bull. 2000;52:319-33010922509Google ScholarCrossref
28.
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;271:355-3862454966Google ScholarCrossref
29.
Kostovic I, Judas M. Correlation between the sequential ingrowth of afferents and transient patterns of cortical lamination in preterm infants.  Anat Rec. 2002;267:1-611984786Google ScholarCrossref
30.
Ulfig N, Neudorfer F, Bohl J. Transient structures of the human fetal brain: subplate, thalamic reticular complex, ganglionic eminence.  Histol Histopathol. 2000;15:771-79010963122Google Scholar
31.
Kostovic I, Judas M, Petanjek Z, Simic G. Ontogenesis of goal-directed behavior: anatomo-functional considerations.  Int J Psychophysiol. 1995;19:85-1027622411Google ScholarCrossref
32.
Schenk VW, De Vlieger M, Hamersma K, De Weerdt J. Two rhombencephalic anencephalics: a clinico-pathological and electroencephalographic study.  Brain. 1968;91:497-5065723019Google ScholarCrossref
33.
Fisch BJ, Spehlmann R. Fisch and Spehlmann's EEG Primer: Basic Principles of Digital and Analog EEG3rd ed. New York, NY: Elsevier; 1999
34.
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
35.
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
36.
Burgess JA, Tawia SA. When did you first begin to feel it?—locating the beginning of human consciousness.  Bioethics. 1996;10:1-2611653234Google ScholarCrossref
37.
Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation.  Pain. 1994;56:95-1018159446Google ScholarCrossref
38.
Ashwal S, Peabody JL, Schneider S, Tomasi LG, Emery JR, Peckham N. Anencephaly: clinical determination of brain death and neuropathologic studies.  Pediatr Neurol. 1990;6:233-2392206156Google ScholarCrossref
39.
Pilon M, Sullivan SJ. Motor profile of patients in minimally responsive and persistent vegetative states.  Brain Inj. 1996;10:421-4378816096Google ScholarCrossref
40.
Craig KD, Whitfield MF, Grunau RV, Linton J, Hadjistavropoulos HD. Pain in the preterm neonate: behavioural and physiological indices.  Pain. 1993;52:287-2998460047Google ScholarCrossref
41.
Johnston CC, Stevens BJ, Yang F, Horton L. Differential response to pain by very premature neonates.  Pain. 1995;61:471-4797478691Google ScholarCrossref
42.
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;38:438-4458698151Google ScholarCrossref
43.
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;48:131-1429131314Google ScholarCrossref
44.
Hadjistavropoulos HD, Craig KD, Grunau RE, Whitfield MF. Judging pain in infants: behavioural, contextual, and developmental determinants.  Pain. 1997;73:319-3249469521Google ScholarCrossref
45.
Goubet N, Clifton RK, Shah B. Learning about pain in preterm newborns.  J Dev Behav Pediatr. 2001;22:418-42411773806Google ScholarCrossref
46.
Xia C, Yang L, Zhao P, Zhang X. Response to pain by different gestational age neonates.  J Huazhong Univ Sci Technolog Med Sci. 2002;22:84-8612658794Google ScholarCrossref
47.
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
48.
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;19:305-3188071797Google ScholarCrossref
49.
Waxman SG. Clinical observations on the emotional motor system.  Prog Brain Res. 1996;107:595-6048782544Google Scholar
50.
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;110:570-57612205262Google ScholarCrossref
51.
Franck LS, Miaskowski C. Measurement of neonatal responses to painful stimuli: a research review.  J Pain Symptom Manage. 1997;14:343-3789409099Google ScholarCrossref
52.
Teixeira JM, Glover V, Fisk NM. Acute cerebral redistribution in response to invasive procedures in the human fetus.  Am J Obstet Gynecol. 1999;181:1018-102510521770Google ScholarCrossref
53.
Woo JS, Liang ST, Lo RL, Chan FY. Middle cerebral artery Doppler flow velocity waveforms.  Obstet Gynecol. 1987;70:613-6162957623Google Scholar
54.
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;69:705-7092952911Google Scholar
55.
Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma cortisol and beta-endorphin response to intrauterine needling.  Lancet. 1994;344:77-817912391Google ScholarCrossref
56.
Giannakoulopoulos X, Teixeira J, Fisk N, Glover V. Human fetal and maternal noradrenaline responses to invasive procedures.  Pediatr Res. 1999;45:494-49910203140Google ScholarCrossref
57.
Carrasco GA, Van de Kar LD. Neuroendocrine pharmacology of stress.  Eur J Pharmacol. 2003;463:235-27212600714Google ScholarCrossref
58.
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;10:112-1148476472Google ScholarCrossref
59.
Williams RH, Larsen PR. Williams Textbook of Endocrinology10th ed. Philadelphia, Pa: Saunders; 2003
60.
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;103:321-3273344486Google Scholar
61.
Porter FL, Wolf CM, Miller JP. Procedural pain in newborn infants: the influence of intensity and development.  Pediatrics. 1999;104:e1310390299Google ScholarCrossref
62.
Pokela ML. Pain relief can reduce hypoxemia in distressed neonates during routine treatment procedures.  Pediatrics. 1994;93:379-3838115195Google Scholar
63.
Seeds JW, Corke BC, Spielman FJ. Prevention of fetal movement during invasive procedures with pancuronium bromide.  Am J Obstet Gynecol. 1986;155:818-8193766635Google Scholar
64.
Rosen MA. Anesthesia for fetal procedures and surgery.  Yonsei Med J. 2001;42:669-68011754150Google Scholar
65.
Cauldwell CB. Anesthesia for fetal surgery.  Anesthesiol Clin North America. 2002;20:211-22611892506Google ScholarCrossref
66.
Rosen MA. Anesthesia for procedures involving the fetus.  Semin Perinatol. 1991;15:410-4171763346Google Scholar
67.
Smith RP, Gitau R, Glover V, Fisk NM. Pain and stress in the human fetus.  Eur J Obstet Gynecol Reprod Biol. 2000;92:161-16510986451Google ScholarCrossref
68.
White MC, Wolf AR. Pain and stress in the human fetus.  Best Pract Res Clin Anaesthesiol. 2004;18:205-22015171500Google ScholarCrossref
69.
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
70.
Schwarz U, Galinkin JL. Anesthesia for fetal surgery.  Semin Pediatr Surg. 2003;12:196-20112961114Google ScholarCrossref
71.
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;326:1-91530752Google ScholarCrossref
72.
Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response.  Lancet. 1987;1:62-662879174Google ScholarCrossref
73.
Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response.  Pediatrics. 1996;98:925-9308909487Google Scholar
74.
Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination.  Lancet. 1997;349:599-6039057731Google ScholarCrossref
75.
Taylor A, Fisk NM, Glover V. Mode of delivery and subsequent stress response.  Lancet. 2000;355:12010675176Google ScholarCrossref
76.
Myers LB, Bulich LA, Hess P, Miller NM. Fetal endoscopic surgery: indications and anaesthetic management.  Best Pract Res Clin Anaesthesiol. 2004;18:231-25815171502Google ScholarCrossref
77.
Myers LB, Cohen D, Galinkin J, Gaiser R, Kurth CD. Anaesthesia for fetal surgery.  Paediatr Anaesth. 2002;12:569-57812358650Google ScholarCrossref
78.
Gregory GA, Wade JG, Beihl DR, Ong BY, Sitar DS. Fetal anesthetic requirement (MAC) for halothane.  Anesth Analg. 1983;62:9-146849513Google ScholarCrossref
79.
Gaiser RR, Kurth CD. Anesthetic considerations for fetal surgery.  Semin Perinatol. 1999;23:507-51410630546Google ScholarCrossref
80.
Clyburn PA. Early thoughts on “Why Mothers Die 2000-2002.”  Anaesthesia. 2004;59:1157-115915549971Google ScholarCrossref
81.
Munnur U, Suresh MS. Airway problems in pregnancy.  Crit Care Clin. 2004;20:617-64215388192Google ScholarCrossref
82.
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
83.
Atrash HK, Cheek TG, Hogue CJ. Legal abortion mortality and general anesthesia.  Am J Obstet Gynecol. 1988;158:420-4242829630Google Scholar
84.
Atrash HK, MacKay HT, Binkin NJ, Hogue CJ. Legal abortion mortality in the United States: 1972 to 1982.  Am J Obstet Gynecol. 1987;156:605-6123826208Google Scholar
85.
Bartlett LA, Berg CJ, Shulman HB.  et al.  Risk factors for legal induced abortion-related mortality in the United States.  Obstet Gynecol. 2004;103:729-73715051566Google ScholarCrossref
86.
Henshaw SK, Finer LB. The accessibility of abortion services in the United States, 2001.  Perspect Sex Reprod Health. 2003;35:16-2412602753Google ScholarCrossref
87.
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;95:828-83511605920Google ScholarCrossref
88.
Loftus JR, Hill H, Cohen SE. Placental transfer and neonatal effects of epidural sufentanil and fentanyl administered with bupivacaine during labor.  Anesthesiology. 1995;83:300-3087631952Google ScholarCrossref
89.
Rayburn W, Rathke A, Leuschen MP, Chleborad J, Weidner W. Fentanyl citrate analgesia during labor.  Am J Obstet Gynecol. 1989;161:202-2062750805Google ScholarCrossref
90.
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;11:889-8928671346Google ScholarCrossref
91.
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;87:506-5127397084Google ScholarCrossref
92.
Gerdin E, Rane A, Lindberg B. Transplacental transfer of morphine in man.  J Perinat Med. 1990;18:305-3122262875Google ScholarCrossref
93.
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;55:239-24415515301Google Scholar
94.
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;101:251-258Google ScholarCrossref
95.
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;35:221-2261674829Google ScholarCrossref
96.
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;98:1400-140612766649Google ScholarCrossref
Clinical Review
Clinician's Corner
August 24/31, 2005

Fetal Pain: A Systematic Multidisciplinary Review of the Evidence

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.

JAMA. 2005;294(8):947-954. doi:10.1001/jama.294.8.947
Abstract

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.

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