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Published online by Cambridge University Press:  01 November 2008

Department of Obstetrics, Fetal Medicine section, Leiden University Medical Centre, the Netherlands
Department of Obstetrics, Fetal Medicine section, Leiden University Medical Centre, the Netherlands
Department of Obstetrics, Fetal Medicine section, Leiden University Medical Centre, the Netherlands
Department of Obstetrics, Fetal Medicine section, Leiden University Medical Centre, the Netherlands
Phebe N. Adama van Scheltema, MD., Dept of Obstetrics, B3-87, PO BOX 9600, 2300 RC Leiden, The Netherlands.


The concept of fetal pain is becoming more and more relevant since the possibilities for invasive intrauterine treatment are increasing. However, there is much debate as to whether the fetus is mature enough to be able to perceive pain. But what is ‘pain’? One cannot determine whether a fetus feels pain unless one has a conception of what pain is. There is a difference in opinion about what pain really is and that is also the difficulty in studies on fetal pain: we cannot simply ask the fetus whether or not it feels pain. We can only give indirect evidence of possible harmful effects of stressful stimuli on the developing fetus. In this review we will first explore the meaning of ‘pain’. We will then discuss fetal anatomic, neurophysiologic and behavioural development and the responses which are thought to be required to experience pain. Finally, we discuss some ethical considerations and suggestions on fetal anaesthesia.

Research Article
Copyright © Cambridge University Press 2008

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1International Association for the Study of Pain. IASP Pain Terminology. 2008.Google Scholar
2The concise Oxford dictionary of current English. 9th ed. Oxford: Clarendon Press; 1995.Google Scholar
3Almeida, TF, Roizenblatt, S, Tufik, S. Afferent pain pathways: a neuroanatomical review. Brain Res 2004; 1000: 4056.CrossRefGoogle ScholarPubMed
4Anand, KJ, Carr, DB. The neuroanatomy, neurophysiology, and neurochemistry of pain, stress, and analgesia in newborns and children. Pediatr Clin North Am 1989; 36: 795–22.CrossRefGoogle ScholarPubMed
5Anand, KJ, Hickey, PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987; 317: 1321–29.CrossRefGoogle ScholarPubMed
6Fitzgerald, M. Development of pain mechanisms. Br Med Bull 1991; 47: 667–75.CrossRefGoogle ScholarPubMed
7Okado, N. Onset of synapse formation in the human spinal cord. J Comp Neurol 1981; 201: 211–19.CrossRefGoogle ScholarPubMed
8Fitzgerald, M. The development of nociceptive circuits. Nat Rev Neurosci 2005; 6: 507–20.CrossRefGoogle ScholarPubMed
9Kostovic, I, Goldman-Rakic, PS. Transient cholinesterase staining in the mediodorsal nucleus of the thalamus and its connections in the developing human and monkey brain. J Comp Neurol 1983; 219: 431–47.CrossRefGoogle ScholarPubMed
10Lee, SJ, Ralston, HJ, Drey, EA, Partridge, JC, Rosen, MA. Fetal pain: a systematic multidisciplinary review of the evidence. JAMA 2005; 294: 947–54.CrossRefGoogle Scholar
11Brooks, JC, Zambreanu, L, Godinez, A, Craig, AD, Tracey, I. Somatotopic organisation of the human insula to painful heat studied with high resolution functional imaging. Neuroimage 2005; 27: 201209.CrossRefGoogle ScholarPubMed
12Craig, AD. Interoception: the sense of the physiological condition of the body. Curr Opin Neurobiol 2003; 13: 500505.CrossRefGoogle Scholar
13Nandi, D, Aziz, T, Carter, H, Stein, J. Thalamic field potentials in chronic central pain treated by periventricular gray stimulation – a series of eight cases. Pain 2003; 101: 97107.CrossRefGoogle ScholarPubMed
14Nandi, D, Liu, X, Joint, C, Stein, J, Aziz, T. Thalamic field potentials during deep brain stimulation of periventricular gray in chronic pain. Pain 2002; 97: 4751.CrossRefGoogle Scholar
15White, MC, Wolf, AR. Pain and stress in the human fetus. Best Pract Res Clin Anaesthesiol 2004; 18: 205–20.CrossRefGoogle ScholarPubMed
16Lowery, CL, Hardman, MP, Manning, N, Hall, RW, Anand, KJ. Neurodevelopmental changes of fetal pain. Semin Perinatol 2007; 31: 275–82.CrossRefGoogle ScholarPubMed
17Benatar, D, Benatar, M. A pain in the fetus: toward ending confusion about fetal pain. Bioethics 2001; 15: 5776.CrossRefGoogle ScholarPubMed
18van de, Velde, Jani, J, De Buck, F, Deprest, J. Fetal pain perception and pain management. Semin Fetal Neonatal Med 2006; 11: 232–36.CrossRefGoogle Scholar
19Torres, F, Anderson, C. The normal EEG of the human newborn. J Clin Neurophysiol 1985; 2: 89103.CrossRefGoogle ScholarPubMed
20Mellor, DJ, Diesch, TJ, Gunn, AJ, Bennet, L. The importance of ‘awareness’ for understanding fetal pain. Brain Res Brain Res Rev 2005; 49: 455–71.CrossRefGoogle ScholarPubMed
21Giannakoulopoulos, X, Sepulveda, W, Kourtis, P, Glover, V, Fisk, NM. Fetal plasma cortisol and beta-endorphin response to intrauterine needling. Lancet 1994; 344: 7781.CrossRefGoogle ScholarPubMed
22Giannakoulopoulos, X, Teixeira, J, Fisk, N, Glover, V. Human fetal and maternal noradrenaline responses to invasive procedures. Pediatr Res 1999; 45: 494–99.CrossRefGoogle ScholarPubMed
23Gitau, R, Fisk, NM, Teixeira, JM, Cameron, A, Glover, V. Fetal hypothalamic-pituitary-adrenal stress responses to invasive procedures are independent of maternal responses. J Clin Endocrinol Metab 2001; 86: 104109.Google ScholarPubMed
24Gitau, R, Fisk, NM, Glover, V. Human fetal and maternal corticotrophin releasing hormone responses to acute stress. Arch Dis Child Fetal Neonatal Ed 2004; 89: F29F32.CrossRefGoogle ScholarPubMed
25Derbyshire, SW. Locating the beginnings of pain. Bioethics 1999; 13: 131.CrossRefGoogle Scholar
26Derbyshire, SW, Glover, V. The fetus does not feel pain. Conscience 2004; 25: 3235.Google Scholar
27Teixeira, J, Fogliani, R, Giannakoulopoulos, X, Glover, V, Fisk, NM. Fetal haemodynamic stress response to invasive procedures. Lancet 1996; 347: 624.CrossRefGoogle ScholarPubMed
28Vries, JI, Visser, GH, Prechtl, HF. The emergence of fetal behaviour. I. Qualitative aspects. Early Hum Dev 1982; 7: 301–22.CrossRefGoogle ScholarPubMed
29de Vries, JIP, Visser, GHA, Prechtl, HFR. Fetal motility in the first half of pregnancy. In: Prechtl, HFR, editor. Continuity of neural functions from prenatal to postnatal life. Philadelphia: Lippincott; 1984; 4664.Google Scholar
30Andrews, K, Fitzgerald, M. The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation. Pain 1994; 56: 95101.CrossRefGoogle ScholarPubMed
31Burton, IF, Derbyshire, AJ. Sleeping fit caused by excruciating pain in an infant. AMA J Dis Child 1958; 95: 258–60.Google ScholarPubMed
32Marshall, RE, SWMABS. Circumcision I. Effects upon newborn behavior. Inf Behav Dev 1980; 3: 114.CrossRefGoogle Scholar
33Fitzgerald, M, Millard, C, McIntosh, N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia. Pain 1989; 39: 3136.CrossRefGoogle ScholarPubMed
34Johnston, CC, Stevens, BJ. Experience in a neonatal intensive care unit affects pain response. Pediatrics 1996; 98: 925–30.Google Scholar
35Craig, KD, Whitfield, MF, Grunau, RV, Linton, J, Hadjistavropoulos, HD. Pain in the preterm neonate: behavioural and physiological indices. Pain 1993; 52: 287–99.CrossRefGoogle ScholarPubMed
36Andrews, K, Fitzgerald, M. Wound sensitivity as a measure of analgesic effects following surgery in human neonates and infants. Pain 2002; 99: 185–95.CrossRefGoogle ScholarPubMed
37Andrews, KA, Desai, D, Dhillon, HK, Wilcox, DT, Fitzgerald, M. Abdominal sensitivity in the first year of life: comparison of infants with and without prenatally diagnosed unilateral hydronephrosis. Pain 2002; 100: 3546.CrossRefGoogle ScholarPubMed
38Taddio, A, Katz, J, Ilersich, AL, Koren, G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet 1997; 349: 599603.CrossRefGoogle ScholarPubMed
39Reynolds, ML, Fitzgerald, M. Long-term sensory hyperinnervation following neonatal skin wounds. J Comp Neurol 1995; 358: 487–98.CrossRefGoogle ScholarPubMed
40Leader, LR, Baillie, P, Martin, B, Molteno, C, Wynchank, S. Fetal responses to vibrotactile stimulation, a possible predictor of fetal and neonatal outcome. Aust N Z J Obstet Gynaecol 1984; 24: 251–56.CrossRefGoogle ScholarPubMed
41Simons, SH, Tibboel, D. Pain perception development and maturation. Semin Fetal Neonatal Med 2006; 11: 227–31.CrossRefGoogle ScholarPubMed
42Porter, FL, Grunau, RE, Anand, KJ. Long-term effects of pain in infants. J Dev Behav Pediatr 1999; 20: 253–61.CrossRefGoogle ScholarPubMed
43Strigo, IA, Duncan, GH, Boivin, M, Bushnell, MC. Differentiation of visceral and cutaneous pain in the human brain. J Neurophysiol 2003; 89: 3294–303.CrossRefGoogle ScholarPubMed
44Humphrey, T. Some correlations between the appearance of fetal reflexes and the development of the nervous system. Prog Brain Res 1964; 4: 93135.CrossRefGoogle Scholar
45Okado, N, Kojima, T. Ontogeny of the central nervous system: neurogenesis, fibre connection, synaptogenesis and myelination in the spinal cord. In: Precht, HFR, editor. Clinics in developmental medicine: continuity of neural functions from prenatal to postnatal life. Philadelphia: Lippincott Co.; 1984; 3145.Google Scholar
46Konstantinidou, AD, Silos-Santiago, I, Flaris, N, Snider, WD. Development of the primary afferent projection in human spinal cord. J Comp Neurol 1995; 354: 11–2.CrossRefGoogle ScholarPubMed
47Jones, E. Pain. Int J Psychoanal 1957; 38: 255.Google ScholarPubMed
48Grunau, RE, Holsti, L, Whitfield, MF, Ling, E. Are twitches, startles, and body movements pain indicators in extremely low birth weight infants? Clin J Pain 2000; 16: 3745.CrossRefGoogle ScholarPubMed
49Ruda, MA, Ling, QD, Hohmann, AG, Peng, YB, Tachibana, T. Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science 2000; 289: 628–31.CrossRefGoogle ScholarPubMed
50Penn, AA, Shatz, CJ. Brain waves and brain wiring: the role of endogenous and sensory-driven neural activity in development. Pediatr Res 1999; 45: 447–58.CrossRefGoogle ScholarPubMed
51Perlman, JM. Neurobehavioral deficits in premature graduates of intensive care–potential medical and neonatal environmental risk factors. Pediatrics 2001; 108: 1339–348.CrossRefGoogle ScholarPubMed
52Unborn Child Pain Awareness and Prevention Act of 2005. To be codified at Ark Code Ann 20–16, 1101–111. 2005.Google Scholar
53Woman's Right to Know Act. To be codified at Ga Code Ann 31–9A-4. 2005.Google Scholar
54Unborn Child Pain Awareness Act. S51, 109th Cong. 2005.Google Scholar
55Kolenc, AB. Easing abortion's pain: the new fight to help the unborn. America (NY) 2005; 193: 1821.Google ScholarPubMed
56Arthur, J. Fetal pain: a red herring in the abortion debate. Free Inq 2005; 25: 4447.Google ScholarPubMed
57Griffith, S. Fetal death, fetal pain, and the moral standing of a fetus. Public Aff Q 1995; 9: 115–26.Google ScholarPubMed
58McLean, S. Old Law, new medicine. River Orams Press 1999.Google Scholar
59Williams, C. Framing the fetus in medical work: rituals and practices. Soc Sci Med 2005; 60: 2085–95.CrossRefGoogle ScholarPubMed
60Derbyshire, SW. Fetal pain: an infantile debate. Bioethics 2001; 15: 7784.CrossRefGoogle ScholarPubMed
61Glover, V, Fisk, NM. Fetal pain: implications for research and practice. Br J Obstet Gynaecol 1999; 106: 881–86.CrossRefGoogle ScholarPubMed
62Bartlett, LA, Berg, CJ, Shulman, HB, Zane, SB, Green, CA, Whitehead, S, et al. Risk factors for legal induced abortion-related mortality in the United States. Obstet Gynecol 2004; 103: 729–37.CrossRefGoogle ScholarPubMed
63Henshaw, SK, Finer, LB. The accessibility of abortion services in the United States, 2001. Perspect Sex Reprod Health 2003; 35: 1624.CrossRefGoogle ScholarPubMed
64Fisk, 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: 828–35.CrossRefGoogle ScholarPubMed
65Loftus, JR, Hill, H, Cohen, SE. Placental transfer and neonatal effects of epidural sufentanil and fentanyl administered with bupivacaine during labor. Anesthesiology 1995; 83: 300308.CrossRefGoogle ScholarPubMed
66Rayburn, W, Rathke, A, Leuschen, MP, Chleborad, J, Weidner, W. Fentanyl citrate analgesia during labor. Am J Obstet Gynecol 1989; 161: 202206.CrossRefGoogle ScholarPubMed
67Seeds, JW, Corke, BC, Spielman, FJ. Prevention of fetal movement during invasive procedures with pancuronium bromide. Am J Obstet Gynecol 1986; 155: 818819.CrossRefGoogle ScholarPubMed
68Rosen, MA. Anesthesia for procedures involving the fetus. Semin Perinatol 1991; 15: 410–17.Google ScholarPubMed
69Rosen, MA. Anesthesia for fetal procedures and surgery. Yonsei Med J 2001; 42: 669–80.CrossRefGoogle ScholarPubMed
70Cauldwell, CB. Anesthesia for fetal surgery. Anesthesiol Clin North America 2002; 20: 211–26.CrossRefGoogle ScholarPubMed
71Smith, RP, Gitau, R, Glover, V, Fisk, NM. Pain and stress in the human fetus. Eur J Obstet Gynecol Reprod Biol 2000; 92: 161–65.CrossRefGoogle ScholarPubMed
72Schwarz, U, Galinkin, JL. Anesthesia for fetal surgery. Semin Pediatr Surg 2003; 12: 196201.CrossRefGoogle ScholarPubMed
73Lehmann, 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: 221–26.CrossRefGoogle ScholarPubMed
74Strumper, D, Durieux, ME, Gogarten, W, Van, AH, Hartleb, K, Marcus, MA. Fetal plasma concentrations after intraamniotic sufentanil in chronically instrumented pregnant sheep. Anesthesiology 2003; 98: 14001406.CrossRefGoogle ScholarPubMed
75Gregory, GA, Wade, JG, Beihl, DR, Ong, BY, Sitar, DS. Fetal anesthetic requirement (MAC) for halothane. Anesth Analg 1983; 62: 914.CrossRefGoogle ScholarPubMed
76Kan, RE, Hughes, SC, Rosen, MA, Kessin, C, Preston, PG, Lobo, EP. Intravenous remifentanil: placental transfer, maternal and neonatal effects. Anesthesiology 1998; 88: 1467–74.CrossRefGoogle ScholarPubMed
77van de, Velde, Van Schoubroeck, D, Lewi, LE, Marcus, MA, Jani, JC, Missant, C, et al. Remifentanil for fetal immobilization and maternal sedation during fetoscopic surgery: a randomized, double-blind comparison with diazepam. Anesth Analg 2005; 101: 251–58.CrossRefGoogle Scholar
78Szeto, HH, Mann, LI, Bhakthavathsalan, A, Liu, M, Inturrisi, CE. Meperidine pharmacokinetics in the maternal-fetal unit. J Pharmacol Exp Ther 1978; 206: 448–59.Google ScholarPubMed
79Myers, LB, Bulich, LA, Hess, P, Miller, NM. Fetal endoscopic surgery: indications and anaesthetic management. Best Pract Res Clin Anaesthesiol 2004; 18: 231–58.CrossRefGoogle ScholarPubMed