1 The Journal of Maternal-Fetal and Neonatal Medicine, 2012; Early Online: 1–6 Copyright © 2012 Informa UK, Ltd. ISSN 1476-7058 print/ISSN 1476-4954 online DOI: 10.3109/14767058.2011.632040 Due to the progress in fetal surgery, it is important to acquire data about fetal pain. Material and methods: We performed a Medline research from 1995, matching the following key words: “pain” and “fetus”, with the following: “subplate”, “thal- amocortical”, “myelination”, “analgesia”, “anesthesia”, “brain”, “behavioral states”, “substance p”. We focused on: (a) fetal development of nociceptive pathways; (b) fetal electrophysi- ological, endocrinological and behavioral reactions to stimuli and pain. Results: We retrieved 217 papers of which 157 were highly informative; some reported similar data or were only case-reports, and were not quoted. Most endocrinological, behavioral and electrophysiological studies of fetal pain are performed in the third trimester, and they seem to agree that the fetus in the 3rd trimester can experience pain. But the presence of fetal pain in the 2nd trimester is less evident. In favor of a 2nd trimester perception of pain is the early devel- opment of spino-thalamic pathways (approximately from the 20th week), and the connections of the thalamus with the subplate (approximately from the 23rd week). Against this possibility, some authors report the immaturity of the cortex with the consequent lack of awareness, and the almost contin- uous state of sleep of the fetus. Conclusions: Most studies disclose the possibility of fetal pain in the third trimester of gestation. This evidence becomes weaker before this date, though we cannot exclude its increasing presence since the beginning of the second half of the gestation. Keywords: analgesia, fetus, pain Fetal surgery has become a reality: several interventions can be performed to the fetus without cutting the umbilical cord [1,2]. Several reports show that it can be useful in cases of myelom- eningocele [3], kidney anomalies [4,5] or congenital diaphrag- matic hernia [6,7]. Fetal surgical interventions impose to better understand fetal pain: can a fetus actually feel pain? Is fetal pain a scientiic evidence or is it a mere opinion? To this aim, we reviewed the scientiic literature in this ield. We performed a careful Medline search from 1995 throughout 2011, matching the key words “pain” and “fetus”, with the following: “analgesia”, “anesthesia”, “subplate”, “thalamocortical”, “myelination”, “brain”, “behavioral states”, “substance P”. We focused on: (a) fetal development of nociceptive pathways; (b) fetal electrophysiological, endocrinological and behavioral reactions to stimuli and pain. We retrieved 217 papers of which 157 were highly informative; some reported similar data or were only case-reports, and were not quoted. Some of the papers quoted previous basic studies, that we report in the present review. We did not report previous comments, editorials or reviews on this issue, though we carefully considered them. Fetal pain pathways From the periphery to the thalamus he development of pain pathways begins early in the fetal nervous system. At 6 weeks of gestational age (GA), dorsal horn cells in the spinal cord of the human embryo have formed synapses with developing sensory neurons [8,9]. hese sensory neurons reach the skin of the limbs by 11 weeks, the rest of the trunk by 15 weeks and the remaining cutaneous and mucosal surfaces by 20 weeks GA [9–11]. Nociceptive nerve endings in the skin as an adult have the same [12,13] or even higher [14] densities in term fetuses than in adult life. Myelination, previously seen at 20 weeks GA in the human fetus [15,16], has recently been seen to start in the human spinal cord at 12 weeks GA [17] and in the telencephalon around week 14 GA [18]. However, even a lack of myelination does not imply lack of function but rather slower speed of transmission [19]. Substance P appears in the dorsal horn at 8–10 weeks GA [20,21] and enkephalin at 12–14 weeks GA [20,22]. Endorphinergic cells appear in the anterior lobes of the pituitary gland in early fetal life and by 20 weeks gestation they are responding to stimulation by corticotrophin releasing factor [23]. The subplate zone he subplate is a prominent, transient layer of the human fetal cerebral wall which develops around 11 weeks GA, with a developmental peak between 22 and 34 weeks GA and gradually disappears ater 32–34 weeks GA [24]; it is present in the frontal cortex of newborns and disappears ater the sixth postnatal month, but individual subplate-like neurons remain until adulthood [25]. It is the main zone in the human fetal cortex where incoming ibers from the thalamus gather during the crucial phase of cortical target area selection; it is a site of spontaneous electrical activity [26] required to build a framework for the precise organization of cortical connec- tions, to process the thalamocortical information [27–29] and to contribute to the early and transient cortical neuronal circuits involved in the generation of fetal behavior [22]. In non-human mammals, synaptic activity in the subplate facili- tates and reines the connections between thalamus (a crucial REVIEW Is fetal pain a real evidence? Carlo Valerio Bellieni 1,2 & Giuseppe Buonocore 1,3 1 Department of Pediatrics, Obstetrics and Reproduction Medicine, University of Siena, Siena, Italy, 2 Bioethics Committee, Italian Pediatrics Society, and 3 Union of the European Neonatal and Perinatal Societies Correspondence: Carlo V. Bellieni, Neonatal Intensive Care Unit, University Hospital “Le Scotte”, Siena 53100, Italy. Tel: 0039 0577 52183. Fax: 0039 0577 586182. E-mail: cvbellieni@gmail.com (Received 27 August 2011; accepted 26 September 2011) J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Az Sanitaria Liguria on 04/25/12 For personal use only.