Indian Journal of Pain

: 2022  |  Volume : 36  |  Issue : 3  |  Page : 120--127

The myth and half-truths of fetal pain decrypted: A metaverse

Sargam Goel1, Suman Choudhary2, Ashok Kumar Saxena2, Mayank Sonkar2,  
1 Department of Anaesthesia, Hamdard Institute of Medical Sciences and Research, Hakeem Abdul Hameed Centenary Hospital, New Delhi, India
2 Department of Anaesthesiology and Pain Medicine, University College of Medical Sciences (University of Delhi) and GTB Hospital, New Delhi, India

Correspondence Address:
Dr. Sargam Goel
H.No 963-B, D Block, New Friends Colony, New Delhi


Fetal pain is one of the most controversial topics in medicine because of the disagreement between people whether the fetus can perceive pain or not and the absence of any direct objective method for the assessment of fetal pain. Although fetus is incapable of declaring pain, various studies have shown that the mere experience of pain without the aptitude of self-contemplation is worth paying attention to, and that the pain in fetus need not be comparable to that of a mature adult to matter. Furthermore, refusing to acknowledge fetal pain in late preterm fetuses would jeopardize the advances in neonatal care because it would question the use of analgesia in neonates of similar gestational age. This systematic review article examines the neuroanatomical and physiological evidence of nociception in the fetus and its implications, which compel the need for its alleviation. It looks into the adequacy of International Association for the Study of Pain definition of pain to define fetal pain. The article also provides a brief overview of the existing literature on whether safe analgesia and anesthesia techniques exist for abortions and therapeutic fetal procedures. We performed a literature search for English-language articles using the electronic database with keywords: controversy in fetal pain, fetal anaesthesia, fetal analgesia, fetal pain, fetus, neuroanatomy of fetal pain, neurophysiology of fetal pain, nociception, and recent advances in understanding of fetal pain

How to cite this article:
Goel S, Choudhary S, Saxena AK, Sonkar M. The myth and half-truths of fetal pain decrypted: A metaverse.Indian J Pain 2022;36:120-127

How to cite this URL:
Goel S, Choudhary S, Saxena AK, Sonkar M. The myth and half-truths of fetal pain decrypted: A metaverse. Indian J Pain [serial online] 2022 [cited 2022 Dec 2 ];36:120-127
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Full Text


Fetal pain is one of the most controversial topics in medicine because of the disagreement between people whether the fetus can perceive pain or not, and the absence of any direct objective method for fetal pain measurement.

Pain is considered to be a subjective experience and is defined by International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”[1] Thus, pain can be regarded as a conscious experience with sensory and emotional components. Therefore, by this definition, fetal neural tissues cannot experience pain at any stage of their development as they lack cognitive and evaluative experience, with the absence of consciousness until birth. However, the concept of evolving consciousness can be applied to the developing fetus, who may not have the same physical basis for conscious experience as the adults.

The possibility of fetal response to pain was first raised in an article in 1983 by President Ronald Reagan.[2] Subsequently, in 1987, the landmark paper by Anand and Hickey published in The New England Journal of Medicine demonstrated evidence of neonatal pain.[3] They reviewed the findings of multiple studies regarding the anatomy, physiology, behavioral changes, and memory associated with pain, which led to a major consideration that the fetus may also experience pain.[4],[5],[6],[7],[8] Before this, neonatal surgeries were performed without anesthesia and analgesia due to safety concerns, and the traditional belief that the neonate was not capable of perceiving pain.

The first intraperitoneal fetal blood transfusion was carried out in 1963 and the first successful human fetal surgery was done in 1981.[9] Since then, there has been an impressive evolution in therapeutic fetal interventions such as obstructive uropathy, congenital malformations, congenital heart defects, congenital diaphragmatic hernia, tumors excision and ex-utero intrapartum treatment procedures.[10],[11],[12],[13],[14],[15],[16]

Concerns have been raised that fetal surgical procedures during pregnancy may lead not only to an immediate fetal stress response but may also have long-term consequences.[17] These developments have ushered the progress in fetal analgesia and anesthesia. Since then, fetal pain has gained much importance with increasing therapeutic fetal interventions and abortions. The criticism around abortions has been most evident in discussing the age of viability and the upper gestational age limit in the context of induced abortions. Abortion is prohibited beyond 20–24 weeks of gestation based on the potential perception of pain by the fetus.[18]

We performed a systematic review of current literature to examine the evidence for fetal pain, and whether safe analgesia and anesthesia techniques exist for abortions and therapeutic fetal procedures.


Eligibility criteria

All studies published up to December 2021 which focused on fetal pain, anesthesia and analgesia with full text available in English, were eligible for this review. Document restriction and methodology filters were not used. The reasons for study exclusion were duplicated articles concerning fetal pain, and fetal anesthesia and analgesia. This review was conducted in accordance with the current guidelines on systematic literature reviews and adheres to the applicable Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.

Search strategy

English-language articles were identified using the electronic databases, Medline (via Pubmed), Scopus, Science Direct, Embase, and Google Scholar. The following keywords were used during the literature search: Fetus, fetal pain, fetal analgesia, fetal anaesthesia, nociception, neuroanatomy of fetal pain, neurophysiology of fetal pain, controversy in fetal pain, recent advances in understanding of fetal pain. The articles with paid access were obtained by either contacting the author, the National medical library, from the college, or at the expense of the authors. Titles and abstracts of articles retrieved by the database search were screened for relevance. Those articles were excluded that did not specifically address fetal pain perception, or nociception. The included articles were reviewed for additional references.

Study selection

The selection of articles was performed by the authors using predefined screening criteria. Any disagreements regarding inclusion were resolved via discussion between the review authors.

The illustration of study selection is presented in the flowchart in [Figure 1].{Figure 1}

Data extraction

Data were collected from individual articles using a data extraction form. Any discrepancies in the same were resolved via discussion between the authors. Data extraction was based on conclusions of observational and randomized controlled studies, narrative and systematic reviews, and consensus statements.

Quality assessment of studies

The quality of paper and risk of bias was assessed using the PEDro scale.

The PEDro scale was also used to assess the following 11 criteria: Specified eligibility criteria, random allocation, concealed allocation, the similarity of baseline characteristics of the patients, blinding of the patients, therapists and assessors, outcome data of at least 85% of subjects of at least 1 key outcome, intention to treat analysis, between-group statistical comparisons, point measures, and measures of variability. If no, further information was available, we rated the criteria as 'unclear' Maximum score possible was 10, and every study which scored >8 was considered low risk and ≤8 considered high risk.


The electronic database search provided a total of 24,585 citations. After removing duplicate articles, 9857 titles and abstracts of articles in English were screened for relevance. 9615 articles were excluded due to nonrelevance. Out of the remaining 242 articles, 33 full-text articles were finally included for analysis. Of these, 4 were observational studies, 1 was randomized controlled trial, 25 were review articles, 1 was metanalyses, and 1 was a consensus statement.

Neurobiological development of the fetus

Anatomy of the pathways

For an individual to feel pain, the prerequisites are (1) nociceptors, the axons of nociceptors project to the fetal skin at around 11–15 weeks of gestational age (WGA); (2) neuromediators, substance P and enkephalins appear at around 8–10 and 12–14 WGA, respectively; (3) the tracts or the fibers for the nociceptive stimulus to reach the brain; (4) thalamus; and (5) thalamocortical fibers.[11],[19]

At around 12–18 weeks of gestation, the first projections from the thalamus into the cortical subplate become apparent.[10],[11],[20],[21],[22] It has been observed that these projections provide basic anatomy required for pain, and are functionally capable to process thalamic information.[23] The subplate is a transient structure that forms below the cortical plate proper and houses neurons, which migrate to the cortical plate above at 24–28 weeks.[24] It eventually dissolves to become white matter.[25],[26],[27],[28] However since it dissolutes, it may lack a mature function which is an important argument against pain experience before the arrival of thalamic tracts in the cortex proper.[17] Furthermore, neither functional synapses between the thalamus and subplate have been demonstrated in any human study, nor has it been proven that synapses between subplate and cortical plate neurons transmit pain perception in humans.[18]

However, the necessity of an intact cortical system for the fetus to experience pain is highly debated.[29],[30] Various fetal histological and functional imaging studies demonstrating activation within a network of cortical regions correlating with reported pain experience have been reported.[20],[31],[32],[33] These projections begin to form from 23 weeks of gestation, thus indicating that the lower limit of fetal pain experience might be 23 weeks, according to this evidence. This is also the time at which the peripheral free nerve endings and their projection sites within the spinal cord reach full maturity, and the noxious stimulation causes hemodynamic changes in the somatosensory cortex.[17] Studies against this perspective argue that pain occurs even in patients with extensive cortex damage and an anencephalic fetus withdraws from noxious stimulus.[10],[34] Thus, the current evidence supports the possibility of fetal pain before 23 weeks of gestation.

Functionality of the pathways

Assessment of the nociceptive pathways for their activity requires an understanding of a number of fetal responses. First, coordinated facial expressions, and blink and startle responses in the fetus to heel prick and external stimuli such as noise, light and tactile impulses, respectively, have been ascertained by radiological imaging.[35],[36],[37]

Second, continuous cortical electroencephalogram (EEG) recordings have been observed in prematurely born fetuses at 23–24 weeks of gestation,[19] although these may be asynchronous between the hemispheres at this gestational age, indicating cortical immaturity.[38],[39],[40],[41],[42] Studies have also shown somatosensory cortical responses with near-infrared spectroscopy from 24 weeks onward, following painful heel lance and venepuncture.[43],[44] However, EEG activity alone is not a proof of these pathways being operational as a neonate with anencephaly may have EEG activity without a functional neural tissue.[18] However, although such studies provide some information on the development of brain activity in the newborn, these reported findings are specific to the neonate.[11] In neonatology, the gestational age of viability has decreased to 23 weeks, meaning that such preterm neonates are born with predominantly fetal physiology.[45]

Third, a stress response occurs following physical or psychological injury. The randomized trial by Anand and Hickey in 1992 on neonates 4–10 days old, undergoing congenital heart surgery demonstrated that levels of stress hormones such as adrenaline, noradrenaline, glucagon, aldosterone, corticosterone, 11-deoxycorticosterone, and 11-deoxycortisol were significantly higher in the “light anaesthesia group” when compared to “deep anaesthesia group” for up to 24 h after surgery.[46] This study also reported better overall patient outcomes. Furthermore, Radunovic et al. and Giannakoulopoulos et al. described hemodynamic changes and increased cortisol and β-endorphin levels after intrauterine needling, blood transfusion, and repeated cordocenteses in fetuses of more than 18 weeks of gestation.[47],[48],[49] These stress responses can occur in an intact hypothalamic-pituitary-adrenal axis (HPA) at 18 weeks of gestation and can be blunted after the administration of opioid analgesia to the fetus.[45] An argument against is that these neuroendocrine stress responses are not a corroboration for fetal pain, and are not specific to pain because the autonomic nervous system and HPA axis mediate them without conscious cortical processing.[18],[50] Although stress may not necessarily signify pain, it may have a long-term sequelae like altered neurodevelopment, which might be deleterious to the fetus.[45],[51],[52] The evidence of functionality of pain pathways in the fetus is illustrated in [Figure 2].{Figure 2}

The psychology of pain

Deduction of fetal pain from studies based on adults and older children is difficult due to dissimilarities between the immature and mature brain. The fetal brain has many prominent structures like the thalamic reticular nucleus which dissolute after birth. The thalamic reticular nucleus suppresses fetal arousability in intrauterine life.[28]

There are considerable differences in the womb environment of a fetus and a neonate. The fetus lies in a buffered chemical environment to avoid undue energy expenditure. Mellor et al.[53] in 2005 observed sleep-like EEG patterns in the lamb fetus, which entered a more quiescent state together with lack of movement, during hypoxic stress. A continuous sleep-like state is preserved in utero by neuro-inhibiting substances such as adenosine, progesterone, allopregnanolone, pregnenolone, and prostaglandin D2.[54] Adenosine and prostaglandin D2 are believed to be potent sleep inducers. Allopregnanolone and pregnanolone have anesthetic action.[19]

There is a rapid onset of behavioral activity and wakefulness at birth due to intense tactile stimulation and separation of the placenta which is a major source of these inhibitory neurotransmitters in utero.[8] It has been argued in other fetal EEG studies that fetuses spend around 9%–21% of the time in the awake state at term with well-established sleep-wake cycles. The following states have been reported in fetuses: (1) F3 (calm wake); (2) F4 (active wake); (3) F5 (crying).[19],[51]

Although some studies have observed the analgesic and anesthetic effects of these neuro-inhibitors, others have argued that these actions are seen only when they are injected at high doses.[45],[55] This is corroborated by the fact that all fetuses are born awake and cry immediately after birth. Another argument in favor of this is that the blood levels of these substances are similar to the levels present in the expectant mother who is not anesthetised by them.[8] Furthermore, sedation is not equivalent to analgesia thus mandating the need for analgesia and anesthesia for fetal procedures.[19]

Nociception and pain perception are two different entities. First, nociception triggers reflex movement of the affected limb away from the noxious stimulus, without any cortical involvement. On the other hand, pain perception requires the cortex to recognize the stimulus as unpleasant.[56],[57] Second, the spinal reflex pathway for nociception is known to develop earlier than the thalamocortical pathways required for the conscious perception of pain.[18],[19]

Third, the reflex withdrawal from the stimulus and the complex motor and autonomic responses to noxious stimuli are not equivalent to pain, and do not require the perception of pain.[58],[59]

The revised IASP definition of pain 2020 specifies that pain and nociception are different phenomena and that the perception of pain cannot be inferred solely from activity in the sensory neurons or from the reflex motor and autonomic responses to stimuli, as these responses can be evoked in the absence of any perception of pain.[60] To be specific, fetal movement in response to touch does not connote pain. Because the autonomic responses associated with noxious stimulation are also reflexive, these may serve as indirect measures of nociception but not as a measure of pain.[11]

The IASP definition of pain is considered a taxing one, as it considers pain to be a subjective reflection involving cognition, sensation, and affective processes, and therefore shows it as being a constituent part of higher cognitive function.[61]

A number of studies have repudiated the notion of the necessity of a mature emotional and conscious response to painful stimulation. A study by Gitau et al. compared fetuses from 17- to 35-week gestation whose abdomens were accessed to reach the intrahepatic vein for an in utero blood transfusion, to those who received it through the placental cord insertion site.[62] Fetuses in the intrahepatic vein group demonstrated a significant elevation in stress hormones and heart rates, whereas the other group had normal levels of stress hormones, thus showing immediate effects of painful stimulation while still in utero.[45]

According to Derbyshire and IASP definition, each individual learns the meaning of the word “pain” through experiences related to injury in early life.”[63],[64],[65] This concept was supported by a study by Johnson and Stevens who compared two groups of premature babies. Premature babies who had previously been exposed to painful stimulation showed evidence of being more stressed when the same painful procedure was repeated, than those of the same gestational age who had not yet been exposed. This study demonstrated that prematurely born neonates had both immediate effects and the development of a procedural memory.[45]

In contrast to this, Derbyshire et al., in a review article in 2020, proposed that unlike adults who may consciously experience pain bounded by an understanding or a previous pain memory, the fetus experiences pain as “just pain” with no further comprehension of the experience.[10]

How is pain assessed?

As fetuses cannot report pain, indirect measures such as physiological and hemodynamic responses are often considered to represent the stress states. As described earlier, EEG and magnetic resonance imaging have been used for pain perception, none of these have been demonstrated to be valid and objective measures.[11]

The ethical importance of pain

There is an ethical responsibility of relieving fetal pain if it is possible after a particular gestational age. Long-term consequences have been reported in terms of neurodevelopment.[58]

Ruda reported that localized inflammation during the neonatal period permanently alters neuronal circuits that process pain in the spinal cord.[66]

Lowrey et al. studied painful stimulation in human and nonhuman fetuses and discerned that repeated painful stimulation leads to the development of abnormal synapses which caused hyperactive pain responses. This review emphasized the importance of assessing and relieving fetal pain.[67] Refusing to acknowledge fetal pain in late preterm fetuses would jeopardize these advances in care because it would question the use of analgesia in neonates of similar gestational age.

In 2021, the American Society of Anesthesiologists Committees on Obstetric and Pediatric Anesthesiology and the North American Fetal Therapy Network provided consensus guidance on the use of anesthesia for maternal–fetal interventions.[68] They noted that there may be substantial short- and long-term adverse effects on the fetus and its developing central nervous system if the fetal physiological stress response is not blunted. Thus, opioids may be helpful in blunting the acute autonomic responses during complex fetal surgical procedures, which may prevent fetal compromise, even though the fetus may be unable to experience pain at the gestational age when the procedures are typically performed. This could also avoid long-term consequences of nociception and physiological stress on the fetus, and decrease fetal movement to enable the safe execution of procedures (GRADE 2C).

Fetal anesthesia and analgesia

For a long, analgesia in neonates was an unaddressed contentious issue due to the concerns of intraoperative hemodynamic disturbances and postoperative respiratory depression and apneic episodes. However, recent evidence has shown that the benefits outweigh the risks, irrespective of whether neonates feel pain or not. This has also led to reconsideration for fetal pain. Although most of the cortical connections necessary for pain perception develop around 23–30 weeks of gestation, the neuroendocrine and hemodynamic responses to noxious stimuli can be elicited by around18–20 WGA, and fetal analgesia may be helpful in averting the neuroendocrine and hemodynamic alterations.[69]

The objectives of providing adequate fetal anesthesia and analgesia would be (a) fetal immobility during the procedures, (b) averting fetal stress response, (c) uterine atony to prevent uterine contractions and placental separation, (d) prevention of adverse long terms consequences on neurodevelopment and behavior, and (e) improved maternal and fetal cardiovascular instability.[10],[18],[69],[70],[71],[72],[73],[74],[75],[76],[77]

It is a possibility that a surgeon or medical team will judge analgesia or anesthesia as not in the best interest of their fetal patient due to the concerns of adverse effects on normal neural development and the cardiovascular system.[5]

The principle of nonmaleficence means that first, we should do no harm, but pain can be acceptable if it is in good faith to save or improve the life of the patient.[5] This is applicable to procedures aimed at preserving or improving fetal life like therapeutic fetal surgeries, blood transfusions, and the use of instruments for delivery. Therefore, while there have been changes in clinical practice with regard to fetal pain, the practice of fetal surgeries and invasive interventions cannot be influenced merely based on fetal pain, as they aim to improve the quality of future life. Moreover, alleviating pain would not always take precedence over survival and avoidance of long-term complications. This is emphasized by the very fact that treatment of pediatric leukemia is not terminated because of the treatment being exceptionally painful.[6]

The objectives of fetal anesthesia and analgesia may not be pertinent to abortions as they do not preserve or enhance the fetal life, with the actual focus being the avoidance of suffering by being born with painful dysfunctions. Although fetal anesthesia and analgesia for abortions are justified, especially after 18 weeks, the principle of beneficence toward the mother should allow a risk–benefit analysis to ensure the safety of the mother first.

Anesthesia choices for the fetus

General or regional anesthesia is administered for laparotomies and hysterotomies involving fetal surgeries.

General anesthesia

It is more commonly used because it ensures uterine atony and fetal immobilization.[7] Studies in pregnant ewes have showed that inhalational agents at doses capable of anesthetizing the ewe also anaesthetized the fetus. Opioids (10–50 μg/kg fentanyl) and neuromuscular blockers (0.1 mg/kg vecuronium) given intramuscularly to the fetus provide analgesia and immobilization.

Opioids can be administered to the fetus through the umbilical cord or by intramuscular injection in a dose of 20 μg/kg. Remifentanil 0.1 μg/kg/min can be administered to the mother to achieve fetal immobilization and maternal sedation. Intraamniotic opioids when administered to lamb fetuses showed greater plasma concentrations in the fetal lamb as compared with the ewe, suggesting that this route might be considered for humans.[44]

Anesthesia is maintained with inhalational agents at a minimum alveolar concentration (MAC) of 2–3 to provide uterine relaxation for optimum fetal exposure. Fetal hypotension and bradycardia due to high MAC concentrations can be ameliorated using epinephrine 1 μ/kg and atropine 0.02 mg/kg, through intramuscular, intravenous, or intracardiac routes. An arterial line may be used for monitoring the maternal blood pressure. Additional nitroglycerine boluses (50–100 μg IV) or infusions (0.5–1 μg/kg/min) are used to facilitate uterine relaxation.[18]

The recommendations by the Society for Maternal–Fetal Medicine 2021 on the use of analgesia and anesthesia for maternal–fetal procedures are to consider fetal paralytic agents for intrauterine transfusion to avoid fetal movements.[11]

Regional anesthesia

Epidural or combined spinal epidural anesthesia is the anesthesia of choice for minimally invasive procedures, which use needles or endoscopy to access the fetus. Here, uterine relaxation is not necessary. Fetal analgesia and anesthesia are ensured by intramuscular opioids and relaxants.[18]

There is no established technique of fetal analgesia with maternal general or regional anesthesia. Three techniques are commonly suggested: (a) direct drug delivery to the fetus through intravenous or intramuscular routes; (b) transplacental delivery via maternal intravenous infusion of opioids. This may be associated with maternal risks of hypoventilation when used in higher doses to achieve better placental transfer, and (c) intra-amniotic drug delivery. Drug absorption takes place through fetal skin and membranes. In a study on pregnant ewes, intra-amniotic sufentanil injection resulted in fetal plasma levels at doses that would be analgesic in human adults.[78],[79] However, its safety in human fetuses is still unproven.[18]

Deprest et al. performed Fetoscopic Endoluminal Tracheal Occlusion for congenital diaphragmatic hernia repair under GA, RA (combined spinal–epidural), or local anesthesia. In the case of general anesthesia, induction was performed with thiopental, succinylcholine, fentanyl, and vecuronium titrated by peripheral nerve stimulation. For RA, hyperbaric bupivacaine (8 mg) was injected at the L3-L4 or L4-L5 interspace. In the cases of local or regional anesthesia, fentanyl (15 μg/kg) was additionally given to the fetus by intramuscular injection. The authors reported survival benefits with epidural rather than general anesthesia.[15] Similarly, GA or local anesthesia was administered successfully for laser coagulation or amnioreduction for severe twin–twin transfusion syndrome in other fetal interventional studies.[12],[13],[16]


The neuroscientific evidence presented in the recent studies does not outrightly reject the possibility of fetal pain, even though there are a wide range of opinions and controversies at all the stages of its neurobiology. Whether the fetal capacity of pain develops at around 18 weeks of gestation or later after 23 weeks of gestation is still a matter of debate.

The IASP definition of pain is inadequate for the fetus as it restricts pain to mature human beings who can consciously perceive it.[5] Furthermore, fetal pain scales are necessary as markers to assess the degree of pain and to enhance the effectiveness of the current analgesia practices.

Most of the studies reviewed in this article advocate the use of fetal analgesia and anesthesia as the standard procedure except for abortions in early gestation. Fetal anesthesia and analgesia techniques have evolved through clinical observations and experience in in utero interventional procedures. They are indicated for fetal surgery regardless of the existence of fetal pain, to achieve uterine relaxation, fetal immobilization, and to blunt neuroendocrine stress responses. There are limited data on maternal dose for fetal analgesia, maternal safety, and analgesic effectiveness in the fetus. All the proposed techniques are under experimental stages as the in utero procedures are relatively sparse and randomized trials are considered inappropriate and unethical. Hence, it is recommended to find a balance between the pros of analgesia and the cons of neurodevelopmental interference in the fetus, with utmost importance to maternal safety.

This review suggests further studies on the subject of fetal pain to better ascertain the gestational age at which the fetus starts to feel pain and to ensure the well-being of both the mother and the fetus.


Key elements:

Whether the fetal capacity of pain develops at around 18 weeks of gestation or later after 23 weeks of gestation is still a matter of debate, although the current evidence supports the possibility of fetal pain before 23 weeks of gestationAlthough neuroinhibiting substances may cause sleep-like state/sedation in utero, they do not affect the perception of fetal painFurthermore, sedation is not equivalent to analgesia, thus mandating the need for analgesia and anesthesia for fetal proceduresUnrelieved fetal pain is of ethical importance in terms of long-term consequences on their neurodevelopmentRefusing to acknowledge fetal pain in late preterm fetuses would question the use of analgesia in neonates of similar gestational ageThe IASP definition of pain is regarded as inadequate for the fetus as an emotional and conscious response may not be necessary to experience pain.

Research direction:

The development of fetal pain scales as necessary markers to assess the degree of pain and to enhance the effectiveness of the current analgesia practicesFurther studies to ascertain the maternal dose for fetal analgesia, maternal safety, and the analgesic effectiveness in the fetusFurther studies to determine the pitfalls of anesthesia on fetal development.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Bonica JJ. The need of a taxonomy. Pain 1979;6:247-8.
2Reagan R. The Catholic Lawyer The Catholic Lawyer Abortion and the Conscience of the Nation Abortion and the Conscience of the Nation. 1986;30. Available from: [Last accessed on 2022 Nov 19].
3Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987;317:1321-9.
4Humphrey T. Some correlations between the appearance of human fetal reflexes and the development of the nervous system. Prog Brain Res 1964;4:93-135.
5Valman HB, Pearson JF. What the fetus feels. Br Med J 1980;280:233-4.
6Okado N. Onset of synapse formation in the human spinal cord. J Comp Neurol 1981;201:211-9.
7Wozniak W, O'Rahilly R, Olszewska B. The fine structure of the spinal cord in human embryos and early fetuses. J Hirnforsch 1980;21:101-24.
8Molliver ME, Kostović I, van der Loos H. The development of synapses in cerebral cortex of the human fetus. Brain Res 1973;50:403-7.
9Derbyshire SW. Fetal pain and the law: Abortion laws and their relationship to ideas about pain and fetal pain. In: The Routledge Handbook of Philosophy of Pain. Abingdon: Routledge, 2017;7:425-35.
10Derbyshire SW, Bockmann JC. Reconsidering fetal pain. J Med Ethics 2020;46:3-6.
11Norton ME, Cassidy A, Ralston SJ, Chatterjee D, Farmer D, Beasley AD, et al. Society for Maternal-Fetal Medicine Consult Series# 59: The use of analgesia and anesthesia for maternal-fetal procedures. Am J Obstetr Gynecol 2021;225:B2-8.
12Deprest JA, Gratacos E. Obstetrical endoscopy. Curr Opin Obstet Gynecol 1999;11:195-203.
13Deprest JA, Van Schoubroeck D, Van Ballaer PP, Flageole H, Van Assche FA, Vandenberghe K. Alternative technique for Nd: YAG laser coagulation in twin-to-twin transfusion syndrome with anterior placenta. Ultrasound Obstet Gynecol 1998;11:347-52.
14Deprest JA, Evrard VA, Van Schoubroeck D, Vandenberghe K. Endoscopic cord ligation in selective feticide. Lancet 1996;348:890-1.
15Deprest J, Gratacos E, Nicolaides KH, FETO Task Group. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: Evolution of a technique and preliminary results. Ultrasound Obstet Gynecol 2004;24:121-6.
16Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136-44.
17Derbyshire SW. Fetal pain: Do we know enough to do the right thing? Reprod Health Matters 2008;16:117-26.
18Lee SJ, Ralston HJ, Drey EA, Partridge JC, Rosen MA. Fetal pain: A systematic multidisciplinary review of the evidence. JAMA 2005;294:947-54.
19Bellieni CV. New insights into fetal pain. Semin Fetal Neonatal Med 2019;24:101001.
20Kostovic 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.
21Bystron I, Blakemore C, Rakic P. Development of the human cerebral cortex: Boulder Committee revisited. Nat Rev Neurosci 2008;9:110-22.
22Molnár Z, Blakemore C. How do thalamic axons find their way to the cortex? Trends Neurosci 1995;18:389-97.
23Derbyshire SW. Can fetuses feel pain? BMJ 2006;332:909-12.
24Kostović I, Judas M. Transient patterns of cortical lamination during prenatal life: Do they have implications for treatment? Neurosci Biobehav Rev 2007;31:1157-68.
25Kostovic 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;297:441-70.
26Hevner RF. Development of connections in the human visual system during fetal mid-gestation: A DiI-tracing study. J Neuropathol Exp Neurol 2000;59:385-92.
27Kostović 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.
28Ulfig N, Neudörfer F, Bohl J. Transient structures of the human fetal brain: Subplate, thalamic reticular complex, ganglionic eminence. Histol Histopathol 2000;15:771-90.
29Peyron R, Laurent B, García-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 2000;30:263-88.
30Derbyshire SW, Whalley MG, Stenger VA, Oakley DA. Cerebral activation during hypnotically induced and imagined pain. Neuroimage 2004;23:392-401.
31Kostovic 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.
32Krmpotić-Nemanić J, Kostović I, Kelović Z, Nemanić D, Mrzljak L. Development of the human fetal auditory cortex: Growth of afferent fibres. Acta Anat (Basel) 1983;116:69-73.
33Coghill RC, McHaffie JG, Yen YF. Neural correlates of interindividual differences in the subjective experience of pain. Proc Natl Acad Sci U S A 2003;100:8538-42.
34Schenk VW, De Vlieger M, Hamersma K, De Weerdt J. Two rhombencephalic anencephalics: A clinicopathological and electroencephalographic study. Brain 1968;91:497-506.
35Johnston CC, Stevens BJ, Franck LS, Jack A, Stremler R, Platt R. Factors explaining lack of response to heel stick in preterm newborns. J Obstet Gynecol Neonatal Nurs 1999;28:587-94.
36Gingras JL, Mitchell EA, Grattan KE. Fetal homologue of infant crying. Arch Dis Child Fetal Neonatal Ed 2005;90:F415-8.
37Bellieni CV, Severi F, Bocchi C, Caparelli N, Bagnoli F, Buonocore G, et al. Blink-startle reflex habituation in 30-34-week low-risk fetuses. J Perinat Med 2005;33:33-7.
38Torres F, Anderson C. The normal EEG of the human newborn. J Clin Neurophysiol 1985;2:89-103.
39Fisch BJ, Spehlmann R. Fisch and Spehlmann's EEG Primer: Basic Principles of Digital and Analog EEG. 3rd ed. New York, NY: Elsevier; 1999.
40Scher MS. Electroencephalography of the new-born: Normal and abnormal features. In: Niedermeyer E, Lopes da Silva FH, editors. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999. p. 896-946.
41Vanhatalo S, van Nieuwenhuizen O. Fetal pain? Brain Dev 2000;22:145-50.
42Vecchierini MF, André M, d'Allest AM. Normal EEG of premature infants born between 24 and 30 weeks gestational age: Terminology, definitions and maturation aspects. Clin Neurophysiol 2007;37:311-23.
43Verriotis M, Fabrizi L, Lee A, Cooper RJ, Fitzgerald M, Meek J. Mapping cortical responses to somatosensory stimuli in human infants with simultaneous near-infrared spectroscopy and event-related potential recording. eNeuro 2016;3: ENEURO.0026-16.2016.
44Bellieni CV, Buonocore G. Is fetal pain a real evidence? J Matern Fetal Neonatal Med 2012;25:1203-8.
45Pierucci R. Fetal pain: The science behind why it is the medical standard of care. Linacre Q 2020;87:311-6.
46Anand 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.
47Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma cortisol and beta-endorphin response to intrauterine needling. Lancet 1994;344:77-81. doi: 10.1016/s0140-6736(94)91279-3
48Giannakoulopoulos X, Teixeira J, Fisk N, Glover V. Human fetal and maternal noradrenaline responses to invasive procedures. Pediatr Res 1999;45:494-9.
49Radunovic 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;10:112-4.
50Carrasco GA, Van de Kar LD. Neuroendocrine pharmacology of stress. Eur J Pharmacol 2003;463:235-72.
51Van de Velde M, Jani J, De Buck F, Deprest J. Fetal pain perception and pain management. Semin Fetal Neonatal Med 2006;11:232-6.
52Cummings JJ, Benitz WE, Eichenwald EC, Poindexter BB, Stewart DL, Aucott SW, et al. Prevention and management of procedural pain in the neonate: An update. Pediatrics. 2016;137.
53Mellor DJ, Diesch TJ, Gunn AJ, Bennet L. The importance of 'awareness' for understanding fetal pain. Brain Res Brain Res Rev 2005;49:455-71.
54Klak J, Hill M, Parízek A, Havlíková H, Bicíková M, Hampl R, et al. Pregnanolone isomers, pregnenolone and their polar conjugates around parturition. Physiol Res 2003;52:211-21.
55Hering WJ, Ihmsen H, Langer H, Uhrlau C, Dinkel M, Geisslinger G, et al. Pharmacokinetic-pharmacodynamic modeling of the new steroid hypnotic eltanolone in healthy volunteers. Anesthesiology 1996;85:1290-9.
56Benatar D, Benatar M. A pain in the fetus: Toward ending confusion about fetal pain. Bioethics 2001;15:57-76.
57Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain, Subcommittee on Taxonomy - PubMed. Available from: [Last accessed on 2022 Nov 19].
58Woller SA, Eddinger KA, Corr M, Yaksh TL. An overview of pathways encoding nociception. Clin Exp Rheumatol 2017;35 Suppl 107:40-6.
59Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron 2007;55:377-91.
60Raja SN, Carr DB, Cohen M, Finnerup NB, Flor H, Gibson S, et al. The revised International Association for the Study of Pain definition of pain: Concepts, challenges, and compromises. Pain 2020;161:1976-82.
61Merskey H. The definition of pain. Eur Psychiatry 1991;6:153-9.
62Gitau R, Fisk NM, Teixeira JM, Cameron A, Glover V. Fetal hypothalamic-pituitary-adrenal stress responses to invasive procedures are independent of maternal responses. The Journal of Clinical Endocrinology & Metabolism. 2001;86:104-9.
63Kodali BS, Bharadwaj S. Foetal surgery: Anaesthetic implications and strategic management. Indian J Anaesth 2018;62:717-23.
64Derbyshire SW. Locating the beginnings of pain. Bioethics 1999;13:1-31.
65Derbyshire SW. Fetal pain: An infantile debate. Bioethics 2001;15:77-84.
66Ruda MA, Ling QD, Hohmann AG, Peng YB, Tachibana T. Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science 2000;289:628-31.
67Lowery CL, Hardman MP, Manning N, Clancy B, Hall RW, Anand KJ. Neurodevelopmental changes of fetal pain. Seminars in Perinatology 2007;31:275–82.
68Chatterjee D, Arendt KW, Moldenhauer JS, Olutoye OA, Parikh JM, Tran KM, et al. Anesthesia for maternal-fetal interventions: A consensus statement from the American Society of Anesthesiologists Committees on Obstetric and Pediatric Anesthesiology and the North American Fetal Therapy Network. Anesth Analg 2021;132:1164-73.
6967Hoagland MA, Chatterjee D. Anesthesia for fetal surgery. Paediatr Anaesth 2017;27:873.
70Seeds JW, Corke BC, Spielman FJ. Prevention of fetal movement during invasive procedures with pancuronium bromide. Am J Obstet Gynecol 1986;155:818-9.
71Rosen MA. Anesthesia for fetal procedures and surgery. Yonsei Med J 2001;42:669-80.
72Cauldwell CB. Anesthesia for fetal surgery. Anesthesiol Clin North Am 2002;20:211-26.
73Rosen MA. Anesthesia for procedures involving the fetus. Semin Perinatol 1991;15:410-7.
74Smith RP, Gitau R, Glover V, Fisk NM. Pain and stress in the human fetus. Eur J Obstet Gynecol Reprod Biol 2000;92:161-5.
75White MC, Wolf AR. Pain and stress in the human fetus. Best Pract Res Clin Anaesthesiol 2004;18:205-20.
76Rosen MA. Anesthesia and tocolysis for fetal intervention. In: Harrison MR, Golbus MS, Filly RA, editors. The Unborn Patient: Prenatal Diagnosis and Treatment. Orlando, Fla.: Grune & Stratton; 1984. p. 417-33.
77Schwarz U, Galinkin JL. Anesthesia for fetal surgery. Semin Pediatr Surg 2003;12:196-201.
78Lehmann 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;35:221-6.
79Strümper 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;98:1400-6.