Fetal Pain: The Science Behind Why It Is the Medical Standard of Care

Abstract

Despite pain as the fifth vital sign in adult and pediatric care, many still dismiss the fact that immature human beings (whether a fetus, a preterm, or term baby) are capable of being affected by pain. Studies have demonstrated that avoiding, minimizing, and treating pain in babies, particularly when premature, improves their outcomes. Informed by the evidence, treating neonatal pain has become the medical standard of care for physicians in neonatology and anesthesiology. This article provides a brief overview of relevant publications that explain the clinical evolution that has led to the treatment of neonatal pain. This article also examines three arguments against the existence of fetal pain and presents evidence that refutes them. Informed by the research, a revised definition of pain is offered.

The idea that a human fetus is capable of being affected by pain has been dismissed by some as “bogus so-called science” (Apkarian 2018, 1255) and “phony baloney” (Schrier 2019). Yet research has shown that extremely premature babies experience pain, and treating this pain is now the medical standard of care. Over the last twenty years, the care, particularly for our most premature babies, has changed due to new data. Both neonatologists in neonatal intensive care units (NICUs) and anesthesiologists during fetal surgery acknowledge that their patients are pain-capable. Their pain exists. This is a brief overview of relevant publications that explain where the medical standard of care for treating pain in neonates originated, the state of current research, and how the data answer questions about this complex topic.

Until recently, many members of the medical community believed that babies did not feel pain. In 1987, the landmark paper by Drs. Anand, Phil, and Hickey published in The New England Journal of Medicine (hereafter NEJM) demonstrated evidence to the contrary (pp. 1321–26). The authors identified that the “confusion over pain perception (emphasis added), and the accompanying physiologic responses have obscured the mounting evidence that nociception is important in the biology of the neonate.” (Anand, Phil, and Hickey 1987, 1321). Their paper drew upon results from multiple studies as they reviewed the anatomic requirements for pain perception, the associated neurochemical systems, both the physiologic and behavioral changes associated with pain, and the memory of pain in neonates. The authors concluded, “none of the cited data tell us whether neonatal nociceptive activity and associated responses are experienced subjectively.…However, the evidence does show that marked nociceptive activity clearly constitutes a physiological and perhaps even a psychologic form of stress in premature or full-term neonates” (Anand, Phil, and Hickey 1987, 1326). Based on their data, they recommended reevaluating the medical standard of care in favor of providing local and general anesthesia during invasive procedures (Anand, Phil, and Hickey 1987, 1327).

Undisputably corroborating their previous paper’s conclusion, their 1992 NEJM publication was arguably even more demonstrative and, by today’s standards, ethically troubling. This was a randomized trial comparing the outcomes of neonates between four and ten days old who were eligible for surgical repair of their congenital heart defects; in the operating room, one group received “lighter anesthesia,” the other group “deep anesthesia.” When pain was treated, the outcomes were unequivocally better, including statistically significant differences in intraoperative and postoperative markers of stress (including stress hormones, hyperglycemia, lactic acidemia), and fewer postoperative deaths (Anand, Phil, and Hickey 1992, 1). Today, this study could not be ethically repeated. The medical standard and practice of medicine in neonatology, pediatrics, and anesthesiology has changed, and now all fetuses and infants undergoing surgery receive appropriate anesthesia.

Since those papers were written, research in neonatology has evolved, and babies who are physically smaller and even more premature are now routinely cared for in NICUs (Arzuaga and Lee 2011, 1047). For most neonatologists, the edge of viability has decreased to approximately twenty-two- to twenty-three-week gestation, with a number of cases even a bit lower (Raju et al. 2014, 334), which means these little ones are born with predominantly fetal physiology (the fetal period of development extends from the “9th week to term” [Moore and Presaud 1993, 6]). According to the American Academy of Pediatrics’ (AAP) 2016 revised policy, Prevention and Management of Procedural Pain in the Neonate: An Update, even a premature baby’s pain should be treated, minimized, and/or prevented, “not only because it is ethical but also because repeated painful exposures have the potential for deleterious consequences” (Keels et al. 2016, 2). The consequences of experiencing pain include “physiologic instability, altered brain development, and abnormal neurodevelopment, somatsosensory, and stress response systems, which can persist into childhood” (Keels et al. 2016, 2). Those who care for babies, including those with fetal physiology, actively seek to alleviate their pain because it demonstrably affects them, both acutely and chronically.

Today, the pain capability of neonates is so noncontroversial that many NICUs are actively involved in performance improvement projects that have moved from merely decreasing obviously painful procedures to rethinking how the entire NICU environment affects particularly the youngest and most vulnerable patients (Altimier and Phillips 2013, 9; Morris, Cleary, and Soliman 2015, e7). Two examples of practice changes include (1) increased use of “kangaroo care” where the premature baby is placed in skin-to-skin contact with either the mother’s or father’s chest and (2) cue-based care times, by which instead of checking vital signs every three hours, the staff tries not to interrupt sleep and uses, within reason, the babies’ cues that they are awake or in need of being tended to. Multiple centers from the Vermont Oxford Network (an international consortium of more than 1,300 hospitals working to improve neonatal care public. Vermont Oxford Network: Home [vtoxford.org.]) have made these and other changes to intentionally decrease noxious stimuli from a variety of sources. These changes have led to the creation of “small baby units” within NICUs, and many hospitals have presented their versions of small baby units as part of their performance improvement results at VON’s annual national conference, as well as in formal publications (Morris, Cleary, and Soliman 2015, e7). Evidence indicates that our most vulnerable patients are healthier when noxious stimuli is reduced.

Despite the four-page bibliography that informed the 2016 AAP’s policy document on Prevention and Management of Procedural Pain in the Neonate on avoiding, diminishing, and/or treating procedural pain, as well as the clinical/bedside evidence that decreasing noxious stimuli in a premature baby’s environment improves medical outcomes, the debate over fetal pain continues. It persists “in large part because fetal pain is often cited as a reason to restrict access to termination of pregnancy” (Derbyshire and Bockmann 2020, 3).

In addition to overt concerns about abortion access, critics who deny the existence of fetal pain as nonsense cite three main arguments:

1. intrauterine inhibitory chemicals block all fetal pain throughout the pregnancy (Mellor et al. 2005, 455),

2. during fetal development, anatomical structures are present and sufficiently functioning to provide pain capability only late in pregnancy, if at all during gestation (Derbyshire 2010, 647; Lee et al. 2005, 947), and

3. because of the definition of pain, no baby is pain-capable (Derbyshire 2010, 647; Lee et al. 2005, 947).

With regard to the first argument, do chemicals within the uterus anesthetize the fetus? Intrauterine endocrine neuroinhibitors that have this potential exist. However, in a 2017 literature review that questioned whether analgesia was necessary during fetal surgery, the authors found that these neuroinhibitors “do not have an anesthetic effect at normal fetal values, but only when they are artificially injected at high doses” (Bellieni, Vannuccini, and Petraglia 2018, 1242). They concluded that not only is “fetal anesthesia during surgery justified” but that providing maternal anesthesia alone is insufficient to achieve the best fetal outcomes and that, “direct fetal analgesia/anesthesia is mandatory” (Bellieni, Vannuccini, and Petraglia 2018, 1241, 1245).

Additional substances with known sedative properties are present in the womb, but sedation is not equivalent to analgesia (Bellieni 2019, 3). Thus, the makeup of the in utero chemical milieu may participate in providing the ideal place for the fetus to develop, but the milieu is not equipped to blockade the effects of external painful stimuli.

If intentional treatment of fetal pain during second trimester fetal surgeries provides improvements in immediate and long-term surgical outcomes, it then becomes more problematic to argue effectively that an in utero dismemberment procedure is a painless event. Lee et al. paradoxically defended the fetal inability to feel pain but stated that based on the data, “fetal anesthesia and analgesia are warranted” because of “preventing hormonal stress responses associated with poor surgical outcomes” and for “preventing possible adverse effects on long-term neurodevelopment and behavioral responses to pain” (Lee et al. 2005, 951).

With regard to the second argument, there is evidence that peripheral pain receptors are sufficiently connected to the central nervous system, specifically into the thalamus and the cortical subplate, at as early as twelve-week gestation (Sekulic et al. 2016, 1034–35; Ulfig, Feldhaus, and Bohl 2000, 505; Kostović and Judaš 2010, 1119). The appearance of the correct neuroanatomic connections is insufficient to produce a mature ability to feel and interpret pain. However, as Lowery et al. (2007) explain, the multitude of neural elements participating in pain perception is staggering in complexity and cannot be viewed as equivalent to assembling computer parts (p. 276). Pain perception does not flip on and off like a light switch (Lowery et al. 2007, 276). Instead, the research demonstrates that the developing neural elements may be immature, but they are not inactive (Lowery et al. 2007, 276). Noxious stimulation can cause “activation of the hypothalamic pituitary adrenal axis (HPA)…in the absence of cortical activation” (Lowery et al. 2007, 280), producing measurable changes in stress hormones very early in gestation, and early “exposure to pain has been associated with long term alterations in pain response thresholds as well as changes in behavioral responses related to the painful stimuli” (Lowery et al. 2007, 280).

Traumatic insults have also been documented to cause activation of the fetal HPA and “adversely impact” the infant’s neurodevelopment (Sanders and Hall 2017, 3). “The stress a mother experiences during pregnancy” was correlated with later changes in behavioral responses to painful stimulation (heel stick), and “toxic stress” while in the NICU (such as the prolonged absence of a parent and repeated painful procedures without environmental support) “overwhelms the immature brain” (Sanders and Hall 2017, 4). “Although preterm infants may initially have exaggerated responses to acute stress, their autonomic and neuroendocrine responses may become blunted as stresses increase, ultimately leading to hyporesponsivity when faced with chronic stress” (Sanders and Hall 2017, 4). Thus, pain can create measurable changes acutely as well as produce later “procedural memories” (Velde and De Buck 2012, 206) even when the human anatomical nervous system is quite immature.

With regard to the third argument, “knowing that I am in pain” (Derbyshire and Bockmann 2020, 5) is what some individuals claim defines the ability to feel or be affected by pain. This definition is from the International Association for the Study of Pain (IASP), which defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (Merskey 1994, S69). This definition mandates that pain has a sensory and emotional component, which makes consciousness of the pain producing event a requirement for the existence of pain. The problematic aspects of this definition can be demonstrated by adult coma patients. They are neither conscious nor demonstrably upset by pain, yet if medical staff were caught intentionally and needlessly inflecting noxious stimuli on these patients, they would be found medically and ethically liable. No one accuses comatose patients of being incapable of feeling pain because they cannot complain or remember what happened; yet, when the patient is a premature baby or an unborn fetus, “if a conceptual subjectivity is considered necessary for pain…then pain is not possible at any gestational age” (Derbyshire 2010, 647). For those who care for patients with fetal physiology, the IASP’s definition does not reflect clinical reality. Physicians treat the pain of their youngest patients.

Clinical studies that refute the necessity of a mature emotional, conscious response to painful stimulation include a study comparing two groups of premature babies. One group was thirty-two-week gestation at birth and born within the previous four days. The other group was born at twenty-eight-week gestational age but examined at thirty-two weeks (Johnston and Stevens 1996, 925). Infant measurements included heart rates and oxygen saturation levels before, during, and after a heel stick (commonly used for blood draws in this population). Clear statistical differences between the two groups were found. The four-week-old babies, who had experienced this procedure many times previously, had “higher heart rates and lower oxygen saturations than the newborn infants of the same gestational age who had not already had this experience (Johnston and Stevens 1996, 925). Premature babies who had previously been exposed to painful stimulation showed evidence of being more stressed when the same procedure was repeated than those of the same gestational age who had not yet been exposed.

Gitau et al. completed a similar study demonstrating measurably increased stress hormones and elevated heart rates after painful stimulation. They compared fetuses whose abdomens were accessed to reach the intrahepatic vein for an in utero blood transfusion to those who received their transfusion through the placental cord insertion site (Gitau et al. 2001, 104). The fetal gestational ages ranged from seventeen- to thirty-five-week gestation, and all of the fetuses in the intrahepatic vein group had significantly elevated stress hormones; the other group had normal levels of stress hormones (Gitau et al. 2001, 104). This study demonstrated immediate effects of painful stimulation while still in utero. The Johnston and Stevens study demonstrated that prematurely born babies had both immediate effects and the development of a procedural memory. Whether a premature infant or a fetus, none of the study participants had the maturity to be fully conscious yet they were clearly affected.

Because of the consistent laboratory and clinical evidence demonstrating that fetal and premature infants are affected by pain, the IASP’s definition of pain is insufficient. Derbyshire and Bockmann agree stating that the IASP’s definition “restricts pain almost exclusively to fairly mature human beings” but the “evidence…points towards an immediate and unreflective pain experience mediated by the developing function of the nervous system from as early as 12 weeks” (Derbyshire and Bockmann 2020, 5–6). This statement is an important conclusion drawn from their review of the literature. The statement is also important because one of the authors is an advocate for elective abortions rights who previously argued that all babies are incapable of experiencing pain (Derbyshire 2006, 909; Derbyshire 2010, 647). Thus, given the data, even someone who supports abortions admits that pain is possible very early in human development.

Because of the data, the definition of pain should be expanded. Pain is not only an unpleasant sensory and emotional experience; it also is present when noxious stimulation results in either immediate or long-term ramifications. There is a medical and ethical duty to recgonize fetal pain capability.

Conclusion

Denial of fetal pain persists “in large part because fetal pain is often cited as a reason to restrict access to termination of pregnancy or abortion” (Derbyshire and Bockmann 2020, 4). But the data that confirm the existence of fetal pain is extensive and compelling. By evaluating fetal pain capability separately from the discussion about abortion, it is easier to see that the data indicate fetal pain exists. Continuing to deny its existence in order to defend abortion is dishonest and scientifically indefensible.

Biographical Note

Robin Pierucci, MD, MA, is a practicing neonatologist with a master’s degree in bioethics. In addition to her full-time clinical duties within the NICU, she remains active in perinatal palliative care and in ongoing performance improvement projects, particularly care for drug-exposed infants and their families. She has multiple publications in peer and nonpeer reviewed journals and has spoken around the country on multiple perinatal and ethical topics. She is a member of the Catholic Medical Association and recently became an associate scholar with the Charlotte Lozier Institute and a board member of the American College of Pediatrics (ACPeds).