PAIN COLUMN

From the NICU, SunnybrookCanada M5S-1B2; InterdiscipCentre, Toronto, Ontario, CaAddress correspondences toSunnybrook Health SciencesE-mail: lisa.golec@sunnybroo© 2007 Elsevier Inc. All righ1527-3369/07/0704-0220$10doi:10.1053/j.nainr.2007.09.0

“It Will Not Hurt a Bit,” “What You Do NotKnow Cannot Hurt You,” and Other Myths

About Fetal Surgical Pain

Sharyn Gibbins, RN, PhDColumn Editor

Lisa Golec, RRT, BSc, MHSM

Advances in health care have made it possible to carry out anumber of intrauterine procedures before birth in the hopes ofminimizing morbidity and mortality outcomes postnatally.Surgery, ultrasound-guided and endoscopic therapies andterminations1 exemplify some of the potentially painful ante-natal therapies that can occur, with procedures ranging fromblood sampling to thoracotomy, abdominal incision, andresection.2 Fetal surgery is routinely carried out between the26th and 32nd weeks of gestation, with procedures occurring asearly as 20 weeks and as late as 35 weeks.2 Pain is a seriousconcern in fetal surgery, both during the surgery itself as well asthe long-term ramifications that may ensue. “The plasticity ofthe developing nervous system may allow for the greatestimpact of pain to occur in the least maturely born infants.”3

Although the use of fetal analgesia for fetal surgery has beenconsidered,1,4 few infants receive direct analgesia during thesepotentially painful procedures. Why? Three main arguments(myths) may be postulated to explain why fetal analgesia has notevolved in line with fetal surgery: first, the fetus does not feelpain or remember pain, and therefore, analgesia is unnecessary;second, the use of fetal analgesia is not possible or safe, nor arethere data to support it; and third, the fetus' pain managementneeds are covered by maternal analgesia delivered transplacen-tally during the procedure. Herein, we discuss each of thesemyths and give reasons why we believe them to be problematic.It is our belief that our moral responsibility as caregiversdemands that we value the fetus in itself, not simply as a means,and as such, direct pain control consideration ought to be givento the fetus undergoing procedures suspected to cause pain.

Health Sciences Centre, Toronto, Ontario,linary Research, Sunnybrook Health Sciencesnada M5S-1B2.Lisa Golec, RRT, BSc, MHSM, NICU,

Centre, Toronto, Ontario, Canada M5S-1B2.k.ca.ts reserved..00/005

Myth One: Fetuses Do Not Feel Pain orRemember Pain

Current data suggest that by 26 and even as early as 20weeks' gestation, a rudimentary pain pathway may be presentfor the perception of pain.2 “For analgesia to be effective, it isessential that the necessary receptors are present...there areabundant μ opioid receptors in the fetal brain and spinal cordfrom as early as 20 weeks gestation [making] opioids a goodoption for fetal analgesia.”2 Neonatal data from extremely low-birth-weight and low-birth-weight infants confirm the presenceof definitive pain responses in this gestational age group.5

Where surgery itself is concerned, data regarding the long-termeffects of surgery suggest the existence of “alterations in spinalcord connectivity, central sensitization, as well as moregeneralized changes in stress reactivity.”3 These data representa portion of the plethora of research on perinatal pain done overthe past decade, which dispels the common misconceptionsthat preterm infants do not have the same “physiologic responseto painful stimuli” as adults and that what pain experience theydo have “doesn't count” because they do not remember pain.6

Where these data do become problematic, however, relates tothe second myth: that the use of fetal analgesia is not possible orsafe, nor are there data to support it.

Myth Two: The Use of Fetal Analgesia IsNot Possible or Safe, Nor Are There Datato Support It

In 2001, Fisk et al,7 published some preliminary research insupport of the use of fetal analgesia. They administered fentanyldirectly to the fetus through the intrahepatic vein duringintrauterine transfusion. Their data showed a significantdecrease in stress response as measured by a reduction in β-endorphin levels and the prevention of change in the middlecerebral artery pulsatile index. In addition, they noted thatcortisol levels were reduced by 50%; however, these differenceswere not statistically significant. These data provide the “first

evidence that direct analgesia reduces stress responses toinvasive procedures in utero.” Opponents of fetal analgesiamight argue that little is known about appropriate fetal dosing tosupport fetal analgesic use. It is known, however, that the half-life of a drug given to a fetus is shorter that of a neonate, resultingin the need to give 25% more of the drug than would normallybe given to the fetus.2 This knowledge, coupled with validneonatal dosing guidelines, provides a solid starting point fordetermining appropriate fetal dose. Although it may be true thatthere is a paucity of data regarding fetal analgesia, these datasuggest that it is both possible and safe to administer fetalanalgesia during fetal surgical procedures. That being said,current neonatal data may complicate the case for fetal analgesiabecause findings showed that “treatments that work well enoughto relieve pain seem to worsen other outcomes.”6 Further studiesto examine the effects of treatment are therefore required.

The Neurologic Outcomes and Pre-emptive Analgesia inNeonates (NEOPAIN) study8 randomized 900 infants toeither morphine or placebo infusion. Infants who did notreceive open-label morphine in the morphine infusion grouphad higher rates of composite outcome (P = .0338) andsevere intraventricular hemorrhage (IVH) (P = .0209) thanthose in the placebo group. Infants given open-labelmorphine in the morphine infusion group were more likelyto develop severe IVH (P = .0024), and infants receivingopen-label morphine in the placebo control group had worserates of composite outcome than those who did not receiveopen-label morphine (P b .0001). These data appear toprovide strong support against the use of continuousanalgesia in preterm infants. It is important to note, however,that these data predominantly deal with the extendedtreatment of ventilated infants in the Neonatal IntensiveCare Unit (NICU) setting, not the short-term administrationto infants undergoing surgical procedures.

With regard to infants undergoing surgical procedures,studies have shown that term infants who received deepanesthesia (with sufentanil) during cardiac surgery hadsignificantly reduced postoperative stress responses as measuredby levels of β-endorphins, norepinephrine, epinephrine,glucagon, aldosterone, and cortisol. Infants who received lightanesthesia had more hyperglycemia and lactic academia as wellas greater likelihood of sepsis, acidosis, disseminated intravas-cular coagulation, and postoperative death.9,10 Studies withpreterm infants undergoing surgery11 have shown that stress-related hormonal changes precipitate a catabolic state character-ized by glycogenolysis, gluconeogenesis, lipolysis, and mobiliza-tion of gluconeogenic substrates in the postoperative period.Prevention of these metabolic derangements by anesthesia hasbeen suggested as a method of improving postoperative clinicaloutcomes for preterm infants. These data support the belief thatpain management during and after surgery is important for boththe immediate well-being of the patient as well as the long-termoutcomes that may prevail. Although no studies have criticallyexamined fetal pain behaviors or the safety and efficacy of fetalpain management on immediate and long-term outcomes, it isplausible that the responses mimic those observed in theextremely low-birth-weight infant.

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Despite a cornucopia of previously dispelled argumentsagainst neonatal sedation, preterm infants undergoing surgicalprocedures usually receive analgesia. In their book chapter“Ethical issues in the treatment of neonatal and infant pain,”Lantos and Meadow6 ask, “can pain be worse than death?” Theyforward that, “in most clinical situations involving adults,patients are willing to take some gamble on the risk of mortalityin order to achieve better pain relief…most people prefer thepain relief associated with general anaesthesia, even though itmay be associated with slightly higher risks of side effects andmorbidity.” As in the case of any intervention, treatment, ortherapy, attention must be paid to balancing risk against benefit.Outcome concerns notwithstanding, the effectiveness of opioidsfor the relief of infant pain has been demonstrated.6 In asystematic review of 13 studies examining the safety and efficacyof opioids, pain scores using the Premature Infant Pain Profile(PIPP) were significantly reduced.12 If a 26-week infant havingthoracic surgery is given analgesia during surgery despite thepotential risks associated with its administration, why, then,does a 26-week fetus not receive the same treatment? Whatdifferentiates the two other than a little bit of geography?

Myth Three: The Fetus' Pain Needs AreCovered by Maternal Analgesia DeliveredDuring the Procedure

How does the in utero locale of a fetus influenceconsideration of pain? Cultural perceptions of pregnancy aredeeply rooted in a tradition of folklore that views the body of awoman as a sacred metaphor13, the womb, a sacred spaceprotecting and providing for the developing fetus. Does ouradherence to this ideology cause us to naively support a beliefthat the womb will protect and provide even during instances ofingression? During fetal surgery, the mother is anesthetized, andanalgesia given to her flows transplacentally.2 Althoughmaternal analgesia crosses the placenta, assuming it sufficientfor fetal coverage may prove problematic. A trend away fromgeneral anesthetic in obstetrics2 notwithstanding, inhaledanesthetics take longer to elicit their effect in the fetus than inthe mother.1 In addition, Desprats et al14 demonstrated thattransplacental anesthesia may be insufficient. In their study,umbilical cord data sampled for maternal fentanyl at the time ofsurgery showed that, on average, less than 50% of the drugreached the fetus. It is not known whether this decreasedamount of analgesia is sufficient to meet the pain needs of a fetusduring a surgical procedure. Moreover, these data showed“considerable individual variation.”2 Evidently, we cannotnaively assume that maternal analgesia will cover the needs ofthe fetus as well.

Sadly, the generalized lack of consideration of perinatal painis not a myth. “One might wonder how intelligent, dedicatedindividuals who care deeply for their patients could continue toignore pain in infants and neonates that they are caring for.”15 Inthe case of the fetus, fetal pain control and research need toevolve in tandem with fetal surgery. Without wading into acontentious personhood debate, consideration ought to be given

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to the fetus undergoing procedures suspected to cause pain.Indeed, it could be argued that fetal analgesia ought to be usedfor termination procedures as well. “In Britain, most surgicalterminations take place under general anaesthesia, which isbelieved to affect the fetus, though evidence for this is sparse.”2

Although an in-depth discussion about pain management forpregnancy termination is beyond the scope of this editorial,surely, in instances such as these, it would be reasonable, evenhumane, to administer analgesia directly to the fetus, for whichmorbidity and mortality issues are moot. Fetal surgery, with itsintent to minimize morbidity and mortality, in effect enhancesthe value of the fetus. Although the law within our society doesnot predominantly recognize fetal rights, there is a generalrecognition of “fetal interests.”16 In failing to consider theinterests of the fetus where pain is concerned, we fail to value thefetus in itself. Our moral responsibility as caregivers demandsthat we value the fetus in itself, not simply as a means, and assuch, direct pain control consideration ought to be given to thefetus undergoing procedures suspected to cause pain.

References1. Myers LB, Cohen D, Galinkin J, Gaiser R, Kurth CD.

Anaesthesia for fetal surgery. Paediatr Anaesth. 2002;12:569-578.

2. Glover V, Fisk NM. Pain and the human fetus. In: AnandKJS, Stevens BJ, McGrath PJ, editors. Pain in neonates andinfants. 3rd ed. New York: Elsevier; 2007. p. xiv. [329 p].

3. Grunau RE, Tu MT. Long-term consequences of pain inhuman neonates. In: Anand KJS, Stevens BJ, McGrath PJ,editors. Pain in neonates and infants. 3rd ed. New York:Elsevier; 2007. p. xiv. [329 p].

4. Myers L. Anesthesia for fetal intervention and surgery. NewYork: BC Decker Inc; 2005.

5. Gibbins S, Stevens B, McGrath PJ, et al. Comparison ofpain responses in infants of different gestational ages.Neonatology. 2007;93:10-18.

6. Lantos J, Meadow W. Ethical issues in the treatment ofneonatal and infant pain. In: Anand KJS, Stevens BJ,

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McGrath PJ, editors. Pain in neonates and infants. 3rd ed.New York: Elsevier; 2007. p. xiv. [329 p].

7. Fisk NM, Gitau R, Teixeira JM, Giannakoulopoulos X,Cameron AD, Glover VA. Effect of direct fetal opioidanalgesia on fetal hormonal and hemodynamic stressresponse to intrauterine needling. Anesthesiology. 2001;95:828-835.

8. Anand KJ, Hall RW, Desai N, et al. Effects of morphineanalgesia in ventilated preterm neonates: primary outcomesfrom the NEOPAIN randomised trial. Lancet. 2004;363:1673-1682.

9. Anand KJ, Hickey PR. Halothane-morphine compared withhigh-dose sufentanil for anesthesia and postoperativeanalgesia in neonatal cardiac surgery. N Engl J Med. 1992;326:1-9.

10. Anand KJ, Aynsley-Green A. Measuring the severity ofsurgical stress in newborn infants. J Pediatr Surg. 1988;23:297-305.

11. Anand KJ, Brown MJ, Bloom SR, Aynsley-Green A. Studieson the hormonal regulation of fuel metabolism in thehuman newborn infant undergoing anaesthesia andsurgery. Horm Res. 1985;22:115-128.

12. Bellu R, de Waal KA, Zanini R. Opioids for neonatesreceiving mechanical ventilation. Cochrane Database SystRev. 2005:CD004212.

13. Marler J. The body of woman as sacred metaphor. In: PanzaM, Ganzerla MT, editors. Il Mito e il Culto della GrandeDea: Transiti, Metamorfosi, Permanenze. Bologna: Associa-zione Armonie; 2003. p. 9-24.

14. Desprats R, Dumas JC, Giroux M, et al. Maternal andumbilical cord concentrations of fentanyl after epiduralanalgesia for cesarean section. Eur J Obstet Gynecol ReprodBiol. 1991;42:89-94.

15. McGrath PJ, Unruh AM. Neonatal and infant pain in a socialcontext. In: Anand KJS, Stevens BJ, McGrath PJ, editors.Pain in neonates and infants. 3rd ed. New York: Elsevier;2007. p. xiv. [329 p].

16. Dickens BM, Cook RJ. Ethical and legal approaches to thefetal patient. Int J Gynaecol Obstet. 2003;83:85-91.

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