Understanding Fetal Pain A Congressional Staff Briefing June 22, 2004

1. Understanding Fetal PainA Congressional Staff BriefingJune 22, 2004 Jean Wright MD MBA Professor & Chairman of Pediatrics Mercer School of Medicine

2. Understanding Fetal Pain • History of the scientific knowledge • The historical context for regarding fetal pain. • The premature infants demonstrates fetal development • Why isn’t maternal anesthesia enough?

3. History of Scientific Knowledge

4. Fetal Pain - Not a new science • More than 20 years of data • In the early 70's, many pre-term infants were considered too ill to tolerate the effects of anesthesia in order to undergo their needed surgery. • Even by the early 80's, pre-term infants still received minimal anesthesia in the operating room and NICU. The medical community did not think the fetus and the premature infant could feel pain. • Anand in 1987 reported on premature infants that were operated upon without anesthesia. He measured ‘fight and flight’ hormones during and after surgery and clearly demonstrated that these infants not only felt pain, but had an intense response. • He further showed that the untreated pain led to a poorer outcome in these infants.

5. 1987 Turning Point • It wasn't until two landmark articles published in 1987 (Anand and Green, Lancet,1987, and Anand and Hickey NEJM, 1987, with an accompanying editorial by Fletcher) that the practice of pediatric anesthesia began to change broadly. • Fletcher, in that Editorial, comments that "unless a neonatologist had made a concerted effort to study the topic of pain, a subject that has not until now been in the forefront of concern in neonatal care, he or she would not have had easy access to more of the information in the Anand study" • She highlights that among the 201 references, only 20 occurred in medical journals that might have been part of a neonatologist's regular reading.

6. International News • News spread from the scientific community to the lay press and even to discussions in Parliament. • Anand moved to Harvard and he and Hinchey continued the work. This information quickly entered the U.S. Scientific literature in New England Journal of Medicine and other scholarly publications.

7. Practice of Pediatric Anesthesia • The practice of pediatric anesthesia changed. • Care and attention to premature infants included the administration of IV anesthetics, particularly narcotics (Pain relieving substances). • It soon became unacceptable to operate on premature infants without meeting their pain and stress needs.

8. Understanding Fetal Pain • History of the scientific knowledge • The historical context for regarding fetal pain • The premature infants demonstrates fetal development • Why isn’t maternal anesthesia enough?

9. Historical context for regarding Fetal Pain

10. Review of fetal development First Trimester Second Trimester Third Trimester Conception Birth 28 Weeks

11. Review of fetal development Fetal Viability 28 weeks in 1973 First Trimester Second Trimester Third Trimester Conception Birth 28 Weeks

12. Legal Protection of Abortion First Trimester Second Trimester Third Trimester Protected by Roe V. Wade Conception Birth 28 Weeks

13. Legal Protection of Abortion Extended First Trimester Second Trimester Third Trimester Protected by Doe V. Bolton Protected by Roe V. Wade Conception Birth 28 Weeks

14. If 2004 definition of viability was used First Trimester Second Trimester Third Trimester Protected by Doe V. Bolton Protected by Roe V. Wade Conception Birth 23 -4 Weeks

15. Late Term Abortions First Trimester Second Trimester Third Trimester Late Term Abortions Protected by Doe V. Bolton Protected by Roe V. Wade Conception Birth 23 -4 Weeks

16. Current viability challenges even 2nd Trimester abortions First Trimester Second Trimester Third Trimester 2nd Term Abortions Late Term Abortions Protected by Doe V. Bolton Protected by Roe V. Wade Conception Birth 23 -4 Weeks

17. Understanding Fetal Pain • History of the scientific knowledge • The historical context for regarding fetal pain • The premature infants demonstrates fetal development • Why isn’t maternal anesthesia enough?

18. The premature infant demonstrates fetal development

19. The neonatal intensive care view • Premature infants led the way into understanding how the unborn fetus feels pain. • Infants born prematurely have the same anatomy and physiology as their unborn counterparts. • By studying the premature infant outside the womb allowed us to understand what was happening inside the womb. Same gestational age – one inside & one outside the womb

20. The premature infant as teacher of fetal medicine • The premature infants demonstrates fetal development. • The capacity of the fetus to experience pain • Anatomy & Physiology of pain • Increased sensitivity to pain • Fetal consciousness

21. What is Pain? “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. The inability to communicate verbally does not negate the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment.*” *The International Association for the Study of Pain

22. Non-verbal markers of Pain • The human fetus is incapable of verbal expression, therefore other markers of pain must be used. • Anatomical • Functional • Physiologic • Behavioral • These markers correlate with the same markers in children and adults.

23. Anatomic Development 3 • Pain is transmitted from the skin or surface tissues down electrical pathways to the spinal cord. • They connect in the spinal cord and go to the brain. • The brain receives the signals and then sends electrical impulses to other organs for their response. • (Motion, vital signs, hormones). 2 1

24. Starting at the skin • Specialized nerve endings feel pain. • These are seen at 7 weeks around the mouth and face, and cover the entire body by 20 weeks. • They are more densely configured per square inch than on an adult. 7 week fetus Pain Nerve Ending

25. Carrying the signal • Until the nerve fibers are mature and coated with myelin, the pain signals are carried by fibers that will later carry touch. • Neurons in the spinal cord (Dorsal horn neurons) develop before 13 weeks, and grow more complex throughout fetal life. 8 and 13 weeks Nerve fibers penetrate skin

26. Modulating pain response • Over time, we learn to modulate our pain response. The brain sends inhibitory signals to the body to lessen our reactions. • In the fetus, the ability to modulate (or inhibit pain) does not develop until 36 - 40 weeks gestation. • Therefore, pain in the fetus and premature infant is unmodulated or unfiltered until the baby is almost full term in gestation.

27. Brain development • Nerve cells in the brain during the first trimester demonstrate organization, differentiation, elaborate branching, and the presence of neurotransmitters. • The nerve cells develop elaborate axons and dendrites. At the end of the nerves proteins are released when pain is signaled. • These are the same biochemical markers present in adults. • These markers imply a functional role early in development. Axon w/ neurotransmitters

28. Neurotransmitters measured at 19 - 21 weeks • Neurotransmitters bind with specific receptors in a lock and key fashion. • Opioid receptor labeling in the brain stem demonstrate very high densities in supraspinal centers associated with sensory perception. • The neuro-endocrine mechanisms to regulate the pain however, are present, but the fetus’ ability to limit or modulate pain is underdeveloped.

29. Cerebral Cortex • The cerebral cortex begins to form at 8 - 10 week. • A subplate is formed by 15 weeks, and penetrated by fibers from below by 16 weeks. • This development completes the final anatomical links needed for pain transmission to reach the brain. • From 12 - 28 weeks, the number of cortical neurons will increase 10 fold. Feet of 11 week old

30. How do we know it isn’t just a reflex? • Confusion between Knee Jerk Reflex and other reflexes. • Cutaneous Flexor Reflex – often used in pain literature…. • The study of this reflex has been used to establish when connection between the skin and the spinal cord are first made in the fetus. • They have been used to study the maturation of ascending motor pathways. • This reflex has been shown in man to parallel pain perception exactly in terms of threshold, peak intensity, and sensitivity to analgesics. • Has a lower threshold in pre-term neonates than in term neonates or adults Knee Jerk Reflex

31. Physiologic Responses • Medical studies of living fetuses demonstrate the ability to generate ‘fight or flight’ hormones in response to painful stimuli as early as 16 weeks. • Catecholamines, B-endorphins, Cortisol • When the needle is placed in the umbilical vein, (which has no pain fibers); no consistent responses occurred. • When a needle is placed through the liver to give the fetus a transfusion, these hormones are released. The abdominal wall has pain fibers. • And the liver aspiration produced changes proportional to the stimulus.

32. Response to pain relief • The hormonal responses were reduced when fentanyl • a pain relieving opiate • was administered directly to the fetus. Umbilical vein placement 16 week fetus Transabdominal and liver placement

33. Other confirming studies • Blood flow is redistributed in response to painful stimuli. • When invasive procedures are done on fetuses, studies have revealed that blood flow to the brain was decreased within 70 seconds after a painful stimulation in fetus @ 16 weeks gestation • Fetal blood sampling • Body Cavity aspirations • Fetal amniotic shunts • This implies that if the pain signal had not reached the Thalamus in the brain, this redistribution of blood flow would not occur.

34. Increase Sensitivity To Pain • In addition the pain fibers on their face and skin is more per square inch in the 20 - 30th week of gestation. • The skin is very thin, leaving the pain fibers closer to the surface. • When hormonal levels are measured in fetuses, they are 3 - 5 x the level found in full term infants and children. • This is because they lack the inhibitory fibers. Translucent skin photo or 30 - 32 week fetus

35. Fetal Consciousness

36. Fetal Consciousness • Three decades of research demonstrate that preterm infants and fetuses are perceiving, learning, and working to regulate themselves, their environment and their experiences. • Preterm infants favor experiences that are developmentally supportive and actively avoid experiences that are developmentally disruptive.

37. British Commission of Inquiry into Fetal Sentience Consciousness is associated with shifting brain patterns that even in adults is not well understood. We may never have unequivocal evidence for fetal consciousness, since we cannot achieve that for adults. “Fetuses may be conscious from six weeks of gestation.”

38. Increased brain maturity is measurable over time 24 weeks From 20 weeks, fetuses respond to light, sound, taste and touch, with increasingly complex movements. If cortical activity is used to measure consciousness, then the EEG (electroencephalogram) demonstrates that at 19 - 20 weeks of gestation. Somatosensory Evoked Potentials (SEPs) can be recorded from 24 weeks. Fetuses can acquire distinct verbal memories from prenatal experiences (studies in the 3rd trimester) which continues to support that consciousness develops before delivery.

39. Maternal Anesthesia

40. Why isn’t maternal anesthesia enough? • Many obstetrical procedures are done with regional anesthesia (Spinal, epidural and local anesthestics). • These agents do not provide anesthesia for the fetus. • Intravenous anesthetics have to get into the mother’s blood, avoid metabolism by the mother’s liver, cross into the placenta, and reach the fetal circulation in significant amounts to cross into the fetus’ brain. • To reach the infant, a higher maternal dose would have to be given, than is clinically indicated for the mother.

41. Fetal Surgery Implications • Advances into fetal surgery have called for new advances into fetal anesthesia and fetal monitoring.

42. Development of the Late Term Fetus First Trimester Second Trimester Third Trimester Protected by Doe V. Bolton Protected by Roe V. Wade Conception Birth 28 Weeks

43. Time frame for perceiving pain impacts all 3 trimesters First Trimester Second Trimester Third Trimester First Term Abortions 2nd Term Abortions Late Term Abortions Protected by Doe V. Bolton Protected by Roe V. Wade Conception Birth 23 -4 Weeks

44. Timeframe for pain perception during surgical and abortive procedures. First Trimester Second Trimester Third Trimester First Term Abortions 2nd Term Abortions Late Term Abortions Protected by Doe V. Bolton Protected by Roe V. Wade Conception Birth 23 -4 Weeks

45. Summary • Markers of fetal pain perception start at the 7th week and mature over the next 12 weeks. • By week 20, the anatomy of the nervous system and the physiology of responding to the pain impulse draws a clear cause and effect relationship. • Fetal responses are more than reflexes and infer consciousness. • Fetal pain is more intense than that of term infants, and cannot be modulated or inhibited as in term infants. • Maternal anesthesia alone is not enough.

46. References • International Association for the Study of Pain; IASP Pain Terminology. A sample list of frequently used terms from: Classification of Chronic Pain, Second Edition, IASP Task Force on Taxonomy, edited by H. Merskey and N. Bogduk, IASP Press, Seattle, 1994, pp. 209-214. (Website: http://www.iasp-pain.org/terms-p.html) • Anand KJS, Hickey PR. Pain and its effects in the human neonate and fetus. New England Journal of Medicine (1987) 317:1321-1329. • Ward-Platt M, Anand KJS, Aynsley-Green A. Ontogeny of the stress response to surgery in the human fetus, neonate and child. Intensive Care Medicine (1989) 15:844-945. • Anand KJS, Craig KD. New perspectives on the definition of pain. Pain (1996) 67: 3-6. • Anand KJS, Rovnaghi C, Walden M, Churchill J. Consciousness, behavior, and clinical impact of the definition of pain. Pain Forum (1999) 8: 64-73. • Anand KJS, Maze M. Fentanyl, fetuses, and the stress response: signals from the beginnings of pain? Anesthesiology 2001; 95 (4): 823-825. • Bhutta AT, Anand KJS. Vulnerability of the developing brain: neuronal mechanisms. Clinics in Perinatology 2002; 29 (3): 357-372. • Anand KJS, Taylor B. Consciousness and the fetus. American Academy of Pediatrics: Bioethics Newsletter, Jan. 1999, pp.2-3. • Coskun V, Anand KJS. Development of supraspinal pain processing. In: Anand KJS, Stevens BJ, McGrath PJ, editors. Pain in Neonates. Vol. 10. Amsterdam: Elsevier Biomedical Publishers, 2000, pp. 23-54. • Modi N, Glover V. Fetal Pain and Stress. Chapter 11 in: Anand KJS, Stevens BJ, McGrath PJ (editors). Pain in Neonates, 2nd Edition, Elsevier Science Publishers, Amsterdam, 2000, pp. 217-228. • Hepper PG, Shahidullah S. The beginnings of mind--evidence from the behavior of the fetus. J Rep Infant Pscyhol 1994; 12:143-54. • Molliver ME, Kostovic I, Loos Hvd. The development of synapses in cerebral cortex of the human fetus. Brain Research 1973; 50:403-7. • Smith RP, Gitau R, Glover V, Fisk NM. Pain and stress in the human fetus. European Journal of Obstetrics, Gynecology, & Reproductive Biology 2000; 92:161-5. • Partsch CJ, Sippell WG, MacKenzie IZ, Aynsley-Green A. The steroid hormonal milieu of the undisturbed human fetus and mother at 16-20 weeks gestation. Journal of Clinical Endocrinology & Metabolism 1991; 73:969-74. • Teixeira JM, Glover V, Fisk NM. Acute cerebral redistribution in response to invasive procedures in the human fetus. American Journal of Obstetrics & Gynecology 1999; 181:1018-25. • Fitzgerald M. Spontaneous and evoked activity of fetal primary afferents in vivo. Nature 1987; 326:603-5. • Kinney HC, Ottoson CK, White WF. Three-dimensional distribution of 3H-naloxone binding to opiate receptors in the human fetal and infant brainstem. Journal of Comparative Neurology 1990; 291:55-78. • Teixeira J, Fogliani R, Giannakoulopoulos X, Glover V, Fisk NM. Fetal haemodynamic stress response to invasive procedures. Lancet 1996; 347:624. • Kopecky EA, Ryan ML, Barrett JF, et al. Fetal response to maternally administered morphine. American Journal of Obstetrics & Gynecology 2000; 183:424-30. • Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma cortisol and beta-endorphin response to intrauterine needling. Lancet 1994; 344:77-81. • Gitau R, Fisk NM, Teixeira JM, Cameron A, Glover V. Fetal hypothalamic-pituitary-adrenal stress responses to invasive procedures are independent of maternal responses. Journal of Clinical Endocrinology & Metabolism 2001; 86:104-9. • Vanhatalo S, van Nieuwenhuizen O. Fetal pain? Brain & Development 2000; 22:145-50. • Fisk NM, Gitau R, Teixeira JM, Giannakoulopoulos X, Cameron AD, Glover VA. Effect of direct fetal opioid analgesia on fetal hormonal and haemodynamic stress response to intrauterine needling. Anesthesiology 2001; 95:828-835. • Saunders PJ. Do fetuses feel pain? We should give them the benefit of the doubt. British Medical Journal 1997; 314:303. • Giannakoulopoulos X, Teixeira J, Fisk N, Glover V. Human fetal and maternal noradrenaline responses to invasive procedures. Pediatric Research 1999; 45:494-9. • Goldman-Rakic PS. Development of cortical circuitry and cognitive function. Child Development 1987; 58:601-22. • Craig AD. A new view of Pain as a Homeostatic Emotion. Trends in Neurosciences 2003; 26 (6): 303-307.