1. Pain Prior to Birth
Robin Pierucci, MD, MA

2. Parents instinctively know, babies feel pain

3. Painful Definition Problem?
Is the problem a name game?
Definition game of what is required for having “pain”
Baby
Premie
Fetus

4. Both doctors and lawyers have a history of being confused
1. Doctors until the 1990’s performed surgery on babies without anesthesia
2. Lawyers have previously passed and continue to support laws allowing procedures that adults would consider painful to be performed on babies
Both doctors and lawyers have a history of being confused

5. Outline: Fetal Pain Evolution of Neonatal Pain Management
From:
“Babies don’t feel pain”
To:
Medical standard
Defining Pain
The Anatomy of Pain
Fetal vs Premature Physiology
A view from the bedside

6. Looking Back to Move Forward:
The evolution of Pain Management in Neonates

7. Current Standard of Care for Babies:
Pain management “particularly in preterm infants is important not only because it is ethical,
but also because exposure to repeated painful stimuli early in life is known to have short and long term adverse sequalae”.
“Prevention and Management of Procedural Pain in the Neonate: An Update”
COMMITTEE ON FETUS AND NEWBORN and SECTION ON ANESTHESIOLOGY AND PAIN MEDICINE. 2016, Pediatrics
This is an update in 2016.
So what did we believe before? And what drove the change?

8. How do we know this? “The sequalae include: Physiologic instability,
Altered brain development,
Abnormal neurodevelopment, somatosensory and stress response systems,
Which can persist into childhood.”
Committee on Fetus and Newborn 2016, Pediatrics
AAP 2016 update continued
Remember—this is the update and we live in a world that doesn’t consistently believe this. So what drove the changes in the literal standard of medical care for neonatologists and anesthesiologist who directly and intentionally treat neonatal pain?

9. Anesthesia—sort of
400 BC: Assyrians use carotid compression to produce brief unconsciousness before circumcision or cataract surgery.
History of Anesthesia - Interactive Timeline m.org/history-of-anesthesia/

10. Modern Era of Anesthesia
Early to mid 1800’s, introduction of ether and chloroform
1846: Ether introduced at Mass General, Boston.
Early reports justifiably alarming
“Complications included:
sudden cardiac death
incomplete anesthesia,
madness,
death, and a variety of medical problems“
Meyer, 2015, J of Anesth
Meyer, R, Desai, SP, “Accepting Pain Over Comfort: Resistance to the Use of Anesthesia in the Mid-19th Century,” Journal of Anesthesia History, 1 (2015) 116.

11. Early Anesthesia Dosing: more art than science
“By reason of immature cardiovascular and respiratory systems, neonates were assumed to be too sensitive to the depressant effects of anesthetics”
Kuratani 2015 , J Anesth
Risk benefit for neonatal anesthesia in all honestly wasn’t good.
But folks really convinced themselves that babies didn’t feel pain
And it stayed that away for another approximately years

12. A Century of Pediatric Medical Advances
Significantly increase in # of pediatric issues surgically addressed
Longer OR times under anesthesia
Yet, early 1990’s babies still operated on without anesthesia
“Whiskey nipple”: widely used as a sedative supplement to local anesthesia in infants undergoing abdominal procedures

13. “Pain and its Effects in the Human Neonate and Fetus” Anand, Phil, & Hickey (1987) NEJM
The focus on pain perception & confusion over its differentiation from nociceptive activity
have obscured the mounting evidence that nociception is important in the biology of the neonate
“This is true regardless of any philosophical view on consciousness and pain perception in newborns”

14. Documented Ramifications to Causing Neonatal Pain:
Neurophysiological measurable effects:
Behavioral
Neurochemical,
Cardiac,
Hormonal,
and Metabolic changes
Anand, 1987 NEJM
1987, Anand

15. Prospective: Lighter vs Deep Intraoperative Anesthesia
Anand, 1992
Deep Anesthesia: high doses of Sufentanil & post-op opiates x 24 hours (n=30 infants)
Lighter Anesthesia: Halthane and MS followed by postop intermittent morphine and diazepam (n=15)
Blood work was done before during and after sugery

16. Results:
Statistically significant differences in the measurable levels of stress hormones
“beta-endorphin, norepinephrine, epinephrine, glucagon, aldosterone, cortisol and other steroid hormones”
Decreased post-operative complications and improved survival for those who received deep anesthesia
Today here is no IRB on the planet that would allow this study to be repeated. Treating neonatal pain is the standard of care

17. So, why is there a debate?
Problem: how should pain be defined?

18. Defining “Pain”

19. What Defines Pain in Humans?
Physical
Emotional
Psychologic
Spiritual
Defining pain is a little like trying to hold onto quick sand or hearding cats—its very individual and changes!
Not only do humans have physical pain receptors, pain can leave an echo or a footprint in our memory, that can cause us to modify our behavior—both immediately and in the future.

20. International Association for the Study of Pain (IASP)
Definition of pain:
“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”

21. By definition pain is: Unpleasant Physical aspect Emotional aspect
The experience consists of
actual or
potential tissue damage
Pain is our reaction to an assault on our person
It can be both: with physical issues being emotional or and emotional pain manifesting with physical symptoms

22. Can a human have physical pain without an emotional response
Can a human have physical pain without an emotional response? (Pain without conscious awareness?)

23. Arguments:
Due to in-utero neuroinhibitors, the fetus is never awake or aware, and thus, unable to ”truly experience pain”
Mellor 2005, Brain Research Reviews
“If a conceptual subjectivity is considered necessary for pain, then pain is not possible at any gestational age”
Derbyshire 2010, Best Practice & Research Clinical Ob/Gyne

24. Tabor’s Medical Dictionary
Pain includes not only the perception of an uncomfortable stimulus
but also the response to that perception
BUT OUR RESPONSE IS VARIABLE…
Perception can be deceiving: ex: any athlete in the midst of an intense competition—hey your bleeding, I am?
Therefore, perception is situational! Lots of things affect how we perceive an injury

25. Pain Perception, Depends…
(even when awake)

26. The Science: Why Pain Perception Is Situational
Influenced by:
physical, mental,
biochemical,
physiologic, psychologic, social, cultural, and emotional factors
Tabor’s Cyclopedic Medical Dictionary
Result:
Same insult in two different settings could be perceived as either agonizing or a bump
Thus: perception (even if conscious) is an unreliable indicator of “tissue damage”,
Tabor’s cyclopedic medical dictionary
Influence: so in the same person a particular insult may cause a large amount of pain in one setting and minimal in a different setting.

27. Example: Comatose Patient
We never would intentionally burn the patient
And claim there’s no pain because they can’t complain
We hold their hands. We speak to them
The staff goes out of their way to protect them, worrying about inadvertently hurting someone who can’t tell us with their voice that they are uncomfortable

28. The IASP Definition Modification:
“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.”
IASP definition correctly identifies that pain and emotion are linked
BUT: a lack of emotion does not negate nociception
—the sensation of pain that results from one’s body being harmed.

29. While debate continues, it seems unreasonable to err on the side of denying pain relief to the vulnerable
And “confusion has obscured the mounting evidence that nociception is important in the biology of the neonate”
Anand 1987, NEJM
Now, I will propose a different definition, but let me first show you the science that it needs to be based on.

30. Anatomical Requirements
for Pain Perception

31. Pain Receptors
Pain sensation (noxious stimulation) is initially received via receptors located in the skin.
Timing of human fetal rcptr appearance:
7th -8th wk: perioral area
~11th wk: rest of the face, palms of the hand, & soles of the feet
~15th wk: trunk, proximal parts of arms and legs
Lowery, 2007, Seminars in Perinatology
Anand: pain and its effects
Lowery

32. Spinal Sensory Reflex
Noxious stim (via rcptr) activates peripheral sensory n.
Sensory n. synapses within spinal cord with motor n
Motor n signals muscle contraction and limb withdrawal
Specialized free sensory nerve endings then transmit the noxious stimulation from the receptors in the skin to the spinal cord
Within the spinal cord there is an intraneuron that takes the impulse from the doral horn to the ventral horn, where the returning motor nerve is stimulated…

33. Fetal Response to Noxious Stimulation
This reflex (meaning: occurs without cortical/conscious awareness), protectively moves one’s body away from harm
Observed as early as 8 weeks
“at this stage, touching the perioral region will result in movement away” Derbyshire 2010  
Emotionally linked pain is processed in anatomically and physiologically different areas Lowery, et al 2007

34. Emotionally Linked/Conscious Pain
In adults:
Noxious stim of peripheral sensory n. to spinal cord synapse
With spinothalamic n. that run the message up the spinal column to the thalamus
In the thalamus, additional connections with n., bring news of the painful stimulus out to the cerebral cortex
Result: conscious perception of pain Lowery et al, 2007
The complete connection from the peripheral to central nervous system (specifically the cerebral cortex) is thought to be complete around weeks gestation.

35. Arguments:
Due to timing of CNS connections occurring in the mid 2nd trimester, this is when some believe is the earliest possible point of pain perception
Others think even this is too early
Due to chemicals within the uterus that keep the fetus in a sleep like state and claim that the fetus is never actually “awake” until after birth. Mellor, et al, 2005

36. The Fetus is Not Asleep:
“Based on behavioral reactions to noxious stimulation” documented at 26 weeks
“Neurotransmitters related to regulation of arousal are present at the 12th week of gestation”
Serotonin (10th wk)
Catecholamines (11th wk)
Acetylcholiniesterase (12th wk)
Sekulic 2016, J of Pain Res
As a mother who has had 3 different fetuses use her bladder as a trampoline, they are not asleep.
The neurotransmitter’s presence provides the maturing brain with the capacity for arousal

37. Hypothalamic-Pituitary-Adrenal Axis (HPA)
In adults: noxious stress activates the HPA, the link to pain’s emotional component.
Lowery et al, 2007
 B endorphin, a stress hormone known to be made from stimulation of the HPA, has been found in the fetus
Giannakoulopoulos in 1994 and Gitau in 2001

38. Fetal Stress Responses to Invasive Procedures Gitau et al 2005, pg104
Comparison of fetal and maternal levels of stress homrones (cortisol & B endorphin) pre & post transfusion via
piercing the fetal chest to access the intrahaptic vein (IHV) vs
transfusion via needling placental cord insertion (PCI)
Fetal levels of cortisol IHV vs PCI
ditto b-endorphin levels
Maternal levels did not do this.

39. Results: Gitau et al, 2000
Fetal response were independent of the mother’s which did not change during transfusion at either site
“Fetal B-endorphin responses: apparent from 18 wks GA & independent of GA,
Whereas fetal cortisol responses: apparent at 20 wks & were GA dependent”
Findings: “Consistent with the maturation of the fetal pituitary before the fetal adrenal [gland]”
This is huge! Because…

40. The Fetal Brain Responds to Noxious Stim!
Findings of neurotransmitters & increased stress hormones levels after painful stim mean that:
Babies in the fetal stage are neurologically active
Even without the peripheral nerves being directly connected to the cerebral cortex
Adults pain perception is cortex linked event.
Not necessarily so with the babies…
This is actually consistent with additional findings

41. Anencephaly & Hydranencephaly
Sekulic’s 2016 review:
With minimal or absent cortex, these little ones:
React to noxious stimulus
Can be soothed with comfort measures
Express wake/sleep cycles
Sekulic 2016, pg1033
HR changes, facial expression changes—both of being comforted as well as upset

42. Medical Task Force on Anencephaly:
Found that “Anesthetic agents may eliminate the subcortical responses to noxious stimuli…”
“but are not necessary to minimize or prevent suffering.” NEJM, 1990
Their literature review was written back when many babies were still being taken to surgery without anesthesia.
Based on their lit review

43. They May Feel MORE Pain than Term Babies
There is an inhibitory arm of the nociceptive pathway that does not mature until after birth.
The lack of this part of the developing nervous system
“suggests that the fetus is more sensitive to nociception than infants and may explain why newborns show exaggerated behavioral reaction to sensory provocation” Sekulic et al, 2016 pg 1035
This finding also may contribute to the increased sensitivity seen long term

44. 32 wk old premature babies (~4 weeks old)
Study: Experience in NICU Affects Pain Response Johnston & Stevens 1996
32 wk newborns vs
32 wk old premature babies (~4 weeks old)
HR in the older babies statistically higher than the newborns

45. Response to Heelstick Premies in the NICU x4 weeks vs newborns
Decreased oxygen saturations in response to heel pricks.
Johnston CC, Stevens, B,
Pain affects babies who are premature

46. Neuroprotection
Today, NICU’s are relooking at all of the ways extremely premature babies are touched.
New studies: neuroprotection includes not only minimizing obvious pain, but also tending to “a healing environment, partnering with families, positioning and handling, safeguarding sleep, protecting skin, and optimizing nutrition Morris et al, 2015

47. Current Practice/Performance Improvement in the NICU:
Neonatologists are not asking if premature babies can feel pain,
Rather, the focus is on how to better address the entire NICU environment & experience to improve neuroprotection.

48. Fetal vs Premie Physiology
As a neonatologist, most of what I do is care for babies who are born at varying stages of prematurity. Currently, the edge of viability is roughly 22 to 24 weeks gestation, and/or around 500 grams. This begs the question, what differentiates a baby who is a fetus from a baby who is premature?
Is there a difference?

49. Fetus
Definition:
The in utero period of development from from 8 weeks gestation
as defined by the Merriam-Webster Dictionary

50. Embryo
Definition:
The developing human from 3 to 8 weeks after conception
Embryonic Period
Transformation of single cells to different organ systems
Moore and Presaud’s embryology textbook explains that during the fetal period, there is “differentiation and growth of the tissues and organs formed during the [earlier] embryonic period”. Before We Are Born, Essentials of Embryology and Birth Defects, 4th Edition. (Philadelphia, 1993). Pg 6

51. At different times, we look different
Picture your grandparents…wonder what grandma looked like at conception?

52. Human Development
The point is that every single human being progresses through these prenatal phases, just as postnatally every human usually progresses through infancy, toddlerhood, adolescence, and adulthood.

53. 24 Weeks Gestation
If a person is born during the fetal developmental period of the pregnancy, they are no longer called a fetus despite still having a considerable amount of fetal physiology. Birth does not change the fact that baby we call a premie, is still in the fetal period of development. The job of the neonatal intensive care unit (NICU) team is to help the baby born prematurely to safely outgrow his or her degree of fetal physiology so that he or she can survive outside of the womb.

54. There’s no “light-switch” moment
“there is no scientific evidence that function in the multi-layered networks underlying pain perception waits for some cue to be “turned-on”.
Lowery, 2007
A newborn premature baby’s physiology does not flip on or off like a light switch as he or she moves from one side of the uterine wall to the other.
With regards specifically to the immature nervous system and pain perception, the same analogy holds true, “there is no scientific evidence that function in the multi-layered networks underlying pain perception waits for some cue to be “turned-on”. Lowery, pg 278.

55. 3-Dimensional Imaging
“an adult-like pattern of skin innervation is established before the end of the first trimester “
Belle, Godefroy, Couly, Tridimensional Visualization & Analysis of Early Human Development, Cell 2017
However, based on the lab research and clinical evidence reviewed in 2016, “it can be concluded that an early form of pain may appear from the 15th week of gestation onward.” Sekulic pg 1036.
Based on new 3-dimensional imaging published in a 2017, it could even be earlier, since they surprisingly found “an adult-like pattern of skin innervation is established before the end of the first trimester.” Belle M, Godefroy D, Couly G, et al, “Tridimensional Visualization and Analysis of Early Human Development,” Cell, 169 (2017) 161–173.

56. Adjusted Pain Defintion
Pain is the sensation of noxious stimuli which can be linked with an immediate emotional response or instigate a future “procedural memory” that leads to an altered behavioral pattern
As a neonatologist with a privileged place at the bedside, I am both awed by the depth of existing research and humbled by what we still have to discover. Therefore, as a scientifically informed witness to the clinical reactions of my patients, I submit that the what defines pain is
Van De Velde pg 206

57. Summary
Whether a baby is term or maturing through their fetal physiology, there is enough information to always assume noxious stimulation can be deleterious to their present and future health.
Babies feel pain

58. Conclusion
Research informed changes to the medical standard of care for the treatment of neonatal pain is currently inconsistent with what is still legally permissible.
Good medicine is politically blind.
Ditto for the defense of truth. Good law is also politically blind
Excellent medical care is independent of the ebb and flow of election results, good medicine is politically blind. The same is true for the defense of truth; good laws are politically blind too.

59. Conclusion
Given the accumulating truths that have driven the changes in neonatal pain treatment,
this is an invitation for the law to be informed by the same truths that inform today’s medical standard of care.