Fetal pain and analgesia

1. Current Obstetrics & Gynaecology (2000) 10, 214 ^217
2000 Harcourt Publishers Ltd
c
doi:10.1054/cuog.2000.0140, available online at http://www.idealibrary.com on
OPERATIVE TECHNIQUES
Fetal pain and analgesia
K. M. K. Ismail, M.Wilson and M. D. Kilby
Department of Fetal Medicine, Division of Reproductive and Child Health and Department of Anaesthetics, Birmingham Women’s Hospital,
Edgbaston, Birmingham B15 2TG, UK
KEYWORDS Summary The most signi¢cant advance in obstetrics over the past two decades is
fetal pain, fetal awareness, the ability of healthcare professionals to consider the fetus as a separate individual and
fetal analgesia, fetus a potential patient in its own right.The advent of ultrasound made this conceptually pos-
sible and also allowed sonographers to visualize fetal behaviour. With the increasing
number of invasive diagnostic and therapeutic antenatal procedures, the possibility of
fetal awareness to iatrogenic and potentially noxious stimuli has been ethically impor-
tant. This issue urged the Royal College of Obstetricians and Gynaecologists (RCOG)
to set up a Working Party which comprised scientists in neuroanatomy and physiology
, ,
as well as, materno-fetal medicine specialists, anaesthetists and ethicists to review the
available evidence on this subject.
2000 Harcourt Publishers Ltd
c
THE PAIN PATHWA IN THE FETUS
Y enroute to the cortex.4 Thalamic di¡erentiation begins at
6 ^ 8 weeks’ gestation adjacent to the third ventricle.The
The de¢nition of pain proposed by the International As- marked increase in its synaptic contacts, however, only
sociation for the Study of Pain is not adapted to the new- occurs between 15 and 20 weeks of gestation. These do
born or to the fetus because it assumes recognition and not begin to acquire the temporospatial pattern and
verbal expression of an unpleasant experience. structure seen in the mature individual until 20 ^21
For an individual to perceive pain there must be intact weeks’ gestation.7 The spatiotemporal relationship of
sensory innervation, sensory connections in the spinal thalamocortical connection is of crucial importance
cord via the dorsal roots, intact ascending sensory for perception. These connections are ¢rst observed
tracts in the spinal cord and matured thalamic function penetrating the frontal cortical plate at 26 ^34 weeks’
within the central nervous system (CNS). For sensory gestation (Fig. 1).8 Studies of fetal and neonatal electro-
impulses to reach the level of ‘fetal awareness’, it is encephalographic patterns as a method of assessment of
assumed that thalamocortical connections must be functional maturity of the cerebral cortex show inter-
anatomically and functionally intact. mittent electroencephalographic bursts in both cerebral
Although there is evidence that sensory receptors and hemispheres as early as 20 weeks of gestation.These be-
their innervation are present early in the ¢rst trimester,1 come sustained at 22 weeks, and bilaterally synchronous
it is not until 20 weeks’ gestation that these spread to all at 26 ^27 weeks.9
cutaneous and mucous surfaces.2 It is reported, how- Although the neuroanatomical structure is necessary
ever, that these are relatively ‘deep’ receptors until 28 for the conscious appreciation of pain to occur, it is sim-
weeks’ gestation.3 For the sensory information to reach plistic to assume a temporal relationship. The sensation
the spinal cord, a¡erent neurones need to grow into the of pain is likely to be dependent on the functional matur-
dorsal root columns of the spinal cord.4 Electron micro- ity of the CNS rather than structural integrity alone.
scopy and immunocytochemical neuroanatomical meth-
ods show that the development of various types of
a¡erent neurones in the dorsal horn initiates at 13^14 IS ITAPPROPRIATE TOSA THAT THE
Y
weeks of gestation.5 The small diameter C ¢bres respon-
sible for transmitting ‘noxious’ information to the spinal
FETUS IS FEELING PAIN?
cord, however, have not developed by19 weeks’gestation There is no doubt that the fetus ‘reacts’ to intrauterine
(Fig.1).6 diagnostic and therapeutic procedures involving contact
The thalamus is believed to be the major subcortical with its body.These reactions include re£ex body move-
nucleus through which all painful stimuli are transmitted ments, metabolic and hormonal responses.10 Is the
fetus, however, feeling pain or just sensing a stimulus
Correspondence to: MDK.Tel: +44 (0) 121627 2778; E-mail: which is initiating a stress response? An adult person
m.d.kilby@bham.ac.uk under general anaesthetic can show re£ex movements

2. FETAL PAIN AND ANALGESIA 215
Figure 1 Development of the fetal pain pathway
to nociceptive stimuli because he/she can sense the sti- FETAL ANALGESIA
mulus but not necessarily feel it.
‘Stress response’ is a term used to describe responses The current situation is analogous to the ¢eld of neonatal
of an organism to stimuli which signify threat. The term analgesia prior to seminal work in neonates undergo-
does not imply su¡ering, pain or awareness of these ing cardiac surgery conducted by Anand, Sippell and
happenings.4 Though far from resolved, it is widely ac- Aynsley-Green.20 In a controlled trial, they compared the
knowledged that pain is a multidimensional experience hormone stress response in infants randomized to
incorporating sensory, emotional and cognitive factors.11 receive fentanyl (10 mcg/kg), a potent synthetic opioid,
The fetal brain can organize and elaborate stimulus for- or placebo in addition to their routine anaesthetic agents.
mation, encoding in memory the activation of innate re- They demonstrated that not only was the stress response
£ex responses.There, however, is no evidence that these signi¢cantly greater in the non-fentanyl group, but these
‘memories’ are or become conscious.11 A simple physical infants su¡ered a higher incidence of cardiovascular and
reaction to stimuli can be produced at a spinothalamic metabolic complications. This work resulted in a signi¢-
level.This, however, is not in itself indicative of cognitive cant change in anaesthetic attitudes and practice. Analge-
awareness or pain which needs processing by higher sia is now routinely given to neonates, even those born
centres. prematurely, undergoing minor operative procedures.
Awareness is unlikely to occur before the development Evidence for a similar stress response in the fetus in
of the thalamocortical connections which commence at utero was provided by the work of Giannakoupoulos,
26 weeks’ gestation.4,12 That is why The RCOG Working Teixeira and colleagues.21 They compared fetal and ma-
Party recommended that practitioners who undertake ternal plasma noradrenaline responses to invasive fetal
diagnostic or therapeutic surgical procedures upon the venous blood sampling via the placental cord insertion
fetus at or after 21weeks’ gestation (which takes account (not innervated with nociceptor ¢bres) or the intrahepa-
of the uncertainty that attends estimates of gestational tic vein. Fetal noradrenaline levels were signi¢cantly ele-
age) consider the requirements of fetal analgesia and se- vated in blood samples obtained from the intrahepatic
dation.4 They also recommended that practitioners who needling group, whilst maternal levels were similar for
undertake termination of pregnancy at 21 weeks or later both groups.
should consider the requirements for feticide or fetal an- It is possible that we are on the threshold of a similar
algesia and sedation.4 Such an approach is indispensable, change in attitude to the fetus. If nothing else these
not only from the humane point of view, but also because ¢ndings suggest that we proceed with caution.
it may have bene¢cial e¡ects for the fetus.13
Whether the fetus is feeling pain or not, the noxious WHEN SHOULD ANALGESIA FOR
stimulus initiates a stress reaction. Analgesic and anaes-
thetic agents can attenuate these responses. There is
THE FETUS BE CONSIDERED?
growing evidence that early exposure to noxious stimuli Practices with a potential requirement for fetal pain re-
can have an adverse e¡ect on future neural develop- lief represent an emotive spectrum:
ment.14 ^19 Should we then consider fetal analgesia before
. Intrauterine fetal therapy
24 weeks’ gestation and do these agents alter the
sub-sequent development and normal physiological or Therapeutic intrauterine procedures undertaken to
behavioural responsiveness? reduce fetal mortality or morbidity (insertion of fetal

3. 216 CURRENT OBSTETRICS & GYNAECOLOGY
‘pigtail’ shunts and intrauterine transfusions) carry with stronger and we should not abandon it in application to
them the potential for noxious sensation, especially contemporious events.
when they are performed in the third trimester at gesta-
tional ages comparable to preterm infants. The most in-
vasive of these include open intrauterine procedures Local anaesthetics
such as myelomeningocoele repair. Diagnostic proce- Local anaesthetics work by the blockade of sodium chan-
dures only present a potential problem if the fetus itself nels to produce a reversible conduction de¢cit of sen-
undergoes instrumentation (i.e. pleurocentesis). Cannu- sory, autonomic and somatic motor impulses in central
lation of the placenta or umbilical cord does not carry and peripheral nerve pathways.
similar potential for fetal nociception. Traditional classi¢cation of local anaesthetic techni-
. Termination ques into in¢ltration, peripheral nerve and regional
(spinal/epidural) blockade seems less useful in an intrau-
The requirement for fetal analgesia during termination terine population! It is di⁄cult to conceive of a situation
of pregnancy is more controversial. Late termination (at in which regional analgesia of the fetus would be desir-
20 weeks’ gestation or beyond) represents only a very able or how it might be attempted. Local anaesthesia
small fraction of those performed. Nonetheless, the pro- by in¢ltration to a tissue surface may be possible, how-
vision of analgesia for the process presents us with ever the potential for systemic toxicity in the fetus,
unique moral and philosophical dilemmas. Many are per- even when used in very low dose will almost inevitably
formed under maternal general anaesthetic, allowing preclude its use.
transplacental passage to the fetus of these drugs. With
late termination (22 weeks), however, maternal/fetal
Systemic analgesia
sedation and analgesia (usually with benzodiazepines
and opiates) is necessary. Systemic analgesia is usually classi¢ed as opioid or non-
opioid. In addition to the modality of analgesia, however,
. Delivery we must also consider its route of administration.
Perhaps the most controversial area of all is the ex-
perience of the fetus during labour and delivery itself. THE FETAL-MATERNALUNIT
The argument that childbirth is a physiological process
and that analgesia for the fetus is therefore unnecessary (TRANSPLACENTAL)
must be examined objectively. Humanitarian concerns Administration of drugs to mother in order to achieve a
are overriding, and if we have evidence of the fetus ex- therapeutic e¡ect in the fetus is problematic. The most
periencing pain then analgesia should be considered. It common drugs administered via this route are the
would be logical to extend this to assisted vaginal deliv- halogenated hydrocarbon volatile anaesthetic agents
eries, but this is rarely even contemplated. used to maintain general anaesthesia. These cross the
Few would advocate analgesia for the child in sponta- placenta in e¡ective doses to provide anaesthesia to the
neous vaginal delivery.There is good evidence that stress fetus. They do not, however, provide any analgesia, and
response to normal delivery and the concomitant rise in general anaesthesia during pregnancy carries with it sig-
fetal serum catecholamine levels aid respiratory adapta- ni¢cant risks. Intravenous administration of short-acting
tion and resorption of pulmonary amniotic £uid after opioids, such as fentanyl, to the mother is disappointing,
birth.22 This response may be exaggerated in instrumen- since it results in sub-therapeutic fetal serum concentra-
tal vaginal delivery and associated with umbilical cord gas tions.26 Increasing maternal doses carry with them a
changes comparable with hypoxia and fetal distress.23 worsening side-e¡ect pro¢le. The current gold standard
There is already evidence to support that perinatal trau- of practice in open surgical procedures is to provide ma-
matic events might be related to adult self-destructive ternal regional epidural analgesia with local anaesthetic
behaviour.24,25 Analgesia before or immediately after de- agents in addition to general anaesthesia.27 Maternal
livery, in this context, may have a useful role. The e¡ect opioid infusions are often utilized to enhance tocolysis.
of invasive diagnostic procedures during delivery, such as These measures are primarily to prevent preterm labour
fetal blood sampling and applying fetal scalp electrodes, and do not provide fetal analgesia.
is less well characterized.
NON-OPIOID ANALGESIA
APPROACHES TO FETAL PAIN RELIEF Nonsteroidal anti-in£ammatory drugs (NSAIDs) are the
Ethical debate aside, the pragmatic considerations of prototypical non-opioid agents and are widely pre-
how e¡ective analgesia could be delivered to the fetus is scribed for the relief of acute pain. NSAIDs exert their
at best speculative. The relief of acute pain comprises a analgesic e¡ect by irreversible inhibition of acetylate cy-
careful process of risk-bene¢t analysis, balancing the hu- clo-oxygenase (prostaglandin synthetase) resulting in a
manitarian concerns of the removal of su¡ering with the decrease in the synthesis and elaboration of cellular pros-
risk of side-e¡ects from the given analgesic modality. The taglandins. Inhibition of cyclo-oxygenase decreases the
central philosophy of ‘Primum non nocere’ is nowhere formation of prostacyclin, a potent vasodilator and

4. FETAL PAIN AND ANALGESIA 217
inhibitor of platelet aggregation. These activities are 2. Valman H B, Pearson J F. What the fetus feels. BMJ 1980; 280: 233^
exploited in neonatal paediatrics in the treatment of pa- 234.
tent ductus arteriosus, which can be successfully obliter- 3. Payne J, Middleton J, Fitzgerald M. The pattern and timing of cuta-
neous hair follicle innervation in the rat pup and human fetus. Brain
ated with indomethacin therapy. The same e¡ects may Res1991; 173^182.
preclude the use of NSAID agents in large doses in an 4. Royal College of Obstetricians and Gynaecologists. Fetal aware-
intra-uterine population, where PDA closure could be ness report of a working party. London: RCOG,1997 .
disastrous. 5. Rizvi T, Wadhwa S, Bijlani V. Development of spinal substrate for
nociception. Pain[Suppl] 1987; 4: 195.
6. Konstantinidou A D, Silos-Santiago I, Flaris N, Snider W D. Devel-
opment of the primary a¡erent projection in human spinal cord. J
OPIOIDS Comp Neurol 1995; 354: 1 1^12.
Opioids act as agonists at stereospeci¢c opioid recep- 7 Khan A A, Wadhwa S, Bijlani V. Development of lateral geniculate
.
nucleus: an electron microscopic study. Int J Dev Neurosci 1994;
tors present at presynaptic and postsynaptic sites in the
12: 661^ 672.
central and peripheral nervous system. Activation of 8. Klimach V J, Cooke R W. Maturation of somatosensory evoked re-
opioid receptors inhibits the presynaptic release of exci- sponse in preterm infants. Developmental Medicine Child Neu-
tatory neurotransmitters from nociceptive nerve term- rology1988; 30: 208 ^214.
inals. 9. Spehlmann R. In: EEG primer. New Y ork: Elsevier/North-Holland.
1981: 159^165.
The opioids are capable of producing profound analge-
10. Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk N M.
sia, even after the most severe operative insult and are Fetal plasma cortisol and beta-endorphin response to intrauterine
the most promising agents in the context of fetal surgery. needling. Lancet1994; 344: 77^ 81.
Major side-e¡ects of opioid therapy include sedation and 11. Leventhal H. Aperceptual-motor theory of emotion. Adv Exp Psy-
respiratory depression. The fetus is relatively protected chol 1984; 17: 117^175.
12. Fitzgerald M, for the Department of Health. Foetal pain: an update
from the hazardous sequelae of these side-e¡ects, since
of current scienti¢c knowledge. London: DoH,1995.
it relies on the placenta for an oxygenated blood supply 13. Mahieu-Caputo D, Dommergues M, Muuller F, Dumez Y Presse .
independent of intrinsic respiratory drive. Fentanyl, a Med 2000; 29: 663^ 669.
phenopiperidine derivative 75^125 times as potent as 14. Grunau RV E,Whit¢eld M F, Petrie J H, Fryer E L. Early pain experi-
morphine, is the only opioid used to date to speci¢cally ence, child and family factors, as precursors of somatization: a pro-
spective study of extremely premature and full term children. Pain
provide pain relief to the fetus undergoing open sur-
1994; 56: 353^359.
gery.27 In the cases cited, fentanyl was administered by 15. Grunau RV E,Whit¢eld MF, Petrie J H. Pain sensitivity and tempera-
intravenous or intramuscular injection, after exposure ment in extremely low birth weight premature toddlers and pre-
of the fetus in along with pancuronium, a nondepolariz- term and full term controls. Pain 1994; 58: 341^346.
ing neuromuscular blocker to provide paralysis. Whilst 16. Hack M B. School age outcomes in children with birth weights un-
der 750 g. N Engl J Med 1994; 331: 753^759.
fetal intravenous injection, in closed surgery, is possible
17 Taddio A, Goldbach M, Ipp M, Stevens B, Koren G. E¡ect of neonatal
.
with the advances in needle and fetoscopic technology, circumcision on pain responses during vaccination in boys. Lancet
which have driven progress in the ¢eld, there are no cur- 1994; 344: 291^292.
rent reports of its routine use. It must be stressed that at 18. Stevenson J, Aynsley-Green A.The long-term behavioural sequelae
this stage there is no objective evidence for the e⁄cacy of surgery studied in young twins. Proc Br Psychol Soc 1995; 3: 59.
19. Whit¢eld MF,Grunau R E. Behavior, pain perception, and the extre-
of fetal opioid analgesia. Traditional mechanisms for the
mely low birth weight survivor. Clin Perinatol 2000; 27: 363^379.
investigation of pain relief, including visual analogue 20. Anand K J S, Sippell W G, Aynsley-Green A. Randomised Trial of
scores and behavioural indices, are not applicable. Pre- fentanyl anaesthesia in preterm babies undergoing surgery: e¡ects
cisely the same problems of interpretation of the on the stress response. Lancet 1987; 1: 243^248.
response to noxious stimuli confound the search for 21. Giannakoulopoulos X, Tiexeira J, Fisk N, Glover V. Human fetal and
maternal noradrenaline responses to invasive procedures. Ped Res
signs of therapeutic e¡ect.
1999; 45: 494 ^ 499.
22. Walters D V, Walters R E. The role of catecholamines in lung liquid
absorption at birth. Ped Res 1978; 12: 239.
CONCLUSIONS 23. Gulmezoglu A M, Mahomed K, Hofmeyr G J, NikodemV C, Kramer
T Fetal and maternal catecholamine levels at delivery. J Perinat
.
Whilst the debate over the potential for the fetus to feel
Med1996; 24: 687^ 691.
pain continues, humanitarian duty suggests that we 24. Jacobson B, Eklund G, Hamberger L, Linnarson D, Sedvall G,Valver-
carefully examine the implications of delivering e¡ective ius M. Perinatal origin of adult self-destructive behaviour. Acta Psy-
analgesia to the fetus whilst minimizing side-e¡ects in it- chiatr Scand1987; 76: 364 ^371.
self and the mother. The immense challenge of providing 25. Jacobson B, Bygdeman M. Obstetric care and proneness of the o¡-
spring to suicide as adults: case control study1998; 317: 1346 ^1349.
pain relief to this new patient population is matched only
26. Eisele J, We A. Newborn and maternal fentanyl levels at caesarean
by their vulnerability. section. Anesth Analg 1982; 61: 179^180.
27 Adzick N S, Harrison M R. Fetal surgical therapy. Lancet 1994; 343:
.
897^902.
REFERENCES
1. HumpheryT Function of nervous system in prenatal life. In: Stave U
.
(ed). Perinatal Physiology. New York: Plenum Press,1978: 651^ 683.