Context Proposed federal legislation would require physicians to inform women
seeking abortions at 20 or more weeks after fertilization that the fetus feels
pain and to offer anesthesia administered directly to the fetus. This article
examines whether a fetus feels pain and if so, whether safe and effective
techniques exist for providing direct fetal anesthesia or analgesia in the
context of therapeutic procedures or abortion.
Evidence Acquisition Systematic search of PubMed for English-language articles focusing on
human studies related to fetal pain, anesthesia, and analgesia. Included articles
studied fetuses of less than 30 weeks’ gestational age or specifically
addressed fetal pain perception or nociception. Articles were reviewed for
additional references. The search was performed without date limitations and
was current as of June 6, 2005.
Evidence Synthesis Pain perception requires conscious recognition or awareness of a noxious
stimulus. Neither withdrawal reflexes nor hormonal stress responses to invasive
procedures prove the existence of fetal pain, because they can be elicited
by nonpainful stimuli and occur without conscious cortical processing. Fetal
awareness of noxious stimuli requires functional thalamocortical connections.
Thalamocortical fibers begin appearing between 23 to 30 weeks’ gestational
age, while electroencephalography suggests the capacity for functional pain
perception in preterm neonates probably does not exist before 29 or 30 weeks.
For fetal surgery, women may receive general anesthesia and/or analgesics
intended for placental transfer, and parenteral opioids may be administered
to the fetus under direct or sonographic visualization. In these circumstances,
administration of anesthesia and analgesia serves purposes unrelated to reduction
of fetal pain, including inhibition of fetal movement, prevention of fetal
hormonal stress responses, and induction of uterine atony.
Conclusions Evidence regarding the capacity for fetal pain is limited but indicates
that fetal perception of pain is unlikely before the third trimester. Little
or no evidence addresses the effectiveness of direct fetal anesthetic or analgesic
techniques. Similarly, limited or no data exist on the safety of such techniques
for pregnant women in the context of abortion. Anesthetic techniques currently
used during fetal surgery are not directly applicable to abortion procedures.
Over the last several years, many states, including California, Kentucky,
Minnesota, Montana, New York, Oregon, and Virginia, have considered legislation
requiring physicians to inform women seeking abortions that the fetus feels
pain and to offer fetal anesthesia. This year, Arkansas and Georgia enacted
such statutes.1,2 Currently, Congress
is considering legislation requiring physicians to inform women seeking abortions
20 or more weeks after fertilization (ie, 22 weeks’ gestational age)
that the fetus has “physical structures necessary to experience pain,”
as evidenced by “draw[ing] away from surgical instruments.” The
physician must also offer anesthesia or analgesia “administered directly”
to the fetus. Physicians who do not comply may be subject to substantial fines,
license revocation, and civil suits for punitive damages.3
Although this legislation would not affect most US abortions because
only 1.4% are performed at or after 21 weeks’ gestational age,4 this legislation raises important scientific, clinical,
ethical, and policy issues. When does a fetus have the functional capacity
to feel pain? If that capacity exists, what forms of anesthesia or analgesia
are safe and effective for treating fetal pain? As a first step in answering
these questions, we reviewed the literature on fetal pain and fetal anesthesia
and analgesia.
English-language articles involving human participants were searched
using PubMed for (1) fetal pain (16 articles), fetal anesthesia (6 articles), and fetal
analgesia (3 articles); (2) fetus and (anesthesia or analgesia) (1239 articles); (3) Medical Subject
Headings (MeSH) analgesics/administration and dosage and fetus (44 articles); (4) MeSH anesthesia/administration
and dosage and fetus (0 articles); (5) (neurodevelopment or development or anatomy) and (fetus or fetal) and (pain or nociception
or noxious) (306 articles); (6) (thalamocortical
or thalamus or cortex) and (fetus or fetal)
and (pain or nociception or noxious) (13 articles);
(7) (electroencephalog*orEEGorevoked
potential) and (fetusorfetalorpremature neonateorpremature
infantorpreterm neonateorpreterm infant)
and (painornociceptionornoxiousorconscious*) (7 articles); (8) fetal and pain and (response or assessment or facial expression) (112 articles); and (9) facial expression and (fetus or fetal) or ([neonate or neonatal or infant] and [premature or preterm]) and
(pain or nociception or noxious) (360 articles).
The search was performed without date limitations and was current as of June
6, 2005. From these search results, we excluded articles that did not study
fetuses of less than 30 weeks’ gestational age or that did not specifically
address fetal pain perception or nociception. With a focus on topics addressed
by earlier review articles on fetal pain, anesthesia, and analgesia, articles
were reviewed for additional references.
Quiz Ref IDPain is a subjective sensory and emotional experience
that requires the presence of consciousness to permit recognition of a stimulus
as unpleasant.5-7 Although
pain is commonly associated with physical noxious stimuli, such as when one
suffers a wound, pain is fundamentally a psychological construct that may
exist even in the absence of physical stimuli, as seen in phantom limb pain.5,7 The psychological nature
of pain also distinguishes it from nociception, which involves physical activation
of nociceptive pathways without the subjective emotional experience of pain.5,8 For example, nociception without pain
exists below the level of a spinal cord lesion, where reflex withdrawal from
a noxious stimulus occurs without conscious perception of pain (Figure, A).5
Because pain is a psychological construct with emotional content, the
experience of pain is modulated by changing emotional input and may need to
be learned through life experience.7,9,10 Regardless
of whether the emotional content of pain is acquired, the psychological nature
of pain presupposes the presence of functional thalamocortical circuitry required
for conscious perception, as discussed below.
Neuroanatomy and Development.Quiz Ref IDNociception may be characterized by reflex movement in response to a noxious
stimulus, without cortical involvement or conscious pain perception. Nociception
involves peripheral sensory receptors whose afferent fibers synapse in the
spinal cord on interneurons, which synapse on motor neurons that also reside
in the spinal cord. These motor neurons trigger muscle contraction, causing
limb flexion away from a stimulus (Figure,
A).11
In contrast, pain perception requires cortical recognition of the stimulus
as unpleasant. Peripheral sensory receptor afferents synapse on spinal cord
neurons, the axons of which project to the thalamus, which sends afferents
to the cerebral cortex (Figure, B),11 activating any number of cortical regions.12 Sensory receptors and spinal cord synapses required
for nociception develop earlier than the thalamocortical pathways required
for conscious perception of pain (Table).
No human studies have directly examined the development of thalamocortical
circuits associated with pain perception. The developmental age at which thalamic
pain fibers reach the cortex has been inferred from studies of other thalamocortical
circuits, which may or may not develop at the same time as thalamic fibers
mediating cortical perception of pain.
These histological neurodevelopment studies typically describe fetal
maturity in terms of developmental age, representing the number of weeks postovulation
or postfertilization. Clinicians regularly use gestational age, representing
weeks from the first day of the woman’s last menstrual period. When
referring to a fetus at the same point in development, the gestational age
is approximately 2 weeks greater than the developmental age.
A histological study of the visual pathway in 8 human fetuses, each
at a different developmental age, concluded that thalamic projections reach
the visual cortex at 21 to 25 weeks’ developmental age (approximately
23-27 weeks’ gestational age), based on results from a fetus of 24 weeks’
developmental age (26 weeks’ gestational age).18 A
similar 7-fetus study found thalamic afferents reached the auditory cortical
plate at 24 to 26 weeks’ developmental age, with 1 specimen showing
initial cortical plate penetration at 22 weeks’ developmental age (24
weeks’ gestational age).24
In a study of 8 human fetuses, mediodorsal thalamic afferents were first
observed in the cortical plate at 22 weeks’ developmental age (24 weeks’
gestational age).19 While connections between
mediodorsal afferents and the anterior cingulate cortex25 may
be relevant to pain perception,12,26 this
study examined mediodorsal afferents to unspecified regions of the frontal
cortex,19 which serves numerous functions unrelated
to pain perception.19,27
Another histological study of 12 specimens found that afferents from
unspecified thalamic regions reached the developing prefrontal cortex in 1
preterm neonate of 27 weeks’ developmental age, concluding that thalamic
fibers begin entering the cortex between 26 and 28 weeks’ developmental
age (28 and 30 weeks’ gestational age).28 A
different study found that thalamic afferents had not reached the somatosensory
cortical plate by 22 weeks’ developmental age (24 weeks’ gestational
age). By 24 weeks’ developmental age (26 weeks’ gestational age),
the density of cortical plate synapses increased, although these were not
necessarily from thalamic afferents.16 Based
on these studies, direct thalamocortical fibers that are not specific for
pain begin to emerge between 21 and 28 weeks’ developmental age (23
and 30 weeks’ gestational age).
However, others have proposed that thalamocortical connections could
also be established indirectly if thalamic afferents were to synapse on subplate
neurons, which could synapse on cortical plate neurons.29 The
subplate is a transient fetal structure 1 layer deep to the cortical plate
and serves as a “waiting compartment” for various afferents, including
thalamic afferents, en route to the cortical plate.16,29,30 The
subplate recedes after 30 weeks’ developmental age,16,29 while
the cortical plate matures into the 6 layers of the cerebral cortex.28 In contrast to direct thalamocortical fibers, which
are not visible until almost the third trimester, thalamic afferents begin
to reach the somatosensory subplate at 18 weeks’ developmental age (20
weeks’ gestational age)16 and the visual
subplate at 20 to 22 weeks’ gestational age.17 These
afferents appear morphologically mature enough to synapse with subplate neurons,31 although no human study has shown that functional
synapses exist between thalamic afferents and subplate neurons. Subplate neurons
may synapse with cortical plate neurons and direct the growth of thalamic
afferents to their final synaptic targets in the cortical plate.29 Despite
this developmental role, no human study has shown that synapses between subplate
and cortical plate neurons convey information about pain perception from the
thalamus to the developing cortex.
Electroencephalography. The histological presence
of thalamocortical fibers is insufficient to establish capacity for pain perception.
These anatomical structures must also be functional. Although no electroencephalographic
“pain pattern” exists, electroencephalography may be one way of
assessing general cortical function because electroencephalograms (EEGs) measure
summated synaptic potentials from cortical neurons. However, EEG activity
alone does not prove functionality, because neonates with anencephaly who
lack functional neural tissue above the brainstem may still have EEG activity.32
Normal EEG patterns have been characterized for neonates as young as
24 weeks’ postconceptional age (PCA) (ie, the gestational age plus number
of weeks postpartum).22 Electroencephalographic
activity is normally asynchronous between the hemispheres and mostly discontinuous
at less than 27 weeks’ PCA,23,33,34 becoming
mostly continuous around 34 weeks’ PCA.23,34 Interhemispheric
synchrony increases around 29 to 30 weeks’ PCA, then declines, then
increases again, reaching almost complete synchrony by term.22,33 Given
these baseline differences between neonatal and adult EEGs, patterns associated
with impaired consciousness in adults33,35 are
inapplicable to the analysis of neonatal EEGs.
Quiz Ref IDSome investigators contend that EEG patterns denoting
wakefulness indicate when consciousness is first possible.5,36 Wakefulness
is a state of arousal mediated by the brainstem and thalamus in communication
with the cortex.5,22 In preterm
neonates, the earliest EEG pattern representing wakefulness appears around
30 weeks’ PCA.22,23 However,
wakefulness alone is insufficient to establish consciousness, as unconscious
patients in a persistent vegetative state may also have wakeful EEGs.5,36
Somatosensory evoked potentials (SEPs) may also provide evidence of
pain processing in the somatosensory cortex, although they are not used clinically
to test pain pathways. SEPs test the dorsal column tract of the spinal cord,
which transmits visceral pain sensation to the somatosensory cortex via the
thalamus.12 SEPs with distinct and constant
N1 components of normal peak latency are present at 29 weeks’ PCA, indicating
that thalamic connections with the somatosensory cortex are functional at
that time.20,21
Behavioral Studies. Although widely used to
assess pain in neonates, withdrawal reflexes and facial movements do not necessarily
represent conscious perception of pain. Full-term neonates exhibit a “cutaneous
withdrawal reflex” that is activated at a threshold much lower than
that which would produce discomfort in a child or adult.37 This
threshold increases with PCA, suggesting that the capacity of the neonate
to distinguish between noxious and nonnoxious stimuli is maturing.37 Furthermore, flexion withdrawal from tactile stimuli
is a noncortical spinal reflex exhibited by infants with anencephaly38 and by individuals in a persistent vegetative state39 who lack cortical function.
Behavioral studies have also identified a distinct set of neonatal facial
movements present during invasive procedures such as heel lancing but absent
during noninvasive procedures.40-46 These
facial movements, which are similar to those of adults experiencing pain,47,48 were evident in neonates at 28 to
30 weeks’ PCA but not at 25 to 27 weeks’ PCA.40 Facial
movements may not necessarily be cortically controlled.49 One
study found no difference in facial activity during heel lancing of neonates
with and without significant cortical injury, suggesting that facial activity
even around 32 weeks’ PCA may not represent conscious perception of
pain.50
Stress Responses. Hemodynamic and neuroendocrine
changes in fetuses undergoing stressful procedures have also been used to
infer pain perception.51 As early as 16 weeks’
gestational age, fetal cerebral blood flow increases during venipuncture and
transfusions that access the fetal hepatic vein through the innervated fetal
abdominal wall but not during venipuncture and transfusions involving the
noninnervated umbilical cord.52 Increased cerebral
blood flow is not necessarily indicative of pain, as this response is thought
to constitute a “brain sparing” mechanism associated with hypoxia53 and intrauterine growth restriction.54
Other investigators measured increases in fetal plasma concentrations
of cortisol, β-endorphin, and noradrenaline associated with intrauterine
needling procedures, finding that increases during blood sampling from the
hepatic vein were greater than those during sampling from the umbilical cord.55,56 However, these neuroendocrine responses
do not constitute evidence of fetal pain, because the autonomic nervous system
and hypothalamic-pituitary-adrenal axis mediate them without conscious cortical
processing.57 Additionally, these responses
are not specific for painful stimuli. Plasma noradrenaline concentrations
may increase after umbilical cord transfusion,56 and
plasma β-endorphin concentrations may increase after repeated cordocenteses.58 Plasma cortisol and β-endorphin concentrations
increase during innocuous activities such as exercise.59 Moreover,
in adults, neuroendocrine stress responses may persist despite well-controlled
postoperative pain.60
Quiz Ref IDVital signs also have been used to assess neonatal
pain.42,43,45,51,61 However,
heart rate, respiratory rate, and transcutaneous oxygen and carbon dioxide
levels do not necessarily differ significantly between alcohol-swabbing and
lancing the heels of preterm neonates.40 Another
group found that a similar proportion of neonates became hypoxic during tracheal
suction, as well as during nonnoxious routine care such as washing and weighing.62
Fetal Anesthesia and Analgesia
Anesthetics and analgesics are commonly used to alleviate pain and discomfort.
Despite ongoing debate regarding fetal capacity for pain, fetal anesthesia
and analgesia are still warranted for surgical procedures undertaken to promote
fetal health. When long-term fetal well-being is a central consideration,
evidence of fetal pain is unnecessary to justify fetal anesthesia and analgesia
because they serve other purposes unrelated to pain reduction, including (1)
inhibiting fetal movement during a procedure63-65;
(2) achieving uterine atony to improve surgical access to the fetus and to
prevent contractions and placental separation66-70;
(3) preventing hormonal stress responses associated with poor surgical outcomes
in neonates71,72; and (4) preventing
possible adverse effects on long-term neurodevelopment and behavioral responses
to pain.73-75
These objectives are not applicable to abortions. Instead, beneficence
toward the fetus represents the chief justification for using fetal anesthesia
or analgesia during abortion—to relieve suffering if fetal pain exists.
As with any clinical decision, thorough safety and risk-benefit analyses should
be undertaken before performing an intervention. Because the principle of
beneficence also requires the woman’s physician to act in her best interests,
potential fetal benefit must be weighed against real risks to the woman’s
health. The safety and effectiveness of proposed fetal anesthesia and analgesia
techniques are discussed below.
General Anesthesia for Fetal Surgery. Fetal
surgery involving laparotomy, hysterotomy, or both requires general or regional
anesthesia.68,76 Regional anesthesia,
such as epidural anesthesia, does not anesthetize the fetus.76 General
anesthesia is more commonly used because it induces uterine atony and fetal
immobilization.65,77 Studies of
inhalational agents in pregnant ewes determined that a dose capable of anesthetizing
the ewe also anesthetized the fetus.78 Administering
fentanyl, pancuronium, or vecuronium to the fetus intramuscularly may supplement
analgesia or immobilization.64,65,77,79
Quiz Ref IDFor pregnant women, general anesthesia is associated
with increased morbidity and mortality, particularly because of airway-related
complications80-82 and
increased risk of hemorrhage from uterine atony.70 Historically,
general anesthesia was used in abortions, even in the first trimester, until
studies found that general anesthesia was a leading cause of abortion-related
mortality.83-85 In
addition to safety concerns, general anesthesia increases the cost of abortion,
making it prohibitively expensive for the majority of patients who pay out
of pocket.86
Anesthesia and Analgesia in Minimally Invasive Fetal
Procedures. In contrast to fetal surgery requiring regional or general
anesthesia, minimally invasive fetal procedures do not involve maternal laparotomy
or hysterotomy and instead use needles or endoscopy to access the fetus. For
the sake of reducing pain, the increased risks of general anesthesia are unjustified
for these procedures; adults typically undergo similar procedures with no
analgesia or only local analgesia.67 No established
fetal analgesia protocol exists for these procedures, although 3 techniques
have been proposed, namely, direct delivery of medications to the fetus, delivery
of medications to the fetus via maternal intravenous infusion, and intra-amniotic
delivery of medications.
Direct Delivery. One group has examined the
effects of analgesics delivered directly to human fetuses during minimally
invasive procedures.87 Twenty-eight fetuses
that received intravenous fentanyl before hepatic vein blood transfusions
had diminished changes in plasma β-endorphin concentration and cerebral
blood flow, compared with fetuses not receiving fentanyl. The cortisol response
was not significantly decreased with fentanyl. The investigators did not examine
risks for the woman, such as infection or uncontrolled bleeding.76 Furthermore,
reducing the stress response is distinct from reducing pain. For example,
plasma glucose and cortisol concentrations may not differ significantly between
adults with and without postoperative pain.60
Delivery via Maternal Intravenous Infusion. To
achieve presumably effective fetal plasma concentrations of fentanyl by placental
transfer, potentially unsafe doses would need to be administered to the woman.88 Although standard doses of fentanyl are generally
safe for maternal analgesia during labor,89 fentanyl
can pose serious risks such as hypoventilation if maternal doses are significantly
increased to achieve more extensive placental transfer.67,68 Severe
maternal hypoventilation may require endotracheal intubation, which increases
risks and costs for the woman, as described above.
No data exist on the dosing or efficacy of using medications such as
diazepam and morphine for fetal analgesia via maternal intravenous infusion,
although studies have characterized the placental transfer of these medications.90-92 Two related studies
found that low-dose remifentanil via maternal intravenous infusion achieved
fetal immobilization during laser coagulation of placental vessels.93,94 However, immobilization is not the
equivalent of pain reduction, and these procedures did not involve surgery
on the fetus.
Intra-amniotic Delivery. Intra-amniotic injection
would be technically simpler than direct fetal injection, although the drug
must be absorbed through fetal membranes and skin. Intra-amniotic sufentanil
injection in 10 pregnant ewes resulted in fetal plasma concentrations that
would control postoperative pain in human adults.95,96 Sufentanil
concentrations in the ewes also reached adult human therapeutic concentrations
without causing significant hemodynamic changes.96 However,
the study did not evaluate fetal response to noxious stimuli, and no data
exist regarding safety or effectiveness in humans.
Pain is an emotional and psychological experience that requires conscious
recognition of a noxious stimulus. Consequently, the capacity for conscious
perception of pain can arise only after thalamocortical pathways begin to
function, which may occur in the third trimester around 29 to 30 weeks’
gestational age, based on the limited data available. Small-scale histological
studies of human fetuses have found that thalamocortical fibers begin to form
between 23 and 30 weeks’ gestational age, but these studies did not
specifically examine thalamocortical pathways active in pain perception.
While the presence of thalamocortical fibers is necessary for pain perception,
their mere presence is insufficient—this pathway must also be functional.
It has been proposed that transient, functional thalamocortical circuits may
form via subplate neurons around midgestation, but no human study has demonstrated
this early functionality. Instead, constant SEPs appear at 29 weeks’
PCA, and EEG patterns denoting wakefulness appear around 30 weeks’ PCA.
Both of these tests of cortical function suggest that conscious perception
of pain does not begin before the third trimester. Cutaneous withdrawal reflexes
and hormonal stress responses present earlier in development are not explicit
or sufficient evidence of pain perception because they are not specific to
noxious stimuli and are not cortically mediated.
A variety of anesthetic and analgesic techniques have been used for
fetal surgery, including maternal general anesthesia, regional anesthesia,
and administration of medications for placental transfer to the fetus. However,
these techniques are not necessarily applicable to abortions. Surgical procedures
undertaken for fetal benefit use anesthesia to achieve objectives unrelated
to pain control, such as uterine relaxation, fetal immobilization, and possible
prevention of neuroendocrine stress responses associated with poor surgical
outcomes. Thus, fetal anesthesia may be medically indicated for fetal surgery
regardless of whether fetal pain exists.
In the context of abortion, fetal analgesia would be used solely for
beneficence toward the fetus, assuming fetal pain exists. This interest must
be considered in concert with maternal safety and fetal effectiveness of any
proposed anesthetic or analgesic technique. For instance, general anesthesia
increases abortion morbidity and mortality for women and substantially increases
the cost of abortion. Although placental transfer of many opioids and sedative-hypnotics
has been determined, the maternal dose required for fetal analgesia is unknown,
as is the safety for women at such doses. Furthermore, no established protocols
exist for administering anesthesia or analgesia directly to the fetus for
minimally invasive fetal procedures or abortions. Experimental techniques,
such as administration of fentanyl directly to the fetus and intra-amniotic
injection of sufentanil in pregnant ewes, have not been shown to decrease
fetal pain and are of unknown safety in humans.
Because pain perception probably does not function before the third
trimester, discussions of fetal pain for abortions performed before the end
of the second trimester should be noncompulsory. Fetal anesthesia or analgesia
should not be recommended or routinely offered for abortion because current
experimental techniques provide unknown fetal benefit and may increase risks
for the woman. Instead, further research should focus on when pain-related
thalamocortical pathways become functional in humans. If the fetus can feel
pain, additional research may lead to effective fetal anesthesia or analgesia
techniques that are also safe for women.
Corresponding Author: Mark A. Rosen, MD,
Department of Anesthesia and Perioperative Care, University of California,
San Francisco, 513 Parnassus Ave, San Francisco, CA 94143-0648 (rosenm@anesthesia.ucsf.edu).
Financial Disclosures: None reported.
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