Childs Nerv Syst
DOI 10.1007/s00381-017-3437-7
FOCUS SESSION
Anesthesia for myelomeningocele surgery in fetus
Juan Carlos Devoto 1 & Juan Luis Alcalde 2 & Felipe Otayza 3 & Waldo Sepulveda 4
Received: 3 April 2017 / Accepted: 28 April 2017
# Springer-Verlag Berlin Heidelberg 2017
Abstract
Background Administering anesthesia for prenatal repair of
myelomeningocele reveals several issues that are unique to
this new form of treatment. This includes issues such as fetal
well-being, surgical conditions and monitoring, among others.
Exploring, analyzing, and understanding the different vari-
ables that are involved will help us reduce the high level of
risk associated with this surgery.
Objective This review provides a systematic approach to the
issues that are faced by anesthesiologists during fetal surgery.
Keywords Fetal anesthesia . Fetal surgery .
Myelomeningocele surgery . Congenital malformation
Introduction
The aptly named comparative study on the management of
m y e l o m e n i n g o c e l e BM O M S ^ ( M a n a g e m e n t o f
Myelomeningocele Study) was first published in the New
England Journal of Medicine in March 2011 [1]. The findings
of this study demonstrate the benefits of prenatal treatment
* Juan Carlos Devoto
juandevoto@clc.cl
1
Department of Anesthesiology, Fetal Surgery Program, Clínica las
Condes, Lo fontecilla 441 Las Condes, 7591046 Santiago, Chile
2
Department of Gynecology and Obstetrics, Fetal Surgery Program,
Clínica Las Condes, Santiago, Chile
3
Department of Neurosurgery, Fetal Surgery Program, Clínica Las
Condes, Santiago, Chile
4
FETALMED, Materno-fetal Diagnosis Center, Santiago, Chile
and push the boundaries of knowledge beyond the conven-
tional paradigms of medical therapy, opening the doors to a
new challenge for anesthesiologists: fetal surgery.
Much like Vandam’s [48] description of the anesthetic con-
siderations for renal transplantation from 1962, Adzick’s
study [1] heralds the start of a new era in anesthesiology de-
velopment. Indeed, the findings from his study will oblige us
to answer questions that have not been posed before and to
focus on areas of development that are required by this emerg-
ing technique.
The characteristics of myelomeningocele (MMC) are de-
scribed below, followed by an analysis of the main anesthetic
variables that should be taken into consideration:
& Fetal pain
& Anesthetic techniques
& Monitoring
& Uterine relaxation
& Fluid management
Description of the disease
Approximately 10% of children born with MMC die during
infancy. The average global mortality rate of people born with
this condition is 25% in the first 25 years of life, with an
average life expectancy of 30 years [11, 46].
Children with MMC require surgical closure of their lesion
within their first few days of life and often need a
ventriculoperitoneal shunt to avoid the complications associ-
ated with hydrocephalus. The lesion is most often located in
the lumbar and sacral regions (70%), but the seriousness of the
disease is related to the size of the anomaly and its location on
the spine: the more cephalic and larger the anomaly, the more

severe the disability. Furthermore, the functional level of the
neurological defect is higher than the anatomical level by one
or more spinal segments [33].
The disability that is caused by this congenital malforma-
tion (CM) involves a severe neurological deficit, compromis-
ing the body’s motor, sensory, and anal sphincter functions.
The extent of the damage depends on the size of the lesion,
though all children with MMC also present brain
malformations. Type II Arnold-Chiari malformation, almost
always associated with this CM, reveals itself in imaging as
a small posterior fossa and fourth ventricle. This is in addition
to the hindbrain herniation with downward displacement of
the medulla, cerebellum and fourth ventricle toward the fora-
men magnum. In most cases, this defect will later surface as
central hypoventilation, apnea, upper airway dysfunction, vo-
cal cord dysfunction or swallowing dysfunction, all of which
are the consequence of alterations to the affected cranial
nerves. In order to avoid the high level of mortality associated
with this complication, if these symptoms are present and put
the patient at risk then treatment of the Chiari malformation
itself is required. Children with a ventriculoperitoneal shunt
will need to be monitored throughout their whole life and will
often require surgery. Retarded intellectual development has
also been observed among these patients (with an average IQ
of 80), especially among patients who have required a shunt
[26].
Fetal surgery
Given the level of complexity involved, fetal surgery has al-
ways been a long process. The studies that are currently avail-
able have been carried out using a highly selected population
of students, where prenatal surgery for MMC offers the
greatest odds of providing any sort of benefit. Follow-up ul-
trasounds of fetuses with MMC during gestation have shown
that the damage to the central nervous system is progressive.
In this sense, there is a decrease in, or total paralysis of, lower-
limb mobility, as well as an increase in hydrocephaly and the
Arnold-Chiari malformation [21, 43]. A two-hit hypothesis
has therefore been put forward, in which the negative neuro-
logical result that is obtained is the consequence of a combi-
nation of two events: on the one hand, an alteration in the
embryologic formation of the neural tube in the initial stages
of development and, on the other hand, exposure of the neural
tissue to the intrauterine environment.
In addition to this, there have also been studies on animals
that reproduce these findings, where protecting the intrauter-
ine environment from injury allows the neurologic function to
be preserved [17, 24, 28]. These results, together with the
observations detailed previously, finally led to the suggestion
that prenatal repair of MMC may reduce neurologic disability.
Childs Nerv Syst
Reproducing these findings has not been a simple task. It
requires extensive study, preparation, patient selection, and
prenatal assessment, as well as a collective effort between
different specialties, where those involved must share their
knowledge in order to obtain the best possible result.
The first steps were taken by carrying out amniocentesis,
cordocentesis, and chorionic villi biopsies. The level of com-
plexity was then increased through procedures such as laser
ablation of placental vessels and embolization of congenital
cystic adenomatoid malformations of the lung [37, 38, 41].
Physicians also performed shunt insertions in low urinary tract
obstructions and laser ablation of a large acardiac twin [36, 39,
40].
The experience acquired through these procedures finally
culminated in us being able to carry out open fetal surgeries.
Anesthesia for fetal surgergy
Fetal pain
From the anesthetic perspective, fetal surgery poses several
questions that must be answered before being able to deter-
mine the most suitable anesthetic technique. Given its impor-
tance, the first question we must answer is at which stage in its
development a fetus is able to perceive pain. In this sense, we
understand the definition of pain as involve two systems: a
hormonal or neuroendocrine stress response and a negative
emotional perception.
Giannakoulopoulos’ findings reveal that a fetus is capable
of producing a hormonal response to stimuli that are consid-
ered painful, similar to the response in older children and
adults [15]. Furthermore, in his study of fetuses, Teixeira finds
that these painful stimuli also produce a hemodynamic re-
sponse, which is manifested as a decrease in the middle cere-
bral artery pulsatility index [45].
Considering the embryological development of the ner-
vous system, we can see that at 7 weeks the fetus has perioral
cutaneous sensory receptors. These extend to the rest of the
face, the palms of the hands, and the souls of the feet after
11 weeks; the torso, upper arms, and upper legs after 15 weeks,
while they cover the vast majority of the surface of the body
after 20 weeks [3]. The nociceptive sensory pathways reach
the dorsal horn of the spinal cord as early as 8 weeks into
gestation. The spinothalamic tracts are fully developed after
20 weeks and, finally, the thalamocortical tracts develop after
26 to 30 weeks [23].
Although the cerebral cortex is not fully developed by the
end of the pregnancy, it is widely acknowledged that other
areas of the brain, as well as the hypothalamus and the
subcortex, are already active by this point. Furthermore, we
also know that these areas develop through a stimulus-
dependent process of plasticity. We can therefore assume that
Childs Nerv Syst
a fetus can probably perceive pain at the time of surgery but
that this process does not involve the same structures as in an
adult.
Anesthetic technique and the fetus
This stimulus-dependent process of neuronal plasticity leads
us to another fundamental question: what anesthetic drugs can
we be certain of using during fetal development, a highly
vulnerable period given the critical processes of proliferation,
migration, differentiation, synaptogenesis, myelination, and
apoptosis? [32]. We know that neurological development in
animals is affected by administering general anesthetics, even
when administered for short periods of time [6]. Preclinical
studies in animal embryos have shown that exposure to inha-
lation agents and sedative medication causes apoptosis [8, 9],
as well as learning disabilities [29]. This issue has long been
debated and is still the cause of some controversy, as well as
being the topic of the editorial in several anesthesiology mag-
azines [10, 16, 22].
When choosing an anesthetic technique, another important
point to consider is the effect that the anesthetics may have on
the fetus’ cardiovascular system. In vitro studies have shown
that sevoflurane causes dose-dependent myocardial contractil-
ity depression [30]. The use of high concentrations of inhala-
tion agents in fetuses has been reported to lead to ventricular
dysfunction, as well as intraoperative valvular dysfunction
[35], an effect which can be lessened when supplemented with
intravenous anesthesia (propofol and remifentanil) [5].
Remifentanil is a short-acting potent opioid developed in
1993 with singular pharmaceutical characteristics that make it
easy to administer (fast onset and short duration of action).
When administered to pregnant women by continuous infu-
sion, intravenous agents such as these quickly pass through
the placenta. This is demonstrated by the umbilical vein/
maternal artery ratio (UV/MA) of 0.88 and the high level of
metabolism or distribution, reflected in the low umbilical
artery/umbilical vein ratio (UA/UV) of 0.29 [19].
Furthermore, at 26 weeks, the fetus already has a number of
non-specific blood esterases, thus allowing fast metabolism of
this potent analgesic [34]. Despite there being no studies re-
garding the pharmacokinetics of remifentanil in a fetus, the
above information suggests that it is a drug worth considering.
Fetal monitoring
Several methods of monitoring fetal well-being have been
used during surgery. These include continuous or intermittent
recording of the fetal heart rate, measuring the level of oxygen
in the blood, as well as measuring the flow in the fetal vessels
or uterine vessels. The purpose of such monitoring is to detect
any alteration to the fetal perfusion at an early stage and thus
detect any possible signs of fetal hypoxia. Therefore, the
pathophysiology of myocardial ischemia will probably help
us understand which methods are best for detecting such per-
fusions in good time. In this sense, alterations to the fetal heart
rate will clearly be among the final events in this ischemic
cascade. Nowadays, initial ischemic events, also referred to
as diastolic dysfunction or impaired coronary artery flow [35],
are not easy to track directly. However, they do demonstrate
the importance of a real-time ultrasound as a method of intra-
operative monitoring. Using other forms of monitoring that
aim to assess the fetal hemodynamic conditions during preg-
nancy and interpolating the results to the intraoperative phase
of the surgery may allow us to anticipate adverse events. For
example, in the Doppler ultrasound exam of the umbilical
artery, the presence of reverse or absent diastolic flow is con-
sidered a sign of placental insufficiency. Alternatively, the
Doppler ultrasound exam of the ductus venosus provides us
with privileged information regarding the efficiency of the
fetal cardiac function [44]. This is because of its anatomical
location and direct connection with the atrium, which allows
us to detect changes in ventricular compliance.
Another important characteristic of the ductus venosus is
its response to hypoxia, where its main reaction would appear
to be dilatation, presumably in order to ensure an adequate
supply of oxygen and glucose to vital organs such as the heart
and brain [4, 20]. As with the aortic isthmus, which acts as an
effective shunt between two parallel circulations that perfuse
the upper and lower body of the fetus, monitoring the flow
pattern provides reliable information on both cerebral oxygen-
ation as well as placental flow [14].
Uterine relaxation
In order to perform the surgery, one of the key requirements is
to ensure deep relaxation of the myometrium, especially when
carrying out the hysterotomy. If the uterus is not suitable re-
laxed, the removal of amniotic fluid may lead to a compres-
sion of the fetus or umbilical cord, or indeed to abruptio pla-
centae (Fig. 1).
How can we achieve intense uterine relaxation?
Systematic reviews and meta-analyses have been devel-
oped based on preventing premature labor and not on acute
tocolysis or surgery. The inhibition of uterine contractions is
the basis of the drugs used to prevent premature labor, but
there is no consensus with regard to the best tocolytic drug,
or its potency.
We can analyze the different drugs that have been used in
terms of their ability to relax the myometrium, something
which goes beyond simply inhibiting contractions. If we only
consider drugs that can be used during surgery, the literature
describes five groups of such drugs (Table 1):
Nitric oxide donors: The most commonly used is glyceryl
trinitrate (nitroglycerin), an ultra short-acting drug that

Fig. 1 Inadequate uterine relaxation. Notice the pressure of the amniotic
fluid
works by freeing nitric oxide (NO) from the vascular
endothelium, increasing the level of cyclic guanosine
monophosphate (cGMP). It also stops calcium from en-
tering the cell through the second messenger-stimulated
protein kinase G (PKG), thus relaxing the myometrium.
Advantages: Fast-acting and short-lasting, easy to admin-
ister (half-life of 2 min), it has also been used to relax the
uterus during fetal surgery and no deleterious effects on
the fetus have been reported. Disadvantages: Medium
potency. In addition to its hemodynamic effects, its bio-
availability is also highly variable among subjects as it
rapidly metabolizes in the liver, lung, and placenta [25].
Beta-adrenergic agonists: terbutaline, ritodrine,
salbutamol. They work by stimulating the Beta2 adrener-
gic receptors (β2-AR), increasing the cyclic adenosine
monophosphate (cAMP) and therefore activating the
PKG. There are three sub-types of β-AR in the
myometrium, the levels of which increase throughout
the course of gestation. The predominant form of these
sub-types in the myometrium is β 2 -AR (80%).
Advantages: Fast-acting, higher potency than NO
Donors. Disadvantages: The way in which it binds with
the receptors is prolonged and irreversible in the short
term, while widespread use of B2-AR leads to a range
of side effects, including pulmonary edema.
Calcium antagonists: Unlike calcium channel blockers,
which act on the cell membrane (such as Nifedipine),
the use of magnesium may decrease intracellular calcium
Table 1 Intraoperative tocolytics
dose Tocolytics drug
Glyceryl trinitrate
Salbutamol
Magnesium sulfate
Atosiban
Halogenated anesthetics
mac minimum alveolar concentration
Childs Nerv Syst
(Ca+2), possibly preventing Ca+2 release from the sarco-
plasmic reticulum and thus affecting several intracellular
pathways. Advantages: Higher tocolytic potency and
widely used throughout the world. Disadvantages:
Requires a bolus dose, has prolonged effects and can
interact with anesthetic drugs.
Oxytocin-receptor antagonists: These drugs compete
with the receptors for oxytocin. Atosiban, an oxytocin
derivative, is a competitive inhibitor of oxytocin recep-
tors as well as the vasopressin receptor. Advantages:
Same potency as the β2-AR, but with fewer side effects.
Disadvantages: As with magnesium, it requires a bolus
dose, which hinders its intraoperative use. Furthermore,
they also have an effect on the vasopressin receptors.
Halogenated inhaled anesthetics: It is still not known
exactly how halogenated inhaled anesthetics work. It
was first suggested that the effects could be explained
by their elevated lipid solubility. In the last 10 years,
huge strides have been taken in terms of understanding
how they work on a molecular level. This has led to a
change from a theory of a single mechanism to a the-
ory of multiple mechanisms [47]. Recent studies of
Na+ and K+ ionic channels strongly suggest that halo-
genated anesthetics interact with areas of these chan-
nels in order to regulate their functions. This would
explain some of the effects of inhalational agents, giv-
en that the voltage-gated Na+ channels are responsible
for the rapid depolarization of the action potential in
electrically excitable cells such as nerves and muscles,
as well as the heart or myometrium [18]. The ability of
these anesthetics to block the Na + channels would
seem to depend on the agent’s specific pharmacologi-
cal profile, where desflurane is the most effective in-
hibitor of the Na+ currents [27]. Given the high density
of these channels in the neuromuscular junction, one
clinical implication of these findings is that we may
relate the inhibition of these voltage-gated Na+ chan-
nels to the muscular relaxation effect. Advantages:
Extremely potent in terms of relaxing the myometrium
(Fig. 2), an effect which is dose-dependent. Quickly
reaches the levels of concentration required for sur-
gery, especially agents that are less soluble in blood,
Dose
Up to10 mcg/kg/min
10–30 mcg/min
2–4 g (bolus); 1–2 g/h
6.75 mg (bolus); 300 mcg/min (3 h); 100 mcg/min (45 h)
2–3 mac
Childs Nerv Syst
such as desflurane, which is also highly stable: less
than 0.02% is metabolized by the organism.
Disadvantages: Requires high levels of concentration
in order to relax the myometrium (2–3 minimum alve-
olar concentration), which has fetal and maternal he-
modynamic effects.
In conclusion, uterine relaxation is an essential and
critical factor in open fetal surgery. Although there is a
wide range of alternatives available for achieving uterine
relaxation, current research cannot prove wich is the best
option. Based on this research and practical experience,
we can deduce that using a combination of two drugs
probably optimizes the advantages while minimizing the
disadvantages. One such example would be desflurane in
low concentrations, combined with an infusion of
nitroglycerin.
Intraoperative fluids
Patients who undergo fetal surgery present a unique set of
conditions, which facilitate the onset of pulmonary edema.
The physiological changes that are present during the second
trimester of the pregnancy lead the gestation to be character-
ized by a decrease in the plasma colloid osmotic pressure. This
in turn triggers an increase in the hydrostatic pressure gradient
and increases the likelihood of pulmonary edema at lower
levels of pressure than in patients that are not pregnant.
These changes include an increase in the patient’s intravascu-
lar volume status; left ventricular hypertrophy, causing ven-
tricular remodeling and decreased complacency [42] and a
decrease in proteins and plasma sodium. Adzick reports the
occurrence of pulmonary edema in approximately 8% of im-
mediate postoperative patients in Vanderbilt [2]. This high
level is related with the use of tocolytics during surgery [31].
A treatment must necessarily be continued for 48 hours after
the surgery. Reports of pulmonary congestion are particularly
prevalent among the use of nitroglycerin [12, 13] and beta-
adrenergic agonists [31].
Fig. 2 Uterine relaxation obtained using desflurane
The conditions described above therefore led us to consider
a restrictive and goal-directed fluid therapy, where the deci-
sion to provide fluid during surgery is guided by close mon-
itoring and aims to optimize the delivery of oxygen to the
tissue. The traditional monitoring methods used to guide fluid
therapy, such as heart rate, blood pressure, urinary output,
central venous pressure or pulmonary capillary wedge pres-
sure are poor indicators for assessing the intravascular volume
status. We therefore need to use other dynamic variables that
will allow us to assess changes in the volume status caused by
the anesthesia, medication, or surgery. The importance of
responding to this need can be seen in the intensive develop-
ment of monitoring systems that assess changes in the ejection
fraction caused by cyclic changes in intrathoracic pressure
among patients on artificial ventilation, a change that is accen-
tuated by hypovolemia. This can also be examined using a
Doppler ultrasound test, where the ejection fraction is calcu-
lated by multiplying the integral of the flow rate in a blood
vessel, valve or outflow tract (measured by the Doppler sig-
nal) by the area of the cross-section of the blood vessel.
Another way of measuring the volume status using an ultra-
sound is by measuring the area of the ventricle. By under-
standing the limits involved in extrapolated volumes and
knowing that the ventricle does not contract evenly, we are
able to track the changes in the ejection fraction [7]. We can
therefore tell where we are on the Frank-Starling curve and
thus guide how much fluid we provide.
Postoperative management
The patients chosen for MMC surgery must meet fairly strict
inclusion criteria. In general, they are women of childbearing
age with low morbidity. This allows postoperative care to take
place in an obstetric intensive care unit, where there is greater
familiarity with the most important elements of this procedure,
as well as with obstetric complications.
The tocolytics used during in surgery must be continued
during postoperative care, while the mother must be moni-
tored for complications, especially those caused by the use
of magnesium. This must be done by monitoring the
osteotendinous reflexes, the urinary output, the patient’s con-
sciousness and breathing rate, as well as by measuring the
level of plasma (therapeutic range 3.5–7 mEq/L).
Another important point to monitor during this stage is the
water balance, which must remain negative throughout the
time in which the tocolytics are administered parenterally so
as to avoid pulmonary congestion. Traditionally, intensivists
have used urinary chemicals such as urinary sodium to guide
their fluid management. This is also the case with the amount
of sodium and urea that is excreted. However, the accuracy of
this method is affected by the use of diuretics. With this in
mind, it is important to use these values within the context of
the general condition of the patient. In this sense, a decrease in

pulmonary compliance and thus an increase in the breathing
rate can be a sign of the onset of pulmonary congestion.
The postoperative use of analgesia on a fetus is based more
on the doctor’s judgment than on any available scientific ev-
idence. However, wound infiltration with local anesthetic
agents has been used at the end of surgery, taking the duration
of its effect during neonatal surgery as a point of reference.
With the same objective in mind, opioids have also been ad-
ministered to the mother in order to avoid the inhibition of the
prostaglandin biosynthesis effect of the non-steroidal anti-in-
flammatory drugs on the ductus arteriosus and the fetal
kidney.
Conclusion
This systematic review provides information on the most im-
portant characteristics of anesthesia for fetal surgery. Given
their importance, these factors, whether acting independently
or otherwise, can compromise the result of the surgery.
Following Adzick’s publication [1], in which he revealed the
potential benefits of prenatal surgery at the expense of a high
level of risk, several centers have tried to reproduce these
benefits among their own patients. Furthermore, rarely before
have anesthetists understood so clearly the extent to which the
anesthetic technique that is used can influence the result of the
surgery. Although it is still not clear as to which is the best
anesthetic technique, identifying the variables that are in-
volved is the first step toward finding the answer. Given the
level of complexity, we can see that this procedure requires
huge amounts of preparation, with technology playing a fun-
damental role. Furthermore, we can see that the answer may
come from different areas, such as the Pediatric Cardiologist
or the Vascular Interventional Radiologist. Finally, we can see
that finding an answer to these problems is not easy.
Nevertheless, if we want to lower the level of morbidity in-
volved in this procedure, we must continue our research.
Compliance with ethical standards
Conflict of interest All authors declared no conflict of interest.
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