Childs Nerv Syst (2003) 19:574–586

DOI 10.1007/s00381-003-0775-4 O R I G I N A L PA P E R

Cornelia S. von Koch In utero surgery for hydrocephalus

Nalin Gupta
Leslie N. Sutton
Peter P. Sun

Received: 10 April 2003
Published online: 25 July 2003
© Springer-Verlag 2003
C. S. von Koch (✉) · N. Gupta · P. P. Sun
Department of Neurological Surgery,
University of California San Francisco,
Room M-779, 505 Parnassus Avenue,
Box 0112, San Francisco,
CA 94143–0112, USA
e-mail: vonkochc@neurosurg.ucsf.edu
Tel.: +1-415-5022965
Fax: +1-415-7531772
L. N. Sutton
Division of Neurological Surgery,
Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania, USA
P. P. Sun
Division of Neurological Surgery,
Children’s Hospital of Oakland,
Oakland, California, USA
Abstract Introduction: Neonatal
hydrocephalus is one of the most
common congenital anomalies
affecting the nervous system.
Discussion: Currently, ultrasonogra-
phy allows for early detection of fe-
tal ventriculomegaly and presents
the family with several treatment op-
tions: termination of pregnancy, ear-
ly delivery and neonatal shunting,
and delivery at term followed by
shunting. Despite ventricular decom-
pression after birth, the cognitive
outcome is variable as prolonged in
utero hydrocephalus has a detrimen-
tal effect. In the early 1980s, fetal in-
tervention was explored with the in-
tention of improving outcome. How-
ever, patient selection was poor. Fe-
tal ventriculomegaly from other con-
ditions was not adequately distin-
guished from fetal hydrocephalus. In
addition, fetal surgical techniques
were not advanced. Consequently,
the results were poor and a de facto
moratorium on fetal shunting was
imposed. However, recent improve-
ments in fetal imaging, such as mag-
netic resonance imaging, and ad-
vances in fetal surgical techniques
offer the possibility that properly se-
lected fetuses with hydrocephalus
can benefit from an in utero inter-
vention.
Keywords Fetal hydrocephalus ·
Fetal surgery · Ventriculo-amniotic
shunt · Fetal magnetic resonance
imaging

Etiology and pathophysiology brain development or tissue destruction from vascular,

The incidence of hydrocephalus in the newborn ranges
from 0.3 to 2.5 per 1,000 live births [103]. Modern ultra-
sonography, and since the late 1980s, fetal magnetic res-
onance imaging (MRI), have significantly improved the
ability to detect ventricular enlargement as a result of hy-
drocephalus in utero. Ultrasound and MRI can detect fe-
tal ventriculomegaly as early as 17–21 and 8–21 weeks
respectively [6, 83].
Hydrocephalus is the result of a mismatch between
cerebrospinal fluid (CSF) absorption and production. It
usually leads to increased ventricular size and is associ-
ated with increased cerebrospinal fluid pressure. Ventri-
culomegaly, defined simply as ventricular enlargement,
can be a normal anatomical variant or arise from any
mechanism that causes a loss of brain tissue (failure of
anoxic or infectious causes), or secondary to true hydro-
cephalus, which is a pathologic condition. It should be
kept in mind that only CSF drainage in patients with fe-
tal hydrocephalus, and not ventriculomegaly without hy-
drocephalus, may benefit the patient’s outcome. The dis-
tinction between hydrocephalus and ventriculomegaly
without hydrocephalus is not often straightforward on
current imaging, especially ultrasound.
The etiology of fetal hydrocephalus can be grouped in-
to three main categories: obstruction within the ventricu-
lar system; abnormal brain development; and intrauterine
injuries such as infection, hemorrhage, and stroke (see
Table 1). The first usually arises from obstruction of CSF
outflow pathways by mass lesions. The second is presum-
ably from disordered neurogenesis with some cases
caused by a sporadic or inherited genetic defect. The last
 575

Table 1 Categories of fetal hydrocephalus by mechanism

Type Etiology

Ventricular obstruction Congenital tumors (teratoma, choroid plexus tumor, astrocytoma, etc.)
Intraventricular hemorrhage
Abnormalities of brain development X-linked hydrocephalus
Aqueductal stenosis
Acquired intrauterine insult Infectious (toxoplasmosis, varicella, herpes simplex)
Posthemorrhagic

category includes infectious agents such as toxoplasmo-
sis, cytomegalovirus, rubella, mumps, varicella, and para-
influenza. Rarely, overproduction of CSF, usually seen
with choroid plexus tumors, will result in hydrocephalus.
Anomalies of chromosomes 1, 6, 9, 13, 18, 21, 22, or X
have been observed in patients with ventriculomegaly
and hydrocephalus [32, 43, 46, 48, 61, 71, 97, 106, 113].
With prolonged and progressive hydrocephalus ax-
onal degeneration with focal neuronal loss, decrease in
synapses, and gliosis is seen [21, 69, 100, 114]. Thinning
of the cerebral cortex is seen in severe hydrocephalus
cases [18]. White matter suffers from chronic hypoperfu-
sion [9, 19, 68] and early generation of myelin in the
periventricular region in young brains is impaired in rat
models of hydrocephalus [20]. The mechanism of abnor-
mal myelination is unclear and may represent ischemia
and/or the result of toxins present in the CSF. Delayed
myelination is seen on MRI in human infants with hy-
drocephalus [50]. In 8 human fetal cases of untreated hy-
drocephalus, neuronal maturation was studied at time of
death from 20–40 weeks’ gestation [80]. In 2 of these
cases, rapidly progressive hydrocephalus resulted in al-
tered neuronal cell proliferation and migration. In animal
models, neuronal progenitors in the germinal matrix ap-
pear to proliferate but are prohibited from normal migra-
tion [26, 67, 109]. This appears to result in a thickened
germinal matrix. To what extent drainage of hydrocepha-
lus reverses these histologic changes is not clear; howev-
er, reduction in intracranial pressure appears to improve
cerebral blood flow in a rabbit model [19]. In a rat model
of perinatal hydrocephalus, cortical lamination is mostly
restored [60]; however, synapses and neuronal size are
only partly recovered after early shunting [47, 76]. A
summary of several spontaneous rat models of congeni-
tal hydrocephalus has been described by Oi et al. [82].
Ideally, in utero drainage of hydrocephalus would pre-
vent these neuronal changes and serves as the rationale
for further development of this treatment option.
Embryology of CSF pathway development
Normal brain development is closely related to proper
formation of embryonic and fetal CSF. Anencephaly re-
sults from lack of closure of the anterior neuropore.
Once the choroid plexus develops, the roof of the rhomb-
encephalon becomes thin and is thought to allow some
passage of fluid and macromolecules into the subarach-
noid space [59]. The perforations of the roof to form the
fourth ventricular outflow tracts form later [37, 115].
During this time, adequate ventricular distension by CSF
is critical for brain development [77, 85, 102]. Drainage
of ventricles in early chick embryos results in small, dis-
organized brains [24]. In patients with open myelomen-
ingoceles, the continuous release of CSF into the amniot-
ic fluid is thought to play a role in hindbrain herniation
(the Chiari malformations) [70].
The subarachnoid space develops independently of
CSF circulation as a loose mesenchymal condensation
around the neural tube as early as the 5th week [86].
Once the fourth ventricular outlets mature, CSF fills the
subarachnoid spaces. The subarachnoid space is most
prominent during the second trimester and gradually di-
minishes to the neonatal size during the third trimester
[25, 89]. At 26 weeks, arachnoid villi develop as depres-
sions in the sagittal sinus fill with arachnoid tissue. Well-
developed arachnoid villi do not appear until 35 weeks
and are not fully mature until term [44]. It is thought that
early CSF absorption is not carried out by arachnoid
granulations but rather by fenestrations in embryonic
perineural vessels [87].
Diagnosis and imaging
Ultrasound
The radiographic diagnosis of hydrocephalus has tradi-
tionally been performed using ultrasound. Different tech-
niques have been used to measure ventricular size. The
transverse atrial width is commonly used and measured
on each side perpendicular to the ventricular axis.
Fig. 1A shows a fetal brain with normal ventricular size
and Fig. 2A refers to a patient with fetal ventriculomega-
ly. The atrium is the first portion of the ventricular
system to dilate because of the lack of constriction from
the striatum and Laplace’s law. Laplace’s law states that
the larger the radius of a balloon the less pressure is re-
576

Fig. 1A, B Ultrasound of a

20-week-old and MRI of a
22-week-old normal fetal brain.
A Ultrasound in the axial plane
shows normal ventricular size
for age. B Single fast spin echo
axial T2-weighted image of the
fetal brain reveals no obvious
abnormalities

Fig. 2A–D Ultrasound and

MRI of a 22-week-old fetal
brain with suspected aque-
ductal stenosis. A Ultrasound
in the axial plane shows moder-
ate dilation of the lateral and
third ventricles with a normal
posterior fossa and fourth ven-
tricle. The atrium (asterisks)
measured 18.5 mm. Using the
maternal torso coil, single fast
spin echo T2-weighted images
of the fetal brain were obtained
in B the sagittal, C axial, and
D coronal planes. Moderately
dilated lateral and third ventri-
cles are seen with a thinned
cortical mantle, suggesting hy-
drocephalus from aqueductal
stenosis. The posterior fossa,
cerebellum, and brainstem are
well visualized and the fourth
ventricle is not enlarged. No
further anomalies of the brain
were identified

quired to yield the same amount of wall tension. There-
fore, it takes less pressure to dilate the already larger
atrium compared with other components of the ventricu-
lar system. The normal atrial width is 4–8 mm, with
10–12 mm quoted as the upper limit of normal [33, 53,
104]. The smallest atrial width is used to minimize errors
introduced when the atria are not measured in a perfect
perpendicular plane or if the vein of Galen is mistaken
for the medial edge of the atrium [34]. Atrial size is
nearly constant from 15 to 35 weeks’ gestation. Another
measurement is the lateral ventricular ratio, which is the
ratio of the lateral ventricular width (from the parietal
lateral ventricular wall to the midline echo) to the hemi-
spheric width (from the inner table of the cranium to the
midline echo in the same transverse plane) [22, 91]. The
ratio is approximately 0.6 at 15 weeks and progressively

decreases to 0.3 at 24 weeks from whereon it remains
stable until term [58]. The upper limit of normal is con-
sidered 0.4 after 24 weeks gestation. The variation of
this ratio during early gestation makes it less useful than
the measurement of atrial width.
Isolated dilation of the lateral ventricles and the third
ventricle suggests aqueductal stenosis. Third ventricular
size varies with gestational age and measures approxi-
mately 1 mm during the second trimester; but after
32 weeks’ gestation, its width can reach 2 mm. An upper
limit of 3.5 mm has been suggested in one report [52].
As a general rule, cranial enlargement is often seen with
progressive hydrocephalus and contrasts ventriculomeg-
aly with a destructive progress.
MRI
In recent years, fetal MRI has been used as an adjunct to
fetal ultrasound. MRI provides superior anatomic resolu-
tion of the brain, including the cortex, subarachnoid
space, and the ventricular system [39, 64, 92, 95]. Com-
monly, no maternal sedation is needed and a maternal
surface coil is used to acquire predominantly single-shot
fast spin-echo T2-weighted images of the fetal brain in
the sagittal, axial, and coronal planes (Fig. 1B). In stud-
ies comparing ultrasound with MRI, additional CNS ab-
normalities were identified using MRI, such as poren-
cephaly, polymicrogyria, agenesis of the septum pelluci-
dum, and cerebellar hypoplasia [64, 105]. The electro-
magnetic field does not appear to be harmful to the fetus
[29]. Fetal MRI provides more accurate diagnosis of
brain abnormalities and will aid clinicians in selecting
therapeutic options. Three views of a patient with aque-
ductal stenosis-induced hydrocephalus are shown in
Fig. 2B–D. MRI offers the potential to differentiate be-
tween hydrocephalus and ventriculomegaly.
Animal models
Large animal models of fetal hydrocephalus were devel-
oped in monkeys and sheep, mainly to test the feasibility
of in utero treatment. Michejda and Hodgen created fetal
hydrocephalus in rhesus monkeys by serial maternal in-
jections of corticosteroids (triamcinolone acetonide) at
21–25 days’ gestation (term 167 days) [73]. Hydroceph-
alus formed in 90% of fetuses, but was also associated
with major congenital anomalies such as encephalocele,
meningocele, and cranium bifidum, due to the teratogen-
ic effect of the corticosteroid. Hydrocephalus could be
detected as early as 60 days’ gestation using ultrasound.
Intracranial pressures of hydrocephalic fetuses exceeded
100 mm H2O, compared with control animals whose
pressures were 45–55 mm H2O. At the beginning of the
third trimester (115–125 days of gestation), following a
577
maternal hysterotomy, a prosthetic valve was inserted in-
to the frontal horns of lateral ventricles. The valve al-
lowed CSF flow from the ventricle to the amniotic fluid
when ICP was greater than 60 mm H2O. Monkeys with-
out in utero valves developed continued, severe hydro-
cephalus, weakness, seizures, growth retardation, and
most died within 2 weeks of birth. In comparison, treated
monkeys showed superior motor skills and improved
weight gain. Six months postnatally, normal neurobehav-
ioral development was seen in shunted monkeys [72,
75]. Michejda et al. also treated corticosteroid-induced
infantile porencephalic cysts in monkeys with in utero
CSF shunting and reported improved development of
brain tissue compared with monkeys shunted postnatally
[74].
At the University of California San Francisco, fetal
hydrocephalus was created in rhesus monkeys and sheep
using kaolin injections into the cisterna magna of fetuses
during hysterotomy or by puncture of the closed uterus
[28, 41, 78]. Timing for injections ranged from
96–109 days’ gestation for monkeys and 89–128 days’
gestation for sheep (term 145 days). Kaolin induced an
inflammatory reaction in the posterior fossa creating ob-
structive hydrocephalus starting 2 weeks after injection
in 66% of monkeys and 50% of sheep. Thinning of the
cortical mantle and corpus callosum with preservation of
the gray matter was observed in hydrocephalic animals.
During hysterotomy, an in utero shunt was placed into
the frontal horn of the lateral ventricle using a Pudenz
ventricular catheter connected to a Raimondi low-pres-
sure catheter with a one-way distal slit valve 15–20 days
post injection. Ventriculo-amniotic, ventriculo-right atri-
al, and ventriculo-pleural shunting was performed [41].
Placement of all shunt systems was feasible; however,
red thrombi were seen with ventriculo-right atrial shunts.
Red thrombi represent platelet aggregates on the catheter
tip that may dislodge, causing distal emboli in the pul-
monary vasculature. With all shunt systems, improve-
ment in ventriculomegaly, cortical thinning, and survival
was achieved. In several animals, diffusion of kaolin into
the lateral ventricles resulted in gliosis, demyelination,
and cavitation complicating analysis of histologic chang-
es due to hydrocephalus. Complications from shunting
included subdural hematoma/hygroma, shunt infection,
shunt occlusion, and improper shunt tip placement [41].
This model created hydrocephalus in the early third tri-
mester, which is late compared with the corticosteroid
model. Human fetuses with onset of hydrocephalus dur-
ing the second trimester are more likely to suffer signifi-
cant brain damage from progressive hydrocephalus com-
pared with fetuses with onset of hydrocephalus during
the third trimester. The former group of patients may
benefit more from in utero decompression of hydroceph-
alus. Therefore, animal models with early onset of hy-
drocephalus are preferred to more accurately mimic this
patient population.
578

Cambria et al. placed shunts in fetal sheep after kaolin
induced hydrocephalus [10]. The shunt consisted of the
terminal part of the atrial catheter of a pediatric Pudenz
low-pressure valve and drained CSF into the amniotic
cavity. Improvement in ventriculomegaly was seen.
Garzetti et al. placed a small catheter via a suboccipital
approach into the aqueduct of sylvius [38]. No drainage
was performed and fetal obstructive hydrocephalus was
achieved in 4 out of 14 sheep.
Natural history
Comparison of fetal and neonatal hydrocephalus
Many reports have attempted to describe the natural his-
tory of fetal hydrocephalus (for References see Tables 3,
4, 5, 6]. Unfortunately, these data are less than convinc-
ing or consistent. Older studies predate the era of sophis-
ticated imaging and modern genetic testing. As noted
above, the etiology of hydrocephalus is diverse and sub-
tle associated anomalies may have been missed, leading
to an underappreciation of the heterogeneity of the popu-
lation. Biological differences between fetal and neonatal
brain development preclude a simple extrapolation of
outcomes from patients treated for postnatal hydrocepha-
lus. During fetal development, neuronal proliferation and
migration predominate, in contrast with myelination and
dendritic maturation postnatally. Presumably, fetal CSF
dynamics are also different from those of the neonate.
CSF flow with minimal intraventricular pressure is likely
to be necessary for normal fetal brain development [77,
85, 102]. Also, the distinction between ventriculomegaly
and hydrocephalus is difficult, especially in earlier stud-
ies where fetal MRI was not available.
Overall, major series of fetal ventriculomegaly report
a 54–84% incidence of associated cranial and extracrani-
al abnormalities, a mortality rate (excluding terminated
pregnancies) of 8–81%, and normal cognitive develop-
ment in 16–68% of the survivors (Table 2) [11, 12, 16,
27, 42, 56, 90, 91, 99, 103]. These wide ranging results
make it exceedingly difficult to develop historical con-
trols with which to compare experimental therapy. Fetus-
es with associated multisystem anomalies may have
chromosomal defects in up to 36% of cases [79]. How-
ever, a false-negative rate of associated anomalies of
20–60% was seen with ultrasound before the use of fetal
MRI [11, 16, 56]. Fetal MRI was beneficial in detecting

Table 2 Fetal ventriculomegaly

Reference Associated Percentage died Percentage Survivors with
anomalies (%) without termination terminated normal outcomes (%)

[11, 12] 84 62 26 42
[16] 75 53 0 16
[27] 72 8 40 33
[42] 54 31 33 64
[56] 74 41 32 68
[90, 91] 70 81 23 50
[99] 65 24 8 57
[103] 84 71 11 60

Table 3 Fetal hydrocephalus including isolated aqueductal stenosis, Chiari II malformations, and Dandy Walker malformation, without
other severe abnormalities

Reference Number Percentage died Percentage Developmental delay of survivors Shunt

of patientsa without termination terminated postnatal (%)
None Mild Moderate Severe
(%) (%) (%) (%)

[2] 13 0 0 23 54 15 100
[16] 19 61 5 29 44
[27] 16 0 6 53 33 13 0 60
[41] 14 21 0 64 9 27 0 43
[56] 17 7 18 77 15 0 8 64
[65] 37 22 38 17 17 56 28 83
[79] 230b 49 79 48 4 12 8 10
[83] 12 50 0 50 0 0 0 58
[103] 11 10 9 67 22 11 0 90
[107] 25 0 64 56 33 11 0 11
[112] 9 0 22 43 43 0 14 100
a Apparent in utero diagnosis
b In 153 out of 172 pregnancies in which the fetus had Chiari II malformation, pregnancies were electively terminated

Table 4 Outcomes of fetal hydrocephalus by etiology
Etiology (reference)
Aqueductal stenosis [1, 16, 27, 49, 65, 81, 84, 103, 112]
Dandy-Walker syndrome [2, 63, 81, 84, 103, 112]
Chiari II/myelomeningocele [12, 16, 27, 56, 63, 79, 81,
84, 99, 103, 112]
heterotopia, callosal anomalies, and posterior fossa mal-
formations [105]. Often, fetuses with associated anoma-
lies have poor outcomes, irrespective of ventricular en-
largement, due to underlying genetic disorders. There-
fore, early detection of associated anomalies is crucial
for adequate counseling of pregnant mothers. If detected
before the legal limit of abortion termination of pregnan-
cy is an option.
Isolated hydrocephalus
In theory, fetuses with isolated hydrocephalus might ben-
efit from in utero decompression. If causes of isolated
hydrocephalus without associated anomalies are consid-
ered to include aqueductal stenosis, Chiari II malforma-
tion associated with myelomeningocele, and Dandy-
Walker syndrome, several studies have described out-
comes (Table 3) [2, 16, 27, 41, 56, 65, 79, 83, 103, 107,
112]. Mortality rate (not including terminations) was
0–61%. Of those patients surviving 17–77% had normal
neurologic outcome and 10–100% required postnatal
shunt placement. Stable, mild hydrocephalus often did
not require shunting. It is worth subdividing further the
outcomes of fetal hydrocephalus due to aqueductal ste-
nosis, Dandy-Walker malformation, or Chiari II malfor-
mation associated with myelomeningocele (Table 4). Of
59 patients with aqueductal stenosis 14% died; of the
survivors 24% had severe delay, 39% mild to moderate
delay, and 37% developed normally [1, 16, 27, 49, 65,
81, 84, 103, 112]. Thirty-one percent of 16 patients with
Dandy-Walker syndrome had normal development [2,
63, 81, 84, 103, 112]. Of 43 patients with Chiari II mal-
formation with myelomeningocele, death occurred in
23%; of the survivors, severe delay occurred in 12%,
mild to moderate delay in 21%, and normal development
in 67% [12, 16, 27, 56, 63, 79, 81, 84, 99, 103, 112]. The
better neurologic outcomes in patients with Chiari II and
myelomeningocele may in part be due to CSF drainage
in utero through the spinal defect. Inherent in all of these
studies is a selection bias created by termination of preg-
nancies. In a British series, 153 out of 172 fetuses with
ventriculomegaly associated with myelodysplasia were
terminated [79]. Gupta et al. reported that 12% of preg-
579
Number of Percentage Developmental delay of survivors
patients died
None Mild/ Severe
(%) moderate (%) (%)
59 14 37 39 24
16 31
43 23 67 241 12
nancies had been terminated for different etiologies of
fetal ventriculomegaly [45]. It is likely that the most se-
vere cases of fetal hydrocephalus are more likely to be
detected and potentially terminated, suggesting that the
natural history for fetal hydrocephalus may even be
worse.
Timing of diagnosis and outcome
When comparing normal developmental outcome of pa-
tients diagnosed with common etiologies of congenital
hydrocephalus in utero, at birth, or in the neonatal peri-
od, patients diagnosed prenatally usually fare worse (Ta-
ble 5). With aqueductal stenosis improved outcome is
observed the later in gestation the diagnosis of hydro-
cephalus is made. Patients with Dandy-Walker syndrome
appear to do better if diagnosed in the neonatal period. If
hydrocephalus is associated with Chiari II and myelo-
meningocele, developmental outcome is similar if diag-
nosed in utero or neonatally. It is difficult to draw defini-
tive conclusions from these studies, as sample sizes are
often small; however, as a general trend it appears that
patients do better developmentally if hydrocephalus is
diagnosed postnatally. Conversely, patients diagnosed
prenatally appear to have poorer outcomes. This obser-
vation may suggest that fetuses in which hydrocephalus
is detected may benefit from earlier intervention but an
equally valid conclusion is that earlier diagnosis occurs
in those fetuses with more severe abnormalities and
greater degrees of hydrocephalus.
Prognostic factors
Additional factors contributing to poorer outcome from
fetal ventriculomegaly include increased ventricular size
and progression of ventriculomegaly. Mild, isolated fetal
ventriculomegaly (10–12 or 13 mm of atrial diameter)
has an excellent prognosis and may reflect a normal vari-
ant [98, 108]. In these reports, resolution of the ventri-
culomegaly occurred in 30–40% of cases and the rest re-
mained stable. Developmental delay was seen at a simi-
lar rate to the general population, namely 2.5–3%. The
580
Table 5 Normal developmental outcomes
Stage at diagnosis
Fetal hydrocephalus [2, 16, 27, 41, 56, 65, 79, 83, 103, 112]
Hydrocephalus at birth [94]
Neonatal hydrocephalus [40, 54, 55, 62, 93, 101, 110, 111]
incidence of abnormal outcome increases to 23% in iso-
lated ventriculomegaly with atrial width between 12 and
15 mm, but this is related mostly to metabolic or intrin-
sic brain disorders and fetal MRI is helpful [88, 108].
Isolated fetal ventriculomegaly may resolve, remain sta-
ble, or progress. A large British study reported 90% sur-
vival and normal outcome in 70% of fetuses with resolv-
ing ventriculomegaly [4]. For patients with stable ventri-
culomegaly survival was also 90%, but normal outcome
was seen in 50%. In the case of progressive ventriculo-
megaly survival was only 77% and normal outcome re-
corded in 23.5%. Progressive, isolated ventriculomegaly
has a worse prognosis. The rate of progressive fetal ven-
triculomegaly obtained from the limited studies that have
documented serial ultrasonography ranges from 20 to
36% [4, 27, 42, 107, 112]. Aqueductal stenosis was fre-
quently the etiology for progressive fetal ventriculomeg-
aly [65, 112]. Cognitive outcome in progressive, isolated
fetal hydrocephalus was reported in 16 patients (pooling
data from 5 separate studies): 6 had normal intelligence,
4 had mild developmental delay, 3 had moderate devel-
opmental delay, and 3 had severe developmental delay
[27, 42, 56, 103, 112].
With more severe ventriculomegaly, the relationship
between residual cortical thickness in fetal hydrocepha-
lus and cognitive outcome is unclear. Levitsky et al.
found a weak correlation between fetal frontoparietal
cortical mantle thickness and outcome in a group of pa-
tients with fetal aqueductal stenosis [65]. Several fetuses
with progressive, isolated hydrocephalus had a final cor-
tical width of less than 1.5 cm and of the surviving fetus-
es, all had moderate to severe delays after neonatal
shunting [27, 103]. Of 8 patients with fetal hydrocepha-
lus from aqueductal stenosis that were shunted after
birth, none of the infants with a postoperative cortical
mantle width of less than 3 cm had a normal develop-
mental outcome [49]. Other reports, however, do not re-
port a correlation between outcome and brain mantle
width or ventricular size [1, 56, 79].
The time of diagnosis and duration of fetal hydro-
cephalus does seem to correlate with outcome. Of 20 fe-
tuses diagnosed between 24 and 40 weeks’ gestation
with fetal hydrocephalus, those fetuses that were in utero
for more than 1 month after diagnosis had poor out-
comes [81, 84]. Two of these fetuses had significant ven-
triculomegaly, macrocephaly, and further head enlarge-
Aqueductal Dandy-Walker Chiari II/
stenosis (%) syndrome (%) myelomeningocele (%)
37 31 67
46 20
50–65 30–50 70
ment shortly after birth and underwent therapeutic CSF
drainage immediately after birth. Intracranial CSF pres-
sures were 350 and 400 mmHg (normal, 40–50 mmHg).
During a separate ventriculoamniotic shunting procedure
the intrauterine pressure was measured at 160 mmHg
[15]. In fetal hydrocephalus, the fetal brain can be under
significant pressure from increased CSF pressures and
from uterine constriction. Oi et al. suggested that if these
pressures persist for more than 1 month, irreversible
brain damage may occur [81, 83, 84]. In contrast,
Drugan et al. reported good outcome in fetuses with in
utero hydrocephalus for more than 1 month [27].
In a more recent study, Oi et al. incorporated fetal
MRI to better select patients without associated anoma-
lies [83]. Follow-up included IQ measurement and de-
velopmental analysis at a mean of 1.8 years postnatally.
In cases of aqueductal stenosis, communicating hydro-
cephalus, and Chiari II-associated hydrocephalus, the
outcomes were worse when the diagnosis was made be-
fore 32 weeks of gestation. Although not conclusive, it is
reasonable to propose that neuronal maturation is likely
to be affected by the development of hydrocephalus in
the period before lung maturity.
Summary
In summary, the current data describing the natural histo-
ry of fetal ventriculomegaly and hydrocephalus is far
from perfect and biases such as pregnancy terminations
and lack of fetal MRI obscure the results. However,
overall, it appears that fetuses diagnosed early in gesta-
tion with progressive hydrocephalus and no associated
anomalies or infections might benefit from in utero CSF
decompression. Ideally, the natural history of this group
of patients should be analyzed in the current era of fetal
MRI. Some studies have begun to address this issue, but
a multi-center prospective trial may be required to obtain
a large enough sample size to definitively answer the
question.
Surgical experience with human fetal shunts
Initially, treatment of fetal ventriculomegaly was aimed
at minimizing maternal morbidity and mortality. Pro-

gressive and severe ventriculomegaly may result in uter-
ine rupture and prohibits vaginal delivery. In the past,
crude techniques such as trochar drainage of fetal ventri-
cles were used to allow vaginal delivery. As expected,
most fetuses did not survive.
Subsequently, fetal treatment of hydrocephalus was in-
troduced and was based on the assumption that ventricu-
lar decompression is as beneficial to the fetus as it has
been for functional outcome in children. Ultrasound-
guided percutaneous cephalocentesis was first reported
by Birnholz and Frigoletto [7] for drainage of fetal hydro-
cephalus. A 24-week-old fetus was diagnosed with pro-
gressive hydrocephalus and underwent six serial, atrau-
matic CSF reductions until cesarean section at 32 weeks.
Intermittent reduction of ventricular size was achieved
and a ventriculo-peritoneal shunt placed after birth. On
further analysis, the child had agenesis of the corpus cal-
losum, a posterior cyst, mental retardation, and Becker’s
muscular dystrophy, limiting the child’s development.
Multiple ventricular punctures increase the risk of
hemorrhage, porencephaly, and result in only temporary
relief of increased intracranial pressure. To allow for
continuous decompression of hydrocephalic fetal ventri-
cles, Clewell et al. placed a silastic shunt with a one-way
valve into the left lateral ventricle of a fetus via a percu-
taneous ultrasound-guided needle technique [14, 15].
The shunt was advanced through the needle into the ven-
tricle with a stylet and ended in the amniotic cavity. The
fetus was diagnosed with hydrocephalus due to X-linked
aqueductal stenosis at 21 weeks and underwent shunting
at 23 weeks. A decrease in ventricular size was achieved
for 9 weeks until the catheter occluded. The ventricles
enlarged again and the fetus was delivered at 34 weeks
via cesarean section. A ventriculo-peritoneal shunt was
placed postnatally.
Using the same percutaneous technique, Frigoletto et
al. inserted a ventriculo-amniotic shunt into a 24-week-
old fetus with a facial cleft and hydrocephalus [36]. The
first catheter pulled out during insertion and was lost in
the maternal abdomen, the second catheter occluded, and
a third catheter without a valve remained patent until de-
livery and resulted in reduced ventricular size. The neo-
nate developed seizures, diabetes insipidus, sepsis, and
died at 5 weeks. Cultures were negative and it is unclear
if the valve-less catheter caused chemical meningitis
from reflux of amniotic fluid into the ventricles. A fetus
with Dandy-Walker malformation and hydrocephalus un-
derwent a ventriculo-amniotic shunt. Postnatally, the
child was found to have hemiparesis, spastic diplegia,
and developmental delay [23].
The initial outcomes of fetal shunting were not en-
couraging, as poor patient selection was a significant
factor. The outcome of most fetuses was affected by their
associated anomalies. At the Kroc Foundation Sympo-
sium in 1982, the decision was made by scientists in the
field to study in utero treatment of fetal hydrocephalus in
581
a more controlled fashion. The International Fetal Sur-
gery Registry was established and guidelines for patient
selection were established [51]:
1. Presence of a multispecialty team with Level III ultra-
sonography, high-risk obstetric unit, neonatal inten-
sive care, and access to other subspecialties
2. A singleton pregnancy
3. Absence of any other significant anomalies
4. Progressive ventricular dilation
5. A normal karyotype
6. Viral cultures
7. Adequate follow-up
8. Gestational age less than 32 weeks or lung maturity
9. A consensus by the team to proceed
In the period from 1982 to 1985, 41 in utero treatments
for progressive fetal hydrocephalus were reported to the
Registry on a voluntary basis [66]. Two patients under-
went serial ventriculocentesis, whereas all other patients
were treated with ventriculo-amniotic shunts. Most were
silastic shunts with a one-way valve to prevent reflux of
amniotic fluid. The mean age at diagnosis was
25±2.73 weeks’ (range, 18–31) and at treatment
27±2.6 weeks’ (range, 23–33) gestation. Detailed infor-
mation on shunt durability was not recorded. The pre-
dominant primary diagnosis of these fetuses was aque-
ductal stenosis (77%), but other diagnoses included asso-
ciated anomalies (13%), holoprosencephaly (3%), Dan-
dy-Walker syndrome (3%), porencephalic cyst (3%), and
Arnold-Chiari malformation (3%). The fetal death rate
depended on the primary diagnosis and was 13% for
aqueductal stenosis, 40% for associated anomalies,
100% for holoprosencephaly, and 0% for the remaining
diagnosis. Causes of death included 1 fetal demise due to
brainstem injury during shunt insertion, 3 postnatal
deaths from prematurity due to preterm labor within 48 h
of shunt insertion, and 3 postnatal deaths related to asso-
ciated lethal anomalies. These findings translated into a
fetal survival rate of 83% with a procedure-related death
rate of 17%. Of the survivors, 53% had serious neurolog-
ic handicaps, 12% had mild to moderate handicaps, and
35% developed normally. All patients developing nor-
mally had aqueductal stenosis. Of all patients with aque-
ductal stenosis 43% were normal neurologically, 7% de-
veloped mild to moderate handicaps, and 50% had se-
vere handicaps. It is not mentioned if the group with
aqueductal stenosis included fetuses with X-linked hy-
drocephalus that are known to be associated with mental
retardation. Of the survivors with associated anomalies
and porencephalic cysts, all were severely handicapped.
The neonates with Dandy-Walker syndrome and Arnold-
Chiari malformation had mild to moderate handicaps.
Clearly, the primary cause of hydrocephalus affected
outcome. The data in this study was not sufficient to cor-
relate duration of treatment with outcome.
582
Table 6 Outcomes of patients with fetal hydrocephalus from isolated aqueductal stenosis treated with in utero compared with neonatal
shunting
Treatment time Number of
patients
In utero, The Fetal Registry [66] 32
Neonatal [1, 16, 27, 49, 65, 81, 103, 107, 112] 59
Three additional studies reported on surgical treat-
ment of fetal hydrocephalus. A ventriculo-amniotic
shunt was placed at 24–25 weeks’ gestation to treat an
enlarging porencephalic cyst [96]. However, the shunt
was lost and the cyst continued to enlarge. Four ven-
triculo-amniotic shunts were placed to treat fetal hydro-
cephalus [13]. Two shunts had to be replaced after they
became dislodged. All fetuses survived, 2 with almost
normal development and 2 with severe retardation. Of
the babies with severe retardation, it was likely that 1
had X-linked hydrocephalus and the other a diaphrag-
matic hernia with respiratory compromise. Three un-
shunted fetuses developed normally. However, the
causes of hydrocephalus and the timing of diagnosis
and treatment were not clearly stated. A case of repeat-
ed prolonged transabdominal intrauterine ventricular
drainage using an external drainage system was de-
scribed in a fetus with progressive hydrocephalus and
myelomeningocele [3]. At 35 weeks’ gestation the fetus
underwent 53 h of externalized CSF drainage. At deliv-
ery, 1 week later, further CSF was drained. No outcome
data was available.
It was difficult to draw definitive conclusions from
the human surgical experience of fetal hydrocephalus.
Patient selection was hampered by difficulty in recogniz-
ing associated malformations and there was poor adher-
ence to the selection criteria of the registry. Most impor-
tantly, no untreated concurrent control group was avail-
able for comparison. Given selection bias, a comparable
historical control group is difficult to gather from the lit-
erature. Vintzileos et al. reported 9 infants with hydro-
cephalus who were treated postnatally and who would
have been candidates for in utero shunting [112]. The au-
thors compared outcomes of these patients with fetuses
that underwent in utero shunting for aqueductal stenosis
and found no difference. To compare outcomes of hydro-
cephalic fetuses from isolated aqueductal stenosis treated
in utero with those treated in the neonatal period, several
studies were identified and compared with the Fetal Reg-
istry (Table 6). The rates of survival and normal neuro-
logic outcome are remarkably similar. However, the rate
of patients with severe neurologic handicap was higher
in the fetal shunt group. Overall, the clinical outcome of
shunted fetuses was not encouraging. Therefore, a volun-
tary moratorium, pending further information on the nat-
ural history of fetal hydrocephalus, was invoked.
Death Neurologic handicap of survivors
(%)
None (%) Mild/moderate (%) Severe (%)
13 43 7 50
14 37 39 24
Present status
Fetal ventriculomegaly can be diagnosed on ultrasound as
early as 16–17 weeks’ gestation and is often performed
after an abnormal serum α-fetoprotein level is detected at
16 weeks. A multidisciplinary team, including obstetri-
cians, perinatologists, fetal surgeons, and pediatric neuro-
surgeons, should be involved for rapid work-up prior to
the legal limit of pregnancy termination. A careful review
of the family history of X-linked hydrocephalus and neu-
ral tube defects and maternal illness or drug exposure is
obtained. Ideally, a fetal MRI scan is performed to evalu-
ate associated extra- and intracranial anomalies, such as
cortical dysplasia and agenesis of the corpus callosum.
Amniocentesis is necessary for detection of infections,
chromosomal analysis, and α-fetoprotein level. Given the
poor prognosis of fetal hydrocephalus associated with
anomalies, infections, or chromosomal abnormalities, ter-
mination of pregnancy can be offered before the legal
limit of termination. For some families, isolated hydro-
cephalus may be reason enough for abortion of the fetus.
If the family decides that the fetus should be carried
to term, serial ultrasounds are performed to further as-
sess associated anomalies and most importantly to fol-
low the development of hydrocephalus. For patients with
resolving or stable hydrocephalus, the fetus is delivered
at term. In the case of moderate to severe progressive hy-
drocephalus, early delivery is the goal as soon as fetal
lung maturity is documented. This will allow for early
CSF drainage either using a temporary ventricular access
device or via placement of a ventriculoperitoneal shunt.
At the discretion of the obstetrician, cesarean section is
considered for large fetal head size. The benefit of early
delivery and shunting has to be weighed against the risk
of prematurity. Infants delivered at 32 weeks’ gestation
have approximately a 16% chance of weighing less than
1,500 g and have a 7.7% incidence of cerebral palsy [5,
31]. The gestational age-specific mortality at 32 weeks’
gestation is 3.5% and decreases to 0.5% by 36 weeks’
gestation [17]. In infants of less than 2,000 g the inci-
dence of necrotizing enterocolitis is 3–4% and compli-
cates peritoneal placement of a shunt [30]. Further, the
risk of shunt infection is as high as 20% in premature in-
fants [8, 57]. A shunt infection in the newborn can be
devastating, especially if it involves gram-negative or-
ganisms. One series found only 5% of infants with shunt
 583

infections and overt hydrocephalus at birth had a normal
IQ score at a mean follow-up of 7 years, and half had
died by the age of 10 years [94]. These risks of prematu-
rity must be carefully weighed against the less defined
potential benefit of early shunting.
Patients with progressive, severe fetal hydrocephalus
that are diagnosed before 28 weeks’ gestation and have a
cortical mantle thickness of less than 1.5 cm may have
irreversible brain damage by 32 weeks’ gestation. Early
delivery at 32 weeks and shunting would not improve
outcome significantly and is probably not justified. Con-
sequently, a subset of these fetuses may benefit from in
utero shunting. However, careful patient selection is cru-
cial and fetal shunting should only be considered in a
tertiary medical center specializing in fetal surgery and
in the context of a clinical trial.
Future directions
Even though clinical outcomes for fetal shunting have
not been encouraging, it may be time to re-evaluate in
utero treatment options for a subset of fetuses with hy-
drocephalus. Imaging capabilities have significantly im-
proved since the 1980s, including fetal MRI and ultra-
sound [35], allowing more accurate patient selection.
Furthermore, significant progress has been made in pre-
natal diagnosis, such as rapid fetal blood sampling and
chorionic villus polymerase chain reaction analysis for
genetic disorders. Advances in fetal surgery techniques
have shown that open or fetoscopic shunting procedures
are likely to be safer and more effective than the percuta-
neous ultrasound-guided technique. It remains to be de-
fined who represents the ideal candidate for fetal shunt-
ing. Outcomes in patients with isolated fetal hydrocepha-
lus are worse than those in neonatal and pediatric cases
with the same etiologies (Table 5). Neurodevelopment is
likely to be irreversibly impaired by fetal hydrocephalus
and cannot be rescued by postnatal shunting. This irre-
versible damage may occur after only 1 month and be-
fore fetal lung maturity, prohibiting early fetal delivery
as a means of treatment. Therefore, carefully selected pa-
tients with fetal hydrocephalus may benefit from in utero
Table 7 Ideal patient for in utero treatment of fetal hydrocephalus
Characteristic of patient
Isolated hydrocephalus from non-X-linked aqueductal stenosis
Diagnosis before 28 weeks’ gestation
Moderate to severe hydrocephalus that is progressive
No associated anomalies on fetal MRI
No chromosomal anomalies or infections
Surgery at a level III medical center specializing in fetal surgery
Table 8 Shunt requirements for in utero treatment of fetal hydro-
cephalus
Shunt requirement
Safe and simple insertion
Fixation to scalp to prevent pull-out
Prolonged drainage without malfunction
One-way valve to prevent reflux of amniotic fluid or bacteria
Re-establish CSF dynamics
Prevent overdrainage
decompression. The characteristics of the “ideal” fetal
candidate and requirements for shunt hardware are listed
in Tables 7 and 8 respectively. Hydrocephalus should be
diagnosed early and be severe enough to produce irre-
versible brain damage before the time of fetal lung matu-
rity. Most importantly, no associated abnormalities, in-
fections, or chromosomal anomalies can be present and
MRI confirmation is necessary. The shunt system needs
to be simple, safe, and probably placed endoscopically or
during open fetal surgery. Overdrainage has to be avoid-
ed to prevent subdural hematoma or hygroma formation.
Also, normal brain development is thought to require ad-
equate CSF pressure, therefore, overshunting may risk
altered brain development [77, 85, 102].
In summary, in utero treatment of fetal hydrocephalus
did not have an encouraging beginning, but recent im-
provements in imaging, patient selection, and fetal sur-
gery techniques suggest that this topic merits further
evaluation. However, it is imperative that before pro-
ceeding with any human studies, further animal experi-
ments are carried out to define the mechanism of brain
injury caused by hydrocephalus and the therapeutic win-
dow where shunting may be effective.

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