Cirugia fetal

Clinical Expert Series
Fetal Surgery
Principles, Indications, and Evidence
Katharine D. Wenstrom, MD, and Stephen R. Carr, MD
Since the first human fetal surgery was reported in 1965, several different fetal surgical
procedures have been developed and perfected, resulting in significantly improved outcomes
for many fetuses. The currently accepted list of fetal conditions for which antenatal surgery is
considered include lower urinary tract obstruction, twin–twin transfusion syndrome, myelome-
ningocele, congenital diaphragmatic hernia, neck masses occluding the trachea, and tumors
such as congenital cystic adenomatoid malformation or sacrococcygeal teratoma when associ-
ated with developing fetal hydrops. Until recently, it has been difficult to determine the true
benefits of several fetal surgeries because outcomes were reported as uncontrolled case series.
However, several prospective randomized trials have been attempted and others are ongoing,
supporting a more evidence-based approach to antenatal intervention. Problems that have yet
to be completely overcome include the inability to identify ideal fetal candidates for antenatal
intervention, to determine the optimal timing of intervention, and to prevent preterm birth after
fetal surgery. Confronting a fetal abnormality raises unique and complex issues for the family.
For this reason, in addition to a maternal-fetal medicine specialist experienced in prenatal
diagnosis, a pediatric surgeon, an experienced operating room team including a knowledgeable
anesthesiologist, and a neonatologist, the family considering fetal surgery should have access to
psychosocial support and a bioethicist.
(Obstet Gynecol 2014;124:817–35)
DOI: 10.1097/AOG.0000000000000476
BACKGROUND
Brief History of Fetal Surgery
Although the first documented nonhuman fetal sur-
gery was reported by Cohnstein and Zuntz in 1884,1
it
was not until the 1940s that techniques were devel-
oped that allowed the (rat) fetus to be removed from
the uterus, treated surgically, successfully returned to
the uterus, and the pregnancy to continue.2
The
human fetus, however, did not become a patient until
1963, when Liley devised a technique for fetal trans-
fusion.3
At the time, before ultrasonographic fetal
diagnosis was possible, the only condition suitable
for fetal therapy was erythroblastosis fetalis, because
it could be predicted using only the obstetric history
and maternal blood tests and was lethal without inter-
vention. Liley’s technique required radiographs and
large-bore Touhy needles; radio-opaque contrast
medium was blindly injected into the amniotic fluid,
the fetus was given time to swallow it, and the location
of the fetus within the uterus was then determined by
X-ray. A 17-gauge Touhy needle was then guided
through the maternal abdomen and uterus and into
the presumed location of the fetal abdominal cavity,
and red cells were injected; it was assumed that the
red cells would eventually be absorbed by the sub-
diaphragmatic lymphatics. Although lymphatic
absorption of red cells was suboptimal at best, and
limited in the setting of fetal hydrops, the main draw-
back of this technique was the potential for damaging
From the Women & Infants Hospital of Rhode Island, Warren G. Alpert Med-
ical School of Brown University, Providence, Rhode Island.
Dr. Rouse, Associate Editor of Obstetrics & Gynecology, was not involved in
the review or decision to publish this article.
Continuing medical education for this article is available at http://links.lww.
com/AOG/A553.
Corresponding author: Katharine D. Wenstrom, MD, Women & Infants Hos-
pital of Rhode Island, Department of Obstetrics and Gynecology, Division of
Maternal-Fetal Medicine, 101 Dudley Street, Providence, RI 02905; e-mail:
kwenstrom@wihri.org.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2014 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/14
VOL. 124, NO. 4, OCTOBER 2014 OBSTETRICS & GYNECOLOGY 817

fetal organs by blindly injecting contrast medium into
fetal tissues or blindly inserting a 17-gauge needle into
the enlarged fetal liver or spleen or kidney, lung, or
pericardium.4
Then, in 1965, Adamson and col-
leagues5
reported the first human fetal surgery, in
which the fetal breech was delivered through a hyster-
otomy and a catheter sewn into the fetal peritoneal
cavity, through which blood could be infused. The first
four reported cases did not result in living newborns for
the same reasons that fetal surgeries today are some-
times unsuccessful; the development of intra-amniotic
infection and preterm labor resulted in preterm deliv-
ery and fetal or neonatal death. The presumption that
the fetuses would have died anyway from erythroblas-
tosis justified the therapeutic attempts and, in retro-
spect, illustrated one of the currently acknowledged
tenets of fetal surgery: the fetal condition must be seri-
ous and life-threatening, and the outcome without
intervention should be morbid or lethal.
Ironically, because current fetal surgical techni-
ques have been enabled by and are completely
dependent on real-time ultrasound technology, it
was the development of obstetric ultrasonography
that sidelined efforts to perfect fetal surgery. Diagnos-
tic ultrasonography was developed in the late 1950s
and applied to obstetrics in the 1960s; the use of real-
time ultrasonography for obstetric evaluation was first
described in 1968.6
When it became possible to per-
form a fetal transfusion relatively noninvasively using
ultrasound guidance,7,8
efforts to access the fetus
through fetal surgery ceased. Simultaneously, pediat-
ric surgical techniques advanced rapidly, so that most
fetal abnormalities could be corrected after birth. In
an early review of fetal surgery, Adamson stated that
“it appears unlikely that even in the distant future fetal
surgery will become a field of major concern to the
clinician since most abnormalities requiring surgical
correction can be dealt with after birth.”9
Presciently,
he noted that the only likely exceptions to this
conclusion were hydrocephalus, fetal neoplasms, and
diaphragmatic hernia.
The burgeoning use of obstetric ultrasonography
in the 1970s and the increasing ability to provide
accurate prenatal diagnoses eventually re-energized
efforts to establish safe and effective techniques for
fetal surgery. In 1982, Harrison, summarizing the first
meeting of the group that would become the Interna-
tional Fetal Medicine and Surgery Society, noted that
diaphragmatic hernia, hydronephrosis, and hydro-
cephalus were defects that might be amenable to
prenatal therapy because they were simple structural
defects that nevertheless prevented normal fetal
development.10
That same year Harrison and his
group made the first report of an open fetal surgery
performed at 21 weeks of gestation for congenital
hydronephrosis.11
The necessity of perfecting surgical
techniques in animal models was recognized early,
and Harrison’s group first developed the surgical pro-
cedure using fetal lambs.12
Importantly, because pri-
mates are a better model for human fetuses, in part
because they are more susceptible to preterm labor
than other experimental animals, this group then
refined their anesthetic and surgical techniques in
a monkey model.13
Although the surgery was a success
in that the pregnancy continued for another 14 weeks,
at birth it was clear that the fetal kidneys had been
irrevocably damaged. The newborn had features of
oligohydramnios deformation sequence and died of
pulmonary hypoplasia. Nearly simultaneously, Clewell
and his team14
performed the first open fetal surgery
for ventriculoamniotic shunt placement in a 22-week
fetus with presumed isolated hydrocephalus. This pro-
cedure was also deemed successful in that the fetal
ventricles remained decompressed and the pregnancy
was stable until 32 weeks, when sudden ventricular
enlargement prompted delivery. Unfortunately, the
fetus was discovered to have X-linked hydrocephalus
and had a poor cognitive outcome. These cases illus-
trated one of the most challenging aspects of fetal
surgery: the difficulty of accurately diagnosing the
fetal condition and determining the prognosis to iden-
tify those fetuses most likely to benefit from prenatal
intervention.
Prenatal surgical procedures for other malforma-
tions were subsequently reported; some were perfected
over time and some were abandoned, but all were
complicated by the lack of effective tocolytic therapies
and the overwhelming risk of preterm birth. Excision
or debulking of pulmonary masses or sacrococcygeal
teratomas in the setting of impending or full-blown
fetal hydrops proved to be life-saving in some
cases,15,16
whereas ventricular shunting for hydroceph-
alus was abandoned largely because it was not possible
to determine which fetuses would benefit from the
intervention.17
Importantly, as neonatal care of preterm
newborns has improved, and with the advent of beta-
methasone, magnesium sulfate for neuroprotection,
and surfactant, elective preterm delivery has become
preferable to fetal intervention in many cases.
Although great progress has been made in the past
30 years, efforts to perfect prenatal surgery for a variety
of fetal anomalies continue to be complicated by the
challenge of selecting appropriate candidates for surgery
and the inability to prevent preterm delivery. The
reader is referred to several previous excellent reviews
of maternal-fetal surgery, including the comprehensive
818 Wenstrom and Carr Review of Fetal Surgery OBSTETRICS & GYNECOLOGY

technical brief by Hartmann et al, a review of the fun-
damental issues of fetal surgery by Chescheir, and a his-
tory of the leaders of fetal surgery by Bruner.18–20
Importantly, accumulated experience has served
to confirm the basic requirements for fetal surgery
proposed by the fledgling International Fetal Medi-
cine and Surgery Society in 1982 (Box 1).10
Although
these requirements were originally developed to guide
the development of new fetal surgeries, it can be
argued that they apply to any fetal surgery being con-
sidered today. Among these, the importance of having
a multidisciplinary team involved in the prenatal eval-
uation, the surgical therapy, and the postnatal care
cannot be overemphasized. Because confronting a fetal
abnormality raises unique and complex issues for the
family, in addition to a maternal-medicine specialist
experienced in prenatal diagnosis, a pediatric surgeon,
an experienced operating room team including
a knowledgeable anesthesiologist, and a neonatologist,
the family should have access to psychosocial support
and a bioethicist.21
This report summarizes data regarding maternal-
fetal surgical procedures that have been tested and
perfected and are currently considered standard of
care in experienced hands. It is beyond the scope of
this review to include a discussion of all fetal
procedures currently undergoing development.
CONDITIONS TREATED WITH CLOSED
SURGICAL THERAPIES
Technique
“Closed” fetal surgeries are procedures performed by
inserting needles, catheters, or trocars through the
uterine wall without the need for a hysterotomy,
although for some procedures the uterus is first
exposed using mini-laparotomy. Some of these proce-
dures (such as bladder shunt placement) can be per-
formed under local anesthesia or sedation. Others, such
as laser photocoagulation of placental vessels, need to be
performed under regional anesthesia (spinal or epidural)
if the uterus is exposed by mini-laparotomy first. All
closed procedures are performed under direct ultra-
sound guidance and usually involve only one uterine
puncture, approximately 2.4 mm, to allow the insertion
of a trocar through which a shunt or semi-rigid endo-
scope can be passed.
Intrauterine Fetal Transfusion
As noted, the advent of real-time ultrasound technol-
ogy allowed dramatic advancements in the technique
for fetal blood transfusion. In 1983, Daffos reported
using ultrasound guidance to obtain fetal blood
samples from the umbilical vein, and in 1986,
Grannum et al reported performing four ultrasound-
guided fetal red blood cell transfusions directly into
the umbilical vein.22,23
This intravascular technique
was quickly adopted, and subsequent case control
studies confirmed the superiority of this approach.
One study that compared the outcomes of 75 fetuses
treated with intraperitoneal transfusion with the out-
comes of 44 fetuses treated with umbilical vein trans-
fusion confirmed that the intravascular technique
resulted in a statistically significant increase in survival
(91% compared with 66%; P,.005), fewer complica-
tions (10% compared with 38%; P5.003), and more
advanced gestational age at delivery (34.1 compared
with 30.7 weeks; P5.01).24
The technique for intravas-
cular fetal transfusion has been perfected over time
and has long been considered standard of care for
anemic fetuses.25
Although initially the decision to
perform a transfusion was based on maternal antibody
titers and amniotic fluid bilirubin levels (which reflect
the degree of fetal hemolysis), in 2000, Mari et al26
reported that the peak systolic velocity of blood flow
through the middle cerebral artery had 100% sensitiv-
ity to detect a fetal hemoglobin level less than 0.65
multiples of the median with a 0% false-negative rate
and a 12% false-positive rate, and amniocentesis was
Box 1. Basic Requirements for Fetal Surgery
1. The anatomic malformations suitable for in utero
treatment are simple structural defects that interfere
with organ development but that might allow nor-
mal fetal development to proceed if corrected.
2. The fetus should be a singleton with no additional
structural or genetic anomalies.
3. The natural history of the defect and fetal disease
must be known, with intervention justified only if
there is reasonable probability of benefit.
4. Before consideration of surgery, careful serial
assessment of anatomy and organ function must
be performed to exclude fetuses affected mildly
enough that they could wait for postnatal therapy,
as well as fetuses so severely affected that they can-
not be saved.
5. The family must be counseled about risk and bene-
fits and should agree to treatment including long-
term follow-up.
6. A multidisciplinary team including a maternal-
medicine specialist experienced in prenatal diagno-
sis, a pediatric surgeon, and a neonatologist should
agree on the plan for treatment.
7. There should be access to a level III high-risk obstet-
ric unit and intensive care nursery and to bioethical
and psychosocial consultation.
Data from Harrison MR, Filly RA, Golbus MS, Berkowitz RL,
Callen PW, Canty TG, et al. Occasional notes: fetal treatment
1982. N Engl J Med 1982;307:1651–2.
VOL. 124, NO. 4, OCTOBER 2014 Wenstrom and Carr Review of Fetal Surgery 819

no longer needed to identify anemic fetuses. Although
the use of Rh immune globulin has drastically
reduced the incidence of RhD disease, isoimmuniza-
tion to other red cell antigens makes fetal intrauterine
transfusion the most common fetal therapy performed
today.
CLOSED SURGICAL THERAPIES
Lower Urinary Tract Obstruction
Lower urinary tract obstruction results from obstruc-
tion of the urethra. Although some degree of obstruc-
tion is identified in up to 1% of all fetuses, most
blockages are minor and not associated with morbid-
ity.27
Complete unrelenting obstruction, however, has
severe and well-documented consequences, including
bladder dilation, hydrouretronephrosis, renal dyspla-
sia, and, as a result of anhydramnios, pulmonary
hypoplasia; 45% of cases of severe obstruction end
in neonatal death.28
The ultimate effect of the urethral
obstruction is a function of degree and timing: the
more severe the obstruction and the earlier the onset,
the greater the potential for the known consequences.
If complete obstruction occurs before the glomeruli
are fully formed, renal dysplasia results. In a sheep
model, ligation of the urethra at 90 days (comparable
to 160 days or 25 weeks in a human fetus) resulted in
the development of renal fibrosis, whereas ligation at
60 days (106 days or 17 weeks) resulted in renal cystic
dysplasia.29
Improvements in ultrasonography have enhanced
our ability to diagnose lower urinary tract obstruction
at earlier gestational ages, but our ability to discrimi-
nate between the recognized etiologies of lower urinary
tract obstruction remains limited. Although lower
urinary tract obstruction can result from urethral
atresia, the most common etiology is posterior urethral
valves, occurring in approximately 1 out of 1,250
almost exclusively male fetuses.30
In this disorder,
a membrane in the portion of the urethra surrounded
by the prostate results in varying degrees of urethral
obstruction.31
Lower urinary tract obstruction typically
manifests early in gestation with bladder dilation, fol-
lowed by renal pelviceal dilation and then develop-
ment of echogenic renal cortex. High-grade bladder
obstruction typically results in bladder distention soon
after the onset of fetal urine production at 8–10 weeks,
but the diagnosis is usually not made until an anatomic
survey is performed at 18–20 weeks of pregnancy.
There have been numerous attempts to determine
prognosis in lower urinary tract obstruction. Among
the potentially predictive factors that have been
studied are gestational age at diagnosis, appearance
of the renal parenchyma, and oligohydramnios.
Morris et al32
concluded that severe oligohydramnios
and the development of renal cortical cysts are the
most reliable predictors of poor outcome. Prediction
of outcome based on fetal renal function as measured
by fetal urinary electrolytes has also been attempted.
Glick’s criteria,33
which originally included fetal uri-
nary sodium and chloride concentrations and hourly
urine output, with b2 microglobulin, calcium, total
protein, and osmolality added by other investigators,
are commonly used in this setting, but a recent
meta-analysis revealed that there are no individual
analytes or thresholds that demonstrate good clinical
utility in predicting poor renal outcome.34
In that
meta-analysis, only elevated fetal urinary calcium or
elevated fetal urinary sodium showed predictive
potential.
Antenatal intervention for lower urinary tract
obstruction, first described in 1982, has yet to live
up to its early promise, most likely because of our
incomplete understanding of prognostic factors and
the precise timing and natural history of the insults
resulting from lower urinary tract obstruction. Ante-
natal intervention most commonly entails placement
of a vesico-amnionic shunt or ablation of the obstruc-
tion using fetal cystoscopy, both intended to relieve
the lower urinary tract obstruction and thus prevent
some or all of the sequelae. Vesico-amnionic shunt-
ing, which is associated with relatively low morbidity
for the mother, is accomplished using ultrasound
guidance to insert a narrow trocar through the
maternal abdomen and uterus and into the fetal
bladder, through which a double pigtail catheter is
placed so that one end is in the fetal bladder and the
other exits out the fetal abdomen. This procedure can
be performed under local anesthesia and results in
only minor trauma to the uterus. Ablation of the
urethral obstruction is accomplished by performing
fetal cystoscopy; an endoscope is advanced through
a trocar inserted into the fetal bladder, the urethra is
visually inspected, and the obstruction is relieved by
using a laser or hydroablation to remove the tissue
blocking the urethra or by inserting a stent into the
urethra under direct visualization. This procedure
usually requires general anesthesia, so it entails more
risk for the mother.
A recent meta-analysis by Morris et al35
evaluated
the efficacy of antenatal intervention for lower urinary
tract obstruction. Twenty studies were identified, with
369 fetuses included in the evaluation. A total of 261
of the 369 fetuses underwent antenatal intervention;
226 underwent vesico-amnionic shunt, 9 had an open
procedure, and 26 had fetal cystoscopy. Of the 26
fetuses evaluated with cystoscopy, only 14 ultimately

had cystoscopically guided therapy, either posterior
urethral valve ablation by laser or hydroablation or
urethral stent placement. The remainder had vesi-
coamnionic shunts placed after cystoscopy demon-
strated no fixable lesion or the cystoscopically
directed intervention was not successful. Intervention
improved overall perinatal survival compared with no
intervention (odds ratio [OR] 3.82, 95% confidence
interval [CI] 2.14–6.82), but once terminations and
fetal demises were removed from the data set, the only
group that demonstrated benefit from intervention
was the subgroup with poor prognosis (OR 9.36,
95% CI 1.41–62.05). There was no significant
improvement in the rate of survival with normal post-
natal renal function in the group with good prognosis
(OR 2.98, 95% CI 0.45–19.62). No comparison of the
group with good prognosis and the subgroup with
poor prognosis could be made, because no fetuses in
the group with poor prognosis survived with normal
renal function. The authors concluded that prenatal
intervention for lower urinary tract obstruction is
associated with increased perinatal survival (particu-
larly in the subgroup with poor prognosis), but that
intervention is associated with increased incidence of
impaired postnatal renal function.
Despite the relative ease (compared with fetal
cystoscopy) of shunt placement, vesico-amnionic shunt
placement is associated with significant fetal morbidity.
Initial reports documented 4% mortality and 44%
complication rates.36
A more recent series illustrated
the associated morbidities: two of nine catheters had
to be re-inserted; only six of nine fetuses survived
(there was one termination and two deaths attributable
to pulmonary hypoplasia) and three of the six survivors
had some degree of renal impairment (two had end-
stage renal disease and one had mild impairment).37
Fetal cystoscopy, the other modality used to
address lower urinary tract obstruction, offers
improved sensitivity in detecting posterior urethral
valves compared with ultrasonography (87–100%
detection using cystoscopy compared with 45% using
ultrasonography).38,39
It also offers the theoretical
advantage of preserving normal fetal bladder cycling,
which is essential for normal postnatal bladder func-
tion. The most comprehensive analysis of the effect of
fetal cystoscopy on postnatal outcomes is the meta-
analysis of four eligible studies including 63 patients
that was performed by Morris et al38
in 2011.
Although cystoscopy was associated with an increase
in perinatal survival compared with no treatment (OR
20.51, 95% CI 3.87–108.69), it offered no improve-
ment in perinatal survival over vesico-amnionic shunt
(OR 1.49, 95% CI 0.13–16.97).
Although most authorities agree that fetal inter-
vention should be based on an understanding of the
natural history of the disorder being treated, there
are little data in this regard for lower urinary tract
obstruction. One of the only studies to address long-
term outcome relative to age at diagnosis is the study
by Ylinen et al,40
in which a cohort of 46 Finnish
neonates, 23 of whom had antenatal diagnoses
and 23 had postnatal diagnoses, were followed for
a mean of 12.5 years. These investigators found
no significant difference between the cohort with
antenatal diagnoses and the cohort with postnatal
diagnoses with respect to poor renal function
(complete renal failure or end-stage renal disease,
mean glomerular filtration rate, age of advancing to
end-stage renal disease, initial or highest creatinine,
presence of vesicoureteral reflux, or incidence of
renal dysplasia). The authors acknowledged that it
is still not clear whether the real damage associated
with lower urinary tract obstruction is caused by the
disturbed urodynamics resulting from antenatal
obstruction or whether the renal dysplasia develops
as a result of the same insult that caused the obstruc-
tion, and thus co-exists with but is not caused by the
lower urinary tract obstruction. Until the etiology
of lower urinary tract obstruction–associated renal
dysplasia is clarified, it will not be possible to accu-
rately identify appropriate candidates for antenatal
intervention.
The almost inescapable conclusion arising from
these data is that we have not as yet demonstrated the
efficacy of intrauterine intervention for lower urinary
tract obstruction. The literature is problematic
because it consists of small case series with widely
differing selection criteria for intervention. Although
meta-analyses overcome some of these limitations,
a prospective randomized trial is needed. The
percutaneous shunting in low urinary tract obstruc-
tion (PLUTO) trial41
proposed to randomize 150 fe-
tuses with lower urinary tract obstruction to either
vesico-amnionic shunt or conservative noninterven-
tional care. It began in 2009 but closed because of
slow enrollment after enlisting only 31 patients.
Although the trial did not reach recruitment goals,
it found that shunted fetuses had better survival than
nonshunted fetuses (relative risk [RR] 3.30, 95% CI
1.02–9.62; P5.03). The study reached no conclu-
sions regarding the benefit (or lack thereof) of vesi-
coamnionic shunting on long-term renal function.
The much-needed high-quality data that we hoped
to see from the PLUTO trial, data that we could
use to inform our choice of interventions, remain
elusive.

Placental Laser Photocoagulation for
Twin–Twin Transfusion Syndrome
Unbalanced placental vascular anastomoses across
a monochorionic, diamnionic placenta underlie the
pathophysiology of twin–twin transfusion syndrome
(Fig. 1) and can present in four ways: arterio-venous,
veno-arterial, arterio-arterial, and veno-venous.
Arterio-venous and veno-arterial anastamoses result
when a placental surface feeder vessel from each
twin perfuses a common cotyledon, and arterio-
arterial and veno-venous anastamoses are connec-
tions on the surface of the placenta that have the
potential for either unidirectional or bidirectional
blood flow. Computer modeling suggests that severe
twin–twin transfusion syndrome results from unidi-
rectional blood flow primarily through arterio-
venous anastamoses, from donor placental arteries
to recipient placental veins,42
but the initiating event
remains unknown. The best estimate of the incidence
of twin–twin transfusion syndrome is that it affects
9% to 15% of monochorionic twin pregnancies,43,44
but our understanding remains incomplete of
why twin–twin transfusion syndrome occurs in
a minority of monochorionic twins when placental anas-
tamoses are nearly ubiquitous in these pregnancies.
Placental injection studies suggest that twin–twin trans-
fusion syndrome is more likely in placentas with
fewer anastamoses and without arterio-arterial
anastamoses.45,46
The imbalance in circulating blood volume that
results from these anastomoses leads to cardiovascular
responses that eventually become maladaptive.
Although the donor twin usually maintains normal
cardiac function, hypervolemia in the recipient twin
results in increased preload, leading to right ventric-
ular hypertrophy, and eventually hypertension and
cardiomyopathy. The increased systemic pressure
may also result in increased right ventricular afterload
and diminished right heart output, contributing to
pulmonic stenosis.47
Eventually, fetal death results;
the mortality rate for untreated progressive twin–twin
transfusion syndrome is approximately 90%.48
The
goal of intervention is to restore more equitable blood
flow between the twins and thus to halt or reverse
cardiac decompensation in the recipient.
Therapies attempted for twin–twin transfusion
syndrome have included selective fetal reduction,
septostomy of the dividing membrane, amnioreduc-
tion, and laser photocoagulation of the surface pla-
cental anastomoses; all except selective reduction
have been tested in randomized trials. Septostomy
allows the amniotic fluid volume in each sac to equil-
ibrate, reversing the oligohydramnios or anhydram-
nios typically seen in the sac of the donor twin, and
amnioreduction is based on the theory that reducing
the amniotic fluid volume alters the hydrostatic pres-
sure on the placental surface vessels and enables
more equal blood flow between the two areas of
the placenta supporting each twin. Studies of septos-
tomy indicate no survival advantage with this tech-
nique and an association with complications such as
preterm rupture of the membranes and the uninten-
tional creation of a monoamniotic cavity. Amniore-
duction has been reported to result in survival rates
of 18% to 83%, but it is also associated with compli-
cations such as preterm rupture of the membranes,
infection, placental abruption, preterm delivery, and
neurologic complications in 5% to 58% of survi-
vors.49
Laser photocoagulation is associated with
similar obstetric complications but with survival
rates of 55% to 69% and neurologic abnormalities
in 5% to 11% of survivors. A Cochrane review found
that laser ablation of placental vessels was associated
with less perinatal death (RR 0.59, 95% CI 0.40–
0.87) and less neonatal death (RR 0.29, 95% CI
0.14–0.61) than amnioreduction.50
Currently, the
therapy of choice is a laser photocoagulation proce-
dure, in which a laser is introduced endoscopically
into the uterus and used to ablate surface placental
vessel anastomoses under ultrasound guidance. This
procedure can be performed under local anesthesia.
However, some groups perform a mini-laparotomy
Fig. 1. Schematic depiction of twin–twin transfusion syn-
drome demonstrating vascular anastomoses between
monochorionic and diamnionic twins. Image courtesy of
Francois Luks, MD. Used with permission.
Wenstrom and Carr. Review of Fetal Surgery. Obstet Gynecol
2014.

first to gain better access to the uterine surface, and
thus greater control of the laser, and this requires
regional anesthesia.
Determining the threshold for intervening in
twin–twin transfusion syndrome is problematic, in
part because of the unpredictable nature of the pro-
gression of the disorder. In an attempt to standardize
nomenclature for this condition, Quintero51
proposed
classifying the progression of twin–twin transfusion
syndrome into five stages based on the degree of fetal
compromise (Table 1). Although a few programs offer
intervention for stage I twin–twin transfusion syn-
drome, most programs consider only Quintero stage
II or higher twin–twin transfusion syndrome to be
sufficient justification for undertaking the risks of in
utero intervention. Because twin–twin transfusion syn-
drome does not always progress linearly through all
the stages, and because a proportion of cases of early
stage twin–twin transfusion syndrome regress sponta-
neously, some programs require persistent Quintero
stage II on more than one occasion more than 24
hours apart to justify those risks. The gestational age
beyond which laser photocoagulation should not be
offered also differs between programs, with some
centers not offering this therapy after 24 weeks and
others not offering it after 25 or 26 weeks. For these
and other reasons, interpreting data from case series
is problematic. The results of two large randomized
trials have been reported, but both were interrupted
before completion. In a trial sponsored by the Eunice
Kennedy Shriver National Institute of Child Health
and Human Development, pregnancies presenting
before 22 weeks and complicated by stage II or higher
twin–twin transfusion syndrome first underwent an am-
nioreduction and were then randomized to laser pho-
tocoagulation or aggressive serial amnioreduction.52
This trial was halted after enrollment of 42 of 146
planned participants, in part because an interim analy-
sis indicated increased mortality in recipient twins after
laser photocoagulation. The Eurofetus trial randomized
pregnancies presenting between 15 weeks and 26
weeks complicated by stage I or higher twin–twin
transfusion syndrome (recipient twin with maximum
vertical amnionic fluid pocket 8 cm or larger up to
20 weeks and 10 cm or larger at more than 20 weeks,
with a distended bladder; donor twin with maximum
vertical amnionic fluid pocket 2 cm or smaller) to laser
photocoagulation or serial amnioreduction.53
This
trial was stopped after enrollment of 142 of 172
planned participants after an interim analysis indi-
cated that laser ablation resulted in better survival
rates at 28 days of life (at least one twin alive at 28
days: 76% compared with 56%, P5.009; RR of death
of both fetuses: 0.63, 95% CI 0.25–0.93) and at 6
months of life (P5.002), as well as fewer neurologic
abnormalities in survivors (no neurologic complica-
tions at 6 months of age: 52% compared with 31%;
P5.003). The Brown University program, which of-
fers laser photocoagulation only to patients with per-
sistent stage II or higher twin–twin transfusion
syndrome, has reported fetal outcomes identical to
those of other programs while taking only approxi-
mately 50% of all evaluated patients to the operating
suite.54
There is a randomized trial underway under
the auspices of the North American Fetal Treatment
Network to determine whether the risks of stage I
twin–twin transfusion syndrome warrant the risks of
in utero intervention.
A number of different strategies have been pro-
posed to maximize the clinical effect of laser ablation.
The most recent contribution to this literature is
a randomized controlled trial of 274 women random-
ized to either standard laser coagulation or coagula-
tion of the entire vascular equator. That study found
that laser coagulation of the entire vascular equator
was associated with a significant reduction in twin
anemia polycythemia sequence (OR 0.16, 95% CI
0.05–0.49) and reduced recurrence of twin–twin trans-
fusion syndrome (OR 0.21, 95% CI 0.04–0.98), but no
difference in perinatal mortality and severe neonatal
morbidity.55
Thoraco-Amniotic Shunting
Fetal pleural effusions occur in every 1 out of 10,000–
15,000 pregnancies. Effusions can be primary or
isolated, meaning that they are not associated with
other fetal anomalies, or secondary, meaning that they
occur in association with or as the result of a variety of
fetal abnormalities. The majority of isolated effusions
Table 1. Staging of Twin–Twin Transfusion
Syndrome
Stage Ultrasonographic Findings
I Maximum vertical amnionic fluid pocket smaller than
2 cm in donor sac; maximum vertical amnionic fluid
pocket larger than 8 cm in recipient sac
II Nonvisualization of bladder in donor twin
III Absent or reversed umbilical artery end-diastolic flow,
reversed ductus venosus a-wave flow, or pulsatile
umbilical vein flow
IV Hydrops in one or both twins
V Death of one or both twins
Data from Quintero RA, Morales WJ, Allen MH, Bornick PW,
Johnson PK, Kruger M. Staging of twin-twin transfusion syn-
drome. J Perinatol 1999;19:550–5.

result from the abnormal drainage of lymph fluid
directly into the pleural space rather than into the
mediastinal lymph nodes; although this would be
called a chylothorax in the neonatal period, the stan-
dard criteria for defining chylothorax cannot be
applied to fetuses because they are not feeding (thus,
triglyceride levels are not elevated) and fetal lympho-
cyte counts are normally high. Secondary effusions can
occur as part of hydrops or as the result of intrathoracic
malformations such as congenital cystic adenomatoid
malformations or bronchopulmonary sequestrations,
congenital infections including herpes simplex or par-
vovirus B19, or genetic abnormalities such as trisomy
21 or Noonan syndrome.56
Associated fetal malformations that may
adversely affect pregnancy outcomes have been
reported in 25% to 75% of cases. In 2011, Ruano
et al57
published their observations of 56 untreated
cases evaluated at their center between 2005 and
2009. Fourteen had isolated pleural effusion, 19 had
pleural effusion and associated structural anomalies,
and 23 had pleural effusion with an abnormal karyo-
type. None of the fetuses with associated structural
anomalies and only 13% of fetuses with karyotypic
abnormalities survived the neonatal period. Because
the prognosis of a secondary effusion appears to be
determined by its cause rather than by the effusion
itself, typically only fetuses with isolated or primary
effusions or survivable lesions such as congenital cystic
adenomatoid malformation or pulmonary sequestra-
tion are considered candidates for prenatal shunting.
The rationale for shunting is that, if an effusion be-
comes severe, the increased hydrostatic pressure within
the fetal thorax can compress developing lung tissue,
resulting in pulmonary hypoplasia, or can compress
the fetal heart, leading to cardiac decompensation or
nonimmune hydrops. Because of the threat of fetal
compromise and the ease with which intrathoracic fluid
can be accessed, isolated pleural effusions offer tempt-
ing targets for practitioners adept with ultrasonography
and needles. However, as with all fetal surgeries, the
natural history of the condition should be understood
and the efficacy of the intervention should be proven
before shunt placement is considered.
The natural history of untreated isolated fetal
pleural effusion has been assessed by several groups.
In the study by Ruano57
that examined 56 fetuses with
pleural effusion, 63% of untreated fetuses with isolated
effusion survived, as did 50% of fetuses with isolated
effusion and hydrops. Rustico et al56
summarized the
outcomes of 54 cases of unshunted isolated pleural
effusion from the published literature. Seventy-three
percent of fetuses with untreated isolated pleural effu-
sion without hydrops survived, as did 35% of fetuses
with hydrops. Unfortunately, these series do not
include data regarding gestational age at delivery, so
it is unclear whether survival was achieved by iatro-
genic preterm birth, which might have had additional
consequences. In a review of 204 published cases of
isolated pleural effusion by Aubard in 1998, sponta-
neous regression occurred in 22%; regression was
most likely in cases identified in the second trimester
and in those with unilateral effusions.58
The unpredict-
able outcome manifest in these series suggests that we
do not yet have a full understanding of the natural
history of this disorder.
For this reason and others, there is no strong
consensus in the literature about indications for
intervention in fetuses with pleural effusion. A
guideline issued by the National Institute for Health
and Clinical Excellence states that invasive fetal
therapy for fetal hydrothorax should be restricted
to fetuses with primary or isolated effusions resulting
in hydrops.59
However, other experienced clinicians
have suggested that criteria for intervention should
include the following: fetal hydrops with the pleural
effusion as the likely etiology; isolated pleural effu-
sion without hydrops occupying more than 50% of
the thoracic cavity, causing the mediastinum to shift
or rapidly increasing in size or associated with
polyhydramnios; or isolated effusion without associ-
ated anomalies.60
Confirming that an effusion is
isolated requires a careful and complete fetal evalu-
ation that generally includes a detailed examination
of fetal anatomy including a fetal echocardiogram,
a fetal karyotype, maternal blood type and antibody
status, Kleihauer-Bettke testing, and virology testing,
including toxoplasmosis, rubella, cytomegalovirus,
herpes simplex virus, and parvovirus B19.
Interventions for draining the fetal chest and
obliterating the potential intrathoracic space include
thoracentesis, thoracoamniotic shunt placement, and
pleurodesis. All are performed under ultrasound
guidance and have known fetal and maternal risks.
A recent report of a single center experience cites
these risks as shunt failure in 22% of cases, premature
rupture of membranes (PROM) in up to 33% of cases,
and intrauterine fetal death directly attributable to the
procedure itself in 7% of cases.61
Pleurodesis, or cre-
ating inflammation that obliterates the pleural space
by injecting an irritant, has the additional risk of in-
hibiting shunt placement as a second-line therapy by
causing the formation of intrathoracic bands.
There have been no published randomized trials
directly comparing pregnancy outcomes in treated
compared with untreated fetal pleural effusions, so we

are left to compare case series and collections of
case series, most of which evaluated hydropic and
nonhyropic fetuses separately. The 2007 report of
Rustico56
included data from 203 published cases of
antenatally treated isolated fetal pleural effusion,
which indicated a survival rate of 77% to 82% in non-
hydropic fetuses and 50% to 62% in hydropic fetuses
treated with thoracentesis or thoracoamniotic shunt-
ing. The survival rate was 60% in the pleurodesis
group, with no difference between hydropic and non-
hydropic fetuses, but the numbers were quite small.
Duerloo et al62
reviewed 108 hydropic fetuses with
pleural effusion culled from the published literature,
treated with thoracentesis, thoracoamniotic shunting,
or pleurodesis. They found very similar survival rates
of 60% to 80% regardless of intervention. Pellegrini
et al63
summarized their large single-center experience
and reported an 85% survival rate in shunted nonhy-
dropic fetuses and a 47% survival rate in shunted hy-
dropic fetuses, for an overall survival rate of 52%. In
2012, Yang et al64
published the largest series of pleu-
rodesis for fetal pleural effusion. Of 49 fetuses with
bilateral pleural effusions attributed to chylothorax,
4 had spontaneous resolution (8.2%) and 14 (31.1%)
did not survive to birth (10 [22.2%] had an intrauter-
ine fetal death and 4 [8.9%] terminated after unsatis-
factory results after pleurodesis). After successful
pleurodesis procedures, the rate of long-term survival
was 14.8% (4/27) for hydropic fetuses and was 66.7%
(12/18) for nonhydropic fetuses.
Our understanding of the natural history of fetal
pleural effusions remains imperfect. Natural history
observational studies suggest that untreated fetal pleural
effusions are associated with 63% to 73% survival in
nonhydropic cases and 35% to 50% in hydropic cases.56
However, in most published series, in utero interven-
tion appears to be associated with a survival rate of 60%
to 85% for isolated nonhydropic fetal pleural effusions
and 50% to 60% for hydropic fetuses. As noted pre-
viously, in most series it is unclear if survival with or
without antenatal treatment was achieved by elective
preterm delivery, so the effect of antenatal treatment
on the prolongation of pregnancy is unknown. At pres-
ent, the available data suggest that intervening in cases
of isolated nonhydropic pleural effusion offers, at most,
a small increase in survival.
CONDITIONS TREATED WITH OPEN
SURGICAL THERAPIES
Technique
“Open” fetal surgery refers to the fact that a hysterot-
omy is performed to gain access to the fetus, and
creating the hysterotomy might be considered the
most challenging part of the surgery. The uterine inci-
sion must be placed well away from the placental
edge, which is located intraoperatively using ultraso-
nography, but must also allow ready access to the
fetus. Once the optimal site is chosen, two full-
thickness stay sutures are placed through the uterus
and into the amniotic cavity at one edge of the
planned incision site, fixing the membranes to the
uterine wall, and the uterine cavity is entered with
a trocar. A uterine stapling device with absorbable
staples is then inserted through the opening created
by the trocar, engaged, and fired along the planned
incision line; the staples fix the membranes to the
uterine wall so that they can be incorporated into
the closure, thus preventing membrane separation.
The edge of the incision corresponding to the trocar
site, which is not covered by staples, is then rendered
hemostatic with a running lock stitch of absorbable
suture. One serious complication that can occur dur-
ing this part of the procedure is bleeding between the
membranes and the uterus, leading to a subchorionic
hematoma, which could potentially dissect the mem-
branes away from the uterine wall. Recognizing this
problem early allows sutures to be placed to tamponade
the bleeding vessels. Ideally, the fetus is positioned
directly beneath the incision site with only minimal
manipulation, and a catheter for the infusion of warm
saline is placed into the uterus to maintain amniotic
fluid volume and prevent umbilical cord compression
and fetal cooling. The fetal heart rate is monitored ultra-
sonographically throughout the procedure, with fetal
resuscitation in the form of position change, increased
amnioinfusion, or maternal measures provided as
needed.
OPEN SURGICAL THERAPIES
Myelominingocele
Neural tube defects, including anencephaly, encepha-
locele, and myelominingocele, are the most common
congenital structural defects worldwide. Before folic
acid supplementation, neural tube defects affected 1–2
per 1,000 pregnancies The fortification of cereal and
grain products in the United States (begun in 1996,
mandatory by January 1998) has been associated with
a 31% decrease in the incidence of neural tube de-
fects.65
Myelominingocele is the result of incomplete
closure of the neural tube, resulting in defective ver-
tebrae that permit the neural placode, meninges, or
both to herniate out of the spinal canal, allowing the
open dura mater to fuse laterally to the dermis and the
open pia pater to fuse to the epidermis.66
The spinal cord
is damaged at the site of and distal to the defect and, as
a consequence, survivors with meningomyelocele

generally live with some degree of bladder and bowel
dysfunction, limited or no independent ambulation, and
ventriculomegaly requiring a ventriculoperitoneal shunt.
Serial observations of affected fetuses and postmortem
and animal studies indicate that the neurologic damage
occurs both as the result of abnormal neurulation and as
a consequence of prenatal exposure of the neural ele-
ments to amniotic fluid and trauma attributable to fetal
movement. This theory is supported by the observation
that only half of affected fetuses have ventriculomegaly
before 24 weeks, but more than 90% have developed
ventriculomegaly by term.67
This theory also provides
the rationale for trying to close the defect during mid-
gestation. Because additional neurologic damage can
occur after birth as the result of ventriculoperitoneal
shunt malfunction, replacement of the ventriculoperito-
neal shunt, and infection, any treatment that reduces the
need for ventriculoperitoneal shunting would also
improve outcome.
The first reported fetal surgery for meningomye-
locele used a laparoscopic approach68
but, because of
disappointing outcomes, this technique was abandoned
in favor of open repair using hysterotomy.69
Subse-
quently, several nonrandomized case series reported
retrospectively and at least two prospective cohort
studies have been published, totaling more than 270
cases worldwide,70
in which outcomes after prenatal
surgery were compared with those of similar patients
undergoing postnatal repair. However, patients (and
their fetuses) who were offered antenatal surgery were
frequently different from those who had postnatal
repair, and rapidly changing standards of postnatal care
for meningomyelocele made historical controls unac-
ceptable. Although most studies described reversal of
hindbrain herniation and significantly lower rates of
postnatal shunt placement in fetuses treated prenatally,
including one study in which the fetal participants were
stratified by lesion level, neurologic follow-up was gen-
erally limited. No study found that prenatal meningo-
myelocele repair improved postnatal urologic function,
and data regarding ultimate bowel and leg function
were limited. Although nonrandom patient selection,
multiple potential sources of bias, and lack of long-term
follow-up of both the child and the mother made it
difficult to determine the potential benefits of this pro-
cedure using existing reports, most experts agreed
there was enough encouraging data to warrant a ran-
domized trial.
The Management of Myelomeningocele Study
trial was an ambitious trial of prenatal compared with
postnatal myelomeningocele repair that was funded
by the Eunice Kennedy Shriver National Institute of
Child Health and Human Development and the
National Institutes of Health and was conducted at
the University of California in San Francisco, the
Children’s Hospital of Philadelphia, and Vanderbilt
University.71
The study is notable for several reasons.
It was the first multicenter, prospective, randomized
controlled trial of maternal-fetal surgery for myelome-
ningocele, and it required that all three centers
develop a multispecialty team of clinicians who could
evaluate all clinical and psychosocial aspects of poten-
tial patients and provide standardized prenatal, surgi-
cal, and perioperative care. Surgeons at all three
centers had to develop and adhere to a strict protocol
covering every aspect of the surgery and perioperative
treatment. It also required the three major centers
performing this surgery to agree not to offer it outside
the trial for the duration of the study (amounting to
a nationwide moratorium on myelomeningocele sur-
gery), which turned out to be 7 years. Although the
criteria for entry into the trial were stringent, there
was no requirement that fetal leg motion still be pres-
ent, a criterion for previous published series that made
it difficult to assess the surgery’s effect on future
mobility. The surgery was offered to patients at 19.0
weeks to 25.0 weeks of gestation with confirmed
euploid fetuses having myelomeningocele located
between T1 and S1, with evidence of hindbrain her-
niation. Women randomized to prenatal surgery had
to stay in the vicinity of their assigned center from the
time of the initial surgery until delivery at 37 weeks;
those assigned to postnatal surgery were required to
return to their center at 37 weeks for delivery, with the
newborn’s postnatal repair performed by the same
team that performed the prenatal repairs. Importantly,
all children in the study underwent physical and neu-
rologic examinations and developmental testing at 12
months and 30 months of age by trained independent
pediatricians and psychologists who were unaware of
the child’s surgical assignment.
The first primary outcome of the study, evaluated
at 12 months of age, was a composite of fetal or
neonatal death or the need for a cerebrospinal shunt.
The second primary outcome, assessed at 30 months
of age, was a composite score of the Mental Devel-
opment Index of the Bayley Scales of Infant Devel-
opment II and the child’s motor function with
adjustment for lesion level (determined by an inde-
pendent group of radiologists). Secondary maternal,
fetal, and neonatal outcomes included surgical and
obstetric complications and neonatal morbidity.
Infant outcomes included the status of the Chiari II
malformation, the timing of the first shunt, locomo-
tion, the Psychomotor Development Index of the
Bayley Scales, scores on the Peabody Developmental

Motor Scales, and the degree of functional impair-
ment and disability.
Power analysis determined that 100 patients per
group were required. One thousand eighty-seven
women underwent screening, but ultimately only
183 were enrolled during the first 7 years of the
study. The Data and Safely Monitoring Committee
recommended that the study be terminated early,
after an interim analysis of the first 134 patients
enrolled revealed that outcomes were better in the
prenatal surgery group (Table 2). Specifically, com-
pared with neonates who underwent postnatal sur-
gery, fetuses treated with prenatal surgery were
significantly less likely to experience fetal or neonatal
death or meet criteria for shunt placement and were
significantly less likely to have any kind of hindbrain
herniation. The hindbrain herniation they did have
was less severe. At 30 months, the children in both
groups had similar scores on the Bayley Mental Devel-
opment Index and similar Wee FIM (a measure of
pediatric functional independence) cognitive scores.
However, those who underwent prenatal surgery were
significantly more likely to have motor function one or
two or more levels better than predicted by the level of
the lesion and had significantly better Bayley Psycho-
motor Development Index and Peabody Developmen-
tal Motor Scales scores. Compared with the postnatal
group, twice as many children in the prenatal surgery
group were walking independently and fewer were not
walking at all. These outcomes were especially surpris-
ing considering that, although the women in the two
groups were similar in almost every way, the fetuses
of women randomized to prenatal surgery actually
had more severe lesions (27% at the L1 to L2 level
compared with 12% in the postnatal group). In addi-
tion, the majority of the antenatal treatment group
delivered preterm; 13% delivered before 30 weeks,
33% delivered at 30 to 34 weeks, and 33% delivered
at 35 to 36 weeks.
The Management of Myelomeningocele Study
trial also revealed significant adverse consequences of
antenatal surgery. In addition to preterm delivery,
women who underwent prenatal surgery were signifi-
cantly more likely to develop pulmonary edema,
placental abruption, oligohydramnios, spontaneous
rupture of the membranes, or spontaneous labor, and
more likely to require a blood transfusion than those
whose child underwent postnatal repair. At the time of
the cesarean delivery, 25% of women who had prenatal
surgery had a very thin hysterotomy site, 9% had an
area of dehiscence within the site, and 1% had
a complete dehiscence. In addition, more children in
the prenatal surgery group required surgery for teth-
ered cord (8% compared with 1%).
Congenital Diaphragmatic Hernia
Congenital diaphragmatic hernia complicates 1 in
every 2,000–3,000 births.72
Although the precise eti-
ology remains uncertain, data from animal models
suggest that an abnormality of nonmuscular mesen-
chymal cell differentiation leads to failure of the pleu-
roperitoneal folds to fuse during weeks 4 to 10.73
Table 2. Management of Myelomeningocele Study Trial Neonatal Outcomes*
Outcome Prenatal Surgery (n578) Postnatal Surgery (n580) RR (95% CI) P
Primary outcome 53 (68) 78 (98) 0.70 (0.58–0.84)†
,.001
Components of primary outcome ,.001
Death 2 (3) 0
Shunt criteria met 51 (65) 74 (92)
Shunt placed without criteria met 0 4 (5)
Shunt placement 31 (40) 66 (82) 0.48 (0.36–0.64) ,.001
Any hindbrain herniation 45/70 (64) 66/69 (96) 0.67 ,.001
Degrees of herniation (0.56–0.81)‡
,.001
None 25/70 (36) 3/69 (4)
Mild 28/70 (40) 20/69 (29)
Moderate 13/70 (19) 31/69 (45)
Severe 4/70 (6) 15/69 (22)
RR, relative risk; CI, confidence interval.
Data are n (%) or n/N (%) unless otherwise specified.
* Percentages may not total 100 because of rounding.
†
The relative risk for the composite primary outcome is reported with a 97.7% confidence interval.
‡
The between-group comparison was performed with the use of the Cochran-Armitage test for trend.
Data from Adzick NS, Thom EA, Spong CY, Brock JW III, Burrows PK, Johnson MP, et al. A randomized trial of prenatal versus postnatal
repair of myelomeningocele. N Engl J Med 2011;364:993–1004. Copyright Ó 2011 Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.

Regardless of the etiology, intrusion of abdominal
contents into the thoracic cavity during the critical
period for development of bronchi and pulmonary
arteries (up to week 16) leads to diminished branching
of bronchioles, decreased overall arterial cross-
sectional area, and increased muscularization of the
pulmonary arterial system.74
This abnormal pulmo-
nary development results in pulmonary hypoplasia
and pulmonary hypertension, the major causes of
morbidity in neonates with congenital diaphragmatic
hernia.
There are three types of congenital diaphragmatic
hernia. The majority (95%) are the Bochdalek type, or
defects of the postero-lateral diaphragm, most of
which are left-sided. Other more rare types include
the Morgagni type (parasternal defect) and defects of
the central tendon.75
Prenatal diagnosis of congenital
diaphragmatic hernia relies on several classic ultra-
sound findings, including abdominal organs (stomach,
intestines, liver) seen in the thoracic cavity, displace-
ment of the heart to the hemithorax contralateral to
the defect, cardiac axis shift, and polyhydramnios.
Approximately two thirds of cases of isolated congen-
ital diaphragmatic hernia are identified in the second
and third trimesters,76
with higher detection rates re-
ported by specialty centers. In approximately 26–58%
of congenital diaphragmatic hernia cases, the hernia is
accompanied by additional unrelated anomalies or
occurs as part of a genetic syndrome.77
Because the
survival rate for these cases is very poor regardless of
the type and timing of intervention, they are usually
not considered for antenatal fetal therapy.
Over the past 30 years, the overall survival of
neonates with isolated congenital diaphragmatic her-
nia has increased from 50% to 70% to 80%.78
Although the diagnosis and treatment of antenatally
diagnosed congenital diaphragmatic hernia have
evolved during this time, the improved survival is
primarily attributable to significant advances in post-
natal care, including the use of extracorporeal mem-
brane oxygenation, nitric oxide, and other modalities.
This has made it more challenging to demonstrate the
efficacy of in utero intervention. In view of current
satisfactory survival rates with postnatal care at a ter-
tiary center, most investigators now offer prenatal
intervention to only the severest cases with the worst
prognosis and lowest life expectancy. Early work uti-
lizing hysterotomy and fetal thoracotomy for dia-
phragmatic hernia repair was promising, but clinical
trials showed no increase in survival over standard
postnatal care,79
and this approach was abandoned.
In the 1990s, experimental work in a sheep model
of congenital diaphragmatic hernia demonstrated that
tracheal occlusion could accelerate fetal lung growth,
prevent pulmonary hypoplasia, and restore normal
physiologic lung function.80
The presumed mecha-
nism is that obstruction of the normal efflux of fetal
lung fluid leads to an increase in transpulmonic pres-
sure, resulting in large, fluid-filled lungs. Early human
trials of tracheal occlusion also utilized hysterotomy
and an open fetal technique.81,82
These trials demon-
strated greater than predicted survival in treated
fetuses (33% compared with 13%, respectively), but
the results were difficult to interpret because they
were not randomized and the majority of cases
resulted in preterm birth.
To minimize the risks of preterm labor and
premature rupture of membranes, the fetal surgery
community developed minimally invasive techniques
to achieve reversible tracheal occlusion.83
In the first
randomized controlled trial of percutaneous fetal tra-
cheal occlusion, fetuses with severe left-side congeni-
tal diaphragmatic hernia were randomly assigned to
either in utero tracheal occlusion (two cases of a tra-
cheal clip, six cases of endotracheal balloon) or stan-
dard care.84
All study pregnancies were delivered by
ex utero intrapartum treatment (EXIT, discussed
below). Enrollment was stopped at 24 cases because
of an unexpectedly high survival rate in the postnatal
treatment group, and there was no demonstrated ben-
efit associated with in utero intervention; a high rate of
preterm delivery in the prenatal intervention group
likely influenced this outcome. In a more recent
trial,85
patients with severe congenital diaphragmatic
hernia were randomized to either fetoscopic endotra-
cheal occlusion (n520) or standard postnatal manage-
ment (n521). Fifty percent of fetuses in the fetoscopic
endotracheal occlusion group survived to 6 months of
age, whereas 6-month survival was only 4.8% in the
postnatal treatment group.
The discrepant outcomes of these two trials likely
result from differences in the study participants.
Although both studies included only cases of “severe”
congenital diaphragmatic hernia, the thresholds used
to define severe congenital diaphragmatic hernia dif-
fered. Congenital diaphragmatic hernia severity has
been estimated by the lung-to-head ratio, in which
the area of the lung contralateral to the congenital
diaphragmatic hernia is divided by the head circum-
ference. Although increasing lung-to-head ratio is gen-
erally associated with improved survival, a wide range
of outcomes after antenatal intervention has been re-
ported. This disparity likely results from variations in
measurement techniques, as well as a spectrum of ges-
tational ages at the time of the surgery, and inclusion
of both left congenital diaphragmatic hernia and right

congenital diaphragmatic hernia and both liver-up
and liver-down cases. Recent studies and conven-
tional wisdom suggest that the liver-up position is
associated with a decreased chance of survival,86,87
but it remains uncertain whether liver position is truly
an independent predictor.88
Based on findings that the
lung-to-head ratio increases with gestational age, Jani
et al89
proposed an observed-to-expected lung-to-head
ratio that is truly gestational age–independent. The
observed-to-expected lung-to-head ratio has the advan-
tage of being applicable to both left-sided and right-
sided congenital diaphragmatic hernias, and logistic
regression demonstrated that it predicted survival
independent of the position of the liver above
or below the level of the diaphragm. Magnetic reso-
nance imaging–based calculations likely offer increased
accuracy in determining fetal lung volumes, and a mag-
netic resonance imaging–based observed-to-expected
fetal lung volume of 30% appears to be a threshold
above which survival improves and below which sur-
vival decreases.90
A consensus on the timing of in utero interven-
tion has evolved. Maximal benefit for lung develop-
ment requires that the tracheal occlusion be
performed as early as possible, but evidence suggests
that tracheal occlusion before 26 weeks increases the
risk of tracheal damage91
; therefore, current practice is
to occlude the fetal trachea at 26–28 weeks. Greater
benefit is derived from occluding the trachea as long
as possible, but the increased risk of preterm delivery
and the potential of neonatal death from an occluded
trachea have led to a consensus to remove the occlu-
sive balloon at 34 weeks. This can be performed either
by percutaneous balloon deflation (by needling)
under ultrasound guidance or by endoscopic removal.
Alternatively, a planned EXIT procedure can be
performed.
Improvement in the survival of neonates who
receive standard postnatal surgery and support de-
mands that in utero intervention be offered only in
those cases in which standard postnatal treatment will
likely not be successful. Improved methods for
identifying those fetuses at greatest risk are making
it possible to accomplish that, but, as with in utero
intervention for bladder outlet obstruction, proof of
efficacy remains elusive, and in utero intervention
must be considered experimental. An indication that
we are on the right path comes from a secondary
analysis of the fetoscopic endotracheal occlusion
registry of 210 consecutive procedures. This analysis
showed that fetuses with congenital diaphragmatic
hernia with poor prognosis (observed-to-expected
lung-to-head ratio of less than 25% in left-side defects
and less than 45% in right-side defects) treated
antenatally have experienced morbidities similar to
those fetuses with moderate congenital diaphragmatic
hernia managed expectantly.92
Fetal Tumors
Fortunately, fetal tumors are rare, occurring in 4–8
per 100,000 births.93
Although the widespread use
of antenatal ultrasonography has led to the antenatal
diagnosis of many fetal tumors, most are best treated
after delivery. Certain fetal tumors, however, can dis-
rupt fetal development or lead to fetal death by caus-
ing the development of hydrops. The most common
tumor in this category is sacrococcygeal teratoma,
with an incidence of 1 out of 35,000 to 40,000 births.94
Sacrococcygeal teratomas are derived from abnormal
growth of the pluripotent cells in the Hensen node,
and thus contain tissues of endodermal, mesodermal,
and ectodermal origin with both solid and cystic com-
ponents. They usually appear as a mass of mixed
echogenicity extending from the sacrum or growing
from the sacrum into the pelvis. Because they are
often highly vascular, contain arterio-venous shunts,
and may grow rapidly, sacrococcygeal teratomas can
lead to fetal compromise through vascular steal phe-
nomena, leading to high-output fetal cardiac failure.
Tumor tissue may also be fragile, with spontaneous
bleeding occurring when the enlarging tumor is com-
pressed against the uterine wall or during labor or
delivery. Fetuses with sacrococcygeal teratomas can
have additional anomalies, mostly occurring as the
consequence of deformation by the sacrococcygeal
teratoma, which can affect prognosis. These include
rectal stenosis or atresia, hydrocolpos, urinary tract
obstruction and related renal anomalies, pulmonary
hypoplasia resulting from oligohydramnios, and hip
dislocation or club foot.95
Several studies have attempted to delineate the
natural course of untreated sacrococcygeal teratomas
and to identify factors that indicate poor prognosis.
Early case series of sacrococcygeal teratoma were
likely negatively skewed by the fact that many pre-
natal cases were discovered during a work-up for
hydramnios or other pregnancy complications. More
recent series including cases identified during routine
targeted ultrasound examination suggest that the
majority of fetuses with incidentally diagnosed sacro-
coccygeal teratomas survive to delivery without
intervention and do well after neonatal surgery.96
However, a small proportion of fetuses with sacrococ-
cygeal teratomas have fast-growing, highly vascular
tumors and are at risk of prenatal death as the result
of heart failure or bleeding, making hydrops the

strongest predictor of an adverse outcome.97
Other
reported predictors include a ratio of tumor volume
to fetal weight of 0.12 or more, tumors with mostly
solid rather than cystic elements, rapid tumor growth,
impaired fetal cardiac function or cardiomegaly, and
the development of complications such as hydramnios
or the mirror syndrome (maternal features of pre-
eclampsia mirroring fetal hydrops).96,98,99
The development of hydrops at a gestational age
at which neonatal survival is likely usually prompts
delivery, whereas impending hydrops in an immature
fetus raises the possibility of fetal therapy. Current
interventions include open fetal surgical debulking,
shunt placement in large cystic lesions, and radio-
frequency ablation, with a wide range of reported
survival rates; the high rate of adverse outcomes
reported by fetal treatment centers may reflect the
increased severity of referred cases. Hedrick et al95
reported a series of 30 cases of sacrococcygeal terato-
mas managed at one center in which the criteria for
open fetal surgical treatment included sacrococcygeal
teratomas in a singleton euploid fetus without other
anomalies and impending high-output cardiac failure
at less than 30 weeks of gestation. Of the 26 ongoing
pregnancies, only four fetuses met the criteria for
open fetal surgery and underwent antenatal surgical
debulking, and three of these survived. Ten fetuses
had other interventions (amnioreduction, amnioinfu-
sion, or cyst aspiration), and nine survived. However,
of the remaining 12 pregnancies, five resulted in fetal
death before intervention (three were hydropic, one
had partial tumor rupture and pericardial and pleural
effusions, and one had no autopsy), three resulted in
death after preterm delivery performed for antenatal
tumor rupture and hemorrhage, two died of tumor
rupture during neonatal surgery, and one died as the
result of pulmonary hypoplasia. Thus, the overall sur-
vival rate for sacrococcygeal teratomas in this series
was only 46% (12/26).
In contrast, Lee et al100
reported a series of 32
fetuses with sacrococcygeal teratomas treated at one
center; eight were treated antenatally with radiofre-
quency ablation, shunt placement, or cyst aspiration,
and the overall survival rate was 91% (although 10
fetuses were lost to follow-up). The criteria for radio-
frequency ablation in this series included a rapidly
growing, highly vascular mass and cardiomegaly.
Although eight fetuses were treated with radiofre-
quency ablation, it was successful in only one fetus;
the other seven were delivered preterm at 25 to 31
weeks, and five survived. Makin et al101
published
a series of 29 cases treated over an 11-year period,
which included 17 fetuses not requiring antenatal ther-
apy and delivered at a mean gestational age of 38
weeks; 16 of these survived. Of the other 12 fetuses,
seven had hydrops, two had hydramnios (one with
cardiomegaly), one had fetal bladder obstruction,
two had a cyst so large it would obstruct delivery,
and all underwent antenatal therapies including laser
vessel ablation (n54), alcohol sclerosis (n53), cyst
drainage (n52), amniodrainage (n52), and vesi-
coamniotic shunt (n51). The five fetuses without hy-
drops survived, but six of the seven hydropic fetuses
died. The overall survival rate in this series was 76%.
The literature on sacrococcygeal teratomas sug-
gests that therapy to try to reverse full-blown fetal
hydrops is frequently unsuccessful, yet our ability to
identify impending cardiac decompensation and thus
candidates for possible antenatal intervention is imper-
fect. Importantly, prenatal therapy is not possible in
many cases because the impending decompensation
includes hydramnios, placentomegaly, and preterm
labor. One report suggests that a policy of preterm
delivery for fetuses with impending hydrops before 32
weeks is a reasonable strategy; of nine fetuses delivered
at 26–31 weeks for evolving hydrops, rapid tumor
growth, nonreassuring fetal status, or preterm labor,
four survived.102
The literature on fetal thoracic masses such as
congenital cystic adenomatoid malformation or pul-
monary sequestration is very similar to that on
sacrococcygeal teratomas. Most of these thoracic
masses are well-tolerated by the fetus and successfully
treated after birth, whereas others can lead to antena-
tal cardiac decompensation and hydrops. As with
sacrococcygeal teratomas, the prognosis for fetuses
with hydrops in this setting is dismal. Impending
cardiac decompensation at an early gestational age is
an indication for fetal therapy, usually in the form of
open surgery for mass resection or the placement of
a thoraco-amniotic shunt. A review of the outcomes of
a series of fetuses with congenital cystic adenomatoid
malformation or pulmonary sequestration from one of
the world’s largest fetal treatment centers confirms
that, for nonhydropic fetuses, survival without antena-
tal surgery is excellent (98% survival for 125 cases of
congenital cystic adenomatoid malformation; 100%
survival for 23 cases of pulmonary sequestration).103
The survival rate for the 48 ongoing hydropic preg-
nancies complicated by fetal congenital cystic adeno-
matoid malformation was zero for the 14 patients who
elected no intervention and 57% for the 23 patients
who had open fetal surgery; other treatments included
percutaneous intervention (one of five survived) and
EXIT to immediate postnatal surgery (one of three
survived). Interestingly, in this series three patients

elected to have maternal steroid treatment followed
by delivery at 21–24 weeks, and all survived, suggest-
ing that early delivery in the presence of hydrops is
also a viable treatment option for thoracic mass
lesions.
Conditions Treated With the Ex Utero
Intrapartum Treatment Procedure
The EXIT procedure was developed for the delivery
of fetuses with congenital diaphragmatic hernia trea-
ted with antenatal tracheal clipping, to allow time to
remove the clip and establish an airway before the
fetus was separated from the placenta.104
It has since
been applied to cases of airway obstruction from
a variety of other causes. In this procedure, the patient
(and fetus) undergoes general anesthesia with neuro-
muscular blockade, a hysterotomy is created with
a stapling devise using absorbable sutures, and the
fetal head and shoulders are delivered through the
incision. While the placenta is still providing gas
exchange, fetal intubation by laryngoscopy or rigid
bronchoscopy, tracheostomy, or even tumor resection
can be performed to establish an airway. Bleeding is
controlled by the staples on the edge of the incision
and by coordination between the surgeon and anes-
thesiologist regarding the timing of decreasing the
inhaled anesthetic and the administration of oxyto-
cin. To prevent the collapse of the uterine cavity and
possible placental separation or umbilical cord com-
pression, warm saline can be infused into the uterus.
In addition to facilitating the removal of tracheal
clips, the EXIT procedure has now been used suc-
cessfully for fetuses with congenital high airway
obstruction syndrome (the absence or blockage of
the larynx or trachea)105
and a variety of anomalies
including neck masses that compress the trachea, or-
al tumors, dysgnathia complex, and persistent medi-
astinal compression associated with lung masses.106–
110
In one review of 52 cases in which the EXIT
procedure was performed for tracheal clip or balloon
removal in fetuses with congenital diaphragmatic
hernia or for neck masses, the average operating time
was 45625 minutes and the average blood loss was
9706510 mL.111
However, this review also noted
that successful completion of the procedure without
fetal or maternal compromise has been reported after
150 minutes before delivery.
SUMMARY
Developing the fetal surgical procedures described in
this review required the contributions of a large
number of physician scientists over many, many
years. First, pediatricians and neonatologists identified
structural congenital anomalies that are lethal or
highly morbid because they prevent normal develop-
ment. Geneticists, embryologists, and pathologists
then worked to determine the etiologies of these
malformations and to predict the developmental out-
come if the defects could be corrected or ameliorated
before birth. Maternal-fetal medicine specialists and
radiologists developed imaging techniques to accu-
rately diagnose these defects prenatally. Pediatric
surgeons then worked to adapt neonatal surgical
procedures to the antenatal period and to perfect
those techniques using animal models. Anesthesiolo-
gists, surgeons, and maternal-fetal medicine specialists
worked together to safely apply those surgical proce-
dures to human fetuses while minimizing maternal risk.
Maternal-fetal medicine specialists cared for postsurgical
patients and developed protocols to minimize compli-
cations, including the risk of preterm birth. Neonatolo-
gists cared for the former fetal patients, who were likely
to have been born preterm, and devised a variety of
supportive therapies. Social workers and bioethicists
provided parental support throughout. Once these steps
had been accomplished, the procedures began to be
tested in small series, allowing colleagues to exchange
ideas and suggest procedural modifications. Eventually,
the data regarding some surgeries seemed promising
enough that they could be evaluated in prospective
randomized trials, a task that required the collaboration
of hundreds of practitioners at multiple centers because
the fetal defects being treated are rare.
The surgical procedures described in this review
are the result of all these efforts, expended over many,
many years by a wide variety of specialists, and are
thus remarkable in many ways. It is therefore with
a spirit of optimism, not criticism, that we must
acknowledge that in nearly every case the procedures
have not yet been perfected. The primary problems
continue to be accurately identifying which fetuses
will die or be severely injured without intervention,
but still will have the capacity to recover relatively
normal function if fetal surgery is performed, and
prevention of preterm delivery after fetal intervention.
Advances in neonatal care, which have resulted in the
survival of neonates who surely would have died even
15–20 years ago, have made the perfection of some
fetal procedures less urgent. However, there are still
some anomalies, especially those leading to perma-
nent renal or neurologic damage, that will continue
to be devastating regardless of neonatal care, and it is
for these anomalies that prenatal surgery holds the
most promise.
The tremendous resources required to perform
fetal surgery, including the considerable investment in

training that is required of a fetal surgeon, together with
the relative rarity of most of the conditions for which
fetal surgery is attempted, demand that the number of
fetal surgery centers be limited so that each can care for
enough patients to justify their cost and maintain the
skills of the fetal interventionists. At present there is no
consensus on how many procedures each center or
provider should perform each year to maintain their
skills or, for that matter, how many procedures should
be performed before a surgeon is considered qualified.
The societies of the various specialists involved in fetal
surgery must collaborate on criteria for initial and
ongoing certification of fetal surgery centers and fetal
surgeons so that the considerable progress that has
been achieved so far can continue, and maternal and
fetal patients can continue to receive the safest and
most effective therapies.
REFERENCES
1. Cohnstein J, Zuntz N. Untersuchungen über das Blut, den
Kreislauf und die Athmung beim Säugethier-Fötus. Archiv
für die gesamte Physiologie des Menschen und der Tiere
1884;34:173–233.
2. Wells LJ. Effects of androgen upon reproductive organs of
normal and castrated fetuses with note on adrenalectomy. Proc
Soc Exp Biol Med 1946;63:417–9.
3. Liley AW. Intrauterine transfusion of foetus in Haemolytic
disease. Br Med J 1963;2:1107–9.
4. Asensio SH. Human fetal surgery. Clin Obstet Gynecol 1974;
17:153–70.
5. Adamsons K Jr, Freda VJ, James LS, Towell ME. Prenatal
treatment of erythroblastosis fetalis following hysterotomy.
Pediatrics 1965;35:848–55.
6. Campbell S. An improved method of fetal cephalometry by
ultrasound. J Obstet Gynaecol Br Commonw 1968;75:568–76.
7. Hobbins JC, Davis CD, Webster J. A new technique utilizing
ultrasound to aid in intrauterine transfusion. J Clin Ultrasound
1976;4:135–7.
8. Rodeck CH, Kemp JR, Holman CA, Whitmore DN,
Karnicki J, Austin MA. Direct intravascular fetal blood trans-
fusion by fetoscopy in severe Rhesus isoimmunisation. Lancet
1981;1:625–7.
9. Adamson K. Current concepts: fetal surgery. N Engl J Med
1966;275:204–5.
10. Harrison MR, Filly RA, Golbus MS, Berkowitz RL,
Callen PW, Canty TG, et al. Fetal treatment. N Engl J Med
1982;307:1651–2.
11. Harrison MR, Golbus MS, Filly RA, Callen PW, Katz M, de
Lorimier AA, et al. Fetal surgery for congenital hydronephro-
sis. N Engl J Med 1982;306:591–3.
12. Harrison MR, Nakayama DK, Noall R, de Lorimier AA. Cor-
rection of congenital hydronephrosis in utero II. Decompres-
sion reverses the effects of obstruction on the fetal lung and
urinary tract. J Pediatr Surg 1982;17:965–74.
13. Harrison MR, Anderson J, Rosen MA, Ross NA,
Hendrickx AG. Fetal surgery in the primate I. Anesthetic,
surgical, and tocolytic management to maximize fetal-
neonatal survival. J Pediatr Surg 1982;17:115–22.
14. Clewell WH, Johnson ML, Meier PR, Newkirk JB, Zide SL,
Hendee RW, et al. A surgical approach to the treatment of
fetal hydrocephalus. N Engl J Med 1982;306:1320–5.
15. Grethel EJ, Wagner AJ, Clifton MS, Cortes RA, Framer DL,
Harrison MR, et al. Fetal intervention for mass lesions and
hydrops improved outcome: a 15-year experience. J Pediatr
Surg 2007;42:117–23.
16. Hedrick HL, Flake AW, Crombleholme TM, Howell LJ,
Johnson MP, Wilson RD, et al. Sacrococcygeal teratoma: pre-
natal assessment, fetal intervention, and outcome. J Pediatr
Surg 2004;39:430–8.
17. Manning FA, Harrison MR, Rodeck C. Catheter shunts for fetal
hydronephrosis and hydrocephalus. Report of the International
Fetal Surgery Registry. N Engl J Med 1986;315:336–40.
18. Hartmann KE, McPheeters ML, Chescheir NC, Gillam-
Krakauer M, McKoy JN, Jerome R, et al. Evidence to inform
decisions about maternal-fetal surgery. Obstet Gynecol 2011;
117:1191–204.
19. Chescheir NC. Maternal fetal surgery. Where are we and how
did we get here? Obstet Gynecol 2009;113:717–31.
20. Bruner JP. In their footsteps: a brief history of maternal-fetal
surgery. Clin Perinatol 2003;30:439–47.
21. Bliton MJ. Ethics: “life before birth” and moral complexity in
maternal-fetal surgery for spina bifida. Clin Perinatol 2003;30:
449–64.
22. Daffos F, Capella-Pavlovsky M, Forrestier F. A new procedure
for fetal blood sampling in utero: preliminary results of 65
cases. Am J Obstet Gynecol 1983;146:985–7.
23. Grannum PA, Copel JA, Plaxe SC, Scioscia AL, Hobbins JC.
In utero exchange transfusion by direct intravascular injection
in severe erythroblastosis fetalis. N Engl J Med 1986;314:
1431–4.
24. Harman CR, Bowman JM, Manning FA, Menticoglou SM.
Intrauterine transfusion- intraperitoneal versus intravascular
approach: a case-control study. Am J Obstet Gynecol 1990;
162:1053–9.
25. Moise KJ, Argoti PS. Management and prevention of red cell
alloimmunization in pregnancy. A systematic review. Obstet
Gynecol 2012;120:1132–9.
26. Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R,
Moise KJ Jr, et al. Noninvasive diagnosis by Doppler ultraso-
nography of fetal anemia due to maternal red cell alloimmuniza-
tion. Collaborative Group for Doppler Assessment of the Blood
Velocity in Anemic Fetuses. N Engl J Med 2000;342:9–14.
27. Wu S, Johnson MP. Fetal lower urinary tract obstruction. Clin
Perinatol 2009;36:377–90.
28. Makayama DK, Harrison MR, deLorimer AA. Prognosis of
posterior urethral valves presenting at birth. J Pediatr Surg
1986;21:43–5.
29. Kitagawa H, Pringle KC, Zuccolo J, Stone P, Nakada K,
Kawaguchi F, et al. The pathogenesis of dysplastic kidneys
in urinary tract obstruction in the female lamb model.
J Pediatr Surg 1999;34:1678–83.
30. Gunn TR, Mora JD, Pease P. Antenatal diagnosis of urinary
tract abnormalities by ultrasonography after 28 weeks gesta-
tion: incidence and outcome. Am J Obstet Gynecol 1995;172:
479–86.
31. Krishnan A, de Souza A, Konijeti R, Baskin LS. The anatomy
and embryology of posterior urethral valves. J Urol 2006;175:
1214–20.
32. Morris RK, Malin GL, Kahn KS, Kilby MD. Antenatal ultra-
sound to predict postnatal renal function in congenital lower

urinary tract obstruction: systematic review of test accuracy.
BJOG 2009;116:1290–9.
33. Glick PL, Harrison MR, Golbus MS, Adzick NS, Filly RA,
Callen PW, et al. Management of the fetus with congenital
hydronephrosis II: prognostic criteria and selection for treat-
ment. J Pediatr Surg 1985;20:376–87.
34. Morris RK, Quinlan-Jones E, Kilby M, Kahn KS. Systematic
review of accuracy of fetal urine analysis to predict poor post-
natal renal function in case of congenital urinary tract obstruc-
tion. Prenat Diagn 2007;27:900–11.
35. Morris RK, Malin GL, Kahn KS, Kilby MD. Systematic
review of the effectiveness of antenatal intervention for the
treatment of congenital lower urinary tract obstruction. BJOG
2010;117:382–90.
36. Elder JS, Duckett JW, Snyder HM. Intervention for fetal
obstructive uropathy: has it been effective? Lancet 1987;2:
1007–9.
37. McLorie G, Farhat W, Khoury A, Geary D, Ryan G. Outcome
analysis of vesicoamniotic shunting in a comprehensive pop-
ulation. J Urol 2001;166:1036–40.
38. Morris RK, Ruano R, Kilby MD. Effectiveness of fetal cystos-
copy as a diagnostic and therapeutic intervention for lower
urinary tract obstruction: a systematic review. Ultrasound Ob-
stet Gynecol 2011;37:629–37.
39. Robyr R, Benachi A, Daikha-Dahmane F, Martinovich J,
Dumez Y, Ville Y. Correlation between ultrasound and ana-
tomical findings in fetuses with lower urinary tract obstruction
in the first half of pregnancy. Ultrasound Obstet Gynecol
2005;25:478–82.
40. Ylinen E, la-Houhala M, Wikstrom S. Prognostic factors of
posterior urethral valves and the role of antenatal detection.
Pediatr Nephrol 2004;19:874–9.
41. Morris RK, Kilby MD. An overview of the literature on con-
genital lower urinary tract obstruction and introduction to the
PLUTO trial: percutaneous shunting in lower urinary tract
obstruction. Aust N Z J Obstet Gynaecol 2009;49:6–10.
42. Talbert BG, Bajoria R, Sepulveda W, Bower S, Fisk NM.
Hydrostatic and osmotic pressure gradients produce manifes-
tations of fetofetal transfusion syndrome in a computerized
model of monochorial twin pregnancy. Am J Obstet Gynecol
1996;174:598–608.
43. Sebire NJ, Snijders RJ, Hughes K, Sepulveda W,
Nicolaides KH. The hidden mortality of monchorionic twin
pregnancies. Br J Obstet Gynaecol 1997;104:1203–7.
44. Lewi L, Jani J, Boes AS, Donne E, Van Mieghem T,
Gucciardo L, et al. The natural history of monochorionic twins
and the role of prenatal ultrasound scan. Ultrasound Obstet
Gynecol 2007;30:401–2.
45. Lopriore E, Deprest J, Slaghekke F, Oepkes D,
Middlethorp JM, Vandenbussche FP, et al. Placental charac-
teristics in monochorionic twins with and without twin
anemia-polycythemia sequence. Obstet Gynecol 2008;112:
753–8.
46. Denbow ML, Cox P, Taylor M, Hammal DM, Fisk NM. Pla-
cental angioarchitecture in monchprionic twin pregnancies:
relationship to fetal growth, fetofetal transfusion syndrome,
and pregnancy outcome. Am J Obstet Gynecol 2000;182:
417–26.
47. Simpson LL, Marx GR, Elkadry EA, D’Alton ME. Cardiac
dysfunction in twin-twin transfusion syndrome: a prospective
longitudinal study. Obstet Gynecol 1998;92:557–62.
48. Haverkamp F, Lex C, Hanisch C, Fahnenstitch H, Zerres K.
Neurodevelopmental risks in twin-to-twin transfusion syndrome:
preliminary findings. Eur J Paediatr Neurol 2001;5:21–7.
49. Simpson LL; for the Society of Maternal-Fetal Medicine
(SMFM). Twin-twin transfusion syndrome. Am J Obstet Gy-
necol 2013;208:3–18.
50. Roberts D, Neilson JP, Kilby M, Gates S. Interventions for the
treatment of twin-twin transfusion syndrome review. The Co-
chrane Database of Systematic Reviews 2008, Issue 1. Art.
No.: CD002073. DOI: 10.1002/14651858.CD002073.pub2.
51. Quintero RA, Morales WJ, Allen MH, Bornick PW,
Johnson PK, Kruger M. Staging of twin-twin transfusion syn-
drome. J Perinatol 1999;19:550–5.
52. Crombleholme TM, Shera D, Lee H, Johnson M, D’Alton M,
Porter F, et al. A prospective randomized multicenter trial of
amnioreduction vs selective fetoscopic laser photocoagulation
for the treatment of severe twin-twin transfusion syndrome.
Am J Obstet Gynecol 2007;197:396.e1–9.
53. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y.
Endoscopic laser surgery versus serial amnioreduction for
severe twin-twin transfusion syndrome. N Engl J Med 2004;
351:136–44.
54. Luks FI, Carr SR, Muratore CS, O’Brien BM, Tracy TF. The
pediatric surgeons’ contribution to in utero treatment of twin-
to-twin transfusion syndrome. Ann Surg 2009;250:456–62.
55. Slaghekke F, Lopriore E, Lewi L, Middlethorp J, van
Zwet EW, Weingertner S, et al. Fetoscopic laser coagulation
of the vascular equator versus selective coagulation for twin-to-
twin transfusion syndrome: an open-label randomized trial.
Lancet 2014;383:2144–51.
56. Rustico MA, Lanna M, Coviello D, Smoleniec J, Nicolini U.
Fetal pleural effusion. Prenat Diagn 2007;27:793–9.
57. Ruano R, Ramalho AS, Cardoso AKS, Moise K. Prenatal
diagnosis and natural history of fetuses presenting with pleural
effusion. Prenat Diagn 2011;31:496–9.
58. Aubard J, Derouineau I, Aubard V, Chalifour V, Preux PM.
Primary fetal hydrothorax: a literature review and proposed
antenatal strategy. Fetal Diagn Ther 1998;13:325–33.
59. NICE guideline IPG 190. Insertion of pleuro-amniotic shunt
for fetal pleural effusion. London: National Institute for Health
and Clinical Excellence; 2006.
60. Yinon Y, Grisaru-Granovsky S, Chadda V, Windrim R,
Seaward PGR, Kelly EN, et al. Perinatal outcome following
fetal chest shunt insertion for pleural effusion. Ultrasound Ob-
stet Gynecol 2010;36:58–64.
61. Pellegrini JM, Kohler A, Kohler M, Weingartner AS, Favre R.
Prenatal management and thoracoamniotic shunting in pri-
mary fetal pleural effusions: a single center experience. Prenat
Diagn 2012;32:467–71.
62. Duerloo KL, Devlieger R, Lopriore E, Klumper FJ, Oepkes D.
Isolated fetal hydrothorax with hydrops: a systematic review
of prenatal treatment options. Prenat Diagn 2007;27:893–9.
63. Pellegrini JM, Kohler A, Kohler M, Weingartner AS, Favre R.
Prenatal management and thoracoamniotic shunting in pri-
mary fetal pleural effusions: a single center experience. Prenat
Diagn 2012;32:467–71.
64. Yang YS, Ma GC, Shih JC, Chen CP, Chou CH, Yeh KT,
et al. Experimental treatment of bilateral fetal Chylothorax
using in utero pleurodesis. Ultrasound Obstet Gynecol 2012;
39:56–62.
65. Williams LJ, Mai CT, Edmonds LD, Shaw GM, Kirby RS,
Hobbs CA, et al. Prevalence of spina bifida and anencephaly

during the transition to mandatory folic acid fortification in the
United States. Teratology 2002;66:33–9.
66. Meuli M, Meuli-Simmen C, Hutchins GM, Seller MJ,
Harrison MR, Adzick NS. The spinal cord lesion in human
fetuses with myelomeningocele: implications for fetal surgery.
J Pediatr Surg 1997;32:448–52.
67. Babcook CJ, Goldstein RB, Barth RA, Damato NM,
Callen PW, Filly RA. Prevalence of ventriculomegaly in asso-
ciation with myelomeningocele: correlation with gestational
age and severity of posterior fossa deformity. Radiology
1994;190:703–7.
68. Bruner JP, Richards WO, Tulipan NB, Arney TL. Endoscopic
coverage of fetal myelomeningocele in utero. Am J Obstet
Gynecol 1999;180:153–8.
69. Adzick NS, Sutton LN, Crombleholme TM, Flake AW. Suc-
cessful fetal surgery for spina bifida. Lancet 1998;352:1675–6.
70. Bruner JP. Intrauterine surgery in myelomeningocele. Semin
Fetal Neonatal Med 2007;12:471–6.
71. Adzick NS, Thom EA, Spong CY, Brock JW III, Burrows PK,
Johnson MP, et al. A randomized trial of prenatal versus post-
natal repair of myelomeningocele. N Engl J Med 2011;364:
993–1004.
72. Torfs CP, Curry CJ, Bateson TF. A population based study of
congenital diaphragmatic hernia. Teratology 1992;46:555–65.
73. Clugston RD, Greer JJ. Diaphragm development and con-
genital diaphragmatic hernia. Semin Pediatr Surg 2007;16:
94–100.
74. Miniati D. Pulmonary vascular remodeling. Semin Pediatr
Surg 2007;16:80–7.
75. Holder AM, Klaasens M, Tibboel D, de Klein A, Lee B,
Scott DA. Genetic factors in congenital diaphragmatic hernia.
Am J Hum Genet 2007;80:825–45.
76. Garne E, Haeusler M, Barisic I, Gjergja R, Stoll C,
Clementi M; Euroscan Study Group. Congenital diaphrag-
matic hernia: evaluation of prenatal diagnosis in 20 European
regions. Ultrasound Obstet Gynecol 2002;19:329–33.
77. Skari H, Bjornland K, Haugen G, Egeland T, Emblem R.
Congenital diaphragmatic hernia: a meta analysis of mortality
factors. J Pediatr Surg 2000;35:1187–97.
78. Downward CD, Jaksic T, Garza JJ, Dzakovic A, Nemes L,
Jennings RW. Analysis of an improved survival rate for con-
genital diaphragmatic hernia. J Pediatr Surg 2003;38:729–32.
79. Harrison MR, Adzick NS, Bullars KM, Farrell JA, Howell LJ,
Rosen MA, et al. Correction of congenital diaphragmatic her-
nia in utero VII: a prospective trial. J Pediatr Surg 1997;32:
1637–42.
80. DiFiiore JW, Fauza DO, Slavin R, Wilson JM. Experimental
fetal tracheal ligation reverses the structure and physiological
effects of pulmonary hypoplasia in congenital diaphragmatic
hernia. J Pediatr Surg 1994;29:248–57.
81. Harrison MR, Adzick NS, Flake AW, VandderWall KJ,
Bealer JF, Howell LJ, et al. Correction of congenital diaphrag-
matic hernia in utero VIII: response of the hypoplasic lung to
tracheal occlusion. J Pediatr Surg 1996;31:1339–48.
82. Flake AW, Crombleholme TM, Johnson MP, Howell LJ,
Adzick NS. Treatment of severe congenital diaphragmatic her-
nia by fetal tracheal occlusion: clinical experience with fifteen
cases. Am J Obstet Gynecol 2000;183:1059–66.
83. Deprest J, Gratacos E, Nicolaides KH; FETO Task Group.
Fetoscopic tracheal occlusion (FETO) for severe congenital
diaphragmatic hernia: evolution of a technique and prelimi-
nary results. Ultrasound Obstet Gynecol 2004;24:121–6.
84. Harrison MR, Keller RL, Hawgood SB, Kitterman JA,
Sandberg PL, Farmer DL, et al. A randomized trial of endo-
scopic tracheal occlusion for severe fetal congenital diaphrag-
matic hernia. N Engl J Med 2003;349:1916–24.
85. Ruano R, Yoshizaki CT, Da Silva MM, Ceccons MEJ,
Grasi MS, Tannuri U, et al. A randomized controlled trial of
fetal endoscopic occlusion versus postnatal management of
severe isolated congenital diaphragmatic hernia. Ultrasound
Obstet Gynecol 2012;39:20–7.
86. Seetharamaiah R, Younger JG, Bartlett RH, Hirschl RB.
Factors associated with survival in infants with
congenital diaphragmatic hernia requiring extracorporeal
membrane oxygenation: a report from the Congenital
Diaphragmatic Hernia Study Group. Pediatr Surg 2009;
44:1315–21.
87. Mullassery D, Ba’ath ME, Jesudason EC, Losty PD. Value of
liver Herniation in prediction of outcome in fetal congenital
diaphragmatic hernia: a systematic review and meta-analysis.
Ultrasound Obstet Gynecol 2010;35:609–14.
88. Peralta CFA, Cavoretto P, Csapo B, Vandecruys H,
Nicolaides KH. Assessment of lung area in normal fetuses at
12–22 weeks. Ultrasound Obstet Gynecol 2005;26:718–24.
89. Jani J, Nicolaides KH, Keller RL, Benachi A, Peralta CFA,
Favre R, et al. Observed to expected lung area to head cir-
cumference ratio in the prediction of survival in fetuses with
isolated diaphragmatic hernia. Ultrasound Obstet Gynecol
2007;30:67–71.
90. Cannie M, Jani J, Chaffiiotte C, Vaast P, Derulle P, Houfflin-
Debaege V, et al. Quantification of intrathoracic liver herniation
by magnetic resonance imaging and prediction of postnatal
survival in fetuses with congenital diaphragmatic hernia. Ultra-
sound Obstet Gynecol 2008;32:627–32.
91. Jani J, Valencia C, Cannie M, Vuckovic A, Sellars M,
Nicolaides KH. Tracheal diameter at birth in severe congenital
diaphragmatic hernia treated by fetal endoscopic tracheal
occlusion. Prenat Diagn 2011;31:699–704.
92. Done E, Gratacos E, Nicolaides KH, Allegaerts K, Valencia C,
Castanon M, et al. Predictors of neonatal morbidity in fetuses
with severe isolated congenital diaphragmatic hernia undergo-
ing fetoscopic tracheal occlusion. Ultrasound Obstet Gynecol
2013;42:77–83.
93. Moore SW. Neonatal tumors. Pediatr Surg Int 2013;29:
1217–29.
94. Flake AW. Fetal sacrococcygeal teratoma. Semin Pediatr Surg
1993;2:113–20.
95. Hedricks HL, Flake AW, Crombleholme TM, Howell LJ,
Johnson MP, Wilson RD, et al. Sacrocaccygeal teratoma: pre-
natal assessment, fetal intervention, and outcome. J Pediatr
Surg 2004;39:430–8.
96. Gucciardo L, Uyttebroek A, DeWever I, Renard M, Claus F,
Devlieger R, et al. Prenatal assessment and management of
sacrococcygeal teratoma. Prenat Diagn 2011;31:678–88.
97. Bond SL, Harrison MR, Schmidt KG, Silverman NH,
Flake AW, Slotnick RN, et al. Death due to high output car-
diac failure in fetal sacrocaccygeal teratoma. J Pediatr Surg
1990;25:1287–91.
98. Rodriguez MA, Cass DL, Lazar DA, Cassady CI, Moise KJ,
Johnson A, et al. Tumor volume to fetal weight ratio as an
early prognostic classification for fetal sacrococcygeal tera-
toma. J Pediatr Surg 2011;46:1182–5.
99. Shue E, Bolouri M, Jelin EB, Vu L, Bratton B, Cedars E,
et al. Tumor metrics and morphology predict poor prognosis
in prenatally diagnosed sacrococcygeal teratoma: a 25 years

experience at a single institution. J Pediatr Surg 2013;48:
1225–31.
100. Lee MY, Won HS, Hyun MK, Lee HY, Shim JY, Lee PR,
et al. Perinatal outcome of sacrococcygeal teratome. Prenat
Diagn 2011;31:1217–21.
101. Makin EC, Hyett J, Ade-Ajayi N, Patel S, Nicolaides K,
Davenport M. Outcome of antenatally diagnosed sacrococcy-
geal teratomas: single center experience (1993–2004). J Pediatr
Surg 2006;41:388–93.
102. Roybal JL, Moldenhauer JS, Khalek N, Bebbington MW,
Johnson MP, Hedrick HL, et al. Early delivery as an alterna-
tive management strategy for selected high risk fetal sacrococ-
cygeal teratomas. J Pediatr Surg 2011;46:1325–32.
103. Grethel EJ, Wagner AJ, Clifton MS, Cortes RA, Farmer DL,
Harrison MR, et al. Fetal intervention for mass lesions and
hydrops improves outcome: a 15 year experience. J Pediatr
Surg 2007;42:117–23.
104. Liechty KW, Crombleholme TM, Flake AW, Morgan MA,
Kurth CD, Hubbard AM, et al. Intrapartum airway manage-
ment for giant fetal neck masses: the EXIT (ex utero intra-
partum treatment) procedure. Am J Obstet Gynecol 1997;177:
870–4.
105. Saadai P, Jelin EB, Nijagal A, Schecter SC, Hirose S,
MacKenzie TC, et al. Long-term outcomes after fetal therapy
for congenital high airway obstructive syndrome. J Pediatr
Surg 2012;47:1095–100.
106. Helfer DC, Clivatti J, Yamashita AM, Moron AF. Anesthesia
for ex utero intrapartum treatment (EXIT procedure) in fetus
with prenatal diagnosis of oral and cervical malformations:
case reports. Rev Bras Anestesiol 2012;62:411–23.
107. Laje P, Johnson MP, Howell LJ, Bebbington MW,
Hedrick HL, Flake AW, et al. Ex utero intrapartum treatment
in the management of giant cervical teratomas. J Pediatr Surg
2012;47:1208–16.
108. Lazar DA, Olutoye OO, Moise KJ Jr, Ivey RT, Johnson A,
Ayres N, et al. Ex-utero intrapartum treatment procedure for
giant neck masses-fetal and maternal outcomes. J Pediatr Surg
2011;46:817–22.
109. Baker PA, Aftimos S, Anderson BJ. Airway management dur-
ing an EXIT procedure for a fetus with dysgnathia complex.
Paediatr Anaesth 2004;14:781–6.
110. Cass DL, Olutoye OO, Cassady CI, Zamora IJ, Ivey RT,
Ayres NA, et al. EXIT-to-resection for fetuses with large lung
masses and persistent mediastinal compression near birth.
J Pediatr Surg 2013;48:138–44.
111. Hirose S, Farmer DL, Lee H, Nobuhara KK, Harrison MR.
The ex utero intrapartum treatment procedure: looking back
at the EXIT. J Pediatr Surg 2004;39:375–80.
Moving?
Be sure to notify us of your address change!
College Members
Contact Membership Services
The American College of Obstetricians
and Gynecologists
409 12th Street, SW
PO Box 96920
Washington,DC 20090-6920
Telephone: 800-673-8444,ext2427
202-863-2427
Fax: 202-479-0054
E-mail: membership@acog.org
Replacement issues (Members only):
memberservice@lww.com
Nonmembers
Contact Customer Service
Lippincott Williams & Wilkins
PO Box 1580
Hagerstown, MD 21741-1580
Telephone: 800-638-3030 (United States)
301-223-2300 (Outside United States)
Fax: 301-223-2400
Web: www.lww.com (clickon eitherContact
LWW or Customer Service)
E-mail: orders@lww.com (nonmember
individuals and institutions)
rev 7/2013

Cirugia fetal

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Cirugia fetal

Similar to Cirugia fetal (20)

More from rubenhuaraz

More from rubenhuaraz (14)

Recently uploaded

Recently uploaded (20)

Cirugia fetal