Fetal Cystoscopy for Lower Urinary Tract Obstruction

Patients with severe LUTO will come for clinical evaluation as part of the standard clinical
care at the Fetal Center at Texas Children's Hospital. Once the diagnosis of fetal severe
LUTO is confirmed and the patient is considered for fetal intervention, patient will be
invited to participate in the present study. Fetal cystoscopy will be offered as an optional
experimental procedure.

The following information will be obtained in the standard clinical care visit as usual: a.
demographics (maternal age, parity); b. gestational age at the diagnosis of LUTO; c. fetal
ultrasound findings including documentation of cervical length, gestational age,fetal
bladder size, bladder wall thickness, degree of fetal hydronephrosis, amount of amniotic
fluid, fetal biometry; d. fetal urinary biochemistry; e. fetal echocardiogram findings.

The standard management options for fetal LUTO include expectant management, fetal
vesico-amniotic shunting or termination of pregnancy according to the law. These options
will be offered to all patients as the first set of management options and the gold
standard. In addition, the investigators group will offer the procedure as an alternative
experimental option, with a full explanation of the experimental nature of the procedure,
the technical benefits and difficulties, and the risks and potential benefits of the
procedure and the limited long-term outcomes information. Those patients who request
participation in the present study will be informed that they can, a priori, select a
crossover arm if for any reason the fetal cystoscopic procedure is not possible. They can
elect that a fetal vesico-amniotic shunting be performed or prenatal expectant management or
even termination of pregnancy (as part of the standard management of fetuses with LUTO).

Participation in the study:

Once the patient is deemed eligible, all prenatal standard management options will be
offered first to the patient. Fetal cystoscopy will be offered as an investigational
procedure for evaluation. If the patient opts for the fetal cystoscopy, we will explain that
this procedure can be diagnostic and therapeutic. In order to prevent coercion, the
investigation procedure will be presented to the patient in a manner that is an option and
voluntary, if the patient chooses not to participate in the investigational procedure, the
clinical care will not be affected. Informed consent to participate in the present study
will be obtained. We will also include non-English speaking subjects in the present study.
We will submit a full Spanish consent via amendment for IRB approval after approval of the
English consent. We will not enroll any non-English subjects until we receive final
approval. The study flow is demonstrated in Figure 1 (see attached document).

Description of the fetal cystoscopy procedure (experimental procedure):

Fetal cystoscopy will be performed between 16 0/7 and 25 6/7 weeks at the Pavilion for Women
- TCH. This procedure will be performed under maternal local anesthesia and sedation. In
some cases, according to the anesthesiologist's indication, maternal epidural may be
performed. Fetal anesthesia will be performed by ultrasound-guided injection into fetal arm
or leg of a combination of fentanyl (15µglKg), atropine and vecuronium (0.5-2mg/Kg).

Prophylactic tocolysis will be used in all patients with a protocol employing magnesium
sulfate - 6 gram IV loading dose followed by a 2 gram/hour continuous infusion for 24 hours,
followed by nifedipine 10mg Q6 during until 36 weeks of gestation.

Prophylactic antibiotics will also be used during the procedure using Cefazolin 2 g IV
immediately before the procedure. Nafcillin will be injected into the amniotic cavity at the
conclusion of the procedure. In case the patient has allergies to cephalosporin, clindamycin
600 mg will be used as alternative.

Steroids for fetal lung maturation will be given between 24 and 25 6/7 weeks (two doses of
12 mg betamethasone given 24 hours apart, with the last dose given 48-72 hours before the
procedure), if the procedure is performed during this gestational period.

The procedure will be performed percutaneously under ultrasound-fetoscopic guidance. An 18G
needle will be introduced into the fetal bladder through the maternal abdominal wall and
uterus under ultrasound guidance. Using a Seldinger technique an 8-9Fr Cook trocar will be
inserted through the maternal wall towards the fetal bladder. A curved Storz sheath for 1.3
mm (11530AA, Karl Storz, Tuttlinglen, Germany) or 2.0 mm fetoscopy (26120BA, Karl Storz,
Tuttlingen, Germany) or flexible ureteroscope will be introduced into the Cook catheter into
the fetal bladder. After confirming that the trochar is inside the fetal bladder, urine
samples will be collected for further renal function analysis. The fetoscope will be
advanced toward the bladder neck and the dilated posterior urethra. If a membrane-like
obstruction of the urethral lumen is seen, the diagnosis of PUV will be confirmed and at
this time the valves will be fulgurated using a Diode laser with low energy (15-20W). If
necessary, we will use a guide-wire to perforate the valves. Fulguration of the valves will
be performed very cautiously with the laser fiber almost touching them in order to avoid
damaging peripheral tissues. When the valves are completely disrupted, the urine will be
released through the now patent urethra, which results in emptying the bladder. A
transurethral shunt may be placed depending on the cause of the obstruction (urethral
stenosis). In addition, power Doppler will be applied to confirm passage of fluid through
the patent urethra into the amniotic cavity. However, if a non membrane-like structure is
found, even with the fluid injection or the guide-wire, urethral atresia (UA, US or Prune
Belly syndrome) will be diagnosed and we will not attempt to perforate this structure. A
vesicoamniotic shunting placement will be performed in this situation depending on the
patient's consent prior to the surgery.

The postsurgical care is going to follow the same standard prenatal care after fetal
vesico-amniotic shunting. The expected hospital course is 72 hours as it is also expected
for fetal vesico-amniotic shunting; however, it is possible that the patient will be
hospitalized for complications or preterm labor. The patient will then be discharged home
with recommendations for modified bed rest for the first 2 weeks post discharge, but will
subsequently be allowed to graduate to moderate activity if the uterus is quiescent.
Patients will return on a weekly basis for clinical and ultrasound evaluation. On
ultrasound, fetal kidneys, bladder thickness and dilatation, and amniotic fluid volume will
be assessed. Fetal Surveillance by biophysical profiles and Doppler studies will begin at 34
weeks

Delivery mode will be performed based on the obstetrical management following the
investigators clinical algorithm.

The subjects that undergo fetal cystoscopy will have exactly the same postnatal routine
(standard of care) clinical follow-up that is provided to all infants with LUTO. All infants
with LUTO are followed-up by the pediatric urology and nephrology services and may need
postnatal surgical intervention. At birth, the clinical evaluation will include a renal
ultrasound, voiding cysto-urethrogram (VCUG) as well as clinical laboratory examinations
such as serum creatinine, sodium, calcium, potassium and chloride, and a urine analysis will
be performed as part of the standard clinical care. Information from these routine
examinations will be collected and documented.

Inclusion Criteria:

- Fetus with LUTO, dilated bladder, "keyhole sign" and bilateral hydronephrosis

- Oligohydramnios or Anhydramnios after 18 weeks

- "Favorable urine analysis after 18 weeks (urinary sodium is < 100mEq/L, chloride <
90mEq/L, osmolarity <200mOsm/L and β2-microglobulin <6mg/L 7)

- Absence of chromosomal abnormalities and associated anomalies (Normal karyotype by
invasive testing (amniocentesis or CVS))

- Gestational age at the time of the procedure will be between 16 0/7 weeks and 25 6/7
weeks

Exclusion Criteria:

- Fetal anomaly unrelated to LUTO

- Congenital cardiac anomaly

- Increased risk for preterm labor including short cervical length (<1.5 cm), history
of incompetent cervix with or without cerclage, and previous preterm birth

- Placental abnormalities (previa, abruption, accreta) known at time of enrollment - A
body-mass index ≥ 35

- Contraindications to surgery including previous hysterotomy in active uterine segment

- Technical limitations precluding fetoscopic surgery, such as uterine fibroids, fetal
membrane separation, uterine anomalies incompatible with fetoscopy

- Maternal-fetal Rh isoimmunization, Kell sensitization or neonatal alloimmune
thrombocytopenia affecting the current pregnancy

- Maternal HIV, Hepatitis-B, Hepatitis-C status positive because of the increased risk
of transmission to the fetus during maternal-fetal surgery. If the patient's HIV or
Hepatitis status is unknown, the patient must be tested and found to have negative
results before enrollment

- Maternal medical condition that is a contraindication to surgery or anesthesia

- Patient does not have a support person (ie. Spouse, partner, mother) available to
support the patient for the duration of the pregnancy at Texas Children's
Hospital/Ronald McDonald House

- Patient does not have healthy insurance to cover routine clinical care at Texas
Children's Hospital including prenatal care, prenatal ultrasound, amniocentesis,
tocolysis, admission, delivery, and fetal vesico-amniotic shunting. The exception
will be fetal cystoscopy which is considered an experimental procedure.

- Inability to comply with the travel and follow-up requirements of the trial

- Participation in another intervention study that influences maternal and fetal
morbidity and mortality or participation in this trial in a previous pregnancy

- Patients declining invasive testing

- Family does not meet psychosocial criteria.