Fetal Intervention for Aortic Stenosis and Evolving Hypoplastic Left Heart Syndrome

Fetal aortic stenosis is an anatomically simple birth defect in which there is partial
blockage of the aortic valve, limiting blood flow out of the left side of the heart. If the
blockage becomes severe in fetal life, the left heart structures may stop growing and the
baby may be born with hypoplastic left heart syndrome (HLHS), a lethal condition without
neonatal heart surgery or heart transplantation. Standard treatment for babies born with HLHS
includes three major cardiac operations before the age of 6 years. Postnatal outcomes for
HLHS are uncertain and vary with patient; however, the few adult survivors are currently
suffering substantial medical problems, including a high incidence of neurologic problems.
For fetuses with severe obstruction, fetal intervention may improve outcomes by increasing
flow through the left heart, thus improving left heart function and encouraging continued
growth of the left heart structures. If fetal intervention can preserve left heart function
and growth, this should provide a better prognosis for the baby and allow for biventricular
repair strategies after birth.

This research study is a prospective, non-randomized clinical trial of 30 patients that will
assess the safety and efficacy of in utero percutaneous balloon dilation of fetal aortic
valve with severe stenosis. This technique has been successfully used to perform postnatal
aortic valve dilations for several decades, but has had limited application and study in
utero.

Pregnant women carrying a fetus diagnosed with severe aortic stenosis will be referred to the
University of California, San Francisco Fetal Treatment Center for evaluation, initial
screening and counseling. If all fetal and maternal inclusion criteria are met, the balloon
aortic valvuloplasty operation will be offered to the pregnant woman. Patients who do not
meet study eligibility or decline prenatal intervention will be offered the option to enroll
as a study control.

Inclusion Criteria:

- Pregnant woman carrying a fetus with normal cardiac segmental anatomy and severe
aortic stenosis as defined by:

- Dysplastic/stenotic aortic valve with forward flow, with or without gradient, and
no significant insufficiency

- If mitral insufficiency (incomplete closure of the mitral valve)is present, left
ventricle systolic pressure calculation must be ≥ a normal systemic blood
pressure (BP) for gestational age

- Retrograde aortic arch flow

- Left to right atrial shunting

- Left ventricle length no less than 90% the length of the right ventricle

- Maternal age ≥ 16 years of age;

- Gestational age: 17 0/7-30 6/7 weeks' gestation as determined by clinical information
and evaluation of first ultrasound. (Aortic valve dilation procedure cannot be
performed until 18 0/7 weeks);

- Normal karyotype with written confirmation of results. Results by fluorescence in situ
hybridization (FISH) for aneuploidy will be acceptable if the patient is at 24 weeks
or more; non-invasive testing is acceptable (maternal serum testing for cell-free
fetal DNA, currently commercially available).

- Singleton pregnancy;

- Able to travel to study site for study evaluation, procedures, and visits;

- Support person to travel and stay with patient (support person will be required to
sign the support person consent form);

- Has received pre-authorization for insurance for fetal intervention or has the ability
to self-pay for study treatment

Exclusion Criteria:

- Failure to meet all inclusion criteria;

- Multi-fetal pregnancy;

- Insulin dependent pregestational diabetes;

- Fetal anomaly not related to aortic stenosis. A detailed fetal anatomic ultrasound
will be conducted before consideration for the study and if the finding is abnormal,
the patient will be excluded;

- Current or planned cerclage or documented history of incompetent cervix;

- Placenta previa or placental abruption;

- Short cervix (< 20mm) measured by cervical ultrasound;

- Previous spontaneous delivery prior to 37 weeks of a singleton pregnancy. If the study
candidate had intact membranes and was induced, this is not considered spontaneous.
Stillbirths prior to 37 weeks are not exclusionary.

- Obesity as defined by body mass index of 35 or greater;

- Maternal-fetal Rh isoimmunization, Kell sensitization or a history of neonatal
alloimmune thrombocytopenia;

- Positive maternal HIV status. This is due to the increased risk of transmission to the
fetus during the maternal-fetal procedure. If the patient's HIV status is unknown, the
patient must be tested and found to have negative results before she can be entered
into the fetal treatment group;

- Known Hepatitis C positivity. If the patient's Hepatitis C status is unknown, she does
not need to be screened;

- Other maternal medical condition which is a contraindication to surgery or general
anesthesia, such as asthma, cardiac disease, the refusal of a blood transfusion, or a
previous hysterotomy in the active segment of the uterus;

- Patient does not have a support person (e.g., husband, partner, mother), or that
support person is unwilling to sign the support person consent form;

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

- Patient does not meet other psychosocial criteria to handle the implications of the
study;

- Participation in another intervention study that influences maternal and fetal
morbidity and mortality;

- Maternal hypertension which would increase the risk of preeclampsia or preterm
delivery (including, but not limited to: uncontrolled hypertension, chronic
hypertension with end organ damage and new onset hypertension in current pregnancy).