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Renal Anhydramnios Fetal Therapy (RAFT)

Primary Purpose

Anhydramnios, Potter Syndrome, Lung Hypoplasia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Serial amnioinfusions with isotonic fluid
Spinal needle
Isotonic fluid
Sponsored by
Johns Hopkins University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Anhydramnios focused on measuring Amnioinfusion, Fetal therapy, Bilateral Renal Agenesis, Fetal Renal Failure, Lower Urinary Tract Obstruction (LUTO), Anhydramnios

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Confirmed anhydramnios before 22 weeks GA for patients with fetal renal failure (excluding bilateral renal agenesis)
  2. Consent is signed and first therapeutic amnioinfusion can and does occur before 26 weeks and 0 days GA
  3. Confirmation that the expectant mother does not wish to undergo termination of the pregnancy
  4. Age ≥ 18 years of age for expectant mothers
  5. Willingness to be followed and deliver at a RAFT center
  6. Willingness for postnatal care to be performed at a RAFT center until discharge
  7. Completed consults with Pediatric Nephrology, Neonatology, Transplant Surgery, Pediatric surgery, Maternal-Fetal Medicine Specialist, and Licensed Clinical Social Worker and a Genetic Counselor

Exclusion Criteria:

  1. Cervix less than 2.5 cm in length
  2. No significant pathogenic or likely significant pathogenic findings on Karyotype or Microarray
  3. Other significant congenital anomalies in the fetus
  4. Evidence of chorioamnionitis or abruptio placentae
  5. Evidence of rupture of membranes or chorioamniotic separation
  6. Evidence of preterm labor
  7. Multiple gestation
  8. Severe maternal medical condition in pregnancy.
  9. Maternal depression as assessed by a Beck Depression Inventory score equal to or greater than 17 that is refractory to treatment
  10. Technical limitations precluding amnioinfusion

Sites / Locations

  • University of Southern California/Children's Hospital of Los Angeles/Huntington HospitalRecruiting
  • University of California San FranciscoRecruiting
  • Stanford UniversityRecruiting
  • University of Colorado DenverRecruiting
  • Johns Hopkins HospitalRecruiting
  • Mayo ClinicRecruiting
  • Columbia UniversityRecruiting
  • Children's Hospital of PhiladelphiaRecruiting
  • University of Texas Health Science Center at HoustonRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Serial amnioinfusions with isotonic fluid

Expectant

Arm Description

There are two interventional arms to the trial. Recruitment in the bilateral renal agenesis arm of the trial was stopped in July 2022 after DSMB review. Recruitment is ongoing in the non-bilateral renal agenesis, fetal renal failure with anhydramnios arm of the trial. Patients will undergo amnioinfusions with isotonic fluid every 2-12 days.. A spinal needle will be used to perform the infusion. The latest infusions will begin is 26 weeks gestation. Standard postnatal care will occur at a RAFT center.

Patients will be observed serially by ultrasound, fetal echocardiogram and MRI. Standard postnatal care will occur at a RAFT center.

Outcomes

Primary Outcome Measures

Proportion of neonates surviving to >= 14 days and placement of dialysis access after serial amnioinfusions (defined as use of a dialysis catheter for >=14 continuous days)
The proportion of neonates who survive to >= 14 days and placement of dialysis access as well as the exact confidence interval will be presented for CoBRA and FRF patients separately in the intervention group.

Secondary Outcome Measures

Number of infusions before rupture of membrane among those in the intervention arm
The feasibility of serial amnioinfusions for EPRA will be measured the number of infusions prior to rupture of membrane among those in the intervention arm
Mean gestational age at the time of rupture of membrane among those in the intervention arm
The feasibility of serial amnioinfusions for EPRA will be measured using the mean gestational age at rupture among those in the intervention arm
Mean gestational age at delivery among those in the intervention arm
The feasibility of serial amnioinfusions for EPRA will be measured using the mean gestational age at delivery among those in the intervention arm
Rate of in utero fetal demise among those in the non-intervention arm
We will perform an exploratory study of the in utero natural history of untreated EPRA by examining the rate of in utero fetal demise among those in the non-intervention arm.
Mean gestational age at delivery among those in the non-intervention arm
We will perform an exploratory study of the in utero natural history of untreated EPRA by examining the mean gestational age among those in the non-intervention arm
Correlations between fetal ultrasound, echocardiogram MRI biomarkers as well as amniotic fluid biomarkers, and the success of RAFT for EPRA
The correlations between fetal ultrasound, echocardiogram MRI biomarkers as well as amniotic fluid biomarkers and the success of RAFT for EPRA will be assessed.

Full Information

First Posted
March 27, 2017
Last Updated
June 12, 2023
Sponsor
Johns Hopkins University
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1. Study Identification

Unique Protocol Identification Number
NCT03101891
Brief Title
Renal Anhydramnios Fetal Therapy
Acronym
RAFT
Official Title
Renal Anhydramnios Fetal Therapy (RAFT) Trial
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 21, 2018 (Actual)
Primary Completion Date
April 1, 2025 (Anticipated)
Study Completion Date
April 1, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Johns Hopkins University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Early pregnancy renal anhydramnios or EPRA is a condition where a pregnant woman does not have any amniotic fluid around her fetus because of a problem with the fetus's kidneys. This condition is thought to be fatal once the fetus is born because of inadequate lung growth. The Renal Anhydramnios Fetal Therapy (RAFT) Trial offers eligible pregnant women with a diagnosis of EPRA an experimental therapy of repeated or serial "amnioinfusions" of fluid into the womb. An amnioinfusion involves placing a small needle through the pregnant woman's skin into the womb next to the fetus. Warm sterile fluid with balanced electrolytes and antibiotics is then slowly infused into amniotic space inside the womb. The aim is to help the fetus's lungs grow enough so he or she can survive after birth. These amnioinfusions will be carried out by an expert in fetal interventions at a RAFT center. There is a significant risk of early rupture of membranes and early delivery in subjects who receive amnioinfusions, and any potential trial participants will be counseled about these risks before they decide whether to join the trial. Any eligible patients who, after counseling, elect to terminate the pregnancy will not be eligible to participate in the trial. All eligible patients who choose to join the RAFT trial will be able to choose their assignment into one of two arms of the study: (1) to receive serial amnioinfusions (2) to not receive amnioinfusions but receive monitoring for the remainder of the pregnancy at the RAFT center. Thus, assignment of patients to study arm will not be random, but will be decided by the participant. Fetuses who do survive after birth will require intensive medical management for kidney failure including placement of a dialysis catheter and dialysis therapy with the eventual need for a kidney transplant. Treatment for lung disease secondary to abnormal lung development may also be required. The study will follow babies and their families until non-survival or transplant. Update: Due to recommendations from the RAFT trial Data and Safety Monitoring Board, the trial is no longer open to enrollment for pregnancies complicated by bilateral renal agenesis as of July 19, 2022. Enrollment for patients with pregnancies complicated by other causes of fetal renal failure remains open.
Detailed Description
Amniotic fluid is critical for normal lung development. After the first trimester of pregnancy amniotic fluid is composed nearly completely of fetal urine. The absence of amniotic fluid due to lack of urine production by the fetal kidneys is known as anhydramnios. Early pregnancy renal anhydramnios or EPRA is thought to be 100% lethal after birth if left untreated because of neonatal respiratory failure. The two causes of EPRA are bilateral renal agenesis or fetal renal failure (such as from multicystic dysplastic kidneys or obstructed kidneys). Recently there have been clinical case reports of repeated or serial infusions of isotonic fluid (amnioinfusions) into the amniotic cavity leading to respiratory survival in neonates with a history of EPRA. Some surviving neonates have gone on to undergo successful dialysis and kidney transplant as toddlers. However, no prospective trial has investigated the safety of amnioinfusions in EPRA, the feasibility of doing serial amnioinfusions in EPRA pregnancies without causing rupture of membranes, or the neonatal survival rate after serial amnioinfusions for EPRA. Accordingly the goal of the Renal Anhydramnios Fetal Therapy (RAFT) trial is to determine the safety, feasibility, and efficacy of serial amnioinfusions to promote normal fetal lung development in EPRA. Pregnant patients presenting to a RAFT center with a diagnosis of EPRA will undergo an evaluation including diagnostic amnioinfusion with ultrasound imaging to verify the diagnosis. Counseling by a team of subspecialists including a maternal fetal medicine doctor, a pediatric nephrologist, a pediatric surgeon, a neonatologist, a kidney transplant specialist, a genetic counselor and a social worker will be given to every patient. This counseling is meant to provide the clearest picture possible of what serial amnioinfusions entail and what life will be like for a surviving neonate with no kidney function. Survivors will require urgent dialysis with a peritoneal or hemodialysis catheter. These children are prone to significant infections and often need a gastrostomy tube in order to receive sufficient nutrition. The goal is for these children to ultimately undergo the most robust form of renal replacement therapy with a kidney transplant once they are large enough to tolerate it. Once the diagnosis of EPRA is confirmed, counseling is complete and a patient is deemed eligible for serial amnioinfusions, enrollment into the study will be offered. Patients may choose to enroll in the study, may choose to continue the pregnancy and not be a part of the study or may choose to terminate the pregnancy. If the patients elect to enroll in the study, they will be given a further choice of intervention with serial amnioinfusions or expectant management with repeat imaging. Participants will not be randomized because there is no realistic hope that expectant management will lead to postnatal survival. Patients who do not choose to undergo amnioinfusions but who also do not elect to terminate will provide invaluable insight into the in utero natural history of EPRA if they enroll in the trial. The sample size of this trial is based on a calculation of the number of patients required to adequately determine a postnatal survival rate of amnioinfusions for EPRA with narrow confidence intervals. Postnatal survival will be defined as survival for >=14 days and placement of dialysis access; this is the primary outcome measure. We have determined that 35 maternal/fetal participants are required in order to calculate a survival rate of anywhere from 20-80%. We plan to study two 35 participant cohorts of EPRA patients, those with EPRA from bilateral renal agenesis and those with EPRA from fetal renal failure. We will therefore aim for a total of 70 maternal/fetal pairs with EPRA to undergo serial amnioinfusions. Additionally we will aim to recruit 30 maternal/fetal pairs with EPRA in the expectant management group for a total of 100 participants. During the prenatal portion of the trial we plan to collect a small specimen of amniotic fluid from participants in the amnioinfusion group during each amnioinfusion. This fluid will be assayed for different protein and lipid measures of lung maturity at a research lab at Johns Hopkins. Additionally, in both the amnioinfusion group and the expectant management group we will study ultrasound, MRI and echocardiogram measures of lung growth. We will correlate these biochemical and radiologic markers with survival in order to better understand who is likely to respond to amnioinfusions and why that response is occurring. We also plan to study several secondary and tertiary outcomes in our surviving EPRA patients. These outcomes include survival to discharge from a RAFT center, survival to transplant and quality of life measures for both participants and their families. The changes made to the outcomes are due to the protocol amendment. Update: Due to recommendations from the RAFT trial Data and Safety Monitoring Board, the trial is no longer open to enrollment for pregnancies complicated by bilateral renal agenesis as of July 19, 2022. Enrollment for patients with pregnancies complicated by other causes of fetal renal failure remains open.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anhydramnios, Potter Syndrome, Lung Hypoplasia, Multicystic Dysplastic Kidney, Multicystic Renal Dysplasia, Bilateral, Lower Urinary Tract Obstructive Syndrome, Fetal Renal Anomaly
Keywords
Amnioinfusion, Fetal therapy, Bilateral Renal Agenesis, Fetal Renal Failure, Lower Urinary Tract Obstruction (LUTO), Anhydramnios

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
All eligible patients will be offered participation in the study. Participants can elect for invasive therapy with amnioinfusions or expectant management.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Serial amnioinfusions with isotonic fluid
Arm Type
Experimental
Arm Description
There are two interventional arms to the trial. Recruitment in the bilateral renal agenesis arm of the trial was stopped in July 2022 after DSMB review. Recruitment is ongoing in the non-bilateral renal agenesis, fetal renal failure with anhydramnios arm of the trial. Patients will undergo amnioinfusions with isotonic fluid every 2-12 days.. A spinal needle will be used to perform the infusion. The latest infusions will begin is 26 weeks gestation. Standard postnatal care will occur at a RAFT center.
Arm Title
Expectant
Arm Type
No Intervention
Arm Description
Patients will be observed serially by ultrasound, fetal echocardiogram and MRI. Standard postnatal care will occur at a RAFT center.
Intervention Type
Procedure
Intervention Name(s)
Serial amnioinfusions with isotonic fluid
Other Intervention Name(s)
Renal Anhydramnios Fetal Therapy (RAFT)
Intervention Description
Amnioinfusions will be performed by an expert in fetal procedures with a 20 or 22 gauge needle using sterile technique and ultrasound guidance. Local anesthetic will be employed. The fluid will consist of warmed isotonic fluid. Infusions may take up to 1 hour.
Intervention Type
Device
Intervention Name(s)
Spinal needle
Other Intervention Name(s)
Obstetrics and gynecology needle
Intervention Description
A 20 or 22 gauge spinal needle will be used with sterile technique to access the uterus under ultrasound guidance and to infuse isotonic fluid.
Intervention Type
Drug
Intervention Name(s)
Isotonic fluid
Other Intervention Name(s)
Normal saline, Lactated ringers solution
Intervention Description
Isotonic fluids, including normal saline or lactated ringers solution, will be infused into the uterus through a spinal needle under ultrasound guidance using sterile technique. This fluid will act as replacement amniotic fluid.
Primary Outcome Measure Information:
Title
Proportion of neonates surviving to >= 14 days and placement of dialysis access after serial amnioinfusions (defined as use of a dialysis catheter for >=14 continuous days)
Description
The proportion of neonates who survive to >= 14 days and placement of dialysis access as well as the exact confidence interval will be presented for CoBRA and FRF patients separately in the intervention group.
Time Frame
Birth to either survival to >=14 days and placement of dialysis access, or nonsurvival, up to 3 weeks
Secondary Outcome Measure Information:
Title
Number of infusions before rupture of membrane among those in the intervention arm
Description
The feasibility of serial amnioinfusions for EPRA will be measured the number of infusions prior to rupture of membrane among those in the intervention arm
Time Frame
During the EPRA pregnancy, up to 9 months
Title
Mean gestational age at the time of rupture of membrane among those in the intervention arm
Description
The feasibility of serial amnioinfusions for EPRA will be measured using the mean gestational age at rupture among those in the intervention arm
Time Frame
During the EPRA pregnancy, up to 9 months
Title
Mean gestational age at delivery among those in the intervention arm
Description
The feasibility of serial amnioinfusions for EPRA will be measured using the mean gestational age at delivery among those in the intervention arm
Time Frame
During the EPRA pregnancy, up to 9 months
Title
Rate of in utero fetal demise among those in the non-intervention arm
Description
We will perform an exploratory study of the in utero natural history of untreated EPRA by examining the rate of in utero fetal demise among those in the non-intervention arm.
Time Frame
During the EPRA pregnancy, up to 9 months
Title
Mean gestational age at delivery among those in the non-intervention arm
Description
We will perform an exploratory study of the in utero natural history of untreated EPRA by examining the mean gestational age among those in the non-intervention arm
Time Frame
During the EPRA pregnancy, up to 9 months
Title
Correlations between fetal ultrasound, echocardiogram MRI biomarkers as well as amniotic fluid biomarkers, and the success of RAFT for EPRA
Description
The correlations between fetal ultrasound, echocardiogram MRI biomarkers as well as amniotic fluid biomarkers and the success of RAFT for EPRA will be assessed.
Time Frame
End of follow-up, up to 4 years after transplant

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
Pregnant women are the focus of this study
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Confirmed anhydramnios before 22 weeks GA for patients with fetal renal failure (excluding bilateral renal agenesis) Consent is signed and first therapeutic amnioinfusion can and does occur before 26 weeks and 0 days GA Confirmation that the expectant mother does not wish to undergo termination of the pregnancy Age ≥ 18 years of age for expectant mothers Willingness to be followed and deliver at a RAFT center Willingness for postnatal care to be performed at a RAFT center until discharge Completed consults with Pediatric Nephrology, Neonatology, Transplant Surgery, Pediatric surgery, Maternal-Fetal Medicine Specialist, and Licensed Clinical Social Worker and a Genetic Counselor Exclusion Criteria: Cervix less than 2.5 cm in length No significant pathogenic or likely significant pathogenic findings on Karyotype or Microarray Other significant congenital anomalies in the fetus Evidence of chorioamnionitis or abruptio placentae Evidence of rupture of membranes or chorioamniotic separation Evidence of preterm labor Multiple gestation Severe maternal medical condition in pregnancy. Maternal depression as assessed by a Beck Depression Inventory score equal to or greater than 17 that is refractory to treatment Technical limitations precluding amnioinfusion
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Meredith Atkinson
Phone
4432878951
Email
matkins3@jhmi.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Jena Miller, MD
Phone
844-JHFETAL
Email
jmill260@jhmi.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Meredith Atkinson
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Southern California/Children's Hospital of Los Angeles/Huntington Hospital
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Arlyn Llanes
Phone
626-356-3360
Email
arlyn.llanes@med.usc.edu
First Name & Middle Initial & Last Name & Degree
Ramen Chmait
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristen Gosnell
Phone
415-830-7217
Email
Kristen.Gosnell@ucsf.edu
First Name & Middle Initial & Last Name & Degree
Kristen Gosnell
Phone
417-476-0445
First Name & Middle Initial & Last Name & Degree
Juan Gonzalez
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stanford MFM team
Phone
650-725-5720
Email
mfmresearch@stanford.edu
First Name & Middle Initial & Last Name & Degree
Yair Blumenfeld
Facility Name
University of Colorado Denver
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hilary Hoffman
Phone
720-777-9904
Email
hilary.hoffman@childrenscolorado.org
First Name & Middle Initial & Last Name & Degree
Hilary Hoffman
Phone
408-489-2284
First Name & Middle Initial & Last Name & Degree
Michael Zaretsky
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jena B Miller, MD
Phone
844-543-3825
Email
jmill260@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Meredith Atkinson
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55902
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maureen Lemens, RN
Phone
507-293-1487
Email
Lemens.Maureen@mayo.edu
First Name & Middle Initial & Last Name & Degree
Maura Schenone
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michelle Vanegas
Phone
347-920-1389
Email
mv2716@cumc.columbia.edu
First Name & Middle Initial & Last Name & Degree
Russell Miller
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Susan Spinner
Phone
215-590-5190
Email
spinners@email.chop.edu
First Name & Middle Initial & Last Name & Degree
Susan Spinner
Phone
267-239-3108
First Name & Middle Initial & Last Name & Degree
Julie Moldenhauer
Facility Name
University of Texas Health Science Center at Houston
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Robyn Torpey, RN
Phone
832-325-7288
Email
Robyn.d.torpey@uth.tmc.edu
First Name & Middle Initial & Last Name & Degree
Anthony Johnson

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30897573
Citation
O'Hare EM, Jelin AC, Miller JL, Ruano R, Atkinson MA, Baschat AA, Jelin EB. Amnioinfusions to Treat Early Onset Anhydramnios Caused by Renal Anomalies: Background and Rationale for the Renal Anhydramnios Fetal Therapy Trial. Fetal Diagn Ther. 2019;45(6):365-372. doi: 10.1159/000497472. Epub 2019 Mar 21.
Results Reference
background
PubMed Identifier
31098643
Citation
Huber C, Shazly SA, Blumenfeld YJ, Jelin E, Ruano R. Update on the Prenatal Diagnosis and Outcomes of Fetal Bilateral Renal Agenesis. Obstet Gynecol Surv. 2019 May;74(5):298-302. doi: 10.1097/OGX.0000000000000670.
Results Reference
background
PubMed Identifier
25004316
Citation
Bienstock JL, Birsner ML, Coleman F, Hueppchen NA. Successful in utero intervention for bilateral renal agenesis. Obstet Gynecol. 2014 Aug;124(2 Pt 2 Suppl 1):413-415. doi: 10.1097/AOG.0000000000000339.
Results Reference
result
PubMed Identifier
35918190
Citation
Atkinson MA, Jelin EB, Baschat A, Blumenfeld YJ, Chmait RH, O'Hare E, Moldenhauer JS, Zaretsky MV, Miller RS, Ruano R, Gonzalez JM, Johnson A, Mould WA, Davis JM, Hanley DF, Keiser AM, Rosner M, Miller JL. Design and Protocol of the Renal Anhydramnios Fetal Therapy (RAFT) Trial. Clin Ther. 2022 Aug;44(8):1161-1171. doi: 10.1016/j.clinthera.2022.07.001. Epub 2022 Jul 30.
Results Reference
derived
Links:
URL
http://www.hopkinsmedicine.org/gynecology_obstetrics/specialty_areas/fetal_therapy/
Description
The Center for Fetal Therapy

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