Renal Anhydramnios Fetal Therapy
| Status: | Recruiting |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease, Women's Studies, Nephrology, Urology |
| Therapuetic Areas: | Nephrology / Urology, Reproductive |
| Healthy: | No |
| Age Range: | 18 - 60 |
| Updated: | 3/1/2019 |
| Start Date: | March 18, 2017 |
| End Date: | March 18, 2026 |
| Contact: | Eric B Jelin, MD |
| Email: | ejelin1@jhmi.edu |
| Phone: | 4432873384 |
Renal Anhydramnios Fetal Therapy (RAFT) Trial
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.
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.
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 to successful dialysis
for 15 continuous days; 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.
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 to successful dialysis
for 15 continuous days; 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.
Inclusion Criteria:
- Confirmed anhydramnios before 22 weeks GA for patients with FRF or confirmed diagnosis
of CoBRA
- Eligible for first amnioinfusion before 26 weeks GA
- Confirmation that the expectant mother does not wish to undergo termination of the
pregnancy
- Age greater than 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.
Exclusion Criteria:
- Cervix less than 2.5 cm in length
- Abnormal 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
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