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. Author manuscript; available in PMC: 2023 Jan 18.
Published in final edited form as: Clin Ther. 2022 Jul 30;44(8):1161–1171. doi: 10.1016/j.clinthera.2022.07.001

Design and protocol of the Renal Anhydramnios Fetal Therapy (RAFT) trial

Meredith A Atkinson 1, Eric B Jelin 2, Ahmet Baschat 3, Yair Blumenfeld 4, Ramen Chmait 5, Elizabeth O’Hare 2, Julie Moldenhauer 6, Michael Zaretsky 7, Russell Miller 8, Rodrigo Ruano 9, Juan Gonzalez 10, Anthony Johnson 11, Andrew Mould 12, Jonathan Davis 13, Daniel Hanley 12, Amaris Keiser 14, Mara Rosner 3, Jena L Miller 3
PMCID: PMC9847373  NIHMSID: NIHMS1864882  PMID: 35918190

Abstract

Purpose

Early pregnancy renal anhydramnios secondary to fetal renal failure is usually lethal due to fetal pulmonary hypoplasia. Case reports have indicated neonatal survival to renal transplant for the offspring of early pregnancy renal anhydramnios patients who received serial in-utero amnioinfusions. The Renal Anhydramnios Fetal Therapy (RAFT) trial is a non-randomized, non-blinded multi-center clinical trial designed to assess the efficacy, safety and feasibility of amnioinfusions for patients with pregnancies complicated by early pregnancy renal anhydramnios.

Methods

A consortium of nine North American Fetal Therapy Network (NAFTNet) centers was formed and the RAFT protocol was refined in collaboration with the NAFTNet scientific committee. Enrollment in the trial began in April 2020. Participants elect to receive amnioinfusions or to join the non-intervention observational expectant management group. Eligible pregnant women are at least 18 years of age with a fetal diagnosis of isolated early pregnancy renal anhydramnios.

Findings

The primary study objective is to determine the proportion of neonates surviving to successful dialysis, defined as use of a dialysis catheter for ≥ 14 days. Secondary objectives include (1) to assess maternal safety and feasibility of the intervention (2) to perform an exploratory study of the natural history of untreated early pregnancy renal anhydramnios (3) to examine correlations between prenatal imaging and lung specific factors in amniotic fluid as predictive of the efficacy of serial percutaneous amnioinfusions and (4) to determine short- and long-term outcomes and quality of life in surviving neonates and families enrolled in RAFT.

Implications

The RAFT trial is the first clinical trial investigating the efficacy, safety, and feasibility of amnioinfusions to treat the survival-limiting pulmonary hypoplasia associated with anhydramnios. Although the intervention offers an opportunity to treat a condition known to be almost universally fatal in affected neonates, the potential burdens associated with end stage kidney disease from birth must be acknowledged.

Keywords: Amnioinfusion, renal agenesis, fetal renal failure, pulmonary hypoplasia, anhydramnios, Potter’s Syndrome

Introduction

Severe fetal renal malformations, including congenital bilateral renal agenesiscongenital bilateral renal agenesis and other disorders resulting in fetal renal failure, such as severe lower urinary tract obstruction and bilateral multicystic dysplastic kidney, render the fetus anuric [1]. Since urine produced by the fetal kidneys constitutes nearly all of the amniotic fluid volume (AFV) by 16–20 weeks gestational age, nonfunctional fetal kidneys lead to anhydramnios (no observable amniotic fluid) [2]. Anhydramnios secondary to anuria prior to 22 weeks gestational age or congenital bilateral renal agenesis before 26 weeks gestational age are collectively referred to as early pregnancy renal anhydramnios [3]. Historically termed Potter’s sequence, early pregnancy renal anhydramnios occurs in at least 1 in 2000 pregnancies and is considered universally fatal when left untreated due to severe pulmonary hypoplasia precluding ex utero survival [4,5]. Amniotic fluid is necessary for lung development because it maintains transpulmonary pressure in the tracheobronchial tree. This pressure gradient is essential, leading to alveolar distension, mechanotransduction, and physiologic lung growth [6–8].

Established fetal interventions for lower urinary tract obstruction are currently limited to vesicoamniotic shunting and fetal cystoscopy in fetuses who have renal function and produce urine. These procedures aim to bypass the obstruction via shunt or resolve the obstruction through ablation. The goals of therapy are to restore normal amniotic fluid volume, promote pulmonary development, and potentially limit further kidney damage in infants with lower urinary tract obstruction [9,10]. However, these treatments do not benefit the early pregnancy renal anhydramnios fetus with anuric renal failure. In recent years, there have been anecdotal reports of early pregnancy renal anhydramnios fetuses that received serial amnioinfusions of isotonic fluid and had lung function consistent with survival at birth [11–13]. These early attempts at therapy were motivated in part by reported survival of monoamniotic twins discordant for congenital bilateral renal agenesis in which the congenital bilateral renal agenesis twin did not develop pulmonary hypoplasia due to shared amniotic fluid, indicating the possibility of lung maturation for early pregnancy renal anhydramnios fetuses with fluid replacement [14–17].

The first case report of successful serial amnioinfusions to treat early pregnancy renal anhydramnios received wide attention in the lay press and on social media before the prospective safety, feasibility and efficacy of the intervention were investigated [11,18]. However this early enthusiasm led to additional retrospective reports of amnioinfusions with variable inclusion/exclusion criteria and technique used to treat pulmonary hypoplasia in early pregnancy renal anhydramnios -like fetuses with varying outcomes. In one study, nine fetuses with severe oligo-anhydramnios at variable timepoints in pregnancy and with unclear pathophysiology received serial amnioinfusions in a heterogenous fashion. Six had sufficient pulmonary function at birth for survival. Three of these surviving infants survived to dialysis and renal transplant [3,19]. In another single center retrospective study serial amnioinfusions were administered to eight singleton pregnancies with isolated fetal congenital bilateral renal agenesis; three patients survived past the first 48 hours of life. None survived to hospital discharge [20]. This study included heterogenous amnioinfusion techniques, incomplete genetic evaluations, and multiple non-tertiary delivery hospitals [21]. The maternal safety of repeated amnioinfusions for early pregnancy renal anhydramnios, the feasibility of performing multiple infusions, and the immediate and long-term outcomes for early pregnancy renal anhydramnios neonates remain unknown and an evidence-based approach to the treatment and management of anhydramnios has not been established. Thus, systematic investigation in the setting of a standardized prospective and ethically designed trial was warranted [3].

In 2012, a neonate with congenital bilateral renal agenesis whose mother received experimental amnioinfusions throughout pregnancy did not demonstrate survival-limiting pulmonary hypoplasia at birth [11]. This success increased attention in the lay press about using amnioinfusions as a potential fetal therapy for congenital bilateral renal agenesis [18]. Following this and other case reports of successful prenatal intervention for early pregnancy renal anhydramnios, both a workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Eunice Kennedy Shriver National Instutite of Child Health and Development (NICHD) of the National Institutes of Health and a national ethics symposium were convened to discuss the ethical and practical implications of administering amnioinfusions in the setting of early pregnancy renal anhydramnios [3,22]. These conferences included fetal interventionalists, ethicists, pediatric nephrologists, neonatologists, pediatric surgeons, and previously treated patients and proposed the framework for an ethically sound, regulated prospective trial that became the RAFT trial.

The primary objective of the RAFT trial is to determine the proportion of affected neonates surviving to successful dialysis (defined as ≥ 14 days use of a dialysis catheter) after serial amnioinfusions. Secondary objectives include (1) to determine the maternal safety and feasibility of serial amnioinfusions forearly pregnancy renal anhydramnios, (2) to perform an exploratory study of the in-utero natural history of untreated early pregnancy renal anhydramnios, (3) to examine correlations between prenatal ultrasound, echocardiogram, MRI and lung specific factors in amniotic fluid as predictive biomarkers of the success of serial percutaneous amnioinfusions in terms of neonatal survival and (4) to determine short- and long-term outcomes and quality of life in neonates and families enrolled in RAFT.

Participants and Methods

Design of the trial

The initial RAFT protocol was approved by the John Hopkins University IRB as a pilot single-center feasibility study. National interest in trial participation culminated in the creation of a consortium of nine North American Fetal Therapy Network (NAFTNet) centers who, together with the NAFTNet scientific committee, further refined the protocol in anticipation of use across multiple sites. An R01 grant application to support the multicenter trial was submitted to and successfully funded by the NICHD. The multicenter study utilizes a single IRB, and includes an executive committee, a data safety monitoring board, a clinical coordinating center and a data coordinating center to support and coordinate research efforts. Enrollment into the multicenter study using the refined protocol began in December 2018 and in the NICHD-funded trial in April 2020

RAFT is a non-randomized, non-blinded, prospective, multi-center IRB-approved clinical trial with two parallel intervention groups (congenital bilateral renal agenesis and fetal renal failure) within participants with isolated early pregnancy renal anhydramnios population (ClinicalTrials.gov NCT03101891). There is also an observational expectant management group. Randomization was not planned due to ethical concerns regarding the near-certainty of fetal/neonatal death without the intervention (Figure 1). The public has been represented in this trial from its inception. Previously treated patients and family members were present at the national ethics symposium in 2017 which laid the framework for the RAFT trial [22]. All sample size calculations were based on the intervention group only. Potential participants are referred by a physician or self-referred for enrollment at one of nine participating centers which include the University of Texas Houston, the Mayo clinic, Columbia .University, Johns Hopkins University, Stanford University, University of California San Francisco, University of Colorado, University of Southern California, and The Children’s Hospital of Philadelphia. Table 1 lists RAFT center site qualification criteria.

Figure 1.

Figure 1.

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Study Design. Patients referred to Renal Anhydramnios Fetal Therapy (RAFT) trial center for suspicion of early pregnancy renal anhydramnios (EPRA) will undergo counseling and a diagnostic amnioinfusion. If the diagnosis is confirmed (anhydramnios in the absence of ruptured membranes and absent bladder filling) inclusion and exclusion criteria will be applied (see Table 2). If the parents do not wish to be a part of the study, standard prenatal care will be offered. Once enrolled in the study, participants will have the choice of expectant management or serial amnioinfuslons. Those In the intervention group will be allowed to switch to expectant management If they do not wish to continue amnioinfuslons. All participants will deliver at a RAFT center. They will be enrolled in the North American Renal Trials and Collaborative Studies (NAPRTCS) registry for long-term follow-up in the RAFT trial. FRF=fetal renal failure; Co-BRA=congenltal bilateral renal agenesis; GA=gestational age

Table 1.

RAFT Trial Site Qualification Criteria

1. Board-certified Maternal-Fetal Medicine Specialist who has performed >15 amnioinfusion procedures for anhydramnios.
2. Neonatologists with willingness to provide active management for infants with prenatally diagnosed congenital bilateral renal agenesis and the experience to care for neonates as small as 1.8 kg requiring dialysis.
3. Pediatric nephrologists with experience and willingness to perform dialysis in neonates ≥1.8 kg
4. Pediatric surgeons with experience and willingness to place dialysis catheters in neonates ≥1.8 kg.
5. Multidisciplinary meeting before study initiation to include local PI, study coordinator, maternal-fetal specialist, pediatric surgeon, neonatology and nephrology champions, and hospital administration to ensure that study objectives and procedures are communicated to the entire team.
6. Availability of all required subspecialties and counselors for subject consent.
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Recruitment goals and timeline

The target enrollment is 140 maternal/fetal pairs, with 70 in the intervention group (35 congenital bilateral renal agenesis and 35 fetal renal failure) and approximately 70 in the non-intervention expectant management group. It is estimated that 15–20 participants will be enrolled into the trial each year. Given that amnioinfusion is currently the only potential fetal therapy for early pregnancy renal anhydramnios, all eligible subjects that do not opt for termination will be offered the option of interventional or expectant management. Specific inclusion and exclusion criteria are outlined in Table 2. Feasibility data collected using the electronic health record using ICD-9 and ICD-10 codes for Renal Agenesis Bilateral, Renal Agenesis unspecified, or Potter’s Syndrome over the past 4 years and in the calendar year of 2018 at multiple RAFT centers suggest that the target enrollment of 140 participants is conservative, suggesting that the recruitment goal of 140 maternal-fetal pairs is achievable.. Due to heterogeneous diagnoses within these search codes, it is estimated that about 50% of patients will be eligible for the study, and that 50% of these will consent to participate. The trial has been publicized through NAFTNet, the Society for Maternal Fetal Medicine, clinicaltrials.gov, the Trial Innovation Network, the trial website (www.raft-trial.org), and with printed educational materials at participating centers.

Table 2.

RAFT Inclusion and Exclusion Criteria

Inclusion criteria Exclusion Criteria
1) Confirmed anhydramnios before 22 weeks gestational age
 • Anhydramnios without membrane rupture
 • Absent significant bladder filling (diagnosis may require vesicocentesis for lower urinary tract obstruction)
2) Eligible for first amnioinfusion before 26 weeks gestational age
3) Confirmation that participant does not wish to terminate pregnancy
4) Participant age ≥18 years
5) Willingness to receive prenatal care and deliver at RAFT center
6) Willingness for postnatal care for infant at RAFT center until discharge
7) Prenatal consultations: pediatric nephrology, neonatology, transplant surgery, pediatric surgery, maternal-fetal medicine, licensed clinical social worker and a genetic counselor		 1) Cervix <2.5 cm in length by transabdominal or transvaginal ultrasound
2) Abnormal karyotype or microarray
3) Other clinically relevant congenital anomalies (e.g. cardiac, gastroenterological, neurologic)
4) Evidence of chorioamnionitis or placental abruption
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 ≥ 17 that is refractory to treatment
10) Technical limitations precluding amnioinfusion
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Enrollment under the multicenter protocol began with consent of the first participant in December 2018, with NIH funding in April 2020. Figure 2 shows the results of modelling with optimistic, at-plan and conservative recruitment rates. Amnioinfusions will be administered and neonatal survivors will be followed for up to 4 years of age (Figure 3). Intrapartum assessments will include fetal MRI, lung evaluation, brain evaluation, fetal echocardiogram, and other standard [obstetric] evaluations.

Figure 2.

Figure 2.

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RAFT enrollment model. Explored optimistic (5.5/site-year), at-plan (3.6/site-year) and pessimistic (3/site-year) estimates of combined enrollment rates for the 30 subjects in the expectant management group and 70 subjects in the treatment group. At-plan enrollment completes in 42 months, leaving 18 months of follow-up for the last patient enrolled.

Figure 3.

Figure 3.

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Timeline of study procedures for intervention group. All study visits including delivery will occur at a RAFT center

Study Endpoints

The primary outcome measure is the proportion of neonates surviving to successful dialysis, defined as continuous use of a dialysis catheter for ≥ 14 days. For the secondary objective to determine maternal safety and feasibility of the intervention, outcome measures will include the number of amnioinfusions performed before rupture of membranes, the time interval after initiation of amnioinfusions to rupture of membranes, and mean gestational age at delivery among those in the intervention arm. For the exploratory study of the in-utero natural history of untreated early pregnancy renal anhydramnios in the non-intervention arm, secondary outcome measures will include rate of fetal demise in utero and gestational age at delivery. Correlations between prenatal ultrasound, echocardiogram, MRI and lung specific factors in amniotic fluid as predictive biomarkers of the success of serial percutaneous amnioinfusions will be examined in terms of neonatal survival. Finally, secondary neonatal outcome measures include survival to hospital discharge/transition to outpatient care, survival to successful renal transplantation, and long-term quality of life

Data Safety Monitoring Board (DSMB) and trial stopping rules

The DSMB will first examine the data after the first 5 participants reach the primary outcome variable and then every 10 participants or every 6 months thereafter, which ever is more frequent. If there are no survivors to successful dialysis in the first 5 participants or any survivors in the expectant management group, then the study will be considered for early termination. In addition, if the primary outcome (neonatal survival to ≥14 days use of a dialysis catheter) is successfully reached in fewer than 10% or greater than 90% of participants after 18 participants are enrolled, the DSMB will convene and continuation of the trial will be reviewed. In the event of any instance of a serious adverse event (Table 3) continuation of the study will be reviewed. Finally, additional DSMB meetings may be called at any time in response to adverse events or other study participant experience at the request of the PI, the DSMB chair, or the executive committee chair.

Table 3.

Definition of Serious Adverse Event (SAE) in the RAFT trial

1) Maternal death
2) In utero fetal demise
3) A life-threatening maternal event
4) A persistent or significant maternal incapacity or substantial disruption of the ability to conduct normal life functions
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Participant Screening

Thorough counseling about the multi-dimensional risks of trial participation including possible financial burdens, family stress, opportunity costs, the likely morbidity of neonatal survivors and the near certainty of the requirement for lifelong renal replacement therapy will be the standard and will be conducted prior to enrollment through multidisciplinary consults. A licensed clinical social worker will work with the participant to ensure the appropriate arrangements can be made so that the participant can participate for the entirety of the study.

Intervention

Participants in the intervention group will receive serial amnioinfusions between 18 0/7 and 34 6/7 weeks gestational age after referral to a RAFT center by a physician or self-referral and inclusion into the trial. Subjects will return to the RAFT center every 2–12 days to receive amnioinfusion of isotonic fluid with antibiotics. Either oxacillin (1g) or nafcillin (1g) diluted in 500cc normal saline is used for antibiotic prophylaxis based on each center’s standard operating procedure for amnioinfusions and hospital formulary. Clindamycin 600mg diluted in 500cc normal saline can be used as an alternative for participants with a penicillin allergy. Amnioinfusions of normal saline or lactated ringers will be administered using an FDA-approved 20- or 22- gauge needle with local anesthesia for maternal comfort. The volume of fluid infused at each amnioinfusion will range from 300 mL to 800 mL of warmed isotonic fluid, following general guidelines of 10–20 mL isotonic fluid for each week of pregnancy. The aim is a maximum vertical pocket (MVP) of 4–5 cm measured by transabdominal ultrasound and low-normal amniotic fluid index for gestational age. If preterm premature rupture of membranes (PPROM) does occur, amnioinfusions will cease. This approach will be standard across centers. Delivery and neonatal care will occur at the RAFT center. Figure 3 illustrates the study timeline for intervention participants.

Participants will not be compensated for their participation and will also have the option switch from the intervention group to expectant management group or withdraw from the trial at any time. At enrollment, participants must be at least 18 years of age and be amenable to postnatal dialysis. Participants enrolled in the intervention group must return to the RAFT center for all treatment, from enrollment, up to and including birth.

Expectant management

Participants in the expectant management group will not receive serial amnioinfusions throughout pregnancy. Like the intervention group, these participants will undergo two fetal ultrasounds,, two fetal MRIs, and serial fetal echocardiograms. These fetal imaging studies will be obtained during the study screening period, and again at a 32 week assessment visit. This close monitoring will allow the first ever detailed, standardized view of the in-utero natural history of untreated early pregnancy renal anhydramnios and will allow for a descriptive comparison of these radiologic prenatal markers of lung maturity between the two trial groups as well as a descriptive comparison of maternal/fetal risks. This comparison aims to identify non-invasive imaging signatures in the intervention group indicative of adequate lung development to predict which fetuses are likely to survive postnatally, providing valuable prognostic information to families. Participants in both study arms will have a consultation with a clinical social worker as part of study screening, and will continue to have access to social work support at the fetal center throughout their participation in the study.

Imaging studies

Participants in both the intervention and expectant management group will undergo two fetal MRI examinations. The first MRI exam will occur during the study screening period. The second MRI exam in participants enrolled in the intervention arm will occur at a minimum after four therapeutic amnioinfusions, between 30- and 32-weeks gestational age. For those in the expectant management groups the second fetal MRI will occur at the 32 week assessment visit. The fetal lung (volume and Apparent Diffusion Coefficient (ADC)) and brain (ADC and ventricular size) will be evaluated during the course of enrollment.

Follow-up

Participants will be followed through all study visits during pregnancy and up to delivery. Follow-up will continue up to 4 years of age for surviving neonates. Neonates who survive to discharge from the hospital will be enrolled in the multicenter North American Renal Trials and Collaborative Studies (NAPRTCS) registry (https://naprtcs.org/) to facilitate long-term data collection of end stage kidney disease outcomes.

Data Collection and Management

Trial data will be collected at each trial site and entered into the secure, HIPAA-compliant REDCap platform. Prenatal data will be collected by each RAFT site study team using standardized intake forms, a screening log, and standardized case report forms (CRFs) for each participant visit. There is a “Quality, Risk Management and Monitoring Plan” for the RAFT trial which uses risk-based monitoring as recommended by the U.S. Food and Drug Administraiton. Error and consistency checks are built into the data entry application. The coordinating center will conduct regular audits of the data during the course of the trial every 7–10 days via remote monitoring. Postnatal hospital data will be recorded on the CRFs by the study team at birth (day of life 0), day of life 15, 30, 60, 90 and time of discharge or death. Adverse events (AE) will be reported on standardized AE forms at each center. Data will be entered in near real time from these sites and exports generated at least monthly to be included in the data warehouse at Johns Hopkins data coordinating center. Data related to patient safety and outcomes are source-document verified, and other data are monitored for completeness and plausibility. Together the clinical coordiating and data coordianating centers will review parameters including but not limited to: enrollment, patient disposition (completed, discontinued, and loss to follow-up), and any complications (AEs, serious AEs, and protocol deviations). Long-term follow-up data for neonatal survivors will be collected via the NAPRTCS registry platform and transferred to the data coordinating center every six months.

Results Assessment

Neonatal lung development and short-term survival to dialysis are critical steps for long-term survival of a child with early pregnancy renal anhydramnios. The primary outcome of interest will be neonatal respiratory survival and use of a dialysis catheter for ≥ 14 continuous days. Data analysis will reveal if pulmonary survival after serial amnioinfusions can be predicted based on amniotic fluid contents and prenatal imaging. Lung fluid produced by pneumocytes to distend the tracheobronchial tree are released into the amniotic cavity during fetal breathing movements, therefore allowing analysis of lung secretions by amniotic fluid analysis. Insight into the mechanism of amnioinfusion action may be gained by observing the relationships between protein, lipid, and molecular markers during treatment. Previous investigators have indicated that amniotic fluid protein and lipid ratios and concentrations are predictive of neonatal respiratory distress [23–25]. When there is sufficient residual fluid remaining from the previous amnioinfusion, a clinically safe, fluid sample from the amniotic cavity will be aspirated before each amnioinfusion, processed and sent to Johns Hopkins Biorepository at All Children’s Hospital following a standardized protocol. Other perinatal variables such as gestational age at delivery, delivery mode, Apgar scores, and umbilical cord blood gases will be recorded, along with neonatal pulmonary and renal interventions and success rates. Important morbidities including cardiopulmonary, gastrointestinal, and neurologic outcomes will also be recorded.

The RAFT trial will also allow prospective determination of the maternal and fetal safety of serial amnioinfusions, the number of amnioinfusions without preterm premature rupture of membranes (PPROM) that can be feasibly performed, the rate of chorioamnion separation, the gestational age at delivery after serial amnioinfusions and, in patients that experience PPROM, the latency period until delivery. This first objective will seek to determine the rates of the following potential maternal complications of amnioinfusion: bleeding, chorioamnionitis, placental abruption, uterine rupture, amniotic fluid embolism, and death. Rates of the following potential fetal complications will also be calculated: fetal demise (risk of spontaneous fetal demise with isolated early pregnancy renal anhydramnios is reported to be as high as 1 in 3), fetal injury, and amniotic band syndrome [26]. We hypothesize these rates of potential maternal/fetal complications will be the same as published rates in normal pregnancies that undergo a diagnostic amniocentesis [27]. We hypothesize 75% of patients eligible for RAFT who choose intervention will be able to undergo at least four amnioinfusions before PPROM or preterm labor/delivery occurs.

Long-term survival will be evaluated by: (1) infant survival to hospital discharge on chronic dialysis, (2) survival to renal transplantation, and (3) family-reported health-related quality of life (QOL) with ESRD. Although short-term neonatal dialysis is technically possible in early pregnancy renal anhydramnios infants who received amnioinfusions prenatally, indicators of long-term efficacy must include hospital discharge and transition to home, survival on dialysis to renal transplantation, and QOL that is, ideally, comparable to children on dialysis and with kidney transplants due to other underlying causes of ESRD (as measured using Pediatric Measurement Models for the Pediatric Quality of Life Inventory™ scores [Lyon, France]). QOL will be assessed in infants who survive to hospital discharge and their families every 6 months during the study period. Parents/caregivers will be asked to submit 2 forms for each surviving infant at each 6 month check-in; one PedsQL™ Family Impact Module, and one additional form specific to the age of the infant/child (PedsQL™ Infant Scales up to and including age 24 months, followed by the age-specific End Stage Renal Disease Module for age 2 and above.

Discussion and Conclusion

The RAFT trial is the first clinical trial investigating the efficacy, safety, and feasibility of serial amnioinfusions to treat the survival-limiting pulmonary hypoplasia associated with anhydramnios secondary to fetal renal failure. Although the intervention of amnioinfusion offers an opportunity for the treatment of a condition that is known to be almost universally fatal in affected neonates, the potential burdens associated with the care of neonates with end stage kidney disease from birth must be acknowledged, and participation requires thorough multidisciplinary counseling as part of the study screening process. The RAFT consortium is committed to the open and timely dissemination of research outcomes and recognize that promising new methods, technologies, and immunological insights may arise during the course of research. The data generated by this trial will be presented and disseminated in a timely fashion.

The RAFT trial will be able to produce generalizable knowledge about the extent to which life-sustaining pulmonary function can be achieved by artificial correction of the amniotic fluid volume in pregnancies complicated by anhydramnios secondary to fetal renal failure. Although survival may be possible, the range of morbidities that may affect individuals with severe prenatally acquired renal impairment or even absence of renal tissue altogether cannot yet be estimated. Noting the potential range of health outcomes in patients with renal agenesis, it will be critical to follow outcomes in surviving neonates over time. Despite these significant issues, a robust scientific approach to assess the benefits and risks of serial amnioinfusions to promote lung development is required to generate generalizable knowledge from a systematically recruited, representative cohort of pregnancies complicated by early pregnancy renal anhydramnios, rather than drawing conclusions from individual or single center case reports.

Acknowledgements

The authors wish to acknowledge the contribution of Dr. Eric B. Jelin, who passed away prior to the submission of this manuscript, for his critical and foundational contributions to the design and conduct of the RAFT trial.

Disclosure of Funding Support

This work was supported by the NIH NICHD R01HD100540 and NIH NCATS U24TR001609

Footnotes

Declarations of interest: None

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