Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis

Abstract

ImportanceEarly anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival.ObjectiveTo assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia.Design, Setting, and ParticipantsProspective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies.ExposureEnrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks’ gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age.Main Outcomes and MeasuresThe primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement.ResultsThe trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks’ gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks).Conclusions and RelevanceSerial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden.Trial RegistrationClinicalTrials.gov Identifier: NCT03101891

The genetic etiologies of bilateral renal agenesis

“…Comprehensive counseling becomes especially relevant given technological advances in Medicine that may improve short-and long-term survival outcomes for those afflicted with BRA. 5 We hope that the tabulated data herein will serve to assist perinatal teams in their counseling and in initiating the workup towards achieving an accurate diagnosis.…”

“…The ability to delineate isolated BRA from complex BRA is becoming increasingly important in the era of the Renal Agenesis Fetal Therapy Trial. [3][4][5] BRA is one of the multiple renal pathologies included under the umbrella of CAKUT, an acronym coined for Congenital Anomalies of the Renal and Urinary Tract, which taken altogether are present in approximately 0.1 to >1.0 of births. 1,6,7 Historically, BRA has long been noted to have a preponderance for male sex, with an autopsy study initially reporting approximately three fourths of cases male and one fourth female.…”

Precarious hope: Ethical considerations for offering experimental fetal therapies outside of research after initial studies in humans

“…8 Of the 14 liveborn infants who achieved the primary outcome, only 6 survived to discharge on peritoneal dialysis at a median age of 24 weeks, and 2 of these 6 died after discharge. 9 RAFT provides solid evidence that amnioinfusions improve neonatal survival in BRA which led to unanticipated care needs in these survivors (e.g., management of strokes 8 ), as well as care needs that were anticipated but uncommon and medically challenging (e.g., dialysis in premature and small infants). Long-term pediatric outcomes are still unknown, and future research is needed to identify ways to improve postnatal management.…”

Amniotic fluid stem cell extracellular vesicles promote lung development via TGF-beta modulation in a fetal rat model of oligohydramnios

“…7 Attempts have been made to replenish the normal amniotic fluid volume by serial or continuous infusions with non-amniotic fluids during the mid-and third trimester. [8][9][10][11] However, randomized controlled trials have shown little or no benefit with amnioinfusion for perinatal survival, rather they have highlighted possible associated complications. 8,10,11 One could speculate that re-establishing just fluid volume is not enough, as the amniotic fluid is highly enriched with nutrients that are required for normal organogenesis.…”

“…[8][9][10][11] However, randomized controlled trials have shown little or no benefit with amnioinfusion for perinatal survival, rather they have highlighted possible associated complications. 8,10,11 One could speculate that re-establishing just fluid volume is not enough, as the amniotic fluid is highly enriched with nutrients that are required for normal organogenesis. 12 In particular, lung development is a complex process regulated by multiple signaling pathways involving several molecular species, such as miRNAs, proteins, and lipids.…”