Serial infusions to restore amniotic fluid lost due to lack of fetal renal development before 26 weeks’ gestation improved the rate of live births without maternal safety risks, the RAFT trial found.
Among 18 cases of fetal bilateral renal agenesis, there were 17 live births (94%) at a median gestational age of 32 weeks and 14 survived to at least day 14 (82% of those born live, 95% CI 44-99%), meeting the primary outcome in the nonrandomized trial for a condition that is uniformly lethal otherwise.
A higher number of amnioinfusions (P=0.01), gestational age greater than 32 weeks (P=0.005), and higher birth weight (P=0.03) were all factors associated with survival to 14 days.
No serious maternal complications occurred, although delivery before 37 weeks’ gestation was universal and 61% had preterm prelabor rupture of membranes, Jena Miller, MD, of Johns Hopkins University in Baltimore, and co-authors reported in JAMA.
Miller told MedPage Today that the study “really just gets us over the very first step” of understanding amnioinfusions to prevent lethal pulmonary hypoplasia.
What the trial couldn’t solve was the challenge of managing kidney disease complexities for these patients long-term, Miller said.
Only six (35%) of the neonates survived to hospital discharge with placement of long-term dialysis access. In that group, one died from infectious complications of dialysis at 2 years old, one died from cardiac arrest at age 4 months, and three had strokes. Just two survived long-term.
The trial was stopped early due to “concern for potential harm given the disparity between short- and long-term infant survival and the burden of morbidity in longer-term survivors, especially stroke,” the researchers noted.
Bilateral renal agenesis is the most severe congenital anomaly of the fetal urinary tract. Fetal anuria leads to a lack of amniotic fluid, which depressurizes the airways, impairing pulmonary development and resulting in pulmonary hypoplasia, which has been universally lethal.
Miller said the trial was partially inspired by a case report from colleagues where in one case, after restoring amniotic fluid with amnioinfusions, a child “went on to have sufficient lung function and ultimately was able to be treated for kidney disease.”
In an accompanying editorial, Cynthia Gyamfi-Bannerman, MD, MS, of the University of California San Diego, and co-authors argued that prenatal counseling will now have to include the findings of the RAFT trial.
The trial proves that in cases of bilateral renal agenesis, “survival can be better than zero,” they wrote. “This important work has shown that serial amnioreductions for bilateral renal agenesis have made a once-lethal diagnosis into one with a possibility for survival.”
The editorial called it a missed opportunity that parental interviews were not done to give insight into the families’ perspective. Miller told MedPage Today that a qualitative study on the families’ perspectives is planned to help guide prenatal counseling.
In terms of future research, Miller said that the “next really big step is thinking about the complexities of neonatal management for babies who are born without kidneys or with other forms of fetal renal failure prenatally because … this is a whole new cohort of babies that didn’t exist before.”
The nonrandomized trial took place from December 2018 to July 2022 at nine fetal therapy centers. Centers had to have a maternal-fetal medicine doctor who had performed amnioinfusion procedures for oligohydramnios or anhydramnios at least 15 times before.
The intervention involved ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks’ gestation to maintain normal amniotic fluid levels. An additional three mothers elected not to have the infusions, and entered an expectant management group providing observational data before and after delivery. All of the expectant management fetuses died.
The study authors noted two main limitations: the small sample size and lack of diversity. The sample was 94% white, which the group suggested was in part due to requiring insurance coverage and requiring prenatal and postnatal care at specific participating centers.
The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH.
Miller reported no conflicts of interest. Co-authors reported funding from Travere Pharmaceuticals; personal fees from Merck KGaA, IQVIA, Aspen Neurosciences, Merck, and Biogen; travel support from Merck KGaA and IQVIA; and holding stock options in Aspen Neurosciences.
Gyamfi-Bannerman reported receiving grants from the National Heart, Lung, and Blood Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Minority Health and Health Disparities.
Source Reference: Miller JL, et al “Neonatal survival after serial amnioinfusions for bilateral renal agenesis: The renal anhydramnios fetal therapy trial” JAMA 2023; DOI: 10.1001/jama.2023.21153.
Source Reference: Gyamfi-Bannerman C, et al “Bilateral renal agenesis — interpreting the RAFT trial” JAMA 2023; DOI: 10.1001/jama.2023.22747.