BACKGROUND: The optimal protocol for serial amnioinfusions to maintain amniotic fluid in pregnancies with early-onset fetal renal anhydramnios before 22 weeks is not known. We compared the performance of two different approaches.
METHODS: A secondary analysis was conducted of serial amnioinfusions performed by a single center during the external pilot and feasibility phases of the Renal Anhydramnios Fetal Therapy (RAFT) trial. During the external pilot, higher amnioinfusion volumes were given less frequently; in the feasibility study, smaller volume amnioinfusions were administered more frequently. Procedural details, complications, and obstetric outcomes were compared between the two groups using Pearson\'s χ2 or Fisher\'s exact tests for categorical variables and Student\'s t tests or Wilcoxon rank-sum tests for continuous variables. The adjusted association between procedural details and chorioamniotic separation was obtained through a multivariate repeated measure logistic regression model.
RESULTS: Eleven participants underwent 159 amnioinfusions (external pilot: 3 patients, 21 amnioinfusions; feasibility: 8 patients, 138 amnioinfusions). External pilot participants had fewer amnioinfusions (7 vs. 19.5 in the feasibility group, p = 0.04), larger amnioinfusion volume (750 vs. 500 mL, p < 0.01), and longer interval between amnioinfusions (6 [4-7] vs. 4 [3-5] days, p < 0.01). In the external pilot, chorioamniotic separation was more common (28.6% vs. 5.8%, p < 0.01), preterm prelabor rupture of membranes (PPROM) occurred sooner after amnioinfusion initiation (28 ± 21.5 vs. 75.6 ± 24.1 days, p = 0.03), and duration of maintained amniotic fluid between first and last amnioinfusion was shorter (38 ± 17.3 vs. 71 ± 19 days, p = 0.03), compared to the feasibility group. While delivery gestational age was similar (35.1 ± 1.7 vs. 33.8 ± 1.5 weeks, p = 0.21), feasibility participants maintained amniotic fluid longer.
CONCLUSIONS: Small volume serial amnioinfusions performed more frequently maintain normal amniotic fluid volume longer because of delayed occurrence of PPROM.

Congenital urethral atresia is generally considered to be incompatible with life unless there is either a patent urachus or vesicoamniotic shunt. Here we present the case of a male neonate with anhydramnios detected at 28weeks gestation due to urethral atresia, who was born without evidence of either a patent urachus or vesicoamniotic shunt, who has survived and is not requiring respiratory support at age 5months. While this is a thought-provoking clinical case, it also highlights the importance of early and effective parental engagement in cases of complex congenital anomalies of the urinary tract.

BACKGROUND: Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare disorder of renal tubular development. ARRTD is a severe condition with high risk of fetal demise and early neonatal death, with only limited case reports of survival over 2 years [Clin Kidney J. 2012 Feb 1;5(1):56-8]. Prenatal diagnosis of ARRTD is challenging, and diagnosis has only previously been confirmed after postnatal or post-mortem investigation.
METHODS: To the best of our knowledge, we describe the first reported case of utilizing targeted genetic testing on the chorionic villous sample (CVS) to identify a homozygous variant in the angiotensinogen (AGT) gene.
CONCLUSIONS: By substantiating the diagnosis of ARRTD prenatally, we allow timely and appropriate counseling during pregnancy.

The most severe forms of congenital anomalies of the kidney and urinary tract present in fetal life with early pregnancy renal anhydramnios and are considered lethal due to pulmonary hypoplasia without fetal therapy. Due to the high rate of additional structural anomalies, genetic abnormalities, and associated syndromes, detailed anatomic survey and genetic testing are imperative when stratifying which pregnancies are appropriate for fetal intervention. Restoring amniotic fluid around the fetus is the principal goal of prenatal treatment. The ongoing multi-center Renal Anhydramnios Fetal Therapy (RAFT) trial is assessing the safety and efficacy of serial amnioinfusions to prevent pulmonary hypoplasia so that the underlying renal disease can be addressed.

To determine whether the presence of anhydramnios significantly influences the sonographic estimated fetal weight (EFW) compared to a matched cohort with normal amniotic fluid volume.
The study sample of this retrospective case-control study consisted of 114 pregnant women who presented to a Tertiary Perinatal Clinic between 2015 and 2020. 57 of them presented with an anhydramnios and a matched cohort of 57 women with normal amniotic fluid volume. At time of admission, gestational age varied between 22 + 4 and 42 + 6 weeks of pregnancy. All women underwent detailed ultrasound assessment for EFW and amniotic fluid index. To determine EFW Hadlock\'s estimation formula I was used which is based on measurements of biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL). The EFW was compared with the weight at delivery. The maximum time interval between measurement and delivery was 5 days.
There was neither a significant difference between the case and control group with regard to gestational age at ultrasound in days (median 249 days and 246 days, p = 0.97), nor to gestational age at birth (median 249 days and 247 days, p = 0.98). Concerning the newborns parameters, the body length at birth was not significantly different between the case and control group in centimeters (cm) (median 47 cm and 47 cm, p = 0.79). EFW in gram (g) was lower than birth weight in both groups and did not differ significantly between case and control group (estimated weight median 2247 g and 2421 g, p = 0.46; birth weight median 2440 g and 2475 g, p = 0.47). The difference between EFW and birth weight in percent (%) did not differ between the case and control group (median - 3.9% and - 5.6%, p = 0.70). The maternal parameters showed that the patients in the case group were younger (median 31 years and 38 years p = 0.20) and had a significantly higher body mass index (BMI) (median 27.3 kg/m2 vs 22.0 kg/m2, < 0.001) compared to the control group.
Our study shows for the first time that EFW in women with anhydramnios can be determined sonographically just as accurately as in a matched cohort with normal amniotic fluid volume. A reliable estimation of fetal weight is crucial for optimal assessment of the newborns prognosis and counseling of the parents especially when advising women in the early weeks of pregnancy at the limit of viability.

Anhydramnios secondary to anuria before 22 weeks of gestational age and congenital bilateral renal agenesis before 26 weeks of gestational age are collectively referred to as early-pregnancy renal anhydramnios. Early-pregnancy renal anhydramnios occurs in at least 1 in 2000 pregnancies and is considered universally fatal when left untreated because of severe pulmonary hypoplasia precluding ex utero survival The Renal Anhydramnios Fetal Therapy (RAFT) trial is a nonrandomized, nonblinded, multicenter clinical trial designed to assess the efficacy, safety, and feasibility of amnioinfusions for patients with pregnancies complicated by early-pregnancy renal anhydramnios. The primary objective of this study is to determine the proportion of neonates surviving to successful dialysis, defined as use of a dialysis catheter for ≥14 days.
A consortium of 9 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 may elect to receive amnioinfusions or to join the nonintervention observational expectant management group. Eligible pregnant women must be at least 18 years of age with a fetal diagnosis of isolated early-pregnancy renal anhydramnios.
In addition to the primary study objective stated above, secondary objectives include (1) to assess maternal safety and feasibility of the serial amnioinfusion 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 to investigate 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.
gov identifier: NCT03101891.

Congenital abnormalities of the kidney and urinary tract (CAKUT) represent 20% of prenatally diagnosed congenital abnormalities. Although the majority of these abnormalities do not require intervention either pre or postnatally, there is a subset of patients whose disease is so severe that it may warrant intervention prior to delivery to prevent morbidity and mortality. These cases consist of patients with moderate lower urinary tract obstruction (LUTO) in which vesicocentesis, shunting or cystoscopy are options and patients with early pregnancy renal anhydramnios (EPRA) in whom amnioinfusion therapy may be an option. The main causes of EPRA are congenital bilateral renal agenesis (CoBRA), cystic kidney disease (CKD) and severe LUTO. Untreated, EPRA is universally fatal secondary to anhydramnios induced pulmonary hypoplasia. The evidence regarding therapy for LUTO is limited and the stopped early PLUTO (Percutaneous Shunting in Lower Urinary Tract Obstruction) trial was unable to provide definitive answers about patient selection. Evidence for EPRA therapy is also scant. Serial amnioinfusions have shown promise in cases of EPRA due to CoBRA or renal failure and this treatment modality forms the basis of the ongoing NIH funded RAFT (Renal Anhydramnios Fetal Therapy) trial. At present, there is consensus that treatment for EPRA should only occur in the setting of a clinical trial.

Anhydramnios results from the poor development of the placenta or problems with intrauterine development of the kidneys or urinary tract. Complete lack of amniotic fluid indicates a severe problem with the organs of the urinary system. The genes associated with anhydramnios show very diversity and are not yet well defined.
Whole-exome sequencing (WES) was used for an aborted male case around the 20th week of gestation diagnosed with anhydramnios. The resulted deleterious variants were verified by Sanger sequencing. Pathogenicity of deleterious variants was explored by in silico analysis.
A maternally inherited deleterious frameshift variant, c.1454_1455insC, p.(S486Ffs29) in exon 9 and two paternally inherited missense variants c.1037C > G, p.(Ser346Trp) in exon 7 and c.1465A > G, p.(Asn489Asp) in exon 9 of Angiotensin-I-Converting Enzyme (ACE) gene were found and confirmed by Sanger sequencing. c.1454_1455insC, p.(S486Ffs29) and c.1037C > G, p.(Ser346Trp) were identified as two novel compound heterozygous deleterious variants. The pathogenicity of these deleterious variants was determined by in silico analysis and both the deleterious variants disrupt the structure of the ACE protein.
Two novel compound heterozygous variants were identified in the case with anhydramnios, which may be associated with pathogenicity of anhydramnios. Our data also revealed that the WES approach may provide helpful information for genetic counseling of the families with anhydramnios.

The reason for increased serum creatinine levels in preterm infants often remains unclear. We aimed to determine whether postnatal serum creatinine in preterm infants correlates with intake of amniotic fluid, represented by the amount of amniotic fluid after preterm premature rupture of membranes (PPROM).
74 preterm infants with PPROM > 48 h duration were retrospectively studied. Postnatal creatinine concentration was determined at day 2-5, 10-17 and 26-33 of life and compared between infants with normal intrauterine amniotic volumes, oligohydramnios and anhydramnios.
Mean gestational age of included patients was 29.7 weeks (range: 24.0-36.1 weeks) and mean birth weight was 1452 g (range: 560-2940 g). Serum creatinine concentration was similar at day 2-5 and day 10-17 of life between the three groups. We observed a significant decrease in creatinine concentration from day 2-5 to day 26-33 in infants with normal amniotic fluid volume and oligohydramnios (p = 0.0001 and p = 0.0071, respectively), but not in anhydramnios. On day 26-33 of life, infants with anhydramnios showed significantly higher creatinine levels compared to infants with normal amniotic fluid volume and oligohydramnios (p = 0.0211).
Postnatal serum creatinine of preterm infants at day 26-33 of life is elevated in infants with PPROM-induced anhydramnios, but not in oligohydramnios.

Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare and lethal disorder that causes stillbirth or early neonatal death. Most of the reported cases are diagnosed postnatally by a histopathological hallmark of the absence or paucity of differentiated proximal tubules in kidneys. Prenatal diagnosis of ARRTD is challenging because only a few fetal features (e.g., oligohydramnios/anhydramnios, anuria) are associated with this condition. In this study, we report a fetus with ARRTD, which showed anhydramnios and invisible urinary bladder since the second trimester, followed by growth restriction and reversed end diastolic flow in the middle cerebral artery (MCA-REDF). No morphological anomaly was detected on the fetal kidneys during an ultrasound scan. The baby died of refractory hypotension the day after their birth. Genetic analysis of genes that are involved in the renin-angiotensin-aldosterone system (RAAS), which are the known genetic causes of ARRTD, identified a novel, biparental-origin homozygous c.857-619_1269+243delinsTTGCCTTGC mutation in the AGT gene. The mutation is considered as pathogenic because it is cosegregated with ARRTD and detected in other unrelated ARRTD families. Our findings link the fetal ultrasound manifestations to the ARRTD, highlighting clues that are useful for prenatal diagnosis, which warrants confirmatory genotyping of the RAAS genes including oligohydramnios/anhydramnios, anuria (absent filling of a fetal urinary bladder), MCA-REDF, and a morphologically normal kidney.