Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT05528796 |
| Other study ID # |
R01HD107190 |
| Secondary ID |
R01HD107190 |
| Status |
Enrolling by invitation |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2022 |
| Est. completion date |
February 28, 2027 |
Study information
| Verified date |
January 2024 |
| Source |
University of California, San Francisco |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Non-immune hydrops fetalis (NIHF) is diagnosed on prenatal ultrasound when abnormal fluid
collections are seen in the fetus. NIHF carries significant risks of stillbirth, preterm
birth, and postnatal morbidity and mortality, particularly when the etiology remains unknown
and critical opportunities for focused care and implementation of treatments are missed. In
contrast, when an etiology is found, both pre- and postnatal management are directly
impacted: counseling is focused, risks to the fetus and neonate are accurately anticipated,
surveillance and in utero available treatments such as intrauterine transfusions are
implemented, and postnatal treatments are promptly initiated to optimize outcomes. The
overarching hypothesis is that discovering the precise etiologies of NIHF will create
critical opportunities to improve outcomes through earlier, targeted pre- and postnatal care.
Several important steps remain in order to uncover the genetic etiologies for cases remaining
unsolved and improve care for these pregnancies. The study team proposes a multicenter
collaboration to discover additional genetic diseases and novel variants underlying NIHF in a
prospectively enrolled, large and diverse cohort utilizing whole genome sequencing (WGS) and
RNA sequencing. The team will further perform comprehensive phenotyping to: a) collect
detailed postnatal phenotypes and outcomes, b) re-analyze WGS data utilizing postnatal
phenotype to identify diagnoses missed when sequencing algorithms incorporated only
phenotype, and c) expand the phenotypes of all genetic in utero in utero diseases the
investigators identify to optimize prenatal diagnosis and yield of genomic testing during
pregnancy. Such a focused and comprehensive approach to the evaluation and diagnosis of NIHF
has not previously been performed, particularly in a large and diverse cohort, and it is
expected that this work will significantly improve the ability to understand and reshape the
perinatal care for NIHF. This work will lay the foundation for redefining the approach to
prenatal diagnosis, management, in utero and postnatal care for NIHF, and will create future
opportunities to develop novel diagnostic algorithms and approaches to manage the
complications of specific diseases underlying in utero NIHF.
Description:
The etiology of non-immune hydrops fetalis (NIHF) remains unknown in at least half of all
cases after standard prenatal testing; the comprehensive approach with genomic testing and
detailed phenotyping is critical for better understanding this highly morbid condition and
ultimately improving outcomes. NIHF occurs in up to 1 in 1700 pregnancies and is diagnosed
when abnormal fetal fluid collections (such as pericardial effusion, pleural effusion,
ascites, and skin edema) are detected on prenatal ultrasound. Risks include preterm birth in
57-80% of cases, stillbirth in 17-30%, and neonatal death in 29-50%. When the etiology is
unknown, critical pre- and postnatal opportunities for focused care and prompt initiation of
available treatments are missed. In contrast, when an etiology such as a hereditary anemia or
lysosomal storage disorder is found, prenatal counseling is focused, risks to the fetus and
neonate are accurately anticipated, in utero surveillance and available treatments such as
intrauterine transfusions are implemented, and postnatal treatments are promptly initiated to
optimize outcomes.
Many genetic etiologies may underlie NIHF, particularly single gene disorders missed by
standard microarray and karyotype. Exome sequencing (ES), whole genome sequencing (WGS), and
functional studies are emerging tools for prenatal diagnosis. ES examines >20,000 genes, WGS
examines these genes as well as other structural genomic changes, and functional studies such
as RNA sequencing evaluate downstream effects of genomic changes. Prior to this work, these
approaches had not been used to study NIHF. In a preliminary study of 127 NIHF cases
unexplained by standard genetic testing, the study team identified diagnostic variants in 29%
with ES and a variant of potential significance in another 9%. This yield is much higher than
the 8.5-10% reported for all fetal anomalies with ES, highlighting the burden of single gene
disorders in NIHF. The study team identified genetic diseases with greatly variable ultimate
severity as well as pre- and postnatal management. However, important steps remain to improve
care for these cases: identify additional underlying genetic variants, structural
rearrangements, and candidate genes to more fully understand the genetic etiologies of NIHF;
enroll a larger, racially diverse cohort to decrease disparities in disease identification;
and comprehensively describe in utero and postnatal features of genetic diseases manifesting
with NIHF to expand knowledge of their perinatal phenotypes and optimize the yield of
prenatal sequencing.
The overarching hypothesis is that discovering the precise etiologies of NIHF will create
critical opportunities to improve outcomes through earlier, targeted pre- and postnatal care.
The HyDROPS study (Hydrops: Diagnosing and Re-defining Outcomes with Precision Study) where
127 cases were sequenced was conducted by the PI, and the expert multidisciplinary team is
ideally positioned to carry the next steps (HyDROPS2) forward. The study will enroll from 5
large medical centers across the country to increase racial and ancestral diversity of the
cohort to thoroughly elucidate genetic diseases underlying NIHF, and perform detailed in
utero and postnatal phenotyping to improve the accuracy of prenatal diagnosis. The specific
aims of the study are:
Specific Aim 1: Discover additional genetic diseases and novel genomic variants underlying
NIHF with WGS and RNA sequencing in a large, diverse cohort. Aim 1A) Uncover novel genomic
variants with WGS in HyDROPS cases not explained by ES. Aim 1B) Identify novel genomic
variants with WGS as well as functional consequences of selected variants with RNA sequencing
in a large, prospectively enrolled, racially diverse HyDROPS2 cohort. It is expected to
identify a diagnostic variant in 40% of all unexplained NIHF cases with WGS, a diagnostic
variant in 10% of cases selected to undergo RNA sequencing, as well as many additional
diseases and genomic variants that are critical for understanding the etiologies of NIHF.
Specific Aim 2: Characterize the pre- and postnatal phenotypes for NIHF cases in HyDROPS and
HyDROPS2 to expand knowledge of disease-specific features and optimize diagnostic accuracy.
Aim 2A) Describe postmortem features for demises and longer term outcomes for living cases to
capture phenotypic data missed in utero. Aim 2B) Re-analyze prenatal WGS data using postnatal
phenotype to identify diagnoses missed when only the in utero phenotype was incorporated. Aim
2C) Characterize the prenatal phenotypic features for the full spectrum of genetic diseases
the investigators diagnose underlying NIHF. It is expected that a substantial proportion of
cases will have additional postnatal phenotype important for accurate disease identification,
that re-analyzing WGS data utilizing postnatal phenotype will yield a diagnosis in 20% of
originally negative or inconclusive cases, and that many in utero features of genetic
diseases are underrecognized and thus limit accurate prenatal diagnosis.
Through these aims, the study team will gain a much deeper understanding of the genomic
etiologies and disease-specific in utero features of NIHF. This will lay the groundwork to
redefine the prenatal approach to NIHF through earlier and accurate diagnosis, and to develop
novel, disease-specific in utero management strategies. This precision approach will improve
the course for fetuses and families encountering NIHF.
