Hydrops: Diagnosing & Redefining Outcomes With Precision Study

Study Overview
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Brief Summary
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This is a national, prospective study designed to investigate the genetic etiologies of non-immune hydrops fetalis (NIHF) and other birth defects. At least half of prenatally diagnosed NIHF cases remain of unknown etiology after standard work up, and a substantial proportion of other birth defects remain of unknown etiology as well. The investigators are performing exome sequencing (ES) for the affected fetus or neonate in unexplained cases, as well as enrolling cases with a genetic explanation to represent the full spectrum of diseases underlying NIHF and other birth defects.

Detailed Description
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Up to 1:1700 pregnancies are affected by non-immune hydrops fetalis (NIHF), and this condition is associated with significant perinatal risks ranging from preterm birth to Ballantyne (maternal mirror) syndrome, stillbirth, and neonatal death. Birth defects affect 1:33 pregnancies, and are the leading cause of infant death (contributing to approximately 20% of infant deaths). The investigators are performing exome sequencing (ES) for the affected fetus or neonate in unexplained cases, as well as enrolling cases with a genetic explanation to represent the full spectrum of diseases underlying NIHF and other birth defects. This study is open for enrollment by invitation. In addition to performing ES, the investigators are collecting clinical data prospectively on all cases of NIHF and other birth defects, including demographics, medical and obstetric history, prenatal and delivery course, and postnatal outcomes. The specific research aims include: Create registry of clinical data for cases of NIHF and other birth defects. Investigate genetic variants underlying NIHF and other birth defects via ES. Characterize the features and outcomes of genetic diseases presenting with NIHF and other birth defects. In particular, the researchers are focused on enrolling cases of increased nuchal translucency, cystic hygroma, abnormal fetal fluid collection (even single fluid compartments such as isolated pleural effusion), and/or frank NIHF. This research will contribute novel information about the frequency and types of genetic disorders in fetuses and newborns with a diagnosis of NIHF and other birth defects, enabling providers to more accurately counsel about prognosis and individualize perinatal care. This information will also facilitate informed decision-making for parents, allow the care team to anticipate specific perinatal needs, and enable more precise counseling for the parents about recurrence risks for NIHF and other birth defects. Further, the research will facilitate future aims such as novel fetal therapies for genetic diseases.

Official Title
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Hydrops: Diagnosing & Redefining Outcomes With Precision Study

Conditions
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Hydrops Fetalis, Birth Defect, Fetal Anomaly

Intervention / Treatment
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* Diagnostic Test: Exome sequencing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Singletons or dichorionic twin pregnancies that are diagnosed prenatally with non-immune hydrops fetalis (NIHF) or another birth defect. Cases with chromosomal abnormalities, postnatal samples, and stillbirths will still be included. Exclusion Criteria: Monochorionic twin pregnancies and cases of hydrops fetalis that are attributed to red cell alloimmunization (due to hydrops fetalis caused by different pathophysiologic processes).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: All cases of unexplained non-immune hydrops fetalis (NIHF) or other birth defects enrolled in the study will be offered exome sequencing (ES) for the affected fetus or neonate.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exome sequencing<br>There is only one arm of this study. All enrolled participants with unexplained NIHF or other birth defect will be offered exome sequencing for the affected fetus or neonate. Please refer to the Study Design section for further details. | Diagnostic Test: Exome sequencing<br>* Expansive genetic test performed for affected fetus or neonate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genetic variants detected with exome sequencing that implicate a genetic disease underlying non-immune hydrops fetalis (NIHF) and other birth defects. | Both NIHF and birth defects can be caused by a variety of genetic variants that researchers are continuing to learn more about. Exome sequencing will yield information about the specific genetic variants present in cases of NIHF and other birth defects, and about the specific diseases implicated by these variants. Investigators will determine the proportion of cases seen in the setting of particular genetic variants, and will correlate phenotypic outcomes with specific genotypes. | Turn around time for exome sequencing results is 2-4 weeks for ongoing pregnancies and live infants, and is 8-12 weeks for stillbirths, terminations, and infant demises. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hydrops fetalis, birth defect, fetal anomaly, exome sequencing