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Nonimmune Fetal HydropsNCT03911531

Whole Exome Sequencing and Whole Genome Sequencing for Nonimmune Fetal/Neonatal Hydrops

An observational study of Nonimmune Fetal Hydrops and Nonimmune Hydrops in Neonate, run by Thomas Jefferson University at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Brief Summary: Nonimmune hydrops fetalis (NIHF) is a potentially fatal condition characterized by abnormal fluid accumulation in two or more fetal compartments. Numerous etiologies may lead to NIHF, and the underlying cause often remains unclear (1). Read more about this study

Who is it for?
Ages 16 to 55 years
What is being tested?
Whole Exome Sequencing and Whole Genome Sequencing
How many people
55 participants
Where
1 siteUnited States
Study dates
15 Jan 2019to 31 Dec 2025
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 to 55 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Study population: Patients will be recruited from MFM physicians, paediatricians,and neonatologists.

The following inclusion criteria will apply:

  1. Fetal hydrops identified anytime in pregnancy after the first trimester
  2. Parents are planning to proceed with amniocentesis as a routine workup for hydrops.
  3. Both parents are available for blood sample collection
  4. Normal CMA and normal karyotype if performed
  5. Negative workup for Parvovirus B19, cytomegalovirus, toxoplasmosis, and syphilis
  6. Negative fetomaternal hemorrhage workup as a cause for hydrops For cases of neonatal hydrops, the criteria for invasive prenatal testing will not be required as a postnatal blood sample from the hydropic infant will be the source of proband DNA.

The following exclusion criteria will apply:

  1. Microarray was abnormal or karyotype was abnormal
  2. Hydrops caused by congenital infection
  3. Fetomaternal hemorrhage was a documented etiology for hydrops
  4. Parental DNA cannot be obtained for either parents
  5. Donor egg or donor sperm were utilized for conception
  6. Fetus/Infant diagnosed with lysosomal storage disease
  7. Pregnant woman or father of the baby less than 16 years of age
  8. Hydrops was diagnosed concomitantly with intrauterine fetal demise

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Thomas Jefferson University

    Philadelphia, Pennsylvania, 19107

Other trials in United States

About this study

Brief Summary: Nonimmune hydrops fetalis (NIHF) is a potentially fatal condition characterized by abnormal fluid accumulation in two or more fetal compartments. Numerous etiologies may lead to NIHF, and the underlying cause often remains unclear (1). The current standard of genetic diagnostic testing includes a fetal karyotype and chromosomal microarray (CMA), with an option to pursue single gene testing on amniocytes collected by amniocentesis (2). A large subgroup of the NIHF causes includes single gene disorders that are not diagnosed with the standard genetic workup for hydrops. Currently, nearly 1 in 5 cases of NIHF is defined as idiopathic, meaning there is no identified etiology (2). The investigators believe this is because the causes of NIHF are not completely investigated, specifically single gene disorders. Our research study aims to increase the diagnostic yield by performing whole exome sequencing (WES) and whole genome sequencing (WGS) on prenatal and neonatal NIHF cases when standard genetic testing is negative, identifying known and new genes, thus providing vital information to families regarding the specific diagnosis and risk to future pregnancies. The investigators plan to perform WES as the initial diagnostic test. If WES is negative, then the investigators will proceed to perform WGS.

Read the detailed description

This is a prospective cohort study design for fetuses or neonates affected with NIHF. Mother-father-fetus trios of pregnancies complicated by idiopathic non-immune fetal hydrops will be identified. These patients will be counseled by a Maternal-Fetal Medicine specialist as would be the routine. As part of the routine work-up, amniocentesis will be recommended for karyotype, CMA and an infectious work-up. Amniocentesis will be performed by the Maternal-Fetal Medicine specialist of the referring institution. The patient will also be offered genetic counseling (routine). Subjects will be offered enrollment when inclusion criteria are met. After enrollment, the following samples will be collected: (1) maternal blood (2) paternal blood, (3) fetal DNA isolated from amniocytes (4) neonatal blood when referral is done postnatally. The WES results will be reported to the genetic counselor dedicated to the study. The parents will be contacted by the genetic counselor and counseled on the findings whether they were positive or negative. The result will also be communicated to the patient's primary MFM provider or pediatrician and appropriate referrals to pediatric genetics specialists will be made by the primary provider. In cases where no genetic disorder is identified, the sample will be stored and then subsequently whole genome sequencing will be performed.

Being tested
Whole Exome Sequencing, Whole Genome Sequencing
Keywords
hydrops, prenatal diagnosis, amniocentesis, whole genome sequencing
Medical subject headings
Genetic Diseases, Inborn, Edema

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Whole Exome SequencingDiagnostic test

    Whole exome sequencing (WES) provides more detailed information through greater resolution, identifying single base-pair changes and small insertions and deletions. WES performs sequencing on the protein-coding exons, which are contained in 1-2% of the genome but make up over 85% of all known pathogenic mutations.

  • Whole Genome SequencingDiagnostic test

    Whole Genome Sequencing (WGS) has emerged in recent years as a diagnostic tool that sequences the entire genome and can pick up insertions or deletion of bases, structural variants and intronic single nucleotide variations.

Study groups in NCT03911531
Study groupRoleWhat they receive
FetusesDNA obtained from amniotic fluid samples
Receives: Diagnostic Test: Whole Exome Sequencing; Diagnostic Test: Whole Genome Sequencing
NeonatesDNA obtained from neonatal blood samples
Receives: Diagnostic Test: Whole Exome Sequencing; Diagnostic Test: Whole Genome Sequencing

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Identify known single gene disorders that would not be detected by microarray as a cause of nonimmune fetal hydrops by performing whole exome sequencing (WES)

    Measured: 5 years

  2. Identify novel genetic disorders associated with nonimmune hydrops

    Measured: 5 years

Secondary outcomes (2)
  1. Evaluate the incremental value of whole genome sequencing (WGS) in the evaluation of fetal hydrops when WES is negative

    Measured: 5 years

  2. Better counsel the parents about the etiology of hydrops especially if they desire a subsequent pregnancy

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Apr 2019
  2. Study start15 Jan 2019
  3. Primary completion30 Dec 2025
  4. Study completion31 Dec 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
55 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03911531
Sponsor's protocol ID
IRB18D.728
Status last verified
Jul 2026
First submitted
9 Apr 2019
Last updated
14 Jul 2026
Results posted
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes

Publications

  • Society for Maternal-Fetal Medicine (SMFM); Norton ME, Chauhan SP, Dashe JS. Society for maternal-fetal medicine (SMFM) clinical guideline #7: nonimmune hydrops fetalis. Am J Obstet Gynecol. 2015 Feb;212(2):127-39. doi: 10.1016/j.ajog.2014.12.018. Epub 2014 Dec 31.

    PubMed 25557883
  • Whybra C, Mengel E, Russo A, Bahlmann F, Kampmann C, Beck M, Eich E, Mildenberger E. Lysosomal storage disorder in non-immunological hydrops fetalis (NIHF): more common than assumed? Report of four cases with transient NIHF and a review of the literature. Orphanet J Rare Dis. 2012 Nov 8;7:86. doi: 10.1186/1750-1172-7-86.

    PubMed 23137060
  • Lionel AC, Costain G, Monfared N, Walker S, Reuter MS, Hosseini SM, Thiruvahindrapuram B, Merico D, Jobling R, Nalpathamkalam T, Pellecchia G, Sung WWL, Wang Z, Bikangaga P, Boelman C, Carter MT, Cordeiro D, Cytrynbaum C, Dell SD, Dhir P, Dowling JJ, Heon E, Hewson S, Hiraki L, Inbar-Feigenberg M, Klatt R, Kronick J, Laxer RM, Licht C, MacDonald H, Mercimek-Andrews S, Mendoza-Londono R, Piscione T, Schneider R, Schulze A, Silverman E, Siriwardena K, Snead OC, Sondheimer N, Sutherland J, Vincent A, Wasserman JD, Weksberg R, Shuman C, Carew C, Szego MJ, Hayeems RZ, Basran R, Stavropoulos DJ, Ray PN, Bowdin S, Meyn MS, Cohn RD, Scherer SW, Marshall CR. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. 2018 Apr;20(4):435-443. doi: 10.1038/gim.2017.119. Epub 2017 Aug 3.

    PubMed 28771251
  • Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Nemeth AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sorensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SR, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AO, Bentley D, Donnelly P, McVean G. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015 Jul;47(7):717-726. doi: 10.1038/ng.3304. Epub 2015 May 18.

    PubMed 25985138
  • Rice SM, Makhamreh MM, Wodoslawsky S, Toro M, Critchlow E, Firman B, Liu R, Nallamilli BR, Hegde M, Berger SI, Al-Kouatly HB. High Diagnosis Rate for Nonimmune Hydrops Fetalis With Prenatal Clinical Genome: Expanded Results From the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) Study. Am J Med Genet A. 2026 Aug 20. doi: 10.1002/ajmg.a.70265. Online ahead of print.

    PubMed 42624826
  • Rice SM, Varotsis DF, Wodoslawsky S, Critchlow E, Liu R, McLaren RA Jr, Makhamreh MM, Firman B, Berger SI, Al-Kouatly HB. Prenatal Phenotype of Alkuraya-Kucinskas Syndrome: A Novel Case and Systematic Literature Review. Prenat Diagn. 2024 Oct;44(11):1381-1397. doi: 10.1002/pd.6637. Epub 2024 Sep 3.

    PubMed 39228063
  • Raymond M, Critchlow E, Rice SM, Wodoslawsky S, Berger SI, Hegde M, Empey PE, Al-Kouatly HB. Fetal pharmacogenomics: A promising addition to complex neonatal care. Mol Genet Metab. 2022 Sep-Oct;137(1-2):140-145. doi: 10.1016/j.ymgme.2022.08.002. Epub 2022 Aug 12.

    PubMed 36029725

Questions about this trial

What is this clinical trial studying?

An observational study of Nonimmune Fetal Hydrops and Nonimmune Hydrops in Neonate, run by Thomas Jefferson University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Identify known single gene disorders that would not be detected by microarray as a cause of nonimmune fetal hydrops by performing whole exome sequencing (WES) (time frame: 5 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03911531, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jul 2026.

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