Patient Presentation
A 30-month-old female came to clinic for her health supervision visit. She was well and her mother had no concerns. When the pediatrician was updating the family history the mother became teary. She said that approximately 6 weeks prior she had had a fetus who had had intrauterine fetal demise due to hydrops fetalis. The family history was negative for any additional genetic problems or pregnancy problems in the known family members.

The pertinent physical exam showed a smiley toddler with growth parameters in the 50-75% and normal vital signs. Her examination was normal.

The diagnosis of a healthy female was made. The pediatrician supported the mother’s emotions and after she quickly recovered, they discussed that the investigation for a potential cause was still being completed. “Once all the tests are back I’m supposed to see my doctor and maybe will talk with a genetic counselor. They have said that we may not know what was the cause in the end, and I am resigned to that. Either way I am healthy, so is she (indicating her daughter) and my husband is very very supportive. We’re getting through this pretty well,” she said. The pediatrician also offered supportive mental health services, but the mother declined stating that she already had offers through her own doctor, and through her church.

Discussion
Hydrops fetalis (HF) is defined as “…excessive pathologic fluid accumulation within the fetal soft tissues and body cavities.” The fluid collections need to be in at least 2 abnormal fluid collections including abdominal, pericardial, pleural or skin (generalized edema with > 5 mm skin thickness). HF is classified into immune and non-immune causes. Immune is specifically for red blood cell alloimmunization and the widespread use of Rhesus (Rh) D immune globulin treatment of pregnant women has significantly decreased the number of immune HF pregnancies.

Non-immune HF (NIHF) accounts for ~90% of HF and occurs in 1:1700-3000 pregnancies. The identified NIHF causes vary widely and can be quite rare for some fetuses. Even with extensive evaluations many affected fetuses do not have the cause identified or suspected (maybe 50%). Evaluation may include history, fetal echocardiogram and ultrasound for other structural abnormalities, fetal sampling for genetic, hematological, and infectious causes and pleural fluid analysis. Genetic testing usually includes a karyotype and chromosomal microarray and may include other types of testing (e.g. whole exome sequencing) or other targeted testing. Morbidity for NIHF is very high at 35-98% depending on the potential cause. Live-borne infants are often premature. Recurrence risk in a mother with NIHF varies but in some studies is ~5-6%.

Learning Point
“NIHF should be thought of as a symptom of end-stage of a variety of diseases…” with four main proposed mechanisms and major causes by category:

• Increased hydrostatic capillary pressure
  • Congestive heart failure
    • Structural congenital heart disease
    • Cardiomyopathies
    • Fetal arrhythmia
    • Vascular disorders
  • Hematologic disease – anemia due to red blood cell underproduction or increased destruction
  • Renal disorders
  • Twin-twin transfusion
  • Umbilical cord and placenta disorders
  • Increased intrathoracic pressure
    • High airway obstruction
    • Masses in the thoracic cavity
    • Neurological/muscular problems causing abnormal thoracic musculature movement
• Decreased intravascular osmotic pressure
  • Gastrointestinal problems
  • Inborn errors of metabolism – especially lysosomal storage disorders
• Decreased lymphatic flow
  • Genetic abnormalities and syndromes
  • Aneuploidy is a common cause such as Trisomy 21, Trisomy 18, and Turner syndrome
• Decreased peripheral capillary integrity
  • Infections

Questions for Further Discussion
1. What are causes of intrauterine fetal demise?
2. What are potential maternal complications of hydrops fetalis?
3. What is the role of a neonatologist and general pediatrician for assisting families with hydrops fetalis?

Related Cases

Disease: Hydrops Fetalis | Infant and Newborn Care

Symptom/Presentation: Genetic Disorder | Health Maintenance and Disease Prevention

Specialty: Genetics | Neonatology | Obstetrics / Gynecology

Age: Fetus and Mother | Toddler

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Fetal Health and Development and Rh Incompatibility.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Sparks TN, Thao K, Lianoglou BR, et al. Nonimmune hydrops fetalis: identifying the underlying genetic etiology. Genetics in Medicine. 2019;21(6):1339-1344. doi:10.1038/s41436-018-0352-6

Swearingen C, Colvin ZA, Leuthner SR. Nonimmune Hydrops Fetalis. Clinics in Perinatology. 2020;47(1):105-121. doi:10.1016/j.clp.2019.10.001

Deng Q, Fu F, Yu Q, et al. Nonimmune hydrops fetalis: Genetic analysis and clinical outcome. Prenatal Diagnosis. 2020;40(7):803-812. doi:10.1002/pd.5691

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa