Hydrops Fetalis indicates an excessive accumulation of interstitial fluid in extravascular compartments and body cavities which is characterized by generalized skin edema, ascites, pleural, or pericardial effusion, and placental enlargement. It may be classified into two groups based on the presence or absence of rhesus iso-immunization. Although Rh disease is the major cause of immune-mediated hydrops fetalis, with the decreased prevalence of Rh disease, non-immune causes (eg, cardiovascular diseases, chromosomal abnormalities, lymphatic anomalies, hematologic diseases, etc.) are responsible in the majority of cases. Screening for Rh(D) incompatibility by Rh(D) blood typing and antibody testing are strongly recommended for all pregnant women during their first visit for pregnancy-related care. Also repeated Rh(D) antibody testing for all unsensitized Rh(D)-negative women at 24 to 28 weeks gestation is recommended, unless the biological father is known to be Rh(D) negative. Prognosis is generally poor, and the mortality rate of patients with non-immune hydrops fetalis (NIHF) is approximately 43.2% at 1 year of age, and the presence of either large birth weight, polyhydramnious, or prematurity are associated with a particularly poor prognosis among patients. to be continued...
Hydrops fetalis was first discovered by Dr. John William Ballantyne, a Scottish physician and obstetrician, in 1892.
- Immune Hydrops Fetalis
- Non-Immune Hydrops Fetalis (NIHF)
- This is shown to be originated from developmental defects in microcirculation and lymphatic system, respectively.
- The potential causes may be immune or non-immune, and they often result in anemia and further hypoxia.
- The sympathetic system becomes activated due to hypoxia, and it causes blood redistribution with decreased blood flow to the liver and kidneys.
- Decreased blood flow to the liver and kidneys, results in decreased albumin, increased ADH, and increased activity of RAAS.
- Following these changes, the central venous pressure increases, which further results in decreased lymphatic return.
- As a result, hydrops fetalis (the accumulation of fluid, or edema, in at least two fetal compartments) occurs.
- The pathophysiology of non-immune causes also depend on the underlying conditions, include:
Hydrops Fetalis is caused by either immune or non-immune conditions.
- Immune hydrops fetalis
- Antibodies may occur due to the exposure to non-self RBC antigens during the previous pregnancy or transfusion.
- In the next pregnancy, these antibodies may attack the fetal erythrocytes if the fetus has that antigen.
- Following the red blood cell destruction, hemolytic disease of the fetus and newborn (HDFN) may occur with a wide range of clinical outcome from only mild anemia to high output heart failure and hydrops fetalis.
- Rh disease is the major cause of immune-mediated hydrops fetalis; however, owing to preventative methods developed in the 1970s, the incidence of Rh disease has markedly declined.
- Rh disease can be prevented by the administration of anti-D IgG (Rho (D) Immune Globulin) injections to RhD-negative mothers during pregnancy and/or within 72 hours of the delivery.
- ABO incompatibility usually occurs asymptomatic without any clinically significant outcomes. However, it may rarely cause hemolytic disease of the fetus and newborn (HDFN) which may further results in hydrops fetalis.
- Non-immune hydrops fetalis (NIHF)
- Currently, with the decreased prevalence of Rh disease, non-immune causes are responsible in the majority of cases.
- The most common causes of non-immune hydrops fetalis are cardiovascular diseases, chromosomal abnormalities, lymphatic anomalies, and hematologic diseases. Causes of NIHF include:
- Structural cardiac malformations (especially hypoplastic left heart, endocardial cushion defect)
- Congenital lymphatic dysplasia
- Chromosomal abnormalities (Turner Syndrome, trisomy 13, trisomy 18, trisomy 21)
- Fetomaternal transfusion
- Infections (Parvovirus-B19, CMV, Adenovirus, Enterovirus)
- Twin to twin transfusion syndrome (both donor and recipient fetus)
- Congenital cystic adenomatoid malformation
- Diaphragmatic hernia
- Extrapulmonary sequestration
- Noonan Syndrome
- Urethral Obstruction
- Prune belly syndrome
- Lysosomal storage diseases
- Vascular tumors
- Hepatic tumors
- Meconium peritonitis
- Gastrointestinal obstructions
- Approximately 20% of the NIHF cases are idiopathic.
- Hydrops Fetalis must be differentiated from other diseases that cause generalized skin edema, ascites, pleural, or pericardial effusion, placental enlargement, such as Mirror (Ballantyne) syndrome.
- However, Mirror (Ballantyne) syndrome is also characterized by maternal edema (the mother mirrors the edema present in the fetus), proteinuria, and hypertension.
- Hydrops fetalis must also be differentiated from other conditions that cause ascites such as portal hypertension. In hydrops fetalis, the serum ascites albumin gradient (SAAG) ratio should be less than 11 g/L (indicates that the etiology is not related to portal hypertension).
Epidemiology and Demographics
- In developed countries, the incidence of non-immune hydrops fetalis (NIHF) is 25-79 per 100.000 live born infants worldwide.
- The median gestational age (GA) at diagnosis of NIHF is 23 weeks.
- According to the U.S. Preventive Services Task Force (USPSTF), screening for Rh(D) incompatibility by Rh(D) blood typing and antibody testing are strongly recommended for all pregnant women during their first visit for pregnancy-related care.
- The USPSTF recommends repeated Rh(D) antibody testing for all unsensitized Rh(D)-negative women at 24 to 28 weeks gestation, unless the biological father is known to be Rh(D) negative.
Natural History, Complications, and Prognosis
- Without treatment or termination of pregnancy, the patient will develop conditions of neonatal asphyxia, skin edema, pleural effusion, ascites, polyhydramnios, or multiple malformations, which may eventually lead to intrauterine fetal death or neonatal death.
- Patients rarely survive after the neonatal period, and some of those patients who survive, die at 1 year of age.
- Approximately 68% of patients who survive after 1 year of age, have normal development. However, rest of those patients have developmental delay, mental retardation, and psychomotor retardation with marked growth failure in long-term follow-up.
- Prognosis is generally poor, and the mortality rate of patients with non-immune hydrops fetalis (NIHF) is approximately 43.2% at 1 year of age.
- Deaths usually occur in the neonatal period.
- The cause of deaths after the neonatal period are usually underlying disease rather than hydrops fetalis itself.
- Gestational age is predictive of mortality, as preterm infants with this condition are more likely to die.
- The presence of either large birth weight, polyhydramnious, or prematurity are associated with a particularly poor prognosis among patients.
Diagnostic Study of Choice
There are no established criteria for the diagnosis of hydrops fetalis.
History and Symptoms
- A positive history of Rh(D) incompatibility is suggestive of immune hydrops fetalis.
The physical examination findings in the neonatal period may indicate the underlying diseases.
- The presence of cyanosis on physical examination and resistance to oxygen supplementation is highly suggestive of cardiac diseases.
- The presence of hypotonia on physical examination is highly suggestive of congenital myopathy and congenital hypothyroidism.
- Common physical examination findings of lysosomal storage diseases include hypotonia, facial dysmorphism, hepatomegaly, and cardiomyopathy.
- Common physical examination findings of TORCH infections include hepatomegaly, petechia/purpura, and chorioretinitis.
- Hydrops Fetalis may be caused by maternal TORCH infections, and parvovirus B19 infection, therefore, antibodies against these infections should be checked.
- Sjögren syndrome may cause hydrops fetalis with complete heart blocks and bradyarrhythmias, therefore, Anti-SS-A/SS-B antibodies should be considered in suspected cases.
- An elevated concentration of alpha-fetoprotein (AFP) may suggest fetomaternal hemorrhage, which may result in hydrops fetalis.
- Immune hydrops fetalis can be detected by direct and indirect coombs test.
- Thyroid hormone levels, complete blood count, and metabolic panel also should be checked in the neonatal period.
- A fetal ECG (fECG) may be helpful in the diagnosis of fetal arrythmias. Fetal ECG may show premature contractions, tachyarrhythmias, and bradyarrhythmias.
- Duration of tacyhcardia positively correlated with the presence of hydrops fetalis.
- Ultrasound may be helpful in the diagnosis of hydrops fetalis. Findings on ultrasound suggestive of hydrops fetalis include:
- Increased skin thickness (indicative of generalized skin edema), most prominent in the fetal head and back of the neck. Also may be seen in the thorax and abdomen. It is usually the earliest finding.
- Increased placental thickness (indicative of placental edema)
- Pleural effusion
- Pericardial effusion
- Ultrasonography may detect structural heart diseases, holoprosencephaly, or omphalocele. These associated findings may indicate the etiology of hydrops fetalis and may help in the differential diagnosis.
- Fetal echocardiography may be helpful in the diagnosis of structural heart diseases, cardiomyopathies, arrhythmias, heart failure, and other cardiac diseases. Thus, it may clarify the underlying etiology of non-immune hydrops fetalis (NIHF).
- Genetic tests for non-immune hydrops fetalis include karyotype analysis, which may demonstrate aneuploidy, and chromosomal microarray analysis (CMA) which may further demonstrate copy number variants (CNVs), submicroscopic deletions, and duplications (as small as 50 – 100 kb).
- Even after applying these genetic tests, half of the underlying etiology of NIHF remains unclear.
- A more detailed and broader genetic test, whole exam sequencing (WES), may be helpful in the diagnosis of NIHF.
- Underlying etiologies of NIHF which can be detected by whole exam sequencing include RASopathies (disorders of RAS–MAPK cell-signaling pathway), inborn errors of metabolism, musculoskeletal, lymphatic, cardiovascular, neurologic, hematologic disorders, and others.
- Approximately one-third of NIHF disorders with unclear etiology, Whole exam sequencing (WES) is shown to detect a possible genetic cause.
Other Diagnostic Studies
- Other diagnostic studies for hydrops fetalis include chorionic villous sampling (CVS), which may demonstrate chromosomal abnormalities or Hb Barts disease.
- Vanaparthy R, Mahdy H. PMID 33085361 Check
|pmid=value (help). Missing or empty
- Kontomanolis EN, Fasoulakis Z (2018). "Hydrops Fetalis and THE Parvovirus B-19". Curr Pediatr Rev. 14 (4): 239–252. doi:10.2174/1573396314666180820154340. PMID 30124157.
- Moise KJ (July 2005). "Red blood cell alloimmunization in pregnancy". Semin Hematol. 42 (3): 169–78. doi:10.1053/j.seminhematol.2005.04.007. PMID 16041667.
- Gilja BK, Shah VP (1988). "Hydrops fetalis due to ABO incompatibility". Clin Pediatr (Phila). 27 (4): 210–2. doi:10.1177/000992288802700408. PMID 3349731.
- Bellini C, Donarini G, Paladini D, Calevo MG, Bellini T, Ramenghi LA, Hennekam RC (May 2015). "Etiology of non-immune hydrops fetalis: An update". Am J Med Genet A. 167A (5): 1082–8. doi:10.1002/ajmg.a.36988. PMID 25712632.
- Bellini C, Hennekam RC (March 2012). "Non-immune hydrops fetalis: a short review of etiology and pathophysiology". Am J Med Genet A. 158A (3): 597–605. doi:10.1002/ajmg.a.34438. PMID 22302731.
- Hobson SR, Wallace EM, Chan YF, Edwards AG, Teoh MWT, Khaw AP (2020). "Mirroring preeclampsia: the molecular basis of Ballantyne syndrome". J Matern Fetal Neonatal Med. 33 (5): 768–773. doi:10.1080/14767058.2018.1500550. PMID 30614331.
- Meng, Dahua; Li, Qifei; Hu, Xuehua; Wang, Lifang; Tan, Shuyin; Su, Jiasun; Zhang, Yue; Sun, Weijia; Chen, Biyan; He, Sheng; Lin, Fei; Xie, Bobo; Chen, Shaoke; Agrawal, Pankaj B.; Luo, Shiyu; Fu, Chunyun (2019). "Etiology and Outcome of non-immune Hydrops Fetalis in Southern China: report of 1004 cases". Scientific Reports. 9 (1). doi:10.1038/s41598-019-47050-6. ISSN 2045-2322.
- Steurer MA, Peyvandi S, Baer RJ, MacKenzie T, Li BC, Norton ME, Jelliffe-Pawlowski LL, Moon-Grady AJ (August 2017). "Epidemiology of Live Born Infants with Nonimmune Hydrops Fetalis-Insights from a Population-Based Dataset". J Pediatr. 187: 182–188.e3. doi:10.1016/j.jpeds.2017.04.025. PMID 28533037.
- "Screening for Rh(D) Incompatibility: Recommended Statement - U.S. Preventive Services Task Force - American Family Physician".
- An X, Wang J, Zhuang X, Dai J, Lu C, Li X; et al. (2015). "Clinical Features of Neonates with Hydrops Fetalis". Am J Perinatol. 32 (13): 1231–9. doi:10.1055/s-0035-1552934. PMID 26070120.
- He S, Wang L, Pan P, Wei H, Meng D, Du J; et al. (2017). "Etiology and Perinatal Outcome of Nonimmune Hydrops Fetalis in Southern China". AJP Rep. 7 (2): e111–e115. doi:10.1055/s-0037-1603890. PMC 5468117. PMID 28611934.
- Nakayama H, Kukita J, Hikino S, Nakano H, Hara T (1999). "Long-term outcome of 51 liveborn neonates with non-immune hydrops fetalis". Acta Paediatr. 88 (1): 24–8. doi:10.1080/08035259950170547. PMID 10090542.
- Neu N, Duchon J, Zachariah P (2015) TORCH infections. Clin Perinatol 42 (1):77-103, viii. DOI:10.1016/j.clp.2014.11.001 PMID: 25677998
- Yuan SM (2019) Fetal arrhythmias: Surveillance and management. Hellenic J Cardiol 60 (2):72-81. DOI:10.1016/j.hjc.2018.12.003 PMID: 30576831
- Naheed ZJ, Strasburger JF, Deal BJ, Benson DW, Gidding SS (1996). "Fetal tachycardia: mechanisms and predictors of hydrops fetalis". J Am Coll Cardiol. 27 (7): 1736–40. doi:10.1016/0735-1097(96)00054-x. PMID 8636562.
- Jauniaux E (1997). "Diagnosis and management of early non-immune hydrops fetalis". Prenat Diagn. 17 (13): 1261–8. doi:10.1002/(sici)1097-0223(199712)17:13<1261::aid-pd292>3.0.co;2-c. PMID 9509544.
- Mardy AH, Chetty SP, Norton ME, Sparks TN (August 2019). "A system-based approach to the genetic etiologies of non-immune hydrops fetalis". Prenat Diagn. 39 (9): 732–750. doi:10.1002/pd.5479. PMC 6699893 Check
|pmc=value (help). PMID 31087399.
- Sparks TN, Lianoglou BR, Adami RR, Pluym ID, Holliman K, Duffy J; et al. (2020). "Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis". N Engl J Med. 383 (18): 1746–1756. doi:10.1056/NEJMoa2023643. PMC 7650529 Check
|pmc=value (help). PMID 33027564 Check