E-mail ID : info@iamg.in |
Online Submission |
Click Here For Online Submission |
Instructions for authors |
Genetic Clinics |
Editorial board |
Get Our Newsletter |
Subscribe |
Send Your Feedback |
Feedback Form |
About Us |
IAMG |
GeNeViSTA
Etiology | Proportion
|
| of cases |
I Cardiac anomalies
| 17-35% |
II Chromosomal aberrations
| 7-16% |
III Hematological disorders
| 4-12% |
IV Twin–Twin transfusion | 3-10% |
V Infections TORCHES CLAP (Toxoplasma, Rubella, Herpes simplex, Echovirus, Syphilis, Cytomegalovirus, Coxsackie virus, Leptospirosis, AIDS, Adenovirus, Parvovirus) | 5-7% |
VI Syndromes
| 3-4% |
VII Skeletal dysplasias
| 3-4% |
VIII Gastrointestinal disorders
| 0.5-4% |
IX Renal anomalies
| 2-3% |
X Inborn errors of metabolism
| 1-2% |
XI Placental causes
| 1% |
XII Miscellaneous | 3-15% |
XIII Unknown | 15-25% |
The basic pathophysiological mechanism of fetal hydrops is imbalance in the regulation of fluid between vascular and interstitial spaces. Fluid movements between vascular and interstitial spaces are regulated by filtration of fluid across the capillary wall as described by the Starling equation which states that the fluid movement due to filtration across the wall of a capillary is dependent on the balance between the hydrostatic pressure gradient and the oncotic pressure gradient across the capillary. When these pressure gradients are disturbed due to various pathophysiological mechanisms, there is an increased fluid accumulation in the interstitial spaces, which leads to fetal hydrops. Increased knowledge and understanding of the underlying mechanisms that disturb the fluid equilibrium would therefore be of great importance in identifying potential therapeutic interventions (Bellini et al., 2012).
The pathophysiology underlying the various causes of nonimmune fetal hydrops has been depicted in flow charts 1 and 2 (Bellini et al., 2012).
Detailed antenatal ultrasonography (USG) is the initial diagnostic modality for any case with non-immune fetal hydrops, and apart from detecting the hydrops per se also helps to assess the severity of hydrops and to detect associated malformations (Figure 1). Sonography can even provide important clues to the underlying cause of the hydrops in many cases. Increased nuchal translucency is often the first sign of NIFH due to chromosomal abnormalities. Cases secondary to cardiac abnormality usually show significant cardiomegaly (Skoll et al., 1991). A fetus with anemia-related hydrops is likely to demonstrate the presence of pleural fluid and skin edema (Skoll et al., 1991). The middle cerebral artery peak systolic velocity (MCA PSV) >1.5 MoM (multiples of median) indicates fetal anemia in fetuses of more than 16 weeks of gestation. Fetal hydrops associated with metabolic disorders is usually severe with massive ascites and significant thickening of the skin. Additional USG findings in various fetal infections associated with fetal hydrops include intrauterine growth retardation, polyhydramnios/ oligohydramnios, microcephaly, ventriculomegaly, intracranial calcification, cardiac anomalies, liver calcifications and echogenic bowel (SOGC clinical practice guidelines, 2013). However, in most cases, further investigations are required to clearly diagnose the etiology.
As NIFH is an etiologically heterogeneous condition, each case of NIFH would require stepwise evaluation for all the known causes, in order to ascertain the exact etiological diagnosis. As a significant proportion of cases have a genetic etiology, identification of the exact cause in each case is very important for accurate counseling regarding the recurrence risk and prenatal diagnostic testing for future pregnancies.
Step 1: Fetal imaging
Step 2: Tests in the mother
Step 3: Invasive testing
In case of antenatal doppler evidence of fetal anemia, PCR for Parvovirus B19 and molecular genetic testing for alpha thalassemia should be done in the fetal sample.
Step 4: Postnatal evaluation
Whole body fetal radiographs, detailed fetal dysmorphology evaluation, internal organ dissection and histopathological examination of the fetal organs and the placenta should done in every case. If a specific etiology is identified with this first-tier evaluation, specific cytogenetic or molecular genetic testing can be done in the fetal sample for confirmation of the same. As per various literature reports, perinatal autopsy provides important additional information or changes the ultrasonography-based diagnosis in 22-76% cases.
In cases where autopsy evaluation does not reveal a specific etiology, karyotype and enzyme assays for common NIFH-associated lysosomal storage disorders can be done. In cases where the above evaluation is inconclusive and the cause remains unknown, higher resolution genetic testing techniques i.e. chromosomal microarray and exome sequencing can be done in the fetal DNA sample, for copy number variations and single gene etiologies respectively. Both parents can be tested further, as relevant, for the genetic etiology identified in the fetus.
Prognosis depends upon the etiology, the gestational age at onset and whether pleural effusions are present. In general, the earlier the hydrops occurs, the poorer the prognosis. In particular, pleural effusions and polyhydramnios prior to 20 weeks of gestation are poor prognostic signs because of increased risks of pulmonary hypoplasia and preterm labour/ premature rupture of membranes, respectively. On the other hand, absence of aneuploidy and absence of major structural abnormalities confer a better prognosis. Despite continued advances in perinatal care NIFH continues to be associated with significant mortality (Simpson et al., 2006).
Fetal treatment for NIHF depends on the etiology and gestational age. Some of the therapies for selected etiologies are listed in Table 2 (SOGC clinical practice guidelines, 2013).
Etiology | Therapy
|
Twin to twin transfusion syndrome | Laser ablation of placental anastomoses or selective termination |
Twin-reversal arterial perfusion | Percutaneous radiofrequency ablation |
Cardiac arrhythmias | Maternal transplacental administration of antiarrhythmic medications |
Fetal anemia | Fetal blood sampling followed by intrauterine transfusion |
Fetal hydrothorax/ pleural effusion associated with bronchopulmonary sequestration | Placement of thoracoamniotic shunt/ needle drianage of effusion |
Fetal CPAM - (Congenital pulmonary airway malformation) |
|
Macrocystic | Needle drainage/ Thoracoamniotic shunt |
Microcystic | Corticosteroid therapy |
Large bronchopulmonary sequestration | NdYAG Laser of the feeding vessel |
Fetal thyrotoxicosis | Antithyroid drugs |
NIFH related to fetal toxoplasmosis treated with maternal administration of pyrimethamine and sulfadiazine and NIFH related to fetal syphilis treated with penicillin resolves but the overall prognosis due to cerebral complications remains high. Fetal cytomegalovirus infection has been treated with maternal and direct fetal administration of hyperimmune globulin. However there are only a few reported cases where this therapy was attempted and they did not resolve with this therapy.
Genetic counseling is an integral component of the management of any family with non-immune fetal hydrops. If the cause of hydrops is identified, the nature of abnormality, pattern of inheritance and recurrence risk in future pregnancies can be determined. In cases of hydrops due to cardiovascular anomalies, the recurrence risk depends on the type of anomaly and varies from 3-50%. Hydrops due to infections is less likely to recur. Hydrops due to chromosomal abnormalities usually have a recurrence risk of around 1%, unless they are associated with a familial chromosomal rearrangment, in which case the recurrence risk would be higher, depending on the nature of the chromosomal anomaly. If the fetal hydrops is due to autosomal recessive disorders there is 25% risk of recurrence in the subsequent pregnancies of the couple. If NIFH is due to an autosomal dominant condition, most often it would be due to a de novo mutation, but there would be a small but significant risk of recurrence in subequent pregnancies due to the possibility of gonadal mosaicism for the pathogenic mutation in either parent. Idiopathic NIFH generally has a low recurrence risk. Prenatal testing, as required, can be offered for subsequent pregnancies of the couple through targeted cytogenetic/molecular genetic testing, based on the etiology identified in the affected fetus.
Non-immune fetal hydrops is a significant cause of prenatal and perinatal morbidity and mortality. With the use of advanced genetic testing technologies such as chromosomal microarray and whole exome/ whole genome sequencing, we are likely to identify the underlying genetic basis in a greater proportion of cases with NIFH. This in turn would help to provide a greater insight into the etiopathogenesis of NIFH and help to identify potential therapeutic targets for this condition.
1. Bellini C, et al. Etiology of nonimmune hydrops fetalis: a systematic review. Am J Med Genet A 2009; 149A: 844-851.
2. Bellini C, et al. A diagnostic flow chart for non immune hydrops fetalis. Am J Med Genet A 2009; 149A: 852-853.
3. Bellini C, et al. Immunohistochemistry in non immune hydrops fetalis: A single center experience in 79 fetuses. Am J Med Genet A 2010; 152A: 1189-1196.
4. Bellini C, Hennekam RC. Non-immune hydrops fetalis: a short review of etiology and pathophysiology. Am J Med Genet A 2012; 8A: 597-605.
5. Bellini C, et al. Etiology of non immune fetal hydrops: An update. Am J Med Genet A 2015;167A: 1082-1088.
6. Moise Jr K. Ultrasound evaluation of hydrops fetalis. In: Ultrasonography in Obstetrics and Gynecology. Fifth edition. Ed. Peter W Callen. Elsevier Saunders, Pennsylvania, USA; 2008: p 676- 697.
7. Moreno CA, et al. Non–immune hydrops fetalis: A prospective study of 53 cases. Am J Med Genet A 2013;161A: 3078-3086.
8. Puri RD, et al. Utility of fetal autopsy to corroborate antenatal ultrasound findings. Am J Med Genet A 2016; 170 A: 2119-2126.
9. Skoll MA, et al. Is the ultrasound definition of fluid collections in non- immune hydrops fetalis helpful in defining the underlying cause or predicting outcome? Ultrasound Obstet Gynecol 1991; 1: 309-312.
10. Simpson JH, et al. Severity of non-immune hydrops fetalis at birth continues to predict survival despite advances in perinatal care. Fetal Diagn Ther 2006; 21:380-382.
11. Society of Obstetricians and Gynaecologists of Canada (SOGC) clinical practice guidelines. J Obstet Gynaecol 2013; 35: e1-e14.
Abstract | Download PDF |