The Course, Prognosis, and Hand-Holding of Parents in Nonimmune Hydrops Fetalis—A Case Report with a Brief Review

Abstract

Hydrops fetalis (HF) is a serious fetal condition characterized by abnormal accumulation of fluid in fetal soft tissues and serous cavities. HF can be immune hydrops fetalis (IHF) or nonimmune hydrops fetalis (NIHF) depending upon the presence of antibodies in the mother. We report a case of euploid NIHF who delivered at 34 weeks and had spontaneous recovery. The baby had gross fetal ascites and mild pleural and pericardial effusion. After a thorough workup, no definite cause could be found. However, the ascites spontaneously resolved. The baby had many peaks and valleys during the initial 3 months of life, doing well at 6 months of age and is under follow-up. This case report highlights the practical workup and diagnostic algorithm of NIHF and provides an updated review.

Keywords

absent nasal bone - exome sequencing - fetal ascites - Griscelli's syndrome - lymphatic dysplasia - nonimmune hydrops fetalis

Introduction

Hydrops fetalis (HF) is the accumulation of excess fluid in the fetus in two or more serous cavities. Depending on the severity and cause of hydrops, it may be associated with edema of the fetus (scalp edema or generalized subcutaneous edema), placentomegaly (placental thickness >6 cm), ascites, pleural effusion, and/or pericardial effusion or even hydrocele.[1] [2]

HF can be secondary to Rh isoimmunization or nonimmune origin. It can be easily diagnosed by antenatal ultrasound. The identification of hydrops by ultrasound is very stressful for the family and challenging for the clinician because it requires an extensive search for the etiology, which includes a Pandora's box of diseases. The common causes of nonimmune hydrops fetalis (NIHF) are cardiovascular, chromosomal, and hematologic followed by structural abnormalities in the fetus, complications of multifetal pregnancies, infections, and placental abnormalities.

Even after undergoing an exhaustive list of investigations including whole-exome sequencing (WES), a reasonable number of cases remain undiagnosed.[3] Moreover, the prognosis is also not very satisfying with perinatal loss of 70 to 90%.[4] Only a few treatable causes of hydrops, such as fetal arrhythmia or infection with parvovirus B, carry a better prognosis.

Fetal ascites is an abnormal fluid collection in the fetal peritoneal cavity and is often the first finding of HF. It is present in 80 to 85% of cases of NIHF and sometimes, it is the only predominant finding. If a systematic protocol is followed for diagnostic workup, the etiology behind fetal ascites can be identified in 90% of cases.[5]

Various mechanisms have been implicated in the development of ascites, including lymphatic dysplasia, decreased venous return due to any space-occupying lesion in the thorax, cardiac failure, decreased plasma oncotic pressure as seen in fetal anemia, hepatic insufficiency due to metabolic disorders or congenital nephrosis, increased capillary permeability, urinary tract obstruction, and meconium peritonitis. Aneuploidies and intrauterine infections are rare causes of fetal ascites.

We present a unique case of a postnatally diagnosed nonimmune hydrops baby with no chromosomal aneuploidy with spontaneous resolution and discuss the diagnostic algorithm.

Case Report

A 33-year-old pregnant woman, nonconsanguineous, with one live issue and one abortion, reported to our hospital at 19 weeks period of gestation with an anomaly scan suggestive of a hypoplastic nasal bone. Amniocentesis was done and the sample was sent for rapid aneuploidy testing by fluorescence in-situ hybridization (FISH) and chromosomal microarray to rule out any microdeletions or duplication. Both reports were normal. The pregnancy was continued.

Prenatal blood investigations were within normal limits. The blood group was O positive and antibody screening was negative. Further, follow-up scan at 28 weeks also suggested normal growth and amniotic fluid volume and no associated fetal anomalies. At 34 weeks, she presented in emergency with preterm labor and preterm premature rupture of membranes. The labor progressed well until in the second stage. After delivery of the head, the baby was stuck due to a grossly distended fetal abdomen (ascites; [Fig. 1A]). The delivery was, however, accomplished vaginally. She delivered a male baby with an Apgar score of 2 and 5 at 1 and 5 minutes. This was unexpected as during her follow-up antenatal visits, no such finding was noted. The weight of the baby was 3,020 g and the placenta was also normal. The baby developed respiratory distress soon after birth and was out on continuous positive airway pressure followed by intubation at 15 minutes of life and shifted to the neonatal intensive care unit.

Fig. 1 (A) Baby with ascites and hydrocele; (B) X-ray of baby with pleural effusion.

Postnatally, further workup initially revealed only isolated fetal ascites with no abnormal fluid collection elsewhere or thickness in any other body cavity or part.

Serology testing of the baby for hepatitis B and C, toxoplasma, rubella, cytomegalovirus, herpes simplex virus group of infections, and syphilis was negative and an ultrasound scan of the cranium was normal. Ascitic fluid taping (paracentesis) was done, and it was suggestive of raised protein contents. Urine for routine and microscopy was also suggestive of albuminuria. Neonatal abdominal circumference was more than the 95th centile and moderate hydrocele was noted.

An initial working diagnosis of isolated fetal ascites secondary to congenital nephrosis was kept. However, on a repeat chest X-ray done on day 3 of life, the baby was also found to have bilateral pleural effusion ([Fig. 1B]). An intercostal drain was placed, and a milky fluid was noticed in the tube suggestive of chylothorax. On serial observation, no further accumulation of milky fluid was noticed and on further reconfirmation by lymphoscintigraphy, no anatomical abnormality was found.

The baby was screened for cardiovascular causes, congenital nephrotic syndrome, α thalassemia, glucose-6-phosphate dehydrogenase (G₆PD) deficiency, and gut perforation. All reports came normal ([Table 1]). Additionally, inborn errors of metabolism including amino acid disorders, organic acid disorders, fatty acid oxidation disorders, and other miscellaneous metabolic disorders were screened by “tandem mass spectrometry” and “time-resolved fluoroimmunoassay” screening method. Surprisingly, WES of the baby also did not suggest any pathogenic or likely pathogenic variant.

Table 1 Clinical workup of the case

Differential diagnosis	Investigations	Outcome
Cardiovascular causes: hypoplastic left heart, Ebstein's anomaly, endocardial cushion defects or rhythm abnormalities	CXR 2D ECHO	Small OS ASD, with restrictive PDA with trace pericardial effusion with good biventricular function; not contributing to NIH
Congenital nephrotic syndrome	USG KUB	Normal
	Triglycerides, albumin	Proteinuria + (decreasing trend), elevated triglycerides and borderline albumin
	Spot urine PCR	Elevated initially- decreasing trend later
	24 Urine protein	Nephrotic range proteinuria absent. However, proteinuria resolved spontaneously
	Total proteins/ albumin (4.6–7.0 / 1–100 mg/L)	3.64/2.54
Hematological causes: alpha Thalassemia, fetomaternal hemorrhage, G6PD deficiency	Hemogram	Normal
	HPLC	Normal (hemoglobin HbA—8.6% Hemoglobin HbF—90.0% Unknown peak—1.4%)
	Reticulocyte count	Normal
	Peripheral blood smear	Normal
	G6PD levels	Normal
Congenital infections: TORCH	TORCH panel	Normal
	Fundoscopy	Normal Liver echogenicity was normal
	Cranial ultrasound	No evidence of intracranial calcification or hydrocephalus
	MRI	Liver echogenicity was normal
Lymphatic dysplasia: chylothorax	Triglyceride levels	Pleural fluid was exudative with elevated triglyceride and cholesterol levels. Milky output noted in ICD tube—no recollection. Predominant lymphomononuclear cells (94%)
Genetic abnormality: Noonan syndrome, Trisomy 13,18, 21, etc. & single gene disorders	Karyotype	Normal
	Whole exome sequencing	No pathogenic or likely pathogenic variant detected
Thoracic SOL: CCAM, diaphragmatic hernia, hydrothorax, chylothorax	CXR, USG thorax	Normal
Inborn error of metabolism: mucopolysaccharidosis, Gaucher's disease, GM1 gangliosidosis, etc.	Tandem mass spectrometry and time resolved fluoroimmunoassay	Normal
GI causes: peritonitis, GI obstruction	Paracentesis	Ascitic fluid culture was sterile
		X-ray done had no features suggestive of intestinal obstruction and neonate was passing meconium

Abbreviations: CCAM, congenital cystic adenomatoid malformation; CXR, chest X-ray; ECHO, echocardiogram; GI, gastrointestinal; G₆PD, glucose-6-phosphate dehydrogenase; HPLC, high-performance liquid chromatography; ICD, intercostal drainage; MRI, magnetic resonance imaging; NIH, non immune hydrops; OS-ASD, ostium secundum-atrial septal defect; PCR, protein creatinine ratio; PDA, patent ductus arteriosus; SOL, space occupying lesion; TORCH, toxoplasma, rubella, cytomegalovirus, herpes simplex, and parvo virus; USG, ultrasonography.

There was gradual improvement in the baby's condition. Ascites resolved spontaneously and the baby was discharged on day 18 of life, without any problems. At 1 month of life, on follow-up, the baby appeared hypotonic and again developed mild ascites along with a coincident finding of silvery gray hair. The possibility of Griscelli syndrome, Elejalde syndrome, Chediak-Higashi syndrome, and severe combined immunodeficiency was kept and further evaluation with CD markers and hair microscopy to rule out these differentials turned normal.

Further, at 3 months of life, the baby again got admitted in the pediatric ward with severe pneumonia and required ventilatory support. However, the recovery was good, and the baby is doing fine at 6 months of life with advice for regular long-term follow-up.

Discussion

NIHF is defined as an abnormal accumulation of fluid in the skin and one or more serous cavities of the fetus, including the pleural space, peritoneal cavity, pericardial sac, or placenta. Its frequency is 1 in 2,500 to 1 in 4,000 pregnancies, but the incidence varies with ethnicity. Up to 90% of all cases of hydrops today are nonimmune hydrops.[6]

A detailed workup using a systematic algorithm ([Fig. 2]) can find the cause in 60% of cases and if postnatal evaluation is also included, the definite cause can be elicited in 85% of cases.[7] The initial evaluation should begin with a detailed ultrasound examination to exclude other associated congenital abnormalities. Neonatal and maternal evaluation should be done for the presence of infections. The mother should be screened for isoimmune antibodies, fetomaternal hemorrhage, G₆PD deficiency, and thalassemia. If the findings of hydrops are evident prenatally on sonography, the major chromosomal abnormalities should be ruled out by invasive prenatal testing methods like amniocentesis or chorionic villus sampling. A fetal echocardiogram is required to exclude congenital cardiac anomalies or cardiac arrhythmia.[8] If no cause is found and the baby is delivered, a thorough screening for inborn errors of metabolism and other causes is desirable.

Fig. 2 Diagnostic algorithm of nonimmune hydrops fetalis. AFAFPP, amniotic fluid alfa fetoprotein; CMA, chromosomal microarray; CMV, cytomegalovirus; ELISA, enzyme-linked immunosorbent assay; FBS, fetal blood sample; IUT, intrauterine transfusion; MCA, middle cerebral artery; PSV, peak systolic velocity.

In our case, the woman presented with hypoplastic nasal bone. Absent or hypoplastic nasal bone is an important soft marker for aneuploidy. The likelihood ratio for this soft marker to detect trisomy 21, when other soft markers are absent, is 6.58.[9] Normal results of FISH test for chromosomes 13, 18, and 21 and sex chromosomes aneuploidy and subsequently normal chromosomal microarray report alleviated her anxiety. It was difficult to explain, what made the fetal ascites appear suddenly near 34 weeks.

Favre et al in a cohort of 79 cases of nonimmune fetal ascites observed that if fetal ascites is present in isolation, it has a comparatively better survival rate (52%) than ascites associated with other fetal anomalies (42%). They also documented a lower survival rate in fetuses developing hydrops at an early gestation as compared with those developing in late pregnancy.[10]

In another study of 12 cases of isolated fetal ascites, 10 (80%) survived with two of them requiring intervention for ileal atresia and mild hydrocephalus and for a large pseudocyst and bowel atresia, respectively. However, the two cases that did not survive had early onset hydrops before 20 weeks of gestation.[11] Therefore, the prognosis of NIHF depends not only on the underlying cause but also largely on the timing of presentation.

Congenital chylous ascites or chylothorax may be due to multiple reasons. The most common (50–60%) is the malformation of the lymphatic vessels, as in atresia or stenosis of the major lacteals, mesenteric cysts, and lymphangiomatosis. However, in the remaining 50% of neonates, the chylous ascites is assumed to be due to a condition called “leaky lymphatics,” probably because of a delayed maturation of the lacteals.[12] Another reason (20–25%) is external compression that causes obstruction of the lymphatics, as in malrotation, incarcerated hernia, intussusception, inflammatory enlargement of lymph nodes, and malignancy. In our case since the baby presented with chylothorax on day 3 of life, these differentials were considered and systematically ruled out. Additionally, a thorough screening of inborn errors of metabolism and genetic testing by WES was also performed in consultation with a medical geneticist.

Further, on follow-up, when the baby presented with hypotonia along with silvery hair, differentials of Griscelli's syndrome, Elejalde's syndrome, Chediak–Higashi syndrome, and severe combined immunodeficiency were considered and ruled out.[13]

In a recently published article on a cohort of NIHF in the Indian population, an etiological diagnosis was possible in 75.5% (34/45) of fetuses, while the cause remained unknown in 24.4% (11/45). Only 8.8% (4/45) of the cohort survived without morbidity.[3]

Considering the exhaustive search for the cause, we must be very skeptical in our counselling. Parents need hand-holding and support. They need genetic counselling right from the antenatal period the delivery. Genetic counselling not only discusses the right choice of investigation and inheritance patterns but also helps the couple to make an informed decision about management, timing and place of delivery, postdelivery treatment options and prognosis, and the cost of treatment. Besides the obstetrician and the geneticist, the involvement of a neonatologist, a pediatric surgeon and even a psychologist are very crucial in counselling.

This is an area of further research and study to predict hydrops and its course and prognosis.

Conclusion

NIHF is commoner than IH and has a better prognosis if the gestation is advanced and in the absence of associated structural anomalies. Additionally, a systematic algorithm should be followed to find out the etiology, which is important for appropriate treatment and successful outcomes. Even after extensive workup, many cases of NIHF still remain a dilemma and need an answer. Counselling at every stage is very important to aid the prospective parents in decision making right from opting for the right investigations, right place and timing of delivery, and right postnatal management.

Conflict of Interest

None declared.

Acknowledgment

This work would not be possible without the contributions of colleagues and residents from the Department of Diagnostic and Interventional Radiology and the Department of Medical Genetics. We thank them for their exceptional support.

Authors' Contributions

C.S. designed the concept. D.C. and S.B. helped in literature search. S.K.C. managed the patient and helped in literature search and editing the manuscript. D.C. and C.S. wrote the manuscript. All of the authors read and approved the final manuscript.

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Publication History

Article published online:
12 May 2023