Isolated Fetal Ascites: Etiology and Prognosis - A 10-Year Experience from a Tertiary Referral Care Center in India.

INTRODUCTION: Isolated fetal ascites is an uncommon finding, and it may be difficult to elucidate the underlying pathology. This is more so when there are limited resources to investigate the patient adequately. This study was undertaken to see the etiology of isolated fetal ascites and analyze the outcomes.
MATERIALS AND METHODS: Twenty-three cases of isolated fetal ascites were retrospectively analyzed from December 2007 to June 2018. All cases were investigated with detailed ultrasound with other investigations as required. Postnatal data included gestational age at birth, mode of delivery, weight, and postnatal outcome.
RESULTS: The mean age at diagnosis was 26 gestational weeks. Structural abnormalities without any underlying chromosomal or genetic cause were identified in 10/23 (43.4%) cases with the most common structural abnormality related to the gastrointestinal tract where ultrasound proved to the most useful tool. The overall good prognosis was seen in 13/23 (56.5%) cases.
CONCLUSION: Appropriate perinatal care, timely referral and delivery at tertiary care setup, and timely surgical intervention are measures which can improve the outcome and survival in fetuses diagnosed with isolated fetal ascites. Copyright:

INTRODUCTION

Isolated fetal ascites is defined as accumulation of fluid in the abdominal cavity without involvement of fluid accumulation in any other body cavity or subcutaneous tissue.[1234]

The prevalence of hydrops fetalis ranges from 1//800 to 1/3500 live births. The incidence of isolated fetal ascites is still unknown[5] making the prenatal diagnosis of isolated fetal ascites a rare ultrasound finding.

Various mechanisms have been attributed to the development of isolated fetal ascites and may overlap with the causes leading to hydrops fetalis.

Recent studies have shown that following a systematic protocol can lead to the identification of the cause of isolated fetal ascites in approximately 92% of the cases[6] and proper management of these fetal patients both antenatally (fetal therapy) and postnatally (surgical management) can lead to a survival rate of more than 90%.[7]

The present study was undertaken to evaluate the common etiology and prognosis of isolated fetal ascites in a tertiary care referral center of India over a period of 10 years and to formulate a diagnostic plan and treatment strategy in a case of isolated fetal ascites for better survival and prognosis of these fetal patients.

MATERIALS AND METHODS

This was a retrospective study conducted over a period of 10 years from December 2007 to June 2018 in the department of fetal medicine in a tertiary care center of India after attaining the required clearance waiver from the institutional ethics and review board as it was a retrospective analysis of existing data and in accordance with the Helsinki Declaration of 1975, as revised in 2000. The required consent for sharing of their data, not revealing the individuals identity for medical and research purposes, was taken from all patients before their ultrasound scanning.

Inclusion criteria

All cases of isolated fetal ascites diagnosed at our center or referred after 16 weeks of gestation were included in the study. Reasons for referral included the diagnosis of isolated fetal ascites, suspicion of hydrops, and/or malformation.

Exclusion criteria

Cases of Rh isoimmunization and hydrops were excluded.

Ultrasound examinations were performed using real-time, high-resolution scanning with a Voluson E8 System (GE Healthcare, Milwaukee, WI) with a 3.5-MHz convex probe with 5-90° volume angle, 398 HZ frame rate, and 3–26 cm depth. All examinations were performed by an experienced Fetal Medicine Foundation-UK Anomaly certified specialists.

The protocol for diagnostic workup of fetal ascites at our center is shown in Table 1.[2]

Table 1

Protocol for diagnostic workup of fetal ascites

Initial visit

Maternal blood

Blood group, indirect Coombs test

Infection screening - complete blood count, torch IgM and IgG, viral markers

SS-A, SS-B antibodies (in cases of fetal bradyarrhythmia)

Hb electrophoresis

Ultrasound

Detailed anatomy survey for anomalies and soft marker for aneuploidies

Fetal echocardiography

Fetal Doppler (including MCA PSV)

Measurement of amniotic fluid index

Invasive testing

Amniotic fluid

FISH and/or karyotype (or microarray analysis 2014 onwards)

PCR for torch infections

DNA storage for genetic mutation analysis in selected cases

Cystic fibrosis - common mutation (in cases of intra-abdominal calcifications)

Ascitic fluid*

Cytology

PAS staining (in cases with hepatomegaly)

Protein/albumin

Beta 2 microglobulin (in cases where urinary ascites was suspected)

Perinatal autopsy in selected cases

Follow-up every 2-4 week by ultrasound

*Tapped when ascitic fluid was significant enough to cause thoracic compression and in one case due to oligoamnios as substitute for amniotic fluid. Ig: Immunoglobulin, MCA: Middle cerebral arterial, PSV: Peak systolic velocity, FISH: Fluorescence in situ hybridization, PCR: Polymerase chain reaction, Hb: Hemoglobin, PAS: Periodic acid-Schiff

Follow-up of these fetuses was done regularly. The decision to deliver the babies was taken according to individual cases. Neonatologist/pediatric surgeon's opinion was taken before delivery.

RESULTS

Over the period of 10 years, there were 24 cases of isolated fetal ascites. Out of 24 cases of isolated fetal ascites, one was lost to follow-up. Hence, 23 cases were included in the analysis.

Out of these 23 cases, 6/23 (26.1%) cases presented before 24 gestational weeks and 17/23 (73.9%) cases after 24 gestational weeks.

Demographic profile

The mean gestational age at diagnosis in the present study was 26 gestational weeks.

Causes and prognosis of isolated fetal ascites presenting ≤24 gestational weeks

Out of the six cases with isolated fetal ascites that presented ≤24 gestational weeks, three cases were diagnosed to be idiopathic isolated, two out of which on follow-up were diagnosed to be transient fetal ascites, and both were alive and well on postnatal follow-up. The third fetal patient with idiopathic isolated fetal ascites had a neonatal death, and the parents refused an autopsy examination of the baby.

One of the fetal patients with isolated fetal ascites was found to have hepatitis E positive in mother, but on follow-up, the baby was found to be alive and well on postnatal outcome.

Structural abnormalities leading to isolated fetal ascites were found in two fetal patients presenting before 24-week period of gestation (POG). Parents of both opted for termination. On ultrasound examination, one was found to have intestinal malformation (refused an autopsy) and the other was diagnosed with congenital high airway obstruction syndrome which was confirmed on autopsy examination.

The clinicopathological details and outcomes of cases with isolated fetal ascites presenting before ≤24 gestational weeks are given in Table 2.

Table 2

Clinicopathological details and outcomes of cases with isolated fetal ascites presenting ≤24 gestational weeks

Case	Antenatal ultrasound findings	Ascitic tap evaluation	Karyotype	Genetic tests	Maternal infection screen	Postnatal outcome	Postnatal diagnosis
1	Isolated	-	Normal	-	Hepatitis E	Alive and well	? Secondary to maternal hepatitis E
2	Isolated	-	Normal	-	Negative	Alive and well	Idiopathic, transient
3	Echogenic distended bowel loops	-	Not done	-	Negative	Termination	? Intestinal malformation (refused autopsy)
4	Isolated	-	Normal	-	Negative	Alive and well	Idiopathic, transient
5	Isolated	Bloody ascitic tap	Normal	-	Negative	Neonatal death	Idiopathic (refused autopsy)
6	CHAOS, polyhydramnios	-	Not done	-	Not done	Termination	CHAOS confirmed on autopsy

CHAOS: Congenital high airway obstruction syndrome

Causes and prognosis of isolated fetal ascites presenting >24 gestational weeks

Majority of the fetal patients (17/23) with isolated fetal ascites were diagnosed after 24-week POG and had secondary structural abnormality as a reason for isolated fetal ascites, the most common being gastrointestinal tract (GIT) which was found in five fetal patients (5/17, 29.4%). Four of these were found to be doing well after surgical correction postnatally.

Two (2/17, 11.7%) were diagnosed with genitourinary, and two of the fetal patients (2/17, 11.7%) were diagnosed with genetic abnormality.

Idiopathic isolated fetal ascites was found in three fetal patients (3/17, 17.6%) who presented after 24-week POG.

The clinicopathological details and outcomes of these 17 cases with isolated fetal ascites presenting after 24 weeks are given in Table 3.

Table 3

Clinicopathological details and outcomes of cases with isolated fetal ascites presenting after >24 gestational weeks

Case	Antenatal ultrasound findings	Ascitic tap evaluation	Chromosomal analysis	Genetic testing	Maternal infection screen	Postnatal outcome	Postnatal diagnosis
1	Distended bowel loops, polyhydramnios? Hirschsprung’s disease	-	Normal	-	-ve	Ileostomy Surgery, alive and well	Hirschsprung’s disease confirmed on HPE
2	Distended echogenic bowel, polyhydramnios	-	Normal	-	-ve	PTD at 33 weeks (reduced fetal movements), NND day 7 postbilious vomiting (postnatal ultrasound not done)	Intestinal malformation
3	Intestinal perforation with meconium pseudocyst, polyhydramnios	-	Normal	-	-ve	Ileostomy for long segment ileal atresia, alive and well	Ileal atresia with perforation
4	Polyhydramnios	Ascitic fluid cytology - mainly lymphocytes, no vacuolated cells	Normal	CF common mutation negative, enzyme assay on cord blood for beta-glucosidase, beta-glucuronidase, beta-galactosidase, sphingomyelinase was within normal range	-ve	Postnatal ascitic tap - LDH - 415 U/L, glucose - 22 mg/dL, protein - 2.0 g/L Surgery, alive and well. Postnatal detailed workup for CF was negative as well	Rectal shelf
5	Genitourinary? Hydrocolpos	Not done, hydrocolpos was drained	Normal	-	-ve	Postnatal ascitic tap - LDH - 251 U/L, glucose - 15 mg/dL, protein - 0.1 g/dL Surgery, alive and well	Hydrocolpos
6	Genitourinary Hydronephrotic kidneys - distended urinary bladder followed by collapsed bladder with ascites	Beta 2 microglobulin - 6 mg/L	Normal	-	-ve	Surgery, alive and well (cystoscopy, fulguration of PUV)	PUV
7	Echogenic bowel + cardiomegaly (hypertrophied ventricular walls) + hepatomegaly	-	Normal	CF (comm.-on mutation, -ve, Clinical exome sequencing revealed 2 mutations of unknown significance correlating with familial hypertrophic cardiomyopathy	-ve	Neonatal demise	Hypertrophic cardiomyopathy
8	CHAOS + complex heart disease	-	Normal	-	-ve	Delivery at term, stillbirth	CHAOS
9	Hepatosplenomegaly, oligoamnios	Dark yellow ascitic fluid, Glucose - 64 mg/dL, protein - 2.4 g/dL, LDH - 1639 U/L, cytology - 100% lymphocytes	Could not be done due to paucity of cells in ascitic fluid	Negative for CF common mutation	-ve	LSCS for fetal distress, neonatal Hb 4 g, maternal hemorrhagic dengue fever diagnosed postoperative, neonatal death day 4	Storage disease most likely Niemann-Pick or lethal Gaucher disease on PAS stain on liver HPE
10	CHAOS+B/L renal agenesis	-	Not done	-	-ve	Delivered at 30 weeks, died immediately upon birth	Fraser syndrome on autopsy - additional findings - cryptophthalmos, syndactyly, and ambiguous genitalia
11	Isolated	Hemorrhagic ascitic tap	Normal		-ve	IUFD at 33 weeks	Idiopathic
12	Congenital heart block secondary to maternal SLE	Done to relieve thoracic compression	Normal		-ve	Alive and well At 10 years on medication	Congenital heart block
13	Isolated	Done to relieve thoracic compression	Normal		-ve	One postnatal tap, mild hepatomegaly at birth, alive and well at 5 years	Idiopathic
14	Isolated	Done to relieve thoracic compression	Normal		-ve	Alive and well at 3 years	Idiopathic
15	Isolated	-	Normal		-ve	Alive and well at 3 years	Idiopathic
16	Ascites in Recipient twin of MCDA pair, with DV changes, TTTS Stage IV	-	-		-	Neonatal death	MCDA complication
17	Echogenic bowel? meconium pseudocyst	Done, predominant-l year lymphocytes	Normal		-ve	Alive and well at 3 years	Ileal atresia with perforation repaired at day 16 of life

PTD: Preterm delivery, -ve: Negative, NND: Neonatal death, HPE: Histopathological examination, CHAOS: Congenital high airway obstruction syndrome, LDH: Lactate dehydrogenase, PUV: Posterior urethral valve, LSCS: Lower segment cesarean section, Hb: Hemoglobin, PAS: Periodic acid-Schiff, SLE: Systemic lupus erythematosus, MCDA: Monochorionic diamniotic, TTTS: Twin-twin transfusion syndrome, IV: Intravenous, CF: Cystic Fibrosis

Details of etiology of isolated fetal ascites and follow-up

Structural abnormality

As a protocol, at presentation, a detailed fetal ultrasound was performed to ascertain any structural cause of isolated fetal ascites. Structural abnormalities without any underlying chromosomal or genetic cause were identified in 43.4% (10/23) of the cases.

The most common structural abnormality was related to GIT – 26% (6/23). As aforementioned, five of these fetal patients presented after 24-week POG and only one ≤24-week POG.

Out of these six fetuses, four were operated postnatally and did well (two had ileal atresia with perforation, one had rectal shelf, and one had Hirschsprung's disease). Out of the remaining two cases, one case had suspected GIT abnormality and opted for termination (presented at 18 weeks). The other case had a suspected GIT obstruction. The patient delivered in periphery at 33-week POG and gave a history of bilious vomiting in the neonate and neonatal death after 7 days. No autopsy was done; however, ultrasound had clearly shown dilated bowel loops in this case.

There were two cases of genitourinary abnormality, both presenting after 24-week POG, i.e., 8.6% of the total cases with fetal ascites. Out of these two, one had a posterior urethral valve with urinary ascites and was operated postnatally (cystoscopic fulguration of valve) and is presently doing well. The second case had hydrocolpos [Figure 1] which was drained antenatally due to its large size and was operated after birth. On follow-up, the baby was diagnosed with blind urethra opening into the vagina for which urethroplasty was done. The baby was healthy at 3 years of age.

Figure 1

Hydrocolpos presenting with fetal ascites

Two (8.6%) fetal patients with isolated fetal ascites had Congenital High Airway Obstruction (CHAOS). Out of these two fetal patients, parents of one fetus opted for termination (presented before 20-weeks POG). The second fetal patient (presented after 24-weeks POG) was term stillborn. This fetus also had complex cardiac malformations, which were confirmed on autopsy.

Genetic abnormality

None of the 23 cases had any abnormality on karyotype or microarray. However, three cases (13%) were diagnosed with genetic abnormality – out of these three, one fetus had hypertrophic cardiomyopathy on ultrasonography and on genetic testing was diagnosed with 2 mutations, heterozygous, of unknown significance but reported in association with hypertrophic cardiomyopathy (1st mutation – MYBPC3 [-], [ENST00000545968], Intron 11, c.926 + 1G>A [5' splice sit], 2nd mutation – VCL [+], [ENST00000211998], Exon 14, c.1973T>C [p. Val658Ala]). Missense mutation was considered as pathogenic in view of clinical situation and after discussion with geneticists.

The second had a storage disorder likely Niemann-Pick or lethal Gaucher disease. This case merits detailed discussion in view of its complexity. The patient presented at 30-week 5-day POG with fetal ascites and oligoamnios. There was a history of previous 2 neonatal deaths, which were not investigated. Fetal ascitic fluid was sent for evaluation due to oligoamnios, which was dark yellow in color and showed 100% lymphocytes, increased amount of glucose (64 mg/dL), raised lactate dehydrogenase (1639 U/L), and protein 2.4 g/dL. Fluorescence in situ hybridization (FISH) could not be done due to the paucity of cells in ascitic fluid. The fetus was delivered at 31 weeks in view of fetal distress and was found to have a hemoglobin of 4 g% and low platelets (60,000/cumm). The mother was diagnosed to be suffering from hemorrhagic dengue fever postoperatively (there was no history of fever preoperatively but developed fever postoperatively along with thrombocytopenia that led to the diagnosis). Neonatal death occurred on day 4 due to irreversible shock. The couple was counseled for further genetic testing. A neonatal autopsy showed hepatosplenomegaly [Figure 2], which was seen even on ultrasonography antenatally. Postnatal liver biopsy was suggestive of storage disease, most likely Niemann-Pick or lethal Gaucher disease. This case was complicated with concomitant viral infection, lack of investigation in previous pregnancies, and late presentation.

Figure 2

Neonatal autopsy showing hepatosplenomegaly

The third one was diagnosed with Fraser syndrome (proven on autopsy – congenital high airway obstruction, absent kidneys on ultrasound, cryptophthalmos, syndactyly, and ambiguous genitalia seen postnatal). All three fetuses had neonatal death.

Idiopathic

Out of 23 cases, 5 showed spontaneous antenatal resolution of ascites, and all of them had healthy outcome without any need for postnatal treatment. One of these cases had a history of hepatitis E in mother, with mother also having ascites, and the cause of fetal ascites was attributed to maternal infection. A similar case has been reported before.[7] The rest of the 4 cases were labeled as idiopathic as no cause could be identified, and all cases are doing well with minimum follow-up at 3 years of age.

Other causes

One case was associated with congenital heart block, secondary to maternal systemic lupus erythematosus.

Two cases resulting in intrauterine death and neonatal death, respectively, could not be completely evaluated due to economic constraints – The second case had moderate ascites with normal amniotic fluid on Ultrasound. The patient underwent ascitic tap which was hemorrhagic. The FISH was normal for this fetus. The patient delivered spontaneously at 30 weeks and had neonatal death after 24 h, and no autopsy or other tests were done. The second one had severe ascites and polyhydramnios, which were drained. The FISH was normal. There was an intrauterine death at 33 weeks; parents refused an autopsy and further genetic workup.

Role of paracentesis

Out of these 23 cases, a total of 9 cases had paracentesis, which did not prove to be useful either for management or for ascertaining underlying diagnosis. Paracentesis was done mainly in cases of severe fetal ascites and was done to relieve fetal thoracic compression as the fetal abdomen was massively distended [Figure 3].

Figure 3

Fetal ascites leading to abdominal distension with oligohydramnios

DISCUSSION

Incidence of isolated fetal ascites

The prevalence of fetal hydrops ranges from 1/800 to 1/3500 live births, whereas the incidence of isolated fetal ascites is still not known.[5] In our series, the incidence of isolated fetal ascites was about 1/2000 scans (0.05%). The incidence could be higher in our series because of referral bias.

Likely causes of ascites

In our study, we found structural abnormality without underlying chromosomal/genetic abnormality as the most common cause of fetal ascites. We found that following a proper protocol can greatly aid in reaching the cause of isolated fetal ascites, and even in today's era of fetal magnetic resonance imaging, a detailed ultrasound examination to look for associated anomalies still remains the most useful investigation to identify the underlying cause. Karyotype and ascitic fluid analysis were not helpful for underlying diagnosis in any of the cases. Exome sequencing and perinatal autopsy were helpful in selected cases.

Only a few studies are available to review the various causes of fetal ascites.

Favre et al.[3] in 2004 in a study of 79 fetuses with non-immune ascites reported that the cause of ascites was idiopathic in 15.2%; associated with an organic malformation in 57%; had infectious origin in 16.4% cases and had a genetic cause in 11.4% of cases.

El Bishry[1] in 2007 studied 12 patients with isolated fetal ascites. Ten out of the 12 pregnancies had a viable fetal outcome, with two babies (20%) requiring further bowel surgery. Ascites resolved spontaneously in three pregnancies (30%) antenatally and in two babies (20%) few weeks after delivery. Two babies after delivery were found to have other abnormalities that were not diagnosed antenatally. One had ileal atresia and mild hydrocephalus and the other had large pseudocyst and bowel atresia, and they were both successfully treated surgically.

In 2016, Catania et al.[8] studied isolated fetal ascites and neonatal outcome in 51 cases observed in a tertiary referral center of Italy. An associated anomaly was prenatally identified in 84% of the fetuses. An associated disease was confirmed after birth in 61% of cases in group <24 weeks and in 74% in group >24 weeks. There was a higher incidence of gastrointestinal pathology in the latter group (47% vs. 10%, P = 0.004), with a significant prevalence of meconium peritonitis (32% vs. 4%, P = 0.016). In our study, a cause could be identified in 69.5% of the cases. Out of these, an associated structural abnormality contributed to 58.8% of the cases, an underlying genetic cause in 17.6%, secondary to maternal condition in 11.7%. The cause remained unknown in 30.4%.

Survival rate

Favre et al.[3] in 2004 reviewed 79 cases of nonimmune fetal ascites and found that the mortality rate was 57% overall and ranged from 100% (7/7 cases) for metabolic storage disease to 0% (0/3 cases) in chylous ascites. Ascites before 24 weeks of gestation indicated poor prognosis (78.6% vs. 45% mortality rate after 24 weeks; P = 0.01).

In the study by Catani et al.[8] in 2016, prenatal demise occurred only in patients belonging to Group I (<24 weeks) for an overall incidence of 10%. Overall, the postnatal outcome was good in 63% (n = 32) of the cases, and more than half of them belonged to Group II (>24 weeks) (P = 0.003).

Our study was comparable to the study by Catania et al.[8] where the live-born rate and survival rate were significantly better and differing from that of Favre et al.[3] In pregnancies ≤24 gestational weeks, the live-born rate was 66.6% and the survival rate was 50%. In those diagnosed with fetal ascites for the first time >24 gestational weeks, the live-born rate was 88.2% and the survival rate was 64.7%. This was possibly due to the fact that they were closer to viability (defined as >28 gestational weeks in India) and had more access to pediatric surgery services.

It needs to be noted that a bloody ascitic tap and oligohydramnios were associated with poor outcomes.

Strengths

This study emphasizes that timely diagnosis and management is imperative to the better outcomes of the fetuses with isolated fetal ascites and that expensive diagnostic tests are not necessary in prognosticating outcomes and even a well-performed anomaly scan can be very informative.

Limitations

This was a single tertiary center experience, with most of the cases being referred from other centers. There were economic constraints and lack of appropriate perinatal care in periphery that resulted in poor outcome in at least four cases. Particularly, one case which was obviously due to intestinal malformation which could have survived had the baby delivered in a tertiary care setup with availability of Pediatric surgery services. Furthermore the case of monochorionic diamniotic (MCDA) twins with Twin-to-twin transfusion syndrome (TTTS) could have been managed better with a possible favourable outcome for both twins, had the parents been referred in early pregnancy to a tertiary care setup and managed with Photocoagulation of anastomosing vessels in the placenta. Two cases remained idiopathic, resulting in intrauterine death and neonatal death, respectively, due to similar reason that could not be followed up and thoroughly investigated. This may have falsely increased the “idiopathic” cases.

CONCLUSION AND RECOMMENDATIONS

Appropriate perinatal care, timely referral, and delivery at tertiary care setup are other measures which can improve the outcome for most of the cases and can help achieve at least 75%–80% survival rate

Ascites presenting after 24 gestational weeks has a better prognosis as they are more likely to be associated with correctable structural causes

The results of the present study also showed that detailed ultrasound and serial scans can be a very effective tool for investigating cases with isolated fetal ascites.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.