• Sign Up

Hydrops Fetalis


Hydrops Fetalis

Article Author:
Rachana Vanaparthy
Article Editor:
Heba Mahdy
Updated:
9/28/2020 9:55:01 AM
For CME on this topic:
Hydrops Fetalis CME
PubMed Link:
Hydrops Fetalis

Introduction

Hydrops fetalis is a condition in the fetus characterized by the abnormal interstitial fluid collection in two or more compartments of the fetal body (peritoneal cavity, pleura, and pericardium). An alternative definition discusses liquid accumulation in two fetal anatomical areas or effusion in one site and anasarca.[1] 

Traditionally, the diagnosis was made after the delivery of a massively edematous neonate that was often stillborn. With sonography, hydrops fetalis has become a prenatal diagnosis. With condition progression, edema is invariably a component, often accompanied by placentomegaly and hydramnios. Hydrops fetalis may result from a wide range of conditions with varying pathophysiologies, each with the potential to severely affect the fetus. It is divided into two categories, namely immune and non-immune. If found in association with red cell alloimmunization, it is termed immune hydrops fetalis. Otherwise, it is called non-immune hydrops fetalis. Immune hydrops or erythroblastosis fetalis results from antibodies in the maternal circulation that pass through the placenta and react with the fetal antigens, resulting in fetal hemolysis. Non-immune hydrops result from causes other than antigen-antibody reactions.[2] 

Hydrops fetalis is not a consequence of heart failure but rather hypervolemia and the high vascular permeability of fetuses. In contrast, heart failure is a very late consequence of a long-standing overworked heart.[3]

Etiology

Hydrops is associated with a broad spectrum of disorders. There are two main categories of hydrops fetalis:

Immune hydrops fetalis: Isoimmunization such as Rh isoimmunization and ABO incompatibility, anti-c, C, e, E, Duffy antibodies, and Kell alloimmunization are the causes of immune hydrops fetalis. A detailed discussion of the immune hydrops is beyond the scope of this activity.   

Non-immune hydrops (NIHF): This type of hydrops fetalis accounts for approximately 80 to 90 percent of all cases of the condition. It occurs when an underlying disease, genetic disorder, or birth defect interferes with the fetal body's ability to manage fluid. NIHF can result from many various underlying conditions, such as:

  • Cardiac causes: Paroxysmal supraventricular tachycardia, hypoplastic left heart, endocardial cushion defects, and congenital pulmonary airway malformation
  • Chromosomal anomalies: Turner syndrome, Down syndrome, and Edward syndrome
  • Lymphatic causes: Congenital lymphatic dysplasia
  • Infections: Parvovirus B19 (fifth disease), cytomegalovirus, and syphilis infections in pregnant women
  • Metabolic diseases: Niemann-Pick disease type-C (NPC), Gaucher disease type 2, and beta-glucuronidase enzyme deficiency
  • Tumors: Teratoma (sacrococcygeal teratoma), hepatic tumors, and neuroblastoma
  • Maternal diseases: Diabetes mellitus and hyperthyroidism
  • Urinary causes: Congenital nephrosis and prune belly syndrome
  • Digestive causes: Volvulus and meconium peritonitis  
  • Hematologic causes: Alpha-thalassemia, twin-to-twin transfusion syndrome (TTTS) in monochorionic twin pregnancies, and leukemias
  • Disorders of red blood cell (RBC) metabolism: Glucose phosphate isomerase deficiency, pyruvate kinase deficiency, and glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Disorders of RBC production: Congenital dyserythropoietic anemia, Diamond-Blackfan syndrome, and Fanconi anemia 
  • Disorders of RBC membrane: Hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, and hereditary stomatocytosis syndromes[4]

Epidemiology

The prevalence of non-immune hydrops fetalis (NIHF) ranges from 1 in 1500 to 1 in 4000 births. There is a wide variation in the reported prevalence due to differences in definitions, populations, thoroughness of evaluation, and whether late pregnancy terminations were included. The widespread use of anti-D immunoglobulin dramatically decreased the prevalence of RhD alloimmunization and associated hydrops after 1968 when the drug became available. As a result, NIHF now accounts for almost 90 percent of hydrops fetalis cases.[5]

Pathophysiology

Hydrops fetalis is mainly found in any condition that increases the rate of fluid transudation from the vascular compartment or delay in lymphatic return to the circulation. This is mainly due to the developmental defects in the microcirculation and lymphatic system. Hypoxia is another consequence of both immune and non-immune hydrops fetalis. Hypoxia results in an increase in catecholamines, a decrease in hepatic and renal blood flow because of the redistribution of blood to the brain, heart, adrenals, and ductus venosus. This causes the renin-angiotensin system's activation, an increase in the anti-diuretic hormone, and a decrease in albumin. These mechanisms elevate central venous pressure and lead to a decreased return of lymphatic flow into the systemic circulation and further complicate the loss of intravascular volume, resulting in severe and progressive edema in the fetuses.[6]

Although the pathophysiology of non-immune hydrops fetalis is not completely understood, it often results from various mechanisms depending on the underlying cause. Decreased ventricular filling during diastole is the most common mechanism of NIHF in tachyarrhythmias. In contrast, increased central venous pressure resulting from increased right heart pressure is mainly seen in cardiac tumors and subendocardial fibroelastosis. Obstructed lymphatic drainage in thoracic and abdominal cavities results from masses like cystic hygroma, increased capillary permeability, and decreased osmotic pressure in congenital infections and nephrosis. Hence, the management should mainly focus on reversing the underlying diseases.[7][8]

History and Physical

Hydrops fetalis presents with an abnormal fluid collection in two or more cavities or compartments, mainly pleural effusion, ascites, pericardial effusion, and skin edema. The number of fluid collection sites is directly correlated to the neonatal prognosis. The diagnosis is mainly based on prenatal ultrasound or the postnatal evaluation of the fetus. Other features include anemia, placentomegaly, polyhydramnios, and hepatosplenomegaly. Pleural effusion can be unilateral or bilateral. Mild effusions can cause respiratory distress, and severe effusions result in lung hypoplasia and respiratory or circulatory diseases associated with poor prognosis after birth.[9] Patients can also present with pneumothorax or chylothorax. These are rare and serious clinical conditions with high mortality.[10][11]

Ascites can be an early manifestation of hydrops fetalis and is seen as early as 20 weeks of gestation. As isolated fetal ascites is seen in many other systemic diseases, it is essential to differentiate hydrops fetalis from other causes. Larger ascites can cause bowel compression and pulmonary hypoplasia. The serum ascites albumin gradient (SAAG) ratio of ascites with hydrops fetalis will be less than 11 g/L, which indicates the etiology of non-portal hypertension. Spontaneous resolution with a good prognosis is seen in a few patients.[12] Pericardial effusion in the fetus is transient, which manifests as hydrops in Rh-sensitized females.[13] Skin edema is defined as the subcutaneous tissue thickness on the scalp greater than 5mm. Sometimes, fluid accumulation behind the neck, known as nuchal translucency, and fat under the scalp is mistaken for skin edema.[14]

Anemia in hydrops fetalis is caused mainly by red cell alloimmunization and parvovirus-B19 infection. Other causes include alpha thalassemia, Bart hemoglobin, and a mutation in the alpha-globin chain.[15]

Polyhydramnios is the vertically measured amniotic fluid volume in the single deepest pocket of more than 8 centimeters or amniotic fluid index of more than 24 centimeters.[16] It is caused mainly due to impaired fetal swallowing, impaired renal function, and intestinal obstruction.[10]

Placentomegaly is an abnormally enlarged placenta which occurs due to disruption in the oncotic gradient. It is mainly seen in high cardiac output diseases like anemia and sacrococcygeal teratoma. Placentomegaly and polyhydramnios are considered as predictors of survival.[17]

Hepatosplenomegaly is diagnosed in the second and third trimester of pregnancy. It is usually associated with myeloproliferative disease in trisomy 21.[18]

Neonates with cyanosis and no response to oxygen supplement should raise the suspicion of the presence of underlying cardiac diseases.[19]

Neonates with hypotonia suggest the presence of congenital myopathy and congenital hypothyroidism.[20][21] In addition to hypotonia, the presence of hepatomegaly, cardiomyopathy, and facial dysmorphism suggest metabolic storage diseases.[22] Dermatitis, along with or without hepatosplenomegaly, suggests the presence of TORCH (toxoplasmosis, other infections such as rubella, cytomegalovirus, and herpes simplex) infections.[23]

Evaluation

Hydrops fetalis is mostly an incidental finding on routine prenatal workup. The underlying cause has a direct influence on the development of symptoms and its prognosis. Hydrops due to chromosomal abnormalities is usually detected during early pregnancy, whereas cardiac causes are detected in the second or third trimester. Hence, a detailed prenatal workup should be done in suspected cases. The following are the various diagnostic modalities for the evaluation of hydrops fetalis. 

The first detailed ultrasound is done between 18 to 22 weeks of gestation. The most common findings detected during early pregnancy are ascites and skin edema (>5 mm thickness) in the fetal head, back of the neck, thorax, and abdomen. The cause of generalized skin edema is most probably due to aneuploidy or associated anatomical defects. Polyhydramnios and placental edema are most commonly seen before 20 weeks, whereas pleural effusion and pericardial effusion in the fetus is rarely seen before 15 weeks of gestation.[24]

It is mandatory to look for the possibility of maternal toxoplasma, rubella, cytomegalovirus, herpes (TORCH), and parvovirus B19. Parvovirus B19 infection is most commonly associated with fetal anemia and ascites; however, cytomegalovirus and toxoplasmosis present with congenital malformations like ventriculomegaly, microcephaly, and hyperechogenic bowel. Hence, the antibody screen for TORCH infections should always be considered.[24]

Fetal heart rate, umbilical artery pulsatility index, end-diastolic flow, and middle cerebral artery peak systolic velocity (MCA-PSV) are also helpful in detecting the underlying causes of hydrops. The mean fetal heart rate is increased in trisomy 21. Increased resistance to blood flow in the umbilical artery is seen in trisomy 18 and triploidy.[24] The measurement of MCA-PSV is very sensitive in determining fetal anemia. An MSA-PSV ratio of more than 1.5 is considered to be fetal anemia.[25] Cordocentesis helps find the cause of fetal anemia.[15]

Chorionic villous sampling (CVS) is most frequently done for karyotyping if hydrops fetalis is diagnosed before 15 weeks of gestation.[24] CVS is also done to diagnose Bart hemoglobin (has a high affinity for oxygen and thus ineffective oxygen carrier) in alpha thalassemia, which is an ultimately fatal condition between 10-12 weeks of gestation.[26]

Anti-SS-A/SS-B antibodies in maternal Sjogren syndrome can cause bradyarrhythmias and complete heart block in fetuses, resulting in hydrops' development. However, congenital heart block is the first manifestation to be seen on ultrasound during the first trimester. The prognosis for this is relatively poor.[27]

Elevated alpha-fetoprotein (AFP) during pregnancy indicates the fetomaternal hemorrhage, which causes feal anemia and nonimmune hydrops. Hence, AFP levels are monitored closely.[28]

Direct and indirect Coomb test is used for detecting immune hydrops fetalis, but they do not correlate the disease severity.[2]

Echocardiogram, thyroid hormone levels, complete blood count, and metabolic panel also detect other causes of NIHF after birth.[24]

Treatment / Management

Careful evaluation and monitoring and effective resuscitation techniques are essential in improving the survival rate in affected neonates. Structural heart abnormalities and chromosomal disorders cannot be intervened with, and hence the prognosis is very poor. Therefore, they are excluded first before performing any interventions. Intrauterine interventions like thoracocentesis and peritoneal-amniotic shunt can be performed if the ultrasound detects mediastinal shift, polyhydramnios, fetal edema, or rapid accumulation of fluid, to confirm alveolar development and also helps in releasing the excessive amniotic fluid. In severe anemia and arrhythmias, intrauterine transfusion and antiarrhythmic drugs can be utilized, respectively. Intrauterine transfusions in patients with parvovirus-B19 infections can reverse hydrops, which may sometimes result in healthy live births. A few teratomas can be resected surgically in utero.[10]

Postnatal management includes initial resuscitation, identification, and treatment of the underlying cause. Most of the infants with hydrops fetalis will require endotracheal intubation because of respiratory depression. Thoracentesis, paracentesis, and sometimes cardiocentesis are performed if the neonate presents with pleural effusion, ascites, and pericardial effusion. In cases of severe anemia, a blood transfusion is given.[10] Further, close monitoring is needed if tachyarrhythmias are transient or intermittent. If severe, they are corrected with cardioversion, antiarrhythmic drugs, and pacing.[29]

Despite aggressive treatment, the survival rate is as low as 10 percent with neurodevelopmental and cognitive defects in surviving infants. The recurrence rate is highest in mothers whose infants have chromosomal abnormalities or Rh incompatibility. Hence, autopsies, including histopathologic evaluation, placental examination, molecular and genetic studies, are performed to determine the cause of hydrops.[30]

Differential Diagnosis

  • Neonatal hemochromatosis
  • Congestive cardiac failure
  • Twin-to-twin transfusion syndrome (TTTS)
  • Hepatitis B
  • Hypercalcemia
  • Hypernatremia
  • Hypothrombinemia
  • Maternal diabetes
  • Fetal abdominal cysts
  • Obstructed bowel
  • Obstructed urinary system[31]

Prognosis

The prognosis of hydrops fetalis is dependent mainly on the underlying cause, gestational age at the time of the diagnosis, time of delivery, amount of fetal edema, and intrauterine interventions.[10] Neonates who present with thoracic causes and bronchopulmonary malformations have a good prognosis, while those with chromosomal abnormalities, structural abnormalities, and other genetic metabolic disorders are associated with poor prognosis.[32]

Survival in hydrops fetalis depends on the underlying disease, available fetal therapies to resolve hydrops, and the gestational age of delivery, not on the specific anatomic manifestations of hydrops. In fetuses with hydrops with high cardiothoracic ratios, the cardiovascular profile score may be a useful prognostic indicator. Patients with hydrops who can have a fetal intervention for their underlying condition now benefit from improved survival, especially when hydrops can be resolved, and there is no preterm delivery. While particular physiologic parameters such as the middle cerebral artery peak systolic velocity did not predict survival, the cardiovascular profile score is a useful adjunct to predict survival when the underlying cause results in a high cardiothoracic ratio. Furthermore, the fact that patients with such variable disease processes and cardiac manifestations can converge on the simple anatomic finding of fluid in two compartments suggests a basic fetal distress mechanism that is yet to be discovered.[17]

Complications

  • Spontaneous miscarriage
  • Intrauterine fetal demise
  • Preterm delivery
  • Perinatal deaths
  • Early neonatal deaths

Appendiceal rupture, cystic hygroma, intestinal obstruction, and severe neurodevelopment delay are seen in infants who survive with hydrops fetalis.[33][34]

Deterrence and Patient Education

Hydrops fetalis carries a poor prognosis if fetuses develop pulmonary hypoplasia, have underlying heart diseases, or are diagnosed before 24 weeks of gestation. Termination of pregnancy is considered if hydrops is diagnosed in early gestation with no treatable cause. NIHF is associated with an overall perinatal mortality rate of 50 to 98 percent.[35] 

Prognosis depends upon the etiology, the gestational age at onset, the gestational age at delivery, and whether pleural effusions are present. In general, the earlier hydrops occurs, the poorer the prognosis. In particular, pleural effusions and polyhydramnios before 20 weeks of gestation are poor prognostic signs because of increased risks of pulmonary hypoplasia and preterm prelabour rupture of membranes/preterm delivery, respectively. On the other hand, the absence of aneuploidy and major structural abnormalities confer a better prognosis.[36]

Recurrence in future pregnancies is uncommon unless it is associated with Rh incompatibility or chromosomal abnormalities. Repeated antenatal care with ultrasound surveillance is required every 1 to 2 weeks if the hydrops is resolving, and the mother is frequently evaluated for the signs of mirror syndrome. Patients treated for immune hydrops are delivered at 37 weeks of gestation or when the fetus's lung maturity is confirmed. There is no substantial evidence that a cesarean section has a superior outcome. Delivery is performed in a tertiary center with neonatal intensive care in the presence of an experienced neonatal team. Immediate resuscitation is done, and proper postnatal care is needed for newborn babies.

Enhancing Healthcare Team Outcomes

Carrying a baby with hydrops fetalis can be extremely stressful and challenging for the pregnant woman and her family. A close collaboration between the obstetric providers, maternal-fetal medicine specialists, radiologists, neonatologists, nursing staff, pharmacists, and social support workers is paramount to enhancing the outcome for both the mother and her baby. The wellbeing of both mother and the fetus(s) is considered a priority at all times. When hydrops fetalis is diagnosed in-utero, the interprofessional team should be well prepared to detect the symptoms and signs of fetal hydrops.

Careful evaluation and monitoring are required to look for the development of complications for early detection and subsequent management to prevent perinatal morbidity and mortality. Additionally, pharmacists play a vital role in educating patients and monitoring their compliance with their prescribed medications. The nurse plays a vital role in educating the woman and her family and providing them with the necessary information. Pregnant women carrying a fetus with hydrops fetalis should be treated in a very respectful and sensitive manner. They should be given adequate time to express their views, wishes, and concerns. Their opinions and beliefs should be respected at all times.

Patient awareness helps in the early identification and timely reporting of symptoms. The nurse should ensure proper follow-up and notify the medical team about any untoward change or deterioration of the condition of the mother or the newborn. The social workers should also ensure that pregnant women are getting adequate emotional and financial support to deal with their condition. The members of the interprofessional team should collaborate and discuss with the woman and her family that the etiology of fetal hydrops can not always be determined; therefore, genetic consultation can be useful in estimating their risks and discussing their future pregnancy plans. The coordinated collaboration among the members of the interprofessional team will not only help improve the clinical outcome of the pregnant women but will also help to maximize the emotional, the psychological, as well as the mental wellbeing of women with carrying fetuses with hydrops fetalis. [Level 5]


References

[1] Kontomanolis EN,Fasoulakis Z, Hydrops Fetalis and THE Parvovirus B-19. Current pediatric reviews. 2018     [PubMed PMID: 30124157]
[2] Singla S,Kumar S,Roy KK,Sharma JB,Kachhawa G, Severe hydrops in the infant of a Rhesus D-positive mother due to anti-c antibodies diagnosed antenatally: a case report. Journal of medical case reports. 2010 Feb 18;     [PubMed PMID: 20167104]
[3] Thammavong K,Luewan S,Wanapirak C,Tongsong T, Ultrasound Features of Fetal Anemia Lessons From Hemoglobin Bart Disease. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine. 2020 Aug 20     [PubMed PMID: 32815580]
[4] Randenberg AL, Nonimmune hydrops fetalis part I: etiology and pathophysiology. Neonatal network : NN. 2010 Sep-Oct     [PubMed PMID: 20829175]
[5]     [PubMed PMID: 28533037]
[6]     [PubMed PMID: 25664943]
[7] Apkon M, Pathophysiology of hydrops fetalis. Seminars in perinatology. 1995 Dec;     [PubMed PMID: 8822328]
[8] Norton ME,Chauhan SP,Dashe JS, Society for maternal-fetal medicine (SMFM) clinical guideline #7: nonimmune hydrops fetalis. American journal of obstetrics and gynecology. 2015 Feb     [PubMed PMID: 25557883]
[9] Nakayama A,Oshiro M,Yamada Y,Hattori T,Wakano Y,Hayashi S,Kokubo M,Takemoto K,Honda S,Ieda K,Yamamoto H,Kouwaki M,Yokoi K,Shinohara O,Kato T,Miyata M,Tanaka T,Hayakawa M, Prognostic factors of hydrops fetalis with pleural effusion. Pediatrics international : official journal of the Japan Pediatric Society. 2017 Oct;     [PubMed PMID: 28672054]
[10] An X,Wang J,Zhuang X,Dai J,Lu C,Li X,Yan Y, Clinical Features of Neonates with Hydrops Fetalis. American journal of perinatology. 2015 Nov;     [PubMed PMID: 26070120]
[11] Ibrahim A,Dammas AS, Congenital neonatal chylothorax with hydrops fetalis treated with octreotide. Sudanese journal of paediatrics. 2013;     [PubMed PMID: 27493357]
[12] Abdellatif M,Alsinani S,Al-Balushi Z,Al-Dughaishi T,Abuanza M,Al-Riyami N, Spontaneous resolution of fetal and neonatal ascites after birth. Sultan Qaboos University medical journal. 2013 Feb;     [PubMed PMID: 23573403]
[13] Shenker L,Reed KL,Anderson CF,Kern W, Fetal pericardial effusion. American journal of obstetrics and gynecology. 1989 Jun;     [PubMed PMID: 2660574]
[14] Kurdi W, Non-immune fetal hydrops: Are we doing the appropriate tests each time? Journal of prenatal medicine. 2007 Jan;     [PubMed PMID: 22470821]
[15] Komvilaisak P,Komvilaisak R,Jetsrisuparb A,Wiangnon S,Jirapradittha J,Kiatchoosakun P,Fucharoen G, Fetal Anemia Causing Hydrops Fetalis From an Alpha-Globin Variant: Homozygous Hemoglobin Constant Spring. Journal of pediatric hematology/oncology. 2018 Jul;     [PubMed PMID: 29240037]
[16] Hamza A,Herr D,Solomayer EF,Meyberg-Solomayer G, Polyhydramnios: Causes, Diagnosis and Therapy. Geburtshilfe und Frauenheilkunde. 2013 Dec     [PubMed PMID: 24771905]
[17] Derderian SC,Jeanty C,Fleck SR,Cheng LS,Peyvandi S,Moon-Grady AJ,Farrell J,Hirose S,Gonzalez J,Keller RL,MacKenzie TC, The many faces of hydrops. Journal of pediatric surgery. 2015 Jan;     [PubMed PMID: 25598092]
[18] Smrcek JM,Baschat AA,Germer U,Gloeckner-Hofmann K,Gembruch U, Fetal hydrops and hepatosplenomegaly in the second half of pregnancy: a sign of myeloproliferative disorder in fetuses with trisomy 21. Ultrasound in obstetrics     [PubMed PMID: 11380964]
[19] Knilans TK, Cardiac abnormalities associated with hydrops fetalis. Seminars in perinatology. 1995 Dec;     [PubMed PMID: 8822332]
[20] Afifi AM,Bhatia AR,Eyal F, Hydrops fetalis associated with congenital myotonic dystrophy. American journal of obstetrics and gynecology. 1992 Mar;     [PubMed PMID: 1550167]
[21] Narchi H, Congenital hypothyroidism and nonimmune hydrops fetalis: associated? Pediatrics. 1999 Dec;     [PubMed PMID: 10610498]
[22] Sun A, Lysosomal storage disease overview. Annals of translational medicine. 2018 Dec;     [PubMed PMID: 30740407]
[23] Leung KKY,Hon KL,Yeung A,Leung AKC,Man E, Congenital infections in Hong Kong: an overview of TORCH. Hong Kong medical journal = Xianggang yi xue za zhi. 2020 Apr;     [PubMed PMID: 32245914]
[24] Jauniaux E, Diagnosis and management of early non-immune hydrops fetalis. Prenatal diagnosis. 1997 Dec;     [PubMed PMID: 9509544]
[25] Hernandez-Andrade E,Scheier M,Dezerega V,Carmo A,Nicolaides KH, Fetal middle cerebral artery peak systolic velocity in the investigation of non-immune hydrops. Ultrasound in obstetrics     [PubMed PMID: 15133792]
[26] Al-Allawi NA,Shamdeen MY,Rasheed NS, Homozygosity for the Mediterranean a-thalassemic deletion (hemoglobin Barts hydrops fetalis). Annals of Saudi medicine. 2010 Mar-Apr;     [PubMed PMID: 20220267]
[27] Lai J,Clark TJ,Tan JH,Delaney S,Jolley JA, Ultrasound findings in fetal congenital heart block associated with maternal anti-Ro/SSA and Anti-La/SSB antibodies. Ultrasound quarterly. 2015 Mar     [PubMed PMID: 25706362]
[28] Downing GJ,Kilbride HW,Yeast JD, Nonimmune hydrops fetalis caused by a massive fetomaternal hemorrhage associated with elevated maternal serum alpha-fetoprotein levels. A case report. The Journal of reproductive medicine. 1990 Apr;     [PubMed PMID: 1693688]
[29] Fu DG, Cardiac Arrhythmias: Diagnosis, Symptoms, and Treatments. Cell biochemistry and biophysics. 2015 Nov;     [PubMed PMID: 25737133]
[30]     [PubMed PMID: 12016530]
[31] Machin GA, Differential diagnosis of hydrops fetalis. American journal of medical genetics. 1981;     [PubMed PMID: 6794370]
[32]     [PubMed PMID: 28647738]
[33] Lebel RR,Avery JM,Broome PJ,Gregg AR,Alan C,Mostafa M, Fetal peritonitis due to appendiceal rupture: a rare complication of hydrops. Fetal and pediatric pathology. 2008;     [PubMed PMID: 18633765]
[34] Meng D,Li Q,Hu X,Wang L,Tan S,Su J,Zhang Y,Sun W,Chen B,He S,Lin F,Xie B,Chen S,Agrawal PB,Luo S,Fu C, Etiology and Outcome of non-immune Hydrops Fetalis in Southern China: report of 1004 cases. Scientific reports. 2019 Jul 24;     [PubMed PMID: 31341179]
[35] Carlson DE,Platt LD,Medearis AL,Horenstein J, Prognostic indicators of the resolution of nonimmune hydrops fetalis and survival of the fetus. American journal of obstetrics and gynecology. 1990 Dec     [PubMed PMID: 2256483]
[36]     [PubMed PMID: 7898837]