Cause Of Nonimmune Hydrops Fetalis Research Articles

Non-immune hydrops fetalis

Non-immune hydrops fetalis (NIHF) refers to hydrops in the absence of maternal circulating red-cell antibodies, and constitutes up to 90% of all described hydrops fetalis cases. One-third of hydropic fetuses are discovered incidentally during prenatal sonography in the first or second trimester of gestation. Although hydrops is a fetal condition, in many cases there are associated maternal findings, such as preeclampsia, polyhydramnios, and mirror syndrome (generalized maternal edema, that ‘mirrors’ the edema of the hydropic fetus and placenta). NIHF should be seen as a symptom or clinical phenotype rather than as a disorder, and considered as a non-specific, end-stage status of a wide variety of disorders. Numerous disorders including fetal disorders, maternal diseases (e.g., severe maternal anemia, diabetes and maternal indomethacin use) and placental/cord abnormalities have been associated with NIHF. Despite extensive investigations, the etiology on NIHF may remain unknown in 15% to 25% of patients, even after an autopsy has been performed. Chromosomal abnormalities are the cause of NIHF in 25-70% of the cases. Therefore, fetal or neonatal chromosome analysis is indicated in all cases of NIHF. Abnormalities of the cardiovascular system are responsible for as many as 40% of cases of NIHF. Thoracic abnormalities increase intrathoracic pressure and can obstruct venous return to the heart, leading to peripheral venous congestion, or they may obstruct the lymphatic duct, resulting in lymphedema. Fetal anemia accounts for 10-27% of hydrops. To evaluate the risk of fetal anemia, Doppler measurement of the middle cerebral artery peak systolic velocity should be performed in all hydropic fetuses after 16 weeks of gestation. Parvovirus B19 is the most common infectious agent associated with hydrops. Even in persistent severe anemia, the prognosis is generally good if the fetus is supported by intrauterine fetal transfusions. The development of hydrops in fetuses with a TORCH infection is a poor prognostic indicator. Although hypoproteinemia is frequently proposed as one of the causes of hydrops fetalis, recent studies show that hypoalbuminemia is unlikely to cause the initial development of hydrops. However, it seems to occur as a secondary effect in the cascade of hydrops, and might be the trigger for mild hydrops to evolve into severe hydrops. In addition, not all infants with hypoproteinemia become hydropic, and hydrops fetalis is uncommon in congenital nephrotic syndrome and congenital analbuminemia. In the pathogenesis, inherited metabolic disorders, especially lysosomal storage diseases, are more common than previously thought. Inherited metabolic disorders must be always thought when investigating cases of recurrent NIHF in the same family. It is very important to examine the placenta carefully in cases where hydrops or ascites are present at birth or detected by ultrasound, especially in the transient form. Even if a family does not agree to autopsy, placental examination may be done. Proceedings of the 10 th International Workshop on Neonatology · Cagliari (Italy) · October 22 nd -25 th , 2014 · The last ten years, the next ten years in Neonatology Guest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgiou

Nonimmune hydrops fetalis in a children’s hospital: a six-year series

We aimed to study the profile of nonimmune hydrops fetalis (NIHF) in the local population and identify its outcomes and causes. We carried out a retrospective review of the medical records in KK Women's and Children's hospital, a single tertiary referral centre, for pregnancies with an antenatal diagnosis of NIHF in the six-year period from 1 January 2005 to 31 December 2010. A total of 29 cases of NIHF were identified; 19 (66%) cases underwent karyotype evaluation, 17 (59%) underwent intrauterine infection screening, and all underwent antenatal thalassaemia screening. The median gestational age at diagnosis was 27 (range 12-37) weeks, median gestational age at birth was 33 (range 27-37) weeks, and median birth weight of live births was 2,480 (range 1,230-3,900) g. The aetiologies for NIHF were identified in 20 (69%) cases, which included cardiac anomalies (n = 5), haematological problems (n = 4), congenital tumours (n = 4), genetic/metabolic disorders (n = 4) and cystic hygromas (n = 3). The cause of NIHF was not identified in the remaining 9 (31%) cases. There were 19 live births - 8 (42%) survived and 11 (58%) died in the neonatal period - and one stillbirth. Nine women opted for medical termination of pregnancy following the diagnosis of NIHF. It is important to thoroughly investigate all cases of NIHF and identify its causes in order to provide appropriate antenatal and postnatal counselling. In our series, almost one-third of NIHF cases had no identified aetiology. The neonatal mortality rate was approximately 58%.

Evaluation of Cases with Nonimmune Hydrops Fetalis

Objective: We evaluated the characteristics of babies with nonimmune hydrops fetalis born at our hospital during a four-year period. Material and Methods: All newborns with a prenatal or early neonatal diagnosis of nonimmune hydrops fetalis based on clinical history, physical and laboratory examination during the period between January 2008 and December 2011 were evaluated retrospectively. results: A total of 39 newborns with hydrops fetalis were included in this study. Twenty two infants (56.4%) were diagnosed in the antenatal period, and the etiological factor was evident in the prenatal period in 8 infants (20.5%). The most common finding was skin edema in all patients (100%), while neonatal ascites (84.6%) was the second most common sign. Findings related with nonimmune hydrops fetalis were as follows: congenital heart disease (2/39), arrythmia (2/39), congenital cystic adenomatoid malformation (2/39), chylothorax (2/39), cystic hygroma (1/39), twin-totwin transfusion syndrome (7/39), anemia (3/39), genetic/chromosomal abnormalities (5/39), and perforated intrauterine meconium ileus (1/39). No obvious cause was identified in 35.8% (14/39) of cases and these were classified as idiopathic. The mortality rate was 76.9%, and 16 of them (41%) died within the first 24 hours of life. conclusion: The mortality rate is still very high in nonimmune hydrops fetalis. The most common signs were skin edema and neonatal ascites in the antenatal period. Diseases of organs and systems were frequent among the causes of nonimmune hydrops fetalis. Comprehensive diagnostic testing and examinations should therefore be performed as soon as possible.

Neonatal Bartter syndrome and unilateral ectopic renal cyst as new renal causes of hydrops fetalis: two case reports and review of the literature

Non-immune hydrops fetalis (NIHF) is a challenging entity as it represents the end stage of several different disorders. Renal and genitourinary causes of NIHF are rare and include congenital renal malformations, tumors and ureter-urethra disorders. Herein, two NIHF cases with different renal causes were presented. The first case that had antenatal NIHF was diagnosed neonatal Bartter syndrome. The second case of NIHF with antenatal large cyst in the surrenal gland area required surgery and ectopic renal cyst was diagnosed. To our best of knowledge, these are the first reports of NIHF associated with neonatal Bartter syndrome and ectopic renal cyst in neonates. Although it may be coincidental, these cases suggest that both neonatal Bartter syndrome and unilateral ectopic renal cyst may cause NIHF development in neonates by several different mechanisms. Therefore, these two rare entities should be suspected in cases of NIHF with similar findings.

Fetal hydrops and anemia as signs of Down syndrome

Before the 20th week of gestation, the most common cause of nonimmune hydrops fetalis is chromosomal abnormalities. Herein, we report a case of fetal hydrops, anemia, and intrauterine growth retardation that presented at 27 weeks of gestation with a negative chromosomal abnormality screening. Cordocentesis and karyotype analysis revealed fetal pancytopenia and Down syndrome. Down syndrome rarely presents with fetal hydrops and anemia. Therefore, when hydrops and anemia are diagnosed, especially in the second trimester of gestation, the possibility of Down syndrome should be kept in mind. In addition, if the pregnancy results in a live birth, the baby should be examined for transient abnormal myelopoiesis.

Short-term and long-term outcomes of 214 cases of non-immune hydrops fetalis

Despite advances in diagnosis and management, non-immune hydrops fetalis (NIHF) has a high mortality rate. Perinatal survival depends on the underlying disorder and the gestational age at diagnosis. As prognostic information is limited, this study acquired data regarding the neurological development of perinatal survivors. We performed a retrospective chart review of 214 cases in which NIHF was diagnosed antenatally. We recorded maternal demographic characteristics and interventions and their effectiveness, as well as the short-term outcome (survival) and long-term outcome including developmental quotients. Among the affected fetuses, 91 (42.5%) survived the perinatal period. Fetuses with chylothorax, chyloascites, or meconium peritonitis, and those in whom therapy was effective, had high survival rates irrespective of the type of intrauterine intervention. The subsequent intact survival rate was 28/56 (50.0%), with intact defined as ratio of the number of infants with normal development to the number of all infants followed. In contrast to the perinatal survival rate, the intact survival rate decreased as gestational age at diagnosis advanced. These findings suggest that the long-term intact survival rate depends on the underlying cause of NIHF. Additionally, while survival was improved with intensive perinatal care during the perinatal period, aggressive perinatal intervention was not a prognostic factor for neurological outcome.

Nonimmune Hydrops Fetalis in the Stillborn

To the Editor, I read with interest the excellent article by Taweevisit and Thorner that was recently published online [1]. The article describes a series of 78 stillborn fetuses with hydrops fetalis (HF) from the Central Region of Thailand. The purposes of the study were to analyze the etiology of HF by performing autopsy investigations and to identify the various causes of nonimmune HF (NIHF) occurring in Thailand. All cases were diagnosed as NIHF. The authors established that the most common cause of NIHF in their series was homozygous alphathalassemia, compatible with the geographic origin of the series. Among other results, the authors state that 9 cases (11.5%) had no identifiable etiology and that 2 cases (2.6%) presented a phenotype indicating a chromosomal or genetic disorder. A systematic review of the etiology of NIHF was recently published [2]. All 5437 reviewed cases were categorized using 14 classification groups. Among these 14 groups, the chromosomal group comprised chromosomal abnormalities and the syndromic group included syndromes defined as clusters of structural malformations, while the idiopathic group comprised undiagnosed cases. The link between a cause and the mechanism that may trigger generalized edema of the fetus is not always clear. Although most of the 14 NIHF categories were assigned to a defined pathophysiological pathway that led to congestive heart failure, obstructed lymphatic flow, low-plasma colloid osmotic pressure, or, lastly, a combination of the above, it was not possible to reliably classify patients who had previously been assigned to the chromosomal or syndromic disorders groups. In this systematic review, the authors concluded that a definitive pathophysiological mechanism could not be identified in 33.6% of cases, including chromosomal (13.4%), syndromic (4.4%), and idiopathic (15.8%) groups. Although chromosomal or syndromic entities make up a great deal of reported causes of NIHF, I feel that these disorders are not NIHF causes per se. In an attempt to reduce the unacceptably high number of ‘‘nondiagnosed’’ (or only apparently diagnosed) cases, autopsy examination is strongly recommended. The usefulness of immunohistochemical staining techniques in the etiologic diagnosis of NIHF was recently described [3]. Seventy-nine fetuses with a diagnosis of NIHF (out of a total of 1098 fetuses) were studied using antibodies that specifically stain blood and lymph vessels (CD31, CD34, smooth muscle actin antibody, D2-40). This study demonstrated that applying a standard autopsy protocol, very similar indeed to Taweevisit and Thorner’s methods, allowed for the identification of an etiologic diagnosis in only 42 of 79 cases. Adding immunohistochemical methods and reevaluating all cases, a specific pathogenetic mechanism leading to NIHF was able to be identified in an additional 17 fetuses (59/79). The difference was statistically significant (chi-square test; P 5 0.005). This study underlined that a pathogenetic mechanism of NIHF (ie, lymph-vessel dysfunction linked to congenital dysplasia), although rarely recognized and only speculated, in fact should seriously be taken into consideration. Although immunohistochemical staining methods to detect lymphatic dysplasia are widely available, they are not usually included in the standard protocol for fetal autopsy studies. The article [3] concluded that specific immunohistochemical techniques should be mandatory in the autopsies for fetuses with NIHF.

Hydrops Fetalis

Hydrops fetalis is a complex and fascinating disorder. This article explains the characteristics of each type of hydrops fetalis, immune and non-immune. The etiology and the associated underlying conditions leading to the development of these disorders are also discussed. The ultrasonographic appearance of a classic case of hydrops fetalis is described including variations in its appearance and its numerous differential diagnoses. Several causes of non-immune hydrops fetalis are outlined and briefly discussed. The article concludes with delivery recommendations and discusses a future plan of action for the diagnosis of hydrops fetalis.

Fetal Cardiac Troponin T as a Marker of Poor Prognosis in Nonimmune Hydrops Fetalis

Objective: Severe fetal anemia and cardiac compromise are important causes of nonimmune hydrops fetalis, and fetal recovery also depends on the degree of fetal heart compromise. The aim of this study was to report the fetal cardiac troponin T (cTnT) levels in cases of nonimmune fetal hydrops. Methods: Fetal cTnT was analyzed on 7 occasions in 5 cases of nonimmune fetal hydrops (twice in 2 cases). Results: In 3 of 4 fetuses in which intrauterine death occurred, fetal cTnT levels were increased. The only fetus that survived in this series showed decreased levels of cTnT before birth. Conclusion: Fetal cTnT levels may be a marker of fetal prognosis in cases of fetal hydrops.

La chorioangiomatose : une cause rare d’anasarque fœtoplacentaire non immune. Implications pratiques obstétrico-pédiatriques

We report a case of chorioangiomatosis with hydrops fetalis as a complication. Hydrops fetalis associated with fetal distress led to preterm birth at 33 GW. Resuscitation was needed at birth. A systematic histologic exam showed diffuse chorioangiomatosis. There was no congenital hemangioma. We describe the features of chorioangiomatosis, a rare cause of nonimmune hydrops fetalis. Prenatal diagnosis of chorioangiomatosis before early recognition of severe maternal and fetal complications during pregnancy is infrequent, thus precluding early management of the pregnancy. Reports of associated chorioangioma and infantile hemangioma are frequent, illustrated with a recent pathophysiological hypothesis involving embolism of a placental angioblast as for the cause of congenital hemangioma. Investigations for associated cutaneous or visceral infantile hemangioma should be undertaken when chorioangioma is diagnosed.

Middle cerebral artery peak systolic velocity and ductus venosus velocity in the investigation of nonimmune hydrops

This study was performed to investigate the cause of nonimmune hydrops fetalis by measuring the peak systolic velocity (PSV) in the middle cerebral artery (MCA) and velocity waveforms of the ductus venosus (DV) with Doppler. This cross-sectional study was done on 19 pregnancies referred to three university teaching hospitals for further investigation of nonimmune hydrops fetalis in 2007 and 2008. The MCA-PSV and DV velocity waveforms were recorded in all fetuses. Anemia was investigated in cases with MCA-PSV values greater than 1.50 MoM (multiple of the median). Cardiovascular causes and chromosomal abnormalities were investigated in fetuses with abnormal DV velocity. Four of 19 fetuses had MCA-PSV values greater than 1.50 MoM. The causes of anemia were cytomegalovirus, parvovirus B19 infections, congenital heart disease, and Turner syndrome. Four cases had reversed flow in the DV; three of them had congenital heart disease on echocardiography; and one had a normal echocardiogram, but an abnormal karyotype was detected. Assessment of the MCA-PSV and DV velocity waveforms during sonographic examination of fetuses with nonimmune hydrops fetalis may improve our knowledge about the etiology of this condition.

A Case of Mediastinal Teratoma as a Cause of Nonimmune Hydrops Fetalis, and Literature Review

This article reviews the current literature of mediastinal tumors as the cause of nonimmune hydrops fetalis (NIHF), the outcomes of reported cases, and a general overview of NIHF including diagnosis, workup, and a management algorithm, with particular attention made to intrathoracic lesions and gestation age. We present a unique case report of a premature neonate who initially presented with NIHF at birth and was subsequently diagnosed with a germ cell mediastinal teratoma as the etiology of NIHF. The patient survived for 50 days while having undergone surgical resection and chemotherapy during the hospital course. The patient represents the first reported case of a mediastinal tumor as the etiology of NIHF in the neonatal period and only one of three cases that have been reported to survive in the neonatal period. Survival is dependent on the thoracic lesion's size, location, resectability, impact on the growth and development of other vital organs, and in the case of tumors, malignant potential. Though the combination of mediastinal teratoma and NIHF is rare, it should be included in the diagnostic evaluation of a newborn with NIHF.

Nonimmune Hydrops Fetalis

After completing this article, readers should be able to: 1. Describe the common causes of nonimmune hydrops fetalis (NIHF). 2. Characterize the primary steps in antenatal investigation of NIHF. 3. Describe the clinical interventions required for in utero management of NIHF. 4. Delineate the procedures required for ongoing postnatal management of the neonate who has NIHF. 5. Describe the role of postmortem studies in NIHF. Hydrops fetalis has been a well-recognized fetal and neonatal condition throughout history. Until the latter half of the 20th century, it was believed to be due to Rhesus blood group isoimmunization of the fetus, although Potter described infants who had nonimmune causes of fetal hydrops. The advent of Rho (D) immune globulin resulted in a decline in the incidence of isoimmune fetal hydrops and increasing prominence of nonimmune causes of this severe and highly lethal fetal and neonatal condition. Nonimmune hydrops fetalis (NIHF) is as pathologic accumulation of fluid in the skin and one or more other body compartments of the fetus, including the pleural space, peritoneal cavity, pericardial sac, or placenta. Some authors define NIHF as edema of the skin plus fluid accumulation in two other compartments of the fetus, but the former definition is more common. NIHF is estimated to occur in 1 in 2,500 to 1 in 4,000 pregnancies, but the incidence varies with the ethnic population studied. For example, in Southeast Asia, NIHF is seen in 1 in 500 to 1 in 1,500 pregnancies. In this population, homozygous alpha thalassemia is common, accounting for 57% to 81% of cases of NIHF in some series, although a more recent study from Taiwan showed that homozygous alpha thalassemia accounted for only 31% of NIHF. Variations in the incidence of NIHF have been documented when an infectious epidemic occurs, such as with parvovirus B19 (erythema infectiosum). Fluid accumulates within …

Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional Adrenomedullin gene.

Adrenomedullin, a recently identified potent vasodilator, is expressed widely and has been suggested to have functions ranging from reproduction to blood pressure regulation. To elucidate these functions and define more precisely sites of Adm expression, we replaced the coding region of the Adm gene in mice with a sequence encoding enhanced green fluorescent protein while leaving the Adm promoter intact. We find that Adm(-/-) embryos die at midgestation with extreme hydrops fetalis and cardiovascular abnormalities, including overdeveloped ventricular trabeculae and underdeveloped arterial walls. These data suggest that genetically determined absence of Adm may be one cause of nonimmune hydrops fetalis in humans.

Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional Adrenomedullin gene

Adrenomedullin, a recently identified potent vasodilator, is expressed widely and has been suggested to have functions ranging from reproduction to blood pressure regulation. To elucidate these functions and define more precisely sites of Adm expression, we replaced the coding region of the Adm gene in mice with a sequence encoding enhanced green fluorescent protein while leaving the Adm promoter intact. We find that Adm(-/-) embryos die at midgestation with extreme hydrops fetalis and cardiovascular abnormalities, including overdeveloped ventricular trabeculae and underdeveloped arterial walls. These data suggest that genetically determined absence of Adm may be one cause of nonimmune hydrops fetalis in humans.

Human parvovirus B19 infection during pregnancy and its possible impact on perinatal outcome in the obstetric population of Kuwait

Human Parvovirus B19 has been implicated as a primary aetiological agent in erythema infectiosum and aplastic crisis in patients with chronic haemolytic anaemias. Human Parvovirus B19 is also considered as a cause of non-immune hydrops fetalis and intrauterine fetal death. The purpose of this study is to find out the relation of Parvovirus B19 to pregnancy outcome in Kuwait. (excerpt)

Nonimmune hydrops fetalis.

Nonimmune hydrops fetalis (NIHF) is a term that defines an edematous fetus that does not have erythroblastosis fetalis from isoimmunization. All of the other reasons that a fetus develops NIHF are included in this category. The causes of NIHF range from diseases to structural anomalies to genetic abnormalities. The mere presence of NIHF is a poor prognostic indicator, even with the etiology unknown. Some causes of NIHF are treatable with intrauterine therapies. These currently include cordocentesis to administer intrauterine transfusions or medications and fetal surgery. Prenatal testing to establish an etiology or follow the progress of the fetus is extensive, expensive, and stressful. The mortality rate remains high. Education, counseling, and support of the patient and family are the work of the prenatal period. Delivery room management of the infant with NIHF requires a resuscitation team with a specific plan of care to maximize chances of survival.

Investigation of nonimmune hydrops fetalis: multidisciplinary studies are necessary for diagnosis--review of 94 cases.

This review of 94 cases of nonimmune hydrops fetalis (NIHF) over a 10-year period was undertaken to evaluate the frequency of this pathology among fetal and infant deaths and to determine the most common likely etiologies in a northeastern region of France. NIHF represented 6% of the fetal deaths examined in our laboratory. The combination of findings from morphologic examination of the placenta and fetus with the results of microbiological and cytogenetic investigations (conventional cytogenetic study, fluorescent in situ hybridization [FISH], or DNA ploidy image analysis) led to an etiologic diagnosis for NIHF in two-thirds of the cases and suggested a diagnosis in an additional 23% of cases. The most common causes of NIHF were chromosome abnormalities (33%), infections (16%), and cardiac pathology (13.8%). The detection of a cause for NIHF is important for genetic counseling and management of subsequent pregnancies. Our experience suggests that a diagnosis is possible in a large majority of NIHF when obstetricians and pathologists carefully coordinate the management of prenatal and postnatal investigations and when new techniques, such as molecular biology and DNA quantification, are used.

Long-Term Outcome of 51 Liveborn Neonates With Non-Immune Hydrops Fetalis

To search for an efficient method of management of non-immune hydrops fetalis (NIHF), the clinical outcome of 51 newborns with NIHF was retrospectively assessed in a single centre. As the short-term outcome, the mortality rate was mainly dependent on the causes of NIHF and the presence of pleural effusion. The survival rate of the patients with pleural effusion (7/28; 25%) was significantly lower than that of those without it (14/23; 61%) (p < 0.02). All 7 survivors with pleural effusion were diagnosed antenatally after 29 weeks of gestation and were delivered after 31 weeks of gestation. With respect to the long-term outcome, 13 (68.4%) of 19 patients who survived beyond 1 y of age showed normal development, 2 mild developmental delay at 1 y of age and 1 mental retardation at 8 y of age, while 3 (15.8%) had severe psychomotor retardation with marked growth failure. Two of these three patients were born as very-low-birthweight infants. The follow-up results indicate that pleural drainage in utero and prevention of premature delivery should be proposed to improve the outcome of NIHF patients.

Long-term outcome of 51 liveborn neonates with non-immune hydrops fetalis.

To search for an efficient method of management of non-immune hydrops fetalis (NIHF), the clinical outcome of 51 newborns with NIHF was retrospectively assessed in a single centre. As the short-term outcome, the mortality rate was mainly dependent on the causes of NIHF and the presence of pleural effusion. The survival rate of the patients with pleural effusion (7/28; 25%) was significantly lower than that of those without it (14/23; 61%) (p < 0.02). All 7 survivors with pleural effusion were diagnosed antenatally after 29 weeks of gestation and were delivered after 31 weeks of gestation. With respect to the long-term outcome, 13 (68.4%) of 19 patients who survived beyond 1 y of age showed normal development, 2 mild developmental delay at 1 y of age and 1 mental retardation at 8 y of age, while 3 (15.8%) had severe psychomotor retardation with marked growth failure. Two of these three patients were born as very-low-birthweight infants. The follow-up results indicate that pleural drainage in utero and prevention of premature delivery should be proposed to improve the outcome of NIHF patients.