Diagnosis Of Non-immune Hydrops Fetalis Research Articles

Maternal outcomes of a cohort of pregnancies affected by non-immune hydrops fetalis.

To describe the maternal outcomes of a prospective cohort of non-immune hydrops fetalis (NIHF) pregnancies with negative standard-of-care evaluations. This study was a secondary analysis of a prospective cohort study of NIHF pregnancies with negative work-ups (infection, alloimmune anemia, fetomaternal hemorrhage, and chromosomal disorders). Outcomes were obstetric complications, including pre-eclampsia, mirror syndrome, preterm birth, polyhydramnios, postpartum hemorrhage, and maternal mental health. Forty pregnancies were included. Four patients developed pre-eclampsia (4/40, 10.0%); three occurred postpartum. None was diagnosed with mirror syndrome. Of the 31 continued pregnancies, 16 (51.6%) resulted in early fetal death or stillbirth and 15 (48.4%) resulted in live births. Of the 15 live births, 8 (53.3%) were delivered by primary cesarean delivery; 5 (62.5%) were for hydrops fetalis. Eleven live births (73.3%) were delivered preterm; 9 (81.8%) were indicated, most commonly for fetal indications (7/9, 77.8%). Polyhydramnios occurred in 14/40 (35.0%) cases. Where EBL was recorded (n=37), there were 5(13.5%) cases of postpartum hemorrhage and an additional 3(8.1%) had uterine atony without hemorrhage. Eighteen patients (18/40, 45.0%) had new-onset or exacerbated depression or anxiety symptoms. Our study identified several important adverse outcomes of pregnancies complicated by NIHF with negative standard-of-care evaluations, including a high rate of postpartum pre-eclampsia and worsened mental health. We identified a higher rate of cesarean delivery and preterm birth, both primarily for fetal indications. We also observed the known relationship between polyhydramnios, hemorrhage, and atony, but noted that this risk included pregnancies concluding in dilation and evacuation. Counseling after a diagnosis of NIHF should include these adverse outcomes.

The Cardiovascular Profile Score in Patients with Non-immune Hydrops Fetalis and Cardiac Anomalies — a Pilot Study

The purpose of this paper is to explore whether the cardiovascular profile score (CVPS) correlates with fetal outcome in patients with non-immune hydrops fetalis (NIHF) and cardiac anomalies. In this retrospective study, we included fetuses with NIHF and the suspicion of a cardiac anomaly in prenatal ultrasound. The CVPS was calculated using information obtained by fetal echocardiographic examination. Feto-neonatal mortality (FNM) was defined as intrauterine fetal demise or death in the first 6 months of life. We reviewed 98 patients, who were referred to the Department of Obstetrics and Gynecology of the Johannes Gutenberg University in Mainz with the diagnosis of NIHF between January 2007 and March 2021. By eighteen of them, the suspicion of a cardiac anomaly was raised. After exclusion of six pregnancies (one termination of pregnancy and five because of incomplete data), 12 cases were left for analysis. Mean gestational age at which the CVPS was calculated was 29 + 2 weeks. Two fetuses died in utero. Of the remaining ten hydropic fetuses, three newborns died in the neonatal period, and seven survived after a 6-month surveillance period. Median CVPS of all fetuses was 6 points. Surviving fetuses showed statistically significantly higher CVPS values (median 8 points) than fetuses with FNM (median 5 points, p value = 0.009). Our results point towards a positive association between CVPS and fetal outcome in fetuses with NIHF and cardiac anomalies. The CVPS appears to be a useful marker in the assessment of heart failure in utero.Graphical

Cost-Effectiveness of Exome Sequencing versus Targeted Gene Panels for Prenatal Diagnosis of Non-Immune Hydrops Fetalis

The cost-effectiveness (CE) of targeted gene panels versus exome sequencing (exome) for identifying a genetic diagnosis underlying non-immune hydrops fetalis (NIHF) is not known. Our study evaluated the costs and outcomes of targeted gene panels compared to exome for prenatally-diagnosed NIHF not explained by standard genetic testing.

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.

Hemophagocytic Lymphohistiocytosis With Munc13-4 Mutation: A Cause of Recurrent Fatal Hydrops Fetalis

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disorder of immune regulation that leads to a hyperinflammatory syndrome responsible for fever, hepatosplenomegaly, cytopenia, and coagulopathy. Although presentation usually occurs in early infancy, antenatal presentation is extremely rare. To our knowledge, we are first to report genetically confirmed FHL in 2 consecutive siblings who presented with hydrops fetalis that led to spontaneous intrauterine death at 38 and 30 weeks of gestation. Because the diagnosis of FHL has important implications for genetic counseling, we suggest that FHL be considered in the differential diagnosis of nonimmune hydrops fetalis.

Amniotic fluid amino acid levels in non-immune hydrops fetalis: a case-control study

In a prospective case-control study, we compared the amniotic fluid amino acid levels in non-immune hydrops fetalis (NIHF) and normal fetuses. Eighty fetuses underwent amniocentesis for different reasons at the prenatal diagnosis unit of the Department of Obstetrics and Gynecology, Faculty of Medicine, Dicle University. Forty of these fetuses were diagnosed with NIHF. The study included 40 women each in the NIHF (mean age: 27.69 ± 4.56 years) and control (27.52 ± 5.49 years) groups, who had abnormal double- or triple-screening test values with normal fetuses with gestational ages of 23.26 ± 1.98 and 23.68 ± 1.49 weeks at the time of sample collection, respectively. Amniotic fluid amino acid concentrations (intra-assay variation: 2.26-7.85%; interassay variation: 3.45-8.22%) were measured using EZ:faast kits (EZ:faast GC/FID free (physiological) amino acid kit; Phenomenex, USA) by gas chromatography. The standard for quantitation was a mixture of free amino acids from Phenomenex. The levels of 21 amino acids were measured. The mean phosphoserine and serine levels were significantly lower in the NIHF group, while the taurine, α-aminoadipic acid (aaa), glycine, cysteine, NH(4), and arginine (Arg) levels were significantly higher compared to control. Significant risk variables for the NIHF group and odds coefficients were obtained using a binary logistic regression method. The respective odds ratios and 95% confidence intervals for the risk variables phosphoserine, taurine, aaa, Arg, and NH(4) were 3.31 (1.84-5.97), 2.45 (1.56-3.86), 1.78 (1.18-2.68), 2.18 (1.56-3.04), and 2.41 (1.66-3.49), respectively. The significant difference between NIHF and control fetuses suggests that the amniotic fluid levels of some amino acids may be useful for the diagnosis of NIHF.

Non-immune hydrops fetalis: Clinical experience in newborn infants

Non-immune hydrops fetalis is a condition of excessive accumulation of extravascular fluid without identifiable circulating antibody to erythrocytes membrane antigens. In newborn infants it is characterized by skin oedema and pleural, pericardial or peritoneal effusion. In the era of routine Rh immunization for the prevention of foetal erythroblastosis, non-immune pathophysiologic mechanisms are presented in 76-87% of all hydropic newborns. Non-immune hydrops fetalis can be associated with numerous and various disorders. The mortality rate may exceed 50%. This study was aimed at presenting our clinical experience in treating newborn infants with non-immune hydrops fetalis. A retrospective-prospective study included newborn infants with non-immune hydrops fetalis, who were treated in the Neonatal Intensive Care Unit of Mother and Child Health Institute of Serbia between January 1, 2001 and October 31, 2010. All valid data about aetiology, diagnosis, clinical course and outcome were recorded. The diagnosis of non-immune hydrops fetalis was made in 11 newborns. The etiologic diagnosis was established in 8 patients: anaemia due to fetomaternal transfusion in 4 patients and conatal cytomegalovirus infection, intracranial haemorrhage, isolated pulmonary lymphangiectasia and diffuse skin and mediastinal lymphangiomatosis in the remaining 4 patients. Non-immune hydrops of newborn infant is associated with a high mortality rate and requires complex diagnostic and therapeutic procedures. An optimal management of neonates with non-immune hydrops fetalis demands a multidisciplinary approach to the treatment in a neonatal intensive care unit.

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.

Immunohistochemistry in non‐immune hydrops fetalis: A single center experience in 79 fetuses

The objective of our study was to evaluate the usefulness of immunohistochemical (IHC) staining techniques in the etiological diagnosis of non-immune hydrops fetalis (NIHF). The records of all 1,098 autopsies performed between January 1987 and May 2008, by the Division of Fetal Pathology of the University of Genoa, were reviewed and all 79 fetuses diagnosed with NIHF were re-evaluated. Additional IHC staining using antibodies that specifically stain blood and lymph vessels (CD31, CD34, smooth muscle actin antibody, D2-40) were performed. Results were compared to results from the literature. Our results showed that in 67/79 cases, evaluation by standard autopsy protocol led to an etiologic diagnosis. Furthermore, we were able to identify the pathogenetic mechanisms that eventually caused NIHF in 42/79 cases. Adding IHC staining to all evaluations identified the pathogenetic mechanism in a further 17 cases (total 59/79 cases). Lymphatic dysplasia was diagnosed by standard autopsy protocol in 1/79 (1.3%), while adding IHC staining resulted in 18/79 (22.8%) cases being diagnosed (P = 0.0001). The present rate of 22.8% of lymphatic dysplasia in non-immune hydrops fetalis is significantly higher than reported in the literature (36/818 or 4.4%; P = 0.01). In conclusion, specific IHC staining techniques aimed at detecting lymphatic dysplasia are needed and should be mandatory in autopsies of fetuses with non-immune hydrops fetalis.

Hydrops fetalis and early neonatal multiple organ failure in familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHLH) is a genetic heterogeneous autosomal recessive disorder. We report two siblings with FHLH caused by a PRF1 mutation. The first child died in utero with hydrops fetalis and the second presented soon after birth with fatal multiple organ failure. Post-mortem DNA analysis showed a homozygous c.666C>A (p.His222Gln) mutation in the PRF1 gene in both cases, with their non-consanguineous parents being heterozygous for the same mutation. Review of the literature shows that perinatal presentation of FHLH is rare. Diagnosis is difficult because in most cases histologic examination reveals no hemophagocytosis and the disease is rapidly fatal. The association between hydrops fetalis and FHLH has been reported in four previous reports. We present the first case of hydrops fetalis caused by FHLH, confirmed by DNA analysis. FHLH should be included in the differential diagnosis of non-immune hydrops fetalis and neonatal multiple organ failure.

P13.26: Detectation of human parvovirus B19 in cases of hydrops fetalis in Sao Paulo, Brazil

In this study, forty pregnant women with a median gestation age of 25 weeks with prenatal diagnosis of nonimmune hydrops fetalis and suspected of infection by parvovirus B19 were studied between January 1999 and December 2005. Of the 40 maternal-pairs 20 were confirmed to have a B19 infection based on the detection of B19-DNA in maternal sera and fetal serum and/or amminiotic fluid. IgM antibodies for HPV B19 were detected in the sera of 15 mothers and 20 fetuses. HPV B19 DNA was detected in 19 maternal serum, 10 fetal serum and 13 amminiotic fluid specimens. In all 20 positive cases, ultrasound examination demonstrated fetal hydrops, anemia, hepatosplenomegaly, ascite, cardiophatic and amminiotic fluid disorders. Of the total number of cases with positive prenatal diagnosis, fetal loss occurred in 3 cases, 1 by spontaneous miscarriage and 2 by intrauterine fetal death. The results disclosed the accurate laboratory testing and obstetric ultrasonography, fetal mortality from parvovirus infections coud been reduced considerably, and most pregnancies complicated by maternal parvovirus infection could result in healthy outcomes.

Lysosomal storage diseases in non-immune hydrops fetalis pregnancies

Background At least 20 inborn errors of metabolism may cause hydrops fetalis. Most of these are lysosomal storage diseases. The study proposes a diagnostic flowchart for prenatal diagnosis of non-immune hydrops fetalis. Methods This study contains a series of 75 non-immune hydrops fetalis pregnancies. Mucopolysaccharides, oligosaccharides, neuraminic acid and 21 lysosomal enzymes were measured in amniotic fluid and cultured amniotic cells. Results The study gives reference values for mucopolysaccharides and neuraminic acid at various stages of gestation. Four definite and two probable lysosomal diagnoses were found among the 75 investigated cases (= 5.3–8%). Fetal death was found to cause false positive values for mucopolysaccharides in amniotic fluid. In the galactosialidosis case, two novel mutations were found in the cathepsin A gene. Conclusions Reference values for mucopolysaccharides and neuraminic acid depend on gestational age. In a relatively high percentage of the hydrops foetalis pregnancies, a lysosomal aetiology is found. This study provides a strategy to diagnose lysosomal diseases in hydrops fetalis pregnancies. Awareness of lysosomal storage diseases causing hydrops fetalis is useful as it gives an opportunity for risk evaluation, genetic counseling to parents and targeted prenatal diagnostics for ensuing pregnancies.

Fetal middle cerebral artery peak systolic velocity in the investigation of non-immune hydrops.

In some cases of non-immune hydrops there is congenital or acquired fetal anemia. The aim of this study was to investigate the potential value of fetal middle cerebral artery peak systolic velocity (MCA-PSV) in the assessment and management of non-immune hydrops due to anemia. Fetal MCA-PSV and fetal hemoglobin concentration, in blood obtained by cordocentesis, were measured in 16 singleton pregnancies referred to our unit for further investigations because of a diagnosis of non-immune hydrops fetalis. In all cases a detailed ultrasound examination demonstrated moderate or severe ascites, with or without skin edema, and pericardial or pleural effusions. Furthermore, there were no obvious malformations to account for the hydrops. In each fetus the measured MCA-PSV and hemoglobin concentration were expressed as delta values (the difference in SD from the normal mean for gestation). Regression analysis was used to determine the significance of the association between delta MCA-PSV and delta fetal hemoglobin concentration. In addition, we searched our database to identify the sonographic features and hemoglobin concentration of fetuses with congenital infection. In the 16 cases of non-immune hydrops there were seven with parvovirus B19 infection, one each of alpha-thalassemia and primary cardiomyopathy and seven with no obvious explanation for the hydrops. There was a significant association between delta MCA-PSV and delta hemoglobin concentration (delta hemoglobin = (delta MCA-PSV + 0.1437)/-0.4154; R(2) = 0.7202; P < 0.0001). In 10 of the cases the fetal hemoglobin concentration was more than 4 SD below the normal mean for gestation and in all these cases the MCA-PSV was more than 2 SD above the normal mean for gestation. Our computer search identified an additional nine fetuses with parvovirus B19 infection and in all cases the predominant sonographic finding was ascites and the hemoglobin concentration was more than 4 SD below the normal mean. In contrast, only 3/14 fetuses with cytomegalovirus, toxoplasmosis, coxsackie B or Treponema infection had ascites and only 2/14 had a hemoglobin deficit of 4-6 SD. In the management of non-immune hydrops, measurement of fetal MCA-PSV can help identify the subgroup with fetal anemia.

Characterization of newborns with nonimmune hydrops fetalis admitted to a neonatal intensive care unit.

To determine the incidence and characteristics of nonimmune hydrops fetalis in the newborn population. A retrospective study of the period between 1996 and 2000, including all newborns with a prenatal or early neonatal diagnosis of nonimmune hydrops fetalis, based on clinical history, physical examination, and laboratory evaluation. The following were analyzed: prenatal follow-up, delivery type, gender, birth weight, gestational age, presence of perinatal asphyxia, nutritional classification, etiopathic diagnosis, length of hospital stay, mortality, and age at death. A total of 47 newborns with hydrops fetalis (0.42% of live births), 18 (38.3%) with the immune form and 29 (61.7%) with the nonimmune form, were selected for study. The incidence of nonimmune hydrops fetalis was 1 per 414 neonates. Data was obtained from 21 newborns, with the following characteristics: 19 (90.5%) were suspected from prenatal diagnosis, 18 (85.7%) were born by cesarean delivery, 15 (71.4%) were female, and 10 (47.6%) were asphyxiated. The average weight was 2665.9 g, and the average gestational age was 35 3/7 weeks; 14 (66.6%) were preterm; 18 (85.0 %) appropriate delivery time; and 3 (14.3%) were large for gestational age. The etiopathic diagnosis was determined for 62%, which included cardiovascular (19.0%), infectious (9.5%), placental (4.8%), hematologic (4.7%), genitourinary (4.8%), and tumoral causes (4.8%), and there was a combination of causes in 9.5%. The etiology was classified as idiopathic in 38%. The length of hospital stay was 26.6 +/- 23.6 days, and the mortality rate was 52.4%. The establishment of a suitable etiopathic diagnosis associated with prenatal detection of nonimmune hydrops fetalis can be an important step in reducing the neonatal mortality rate from this condition.

The incidence of, and factors leading to, parvovirus B19-related hydrops fetalis following maternal infection; report of 10 cases and meta-analysis

to clarify the approximation of the frequency of B19-related nonimmune hydrops fetalis (NIHF), and to know the critical period during which maternal infection led to NIHF. we investigated the characteristics of 10 cases of antenatal B19 infection diagnosed over the past 10 years in Miyagi prefecture, Japan, and performed a meta-analysis of these cases and those previously reported in the literature. NIHF caused by intrauterine B19 infection was diagnosed between 11 and 23 weeks of gestation in 10 women over the past 10 years in Miyagi prefecture, Japan. The source of infection was the mother's older child in six out of 10 cases, and children at a kindergarten where the mothers worked in two cases. The interval between the onset of infection and the diagnosis of NIHF ranged from 2 to 6 weeks. B19 infection was responsible for 10 (15.2%) in 66 cases of aetiology unknown NIHF in this study, and for 57 (19.1%) of 299 cases of non-malformed or aetiology-unknown NIHF by meta-analysis of the literature. Meta-analysis of the 165 reported cases of antenatal B19 infection, including the 10 cases described above, showed that there was a 10.2% excess risk of fetal death in women infected with B19 during pregnancy and a 12.40% excess risk in women infected during the first 20 weeks of pregnancy. Transplacental transmission was confirmed in 69 (24.1%) of 286 cases. The mean gestational age at diagnosis of NIHF was 22.8 +/- 5.1 weeks. The mean interval between the onset of maternal infection and diagnosis of NIHF was 6.2 +/- 3.7 weeks. these approximations will be useful for counselling and management for pregnant women. The critical period during which maternal infection led to NIHF correlated with the hepatic period of hematopoietic activity. These findings suggest that parvovirus B19 may have an affinity for erythroid lineage cells at the hepatic stage of hematopoiesis, which may strongly influence the clinical features of feto-maternal B19 infection.

Nonimmune hydrops fetalis in a 49,XXXXY fetus at 16 menstrual weeks

AbstractAmniocentesis of a fetus with a sonography diagnosis of nonimmune hydrops fetalis and bilateral clubfoot deformity at 16 weeks of gestation showed a chromosome constitution 49,XXXXY. © 1993 Wiley‐Liss, Inc.