Nonimmune Hydrops Fetalis Research Articles

Urinary Type Hydrometrocolpos and Polydactyly in Two Newborns: Case Report

Background: Abdominal masses secondary to urinary retention are rare among female neonates and approaching this pathologic condition, inevitably, poses a diagnostic challenge. Hydrometrocolpos is one example of this disease category which is responsible for only 15% of such cases whose association with polydactyly appears to be even less common. The present study aimed to report the accounts of two neonates with cystic abdominal masses diagnosed as urinary type hydrometrocolpos secondary to urogenital sinus anomaly. Autosomal recessive disorders are characterized by vaginal atresia with hydrometrocolpos, polydactyly, congenital heart defects, and non-immune mediated hydrops fetalis. The triad of hydrometrocolpos, polydactyly, and cardiac anomaly in the two patients presented herein is strongly suggestive of a case of McKusick-Kaufman syndrome. Case report: This study reported two neonates with abdominal mass, polydactyly, and genitourinary tract malformation, with no family history. Relief of urinary obstruction by exploratory laparotomy, aspiration of fluid, and vaginal reconstruction gradually reversed the hydronephrosis and renal failure. Conclusion: It can be concluded thatin hydrometrocolpos causing urinary obstruction, decompression of hydrometrocolpos can save the kidneys.

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

(N Engl J Med. 2020;383:1746–1756) Nonimmune hydrops fetalis (NIHF) is a severe disorder associated with a high risk of stillbirth, preterm birth, neonatal death, and neonatal complications. NIHF is a shared presentation of a number of genetic disorders. Using standard genetic testing with karyotyping or chromosomal microarray, the cause of NIHF can be determined in only 25% of cases. Single-gene disorders may substantially contribute to NIHF, but this is not yet clear. This study aimed to explore the use of exome sequencing for diagnosing single-gene disorders in unexplained NIHF cases and establish the diagnostic yield of exome sequencing.

Nonimmune Hydrops Fetalis — More Than Meets the Eye?

(N Engl J Med. 2020;383:1785–1786) Nonimmune Hydrops Fetalis (NIHF) is typically defined as fetal fluid accumulation in two sites and affects up to 1 in 1,700 fetuses. There are multiple causes, including chromosomal abnormalities and structural malformations. Perinatal mortality is high in pregnancies where NIHF is present in the first trimester. In two different studies, diagnostic variants were identified in 9% and 24% of fetuses with NIHF using exome sequencing.

Mucopolysaccharidosis VII in Brazil: natural history and clinical findings

BackgroundMucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, caused by deficiency of the lysosomal enzyme β-glucuronidase, is an ultra-rare disorder with scarce epidemiological data and few publications about natural history and clinical spectrum.MethodsWe conducted a case series report which included retrospective data from all MPS VII patients diagnosed through the “MPS Brazil Network” who were known to be alive in 2020 in Brazil (N = 13). Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population.ResultsThe majority of the patients were from the Northeast region of Brazil. Among the signs and symptoms that raised the clinical suspicion of MPS, coarse face was the most frequent; 58% of the patients had a history of non-immune hydrops fetalis. All the subjects presented short neck and trunk. The majority presented typical phenotypical signs of MPS disorders. They all presented neurodevelopmental delay and cognitive impairment. About half of this cohort had knees deformities. Dysostosis multiplex was identified in almost all patients and cardiomyopathy was less frequent than observed in other types of MPSs. The mean age at diagnosis was 5 years, ranging from 1 to 14 years. Almost all patients (12/13) were homozygous for the c.526C>T (p.Leu176Phe) mutation. A novel variant of the GUSB gene was found, the c.875T>C (p.Leu292Pro), in a compound heterozygous with the c.526C>T (p.Leu176Phe) variant.ConclusionsThis case series is the biggest data collection of MPS VII patients alive in Latin America. The overall clinical picture of the MPS VII patients is very similar to other MPS disorders, including a spectrum of severity and delayed diagnosis.

Molecular detection of human parvovirus B19 in umbilical cord blood: Case study of Tehran, Iran

BackgroundHuman parvovirus B19 (HPVB19) can infect and cause abortion, non-immune hydrops fetalis, and intrauterine fetal death in pregnant women. The present study aimed to determine the molecular prevalence of HPVB19 among pregnant women in Tehran, Iran. MethodsThe present single-center cross-sectional study was conducted by screening testing for HPVB19 infection in pregnant women from February 2016 to July 2020 at Imam Hossein Hospital, Tehran, Iran. Cord blood tissue samples were collected from each pregnant woman and all samples were preserved at −70 °C. Genomic DNA was extracted from all cord blood tissue samples and the presence and frequency of HPVB19 were determined through conventional PCR assay. ResultsA total of 182 cord tissue samples were screened for HPVB19 DNA. The median age of the pregnant women was 28 years ranging from 20 to 49 years. HPBV19 was detected in 8.8% (n = 16/182) of the samples studied. The frequency of HPVB19 in pregnant women with different pregnancy conditions was as follows: IUFD (n = 2/55; 3.6%), term (n = 10/84; 11.9%), and premature (n = 4/86; 4.7%). The lowest (n = 0/25; 0%) and highest (n = 3/5; 60%) prevalence rates of HPVB infection were detected within the 21–30 weeks of gestation and post-term (>40 weeks), respectively. Moreover, the prevalence of HPVB19 infection among pregnant women with Hgb levels >10 was high (9.3%; n = 15/161). ConclusionGiven that no vaccine exists against HPVB19, it is recommended that pregnant women should be routinely screened during pregnancy to ensure immunity against HPVB19.

Value of Exome Sequencing in Diagnosis and Management of Recurrent Non-immune Hydrops Fetalis: A Retrospective Analysis.

The purpose of the study was to use exome sequencing (ES) to study the contribution of single-gene disorders to recurrent non-immune hydrops fetalis (NIHF) and retrospectively evaluate the value of genetic diagnosis on prenatal management and pregnancy outcome. From January 2012 to October 2018, a cohort of 28 fetuses with recurrent NIHF was analyzed by trio ES. Fetuses with immune hydrops, non-genetic factors (including infection, etc.), karyotype, or CNV abnormalities were excluded. Variants were interpreted based on ACMG/AMP guidelines. Fetal therapy was performed on seven fetuses. Of the 28 fetuses, 10 (36%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in eight genes (GBA, GUSB, GBE1, RAPSN, FOXC2, PIEZO1, LZTR1, and FOXP3). Five (18%) fetuses had variant(s) of uncertain significance (VUS). Of the 10 fetuses with definitive molecular diagnosis, five (50%) were diagnosed with inborn errors of metabolism. Among the seven fetuses who received fetal therapy, two had definitive molecular diagnosis and resulted in neonatal death. Among the remaining five fetuses with negative results, four had newborn survival and one had intrauterine fetal death. Trio ES could facilitate genetic diagnosis of recurrent NIHF and improve the prenatal management and pregnancy outcome.

Non-immunologic hydrops fetalis and coronavirus disease (COVID-19) – A case report

Non-immune hydrops fetalis is a severe fetal condition defined as the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities. The prevalence of non-immune hydrops fetalis is unknown. Currently, about 90% of cases of hydrops fetalis are non-immune hydrops fetalis. Non-immune hydrops fetalis causes are multi-factorial. The pathophysiological mechanism of non-immunologic hydrops fetalis is related to abnormal fluid transportation between plasma and tissues. This is due to the increase in hydrostatic capillary pressure and capillary permeability and a reduction of the plasma osmotic pressure or lymphatic flow. A variety of viral infection agents have been associated with non-immune hydrops fetalis like parvovirus B19, herpes simplex virus, cytomegalovirus, Toxoplasma gondii, Treponema pallidum, but even other viruses that attack the maternal and fetus during pregnancy cannot be excluded as possible causes of non-immune hydrops fetalis. We present one case of non-immune hydrops fetalis who was diagnosed intra-uterine, three weeks after recovery from Coronavirus disease (COVID-19). After much investigation, we could not find any known factor that may be the cause of non-immunologic hydrops fetalis. Therefore, we predisposed a possible causal connection between nonimmunologic hydrops fetalis and Coronavirus disease (COVID-19).

Congenital Chylothorax and Hydrops Fetalis: A Novel Neonatal Presentation of RASA1 Mutation

Mutations in the RASA1 gene are known to cause arteriovenous malformations (AVMs), with evidence of associated lymphatic malformations. We report for the first time, to the best of our knowledge, an infant with RASA1 mutation presenting with hydrops fetalis and chylothorax, but without an associated AVM. Previously, researchers studying rodents have found chylothorax associated with RASA1 mutations, and, in previous case reports, researchers have reported on infants with RASA1 mutations born with hydrops fetalis and AVMs. In this report, we describe the case of a "late preterm" female infant born with nonimmune hydrops fetalis and congenital chylothorax who was detected to have a RASA1 deletion on genetic workup. Although classically described phenotypes of RASA1 mutations present with venous malformations, no such malformations were found in this infant on extensive imaging. This combination is a novel and nonclassic presentation of RASA1 mutation. In cases of congenital chylothorax, especially with nonimmune hydrops fetalis, RASA1 mutations should be considered as part of the differential diagnosis and genetic testing should be included as part of a complete workup to allow for screening for associated vascular anomalies.

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

(Abstracted from N Engl J Med 2020;383:1746–1756) Nonimmune hydrops fetalis (NIHF) is a condition complicating approximately 1 in 1700 to 3000 pregnancies where the fetus develops an overload of fluid, causing a wide range of outcomes such as stillbirth, preterm birth, neonatal complications, or neonatal death. Standard genetic testing with microarray or karyotype identifies a genetic cause of hydrops approximately only 25% of the time.

Сравнительный анализ активной и выжидательной тактики ведения беременных с неиммунной водянкой плода

Сравнительный анализ активной и выжидательной тактики ведения беременных с неиммунной водянкой плода

Staged Management of Congenital Chylothorax With Hydrops Fetalis: An Insight Into EXIT Related Procedures.

Background: Idiopathic congenital chylothorax is a rare but serious disease. Advancement in perinatal care and the renovated treatment modalities have brought about significant improvement in patient outcome.Objective: To describe the clinical course of severe forms of idiopathic congenital chylothorax, focusing on the development of recent treatment modalities and their impacts.Design: A retrospective cohort by review of medical records in the NICU of a perinatal referral center in Taiwan. Study period was from January 2006 to June 2017. Neonates with the diagnosis of idiopathic congenital chylothorax with non-immune hydrops fetalis were enrolled. Clinical relevant including demographic data, perinatal interventions, post-natal course, and treatment outcome were described and analyzed.Results: Twenty-eight neonatal patients were included. The median gestational age at birth was 34 (range 27–36) weeks and median birth weight was 2,369 (range 1,430–3,608) g. Prenatal intervention was performed in 39.3% of the patients. Besides, 11 out of the 28 neonates developed tension pneumothorax in the first 24 h and 4 (36.4%) of them died. Sepsis was documented in two patients (7.1%). Overall survival rate was 71.4%. There were five patients enrolled during the last 2 years of the study period. EXIT with intubation was performed in two and octreotide was given to four of these most recent neonates, and all of them survived.Conclusion: Recent advances in the management of these neonates, specifically EXIT with intubation and use of octreotide. Both of them improved patient survival in our cohort, but the evidence of impact has yet to be validated.

966 Progression to nonimmune hydrops fetalis in fetuses with increased nuchal translucency

Risk of progression to nonimmune hydrops fetalis (NIHF) among fetuses with increased nuchal translucency (NT) has not been well described. This limits our ability to accurately counsel about prognosis and implement appropriate surveillance. We aimed to describe the proportion of pregnancies with NT ≥3.5 mm that later develop NIHF, and hypothesized that NIHF would occur in a substantial proportion. We retrospectively included pregnancies with NT ≥3.5 mm from our institution between January 2010 and July 2020, as well as from a national prospective cohort between October 2018 and July 2020. Pregnancies with increased NT but without NIHF at the time of NT measurement were included. Pregnancies with alloimmunization were excluded, as were those terminated in the absence of NIHF because the potential outcome of NIHF could not be determined. NIHF was defined as ≥2 abnormal fetal fluid compartments (pleural or pericardial effusions, ascites, and/or skin edema). The primary outcome was the proportion of pregnancies with NT ≥3.5 mm that progressed to NIHF, and secondary outcomes were the characteristics of pregnancies that progressed. Chi square and Fisher’s exact tests compared proportions. A total of 390 pregnancies had an NT ≥3.5 mm. Of these, 18 already had NIHF at NT ultrasound and 69 pregnancies were terminated in the absence of NIHF; these were excluded. Among 303 pregnancies in the final cohort, NIHF was later diagnosed in 16 (5.3%). Median NT measurement was higher among pregnancies that developed NIHF compared to those that did not (8.0 mm vs 4.3 mm, p<0.001). Risk of NIHF was also higher among those diagnosed with Turner syndrome, a concurrent structural anomaly, and cystic hygroma (Table 1). Among pregnancies with an initial increased NT, risk of later progression to NIHF was 5%. NIHF risk was greater with higher NT measurements, cystic hygroma, Turner syndrome, and a concurrent structural anomaly.

779 The spectrum of lysosomal storage diseases in non-immune hydrops fetalis and potential treatments

We performed a systematic literature review to determine the spectrum of lysosomal storage diseases (LSD) that result in non-immune hydrops fetalis (NIHF) and evaluate the existing therapies available. PubMed and Ovid were reviewed for case series evaluating the workup of NIHF diagnosed in utero or in the neonatal period in human subjects. Search terms were ‘non-immune hydrops,’ ‘non immune hydrops,’ ‘metabolic genetic disorders,’ ‘lysosomal storage disorders,’ ‘inborn errors of metabolism,’ and ‘inherited metabolic diseases.’ The time period searched was 1979 – August 2020. Retrospective case series with at least five cases of fetal and/or neonatal NIHF with reported workup were included. MOOSE guidelines were followed. Twenty-two case series with 2,678 total cases of NIHF were identified. The overall incidence of LSD was 7.2% (194/2,678) in NIHF cases that tested for any LSD. Fifteen different LSD were identified as potential causes of NIHF, with the five most common LSD causes being mucopolysaccharidosis type VII (45/194, 23.2%), galactosialidosis (26/194, 13.4%), infantile sialic acid storage disease (25/194, 12.9%), Gaucher disease (23/194, 11.9%), and GM1-gangliosidosis (22/194,11.3%). Of the fifteen different LSD identified as a cause of NIHF, six have approved postnatal therapies (Table 1) and several have clinical trials investigating potential therapies (Table 2). 43% of LSD identified as causes of NIHF in our review have available approved therapies. Given that 7% of NIHF cases are caused by LSD, and more than 40% of NIHF cases caused by LSD have available therapies, LSD testing should be considered if the standard workup for NIHF is negative.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

940 Frequency of and indications for preterm birth in pregnancies with non-immune hydrops fetalis spectrum disorder

Non-immune hydrops fetalis (NIHF) is associated with poor perinatal outcomes, including preterm birth (PTB). However, the frequency and causes of PTB are not well understood. We hypothesize that PTB is common and frequently iatrogenic in pregnancies complicated by NIHF spectrum. Secondary analysis of a prospective cohort of singleton pregnancies with NIHF spectrum. NIHF spectrum was defined as: isolated nuchal translucency (NT) ≥3.5mm, or 1 or ≥2 effusions (pleural effusion, pericardial effusion, ascites, and/or skin edema). The primary outcome was frequency of PTB (<37 weeks). Secondary outcomes were reasons for PTB (spontaneous, iatrogenic for maternal or fetal indication), PTB by type of effusion(s) and presence of genetic diagnosis. Multivariable logistic regression generated adjusted odds ratios (aOR). Among 152 cases of NIHF spectrum enrolled between 10/2018 and 7/2020, 68 did not result in termination, early spontaneous loss, or stillbirth. Of these, 76% (52/68) delivered preterm at a median gestational age of 33.4 weeks (IQR 30.9-36.5). Among the 52 PTBs, 19 (36.5%) were spontaneous, 9 (17.3%) were iatrogenic due to maternal indications (primarily pre-eclampsia), and 24 (46.2%) were iatrogenic due to fetal indications (primarily non-reassuring antenatal testing or worsening NIHF). PTB occurred in 9.1% (1/11), 77.8% (7/9), and 91.7% (44/48) of isolated enlarged NT, 1 effusion, and ≥2 effusions, respectively (figure). A genetic diagnosis was present in 36.5% of cases with PTB, compared to 18.8% who delivered at term (aOR 2.8, 95% CI 0.4-21.1). Polyhydramnios complicated 50.0% of all PTBs versus only 6.3% of term births (aOR 15.8, 95% CI 1.1-229.8). Pregnancies with 1 or ≥2 effusions frequently result in PTB, most often iatrogenic due to non-reassuring fetal status. Additionally, PTB was observed more frequently in cases with a genetic diagnosis and with polyhydramnios. These data are informative for counseling patients as well as for developing strategies to reduce PTB in this population.

Thrombospondin domain1-related congenital chylothorax in an infant with maple syrup urine disease: a challenging case

Abstract Objectives Congenital chylothorax is a rare entity with various etiologies ranging from anatomical to genetic causes. If associated with non-immune hydrops fetalis mortality rates can reach up to 98%. Treatment is challenging and mostly supportive, with no standard guidelines. Case presentation We describe the unique and challenging course of a late preterm infant with non-immune hydrops fetalis (NIHF), and recurrent chylothorax attributed to homozygous mutations in thrombospondin domain1 (THSD1) gene. The infant was also affected with maple syrup urine disease (MSUD), which further complicated the clinical course. Treatment was supportive by means of chest tubes, intubation, mechanical ventilation, and eventually he was tracheostomized and discharged home on home BiPAP ventilation and required prolonged use of octreotide to prevent re-accumulation of chylothorax. Conclusions THSD1 gene has a role in vascular permeability and its mutation in our patient caused congenital chylothorax and NIHF and is also associated with other features such as vascular malformations.

Frequency and Prognosis of Hydrops Fetalis: A 10-Year Single-Center Experience.

Objective:The study aims to evaluate the etiological distribution and prognosis of newborn infants with hydrops fetalis (HF).Methods:All infants born in our hospital within the past 10 years and hospitalized with the diagnosis of HF were included in this retrospective descriptive study. Demographic characteristics, etiological distributions, treatment interventions, and prognosis information of the infants were recorded retrospectively. Infants with incomplete data were excluded from the study.Results:The mean gestational age of infants with HF was 33.6±3.1 weeks, and the mean birth weight was 2444±792 grams. Of the HF cases, 90.5% were born by cesarean section and the prenatal diagnosis rate was 42.9%. About 57.1% of the infants were intubated during resuscitation at birth in the delivery room. In the NICU, 81% of the cases were intubated and 71.4% received surfactant treatment. The most common HF findings were ascites (81%) and subcutaneous edema (81%). The most common interventional procedures were paracentesis (81%) and thoracentesis (52.4%). Exchange transfusion was performed in 2 cases (9.5%) due to immune HF. The mortality rate in the study group was 52.4%. Considering the etiological distribution of HF cases in the study group, three cases were diagnosed with immune HF (14.3%) and 18 cases with non-immune hydrops fetalis (NIHF) (85.7%). The underlying cause in immune HF cases was rhesus incompatibility. In cases with NIHF, idiopathic (23.8%) and cardiovascular diseases were the most common etiologies. A significant relationship was found between delivery room management and mortality. While the need for intubation in delivery room was significantly higher in non-survivors, the frequency of applying only positive pressure ventilation in the delivery room was significantly higher in survivors. While the rate of survival was 66.7% in immune HF cases, it was 44.4% in NIHF cases.Conclusion:The risk of perinatal mortality in infants with HF is high depending on the underlying cause. In this study, it was determined that HF mostly developed for non-immune reasons, prenatal diagnosis and follow-up were insufficient and the interventions performed in the delivery room were an important factor in predicting mortality in the follow-up of neonates with HF.

Non-immune hydrops fetalis in Saudi family secondary to a rare genetic cause

Background: Non-immune hydrops fetalis (NIHF) is the abnormal accumulation of serous fluid in more than two fetal or neonatal interstitial spaces due to non-immune causes. It is a serious condition that requires extensive medical care as it indicates severe fetal compromise. Severe anemia, infections, heart or lung defects, and liver disease are all possible causes. Less common causes of NIHF include single gene defects and chromosomal abnormalities. Case Presentation: We report a 2-month-old girl born at 32 weeks of gestation and found to have polyhydramnios and massive congenital ascites. Whole exome sequencing (WES) identified a biallelic pathogenic variant c.617G>A p. (Cys206Tyr) in the thrombospondin 1 domain-containing protein 1 (THSD1) gene. She was misdiagnosed to have ascites secondary to liver dysfunction. Conclusion: Rare causes of fetal hydrops like THSD1 mutation need to be excluded in cases of recurrent non-immune hydrops with no obvious etiology.

Meconium peritonitis in trisomy 21 masquerading as hydrops fetalis

Meconium peritonitis (MP) is a rare etiology for nonimmune hydrops fetalis. We report a neonate delivered at 32 weeks' gestation in the context of antenatally diagnosed hydrops fetalis and first-trimester screening at high risk for Trisomy 21. The postnatal abdominal radiograph was striking for gross ascites, the paucity of bowel gas, and widespread calcifications, suggestive of MP and chromosomal analysis confirmed Trisomy 21. Exploratory laparotomy performed on day 3 of life revealed a large pseudocyst, ileal atresia with ileal perforation. MP masquerading as nonimmune hydrops fetalis in Trisomy 21 with ileal atresia is an extremely rare presentation, seldom reported in the literature.

Reversal of Propylthiouracil Induced-Fetal Ascites in Monochorionic Twins

There are various causes in the etiology of fetal ascites and non-immune hydrops fetalis. Pathogenesis of non-immune hydrops fetalis is incompletely understood. The etiology cannot be determined in yet a large part of cases. Here we reported an isolated fetal ascites case in both fetuses, in a monochorionic pregnancy during maternal propylthiouracil (PTU) use. Fetal goiter was detected in both fetuses and after maternal oral tri-iodothyronine treatment, ascites resolved and babies were delivered at 36th week of pregnancy. Anti-thyroid drugs (ATDs) should be used carefully during pregnancy. Fetal hypothyroidism may be associated with fetal hyrdrops. Maternal oral tri-iodothyronine administration may treat fetal hypothyroidism.

Human parvovirus B19: a review of clinical and epidemiological aspects in Brazil.

Since the first evidence of human parvovirus B19 (B19V) infection in late 80s, several studies have been conducted to clarify the spectrum of clinical diseases in Brazil. B19V infection is prevalent in the general population and has exhibited a cyclical pattern of occurrence every 4-5years, with the predominance of genotype 1 over 3b. During epidemic periods the wide range of clinical conditions, such as ertythema infectiosum, arthropathy, transient aplastic crisis, nonimmune hydrops fetalis and B19V-hepatitis were diagnosed. However, many infections are likely asymptomatic or have a self-limiting clinical course and are not readly diagnosed. Besides, the similarity of the symptoms of ertythema infectiosum to other rash diseases and the broadly circulation of arboviruses makes differential diagnosis more difficult. In this article, we provide a historical comprehensive overview of the research on parvovirus B19 conducted in Brazil, with a focus on the clinical and epidemiological aspects of the infection.