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Pediatrics and Neonatology Apr 2014We aimed to define the etiologic and prognostic factors in live-born infants with hydrops fetalis (HF) in our tertiary neonatal intensive care unit over a 10-year period.
AIM
We aimed to define the etiologic and prognostic factors in live-born infants with hydrops fetalis (HF) in our tertiary neonatal intensive care unit over a 10-year period.
METHODS
Medical records of newborn infants with HF during 2002-2011 were reviewed retrospectively. Demographic data, prenatal interventions, clinical and laboratory findings, outcomes, and the results of postmortem examinations were analyzed.
RESULTS
During the study period, 62 newborn infants with HF were identified from 16,200 live-born deliveries and the incidence of HF was 3.8/1000 live births in our hospital. Twenty-eight infants (45.2%) had immune HF, whereas 34 (54.8%) had nonimmune HF. An etiologic factor could be identified in 24 (70.5%) infants with nonimmune HF. Lymphatic dysplasias comprised the majority (23.5%) of the infants with nonimmune HF. Mortality rate was 50%. The presence of two or more serous cavity effusions and gestational age were independently associated with the risk of mortality.
CONCLUSION
Despite the improvements in neonatal care, mortality rate in infants with HF is still high. Gestational age and the extent of serous cavity determine the risk of mortality. Timely and advanced prenatal or postnatal new therapeutic strategies may alter this fatal outcome in appropriate patients.
Topics: Female; Gestational Age; Humans; Hydrops Fetalis; Infant, Newborn; Male; Retrospective Studies
PubMed: 24094760
DOI: 10.1016/j.pedneo.2013.07.008 -
Journal of Medical Genetics Jan 2023Hydrops fetalis, a pathological fluid accumulation in two or more body compartments, is aetiologically heterogeneous. We investigated a consanguineous family with...
BACKGROUND
Hydrops fetalis, a pathological fluid accumulation in two or more body compartments, is aetiologically heterogeneous. We investigated a consanguineous family with recurrent pregnancy loss due to severe early-onset non-immune hydrops fetalis.
METHODS AND RESULTS
Whole exome sequencing in four fetuses with hydrops fetalis revealed that they were homozygous for the angiopoietin-2 () variant Chr8 (GRCh37/Hg19): 6385085T>C, NM_001147.2:c.557A>G. The substitution introduces a cryptic, exonic splice site predicted to result in loss of 10 nucleotides with subsequent shift in reading frame, leading to a premature stop codon. RNA analysis in the heterozygous parents demonstrated loss of detectable mutant allele, indicative of loss-of-function via nonsense-mediated mRNA decay. Serum ANGPT2 levels were reduced in the parents. In a pregnancy with a healthy, heterozygous child, transiently increased fetal nuchal translucency was noted.
CONCLUSION
Pathogenic heterozygous missense variants were recently shown to cause autosomal dominant primary lymphoedema. is a ligand of the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and 2) pathway. It is critical to the formation and remodelling of blood and lymphatic vessels and is involved in vessel maintenance. ANGPT2 knockout mice die from generalised lymphatic dysfunction. We show here that a homozygous pathogenic variant causes loss-of-function and results in severe early-onset hydrops fetalis. This is the first report of an autosomal recessive -related disorder in humans.
Topics: Animals; Female; Humans; Mice; Pregnancy; Angiopoietin-2; Codon, Nonsense; Heterozygote; Hydrops Fetalis; Mutation, Missense; Infant, Newborn
PubMed: 34876502
DOI: 10.1136/jmedgenet-2021-108179 -
American Journal of Obstetrics and... Jan 2022Next-generation sequencing is increasingly used in prenatal diagnosis. Targeted gene panels and exome sequencing are both available, but the comparative diagnostic...
BACKGROUND
Next-generation sequencing is increasingly used in prenatal diagnosis. Targeted gene panels and exome sequencing are both available, but the comparative diagnostic yields of these approaches are not known.
OBJECTIVE
We compared the diagnostic yield of exome sequencing with the simulated application of commercial targeted gene panels in a large cohort of fetuses with nonimmune hydrops fetalis.
STUDY DESIGN
This was a secondary analysis of a cohort study of exome sequencing for nonimmune hydrops fetalis, in which recruitment, exome sequencing, and phenotype-driven variant analysis were completed in 127 pregnancies with features of nonimmune hydrops fetalis. An Internet search was performed to identify commercial laboratories that offer targeted gene panels for the prenatal evaluation of nonimmune hydrops fetalis or for specific disorders associated with nonimmune hydrops fetalis using the terms "non-immune hydrops fetalis," "fetal non-immune hydrops," "hydrops," "cystic hygroma," "lysosomal storage disease," "metabolic disorder," "inborn error of metabolism," "RASopathy," and "Noonan." Our primary outcome was the proportion of all genetic variants identified through exome sequencing that would have been identified if a targeted gene panel had instead been used. The secondary outcomes were the proportion of genetic variants that would have been identified by type of targeted gene panel (general nonimmune hydrops fetalis, RASopathy, or metabolic) and the percent of variants of uncertain significance that would have been identified on the panels, assuming 100% analytical sensitivity and specificity of panels for variants in the included genes.
RESULTS
Exome sequencing identified a pathogenic or likely pathogenic variant in 37 of 127 cases (29%) in a total of 29 genes. A variant of uncertain significance, strongly suspected to be associated with the phenotype, was identified in another 12 cases (9%). We identified 7 laboratories that offer 10 relevant targeted gene panels; 6 are described as RASopathy panels, 3 as nonimmune hydrops fetalis panels, and 1 as a metabolic panel. The median number of genes included on each of these panels is 22, ranging from 11 to 148. Had a nonimmune hydrops fetalis targeted gene panel been used instead of exome sequencing, 13 to 15 of the 29 genes (45%-52%) identified in our nonimmune hydrops fetalis cohort would have been sequenced, and 19 to 24 of the pathogenic variants (51%-62%) would have been detected. The yield was predicted to be the lowest with the metabolic panel (11%) and the highest with the largest nonimmune hydrops fetalis panel (62%). The largest nonimmune hydrops fetalis targeted gene panel would have had a diagnostic yield of 18% compared with 29% with exome sequencing. The exome sequencing platform used provided 30× or more coverage for all of the exons on the commercial targeted gene panels, supporting our assumption of 100% analytical sensitivity for exome sequencing.
CONCLUSION
The broader coverage of exome sequencing for genetically heterogeneous disorders, such as nonimmune hydrops fetalis, made it a superior alternative to targeted gene panel testing.
Topics: Adult; Cohort Studies; Female; Gestational Age; High-Throughput Nucleotide Sequencing; Humans; Hydrops Fetalis; Predictive Value of Tests; Pregnancy; Prenatal Diagnosis; Exome Sequencing
PubMed: 34331894
DOI: 10.1016/j.ajog.2021.07.014 -
Ultrasound in Obstetrics & Gynecology :... Jan 2012To assess the use and efficacy of in-utero pleurodesis for experimental treatment of bilateral fetal chylothorax. (Review)
Review
OBJECTIVE
To assess the use and efficacy of in-utero pleurodesis for experimental treatment of bilateral fetal chylothorax.
METHODS
This was a study of 78 fetuses with bilateral pleural effusion referred to three tertiary referral centers in Taiwan between 2005 and 2009. Fetuses were karyotyped following amniocentesis and the lymphocyte ratio in the pleural effusion was determined following thoracocentesis. Forty-nine (62.8%) fetuses had a normal karyotype and were recognized to have fetal chylothorax; of these, 45 underwent intrapleural injection of 0.1KE OK-432 per side per treatment. We evaluated clinical (hydrops vs. no hydrops) and genetic (mutations in the reported lymphedema-associated loci: VEGFR3, PTPN11, FOXC2, ITGA9) parameters, as well as treatment outcome. Long-term survival was defined as survival to 1 year of age.
RESULTS
The overall long-term survival rate (LSR) was 35.6% (16/45); the LSR for non-hydropic fetuses was 66.7% (12/18) and for hydropic fetuses it was 14.8% (4/27). If we included only fetuses with onset of the condition in the second trimester, excluding those with onset in the third trimester, the LSR decreased to 29.4% (10/34). Notably, 29.6% (8/27) of hydropic fetuses had mutations in three of the four loci examined.
CONCLUSIONS
OK-432 pleurodesis appeared to be an experimental alternative to the gold-standard technique of thoracoamniotic shunting in non-hydropic fetal chylothorax. In hydropic fetuses, pleurodesis appeared less effective.
Topics: Amniocentesis; Chylothorax; Female; Fetal Diseases; Humans; Hydrops Fetalis; Karyotyping; Picibanil; Pleural Effusion; Pleurodesis; Pregnancy; Prognosis; Survival Rate; Taiwan; Ultrasonography, Prenatal
PubMed: 21584887
DOI: 10.1002/uog.9048 -
Genetics in Medicine : Official Journal... Jul 2021Nonimmune hydrops fetalis (NIHF) presents as life-threatening fluid collections in multiple fetal compartments and can be caused by both genetic and non-genetic...
PURPOSE
Nonimmune hydrops fetalis (NIHF) presents as life-threatening fluid collections in multiple fetal compartments and can be caused by both genetic and non-genetic etiologies. We explored incremental diagnostic yield of testing with prenatal exome sequencing (ES) for NIHF following a negative standard NIHF workup.
METHODS
Participants enrolled into the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) study met a strict definition of NIHF and had negative standard-of-care workup. Clinical trio ES from fetal samples and parental blood was performed at a CLIA-certified reference laboratory with clinical reports returned by geneticists and genetic counselors. Negative exomes were reanalyzed with information from subsequent ultrasounds and records.
RESULTS
Twenty-two fetal exomes reported 11 (50%) diagnostic results and five possible diagnoses (22.7%). Diagnosed cases comprised seven de novodominant disorders, three recessive disorders, and one inherited dominant disorder including four Noonan syndromes (PTPN11, RAF1, RIT1, and RRAS2), three musculoskeletal disorders (RYR1, AMER1, and BICD2), two metabolic disorders (sialidosis and multiple sulfatase deficiency), one Kabuki syndrome, and one congenital anemia (KLF1).
CONCLUSION
The etiology of NIHF predicts postnatal prognosis and recurrence risk in future pregnancies. ES provides high incremental diagnostic yield for NIHF after standard-of-care testing and should be considered in the workup.
Topics: Exome; Female; Fetus; Humans; Hydrops Fetalis; Pregnancy; Prenatal Care; Prenatal Diagnosis; Exome Sequencing
PubMed: 33686258
DOI: 10.1038/s41436-021-01121-0 -
Ultrasound in Obstetrics & Gynecology :... Sep 2020Fetal hydrops is associated with increased perinatal morbidity and mortality. The etiology and outcome of fetal hydrops may differ according to the gestational age at...
OBJECTIVE
Fetal hydrops is associated with increased perinatal morbidity and mortality. The etiology and outcome of fetal hydrops may differ according to the gestational age at diagnosis. The aim of this study was to evaluate the cause, evolution and outcome of non-immune fetal hydrops (NIFH), according to the gestational age at diagnosis.
METHODS
This was a retrospective cohort study of all singleton pregnancies complicated by NIFH, at the Fetal Medicine Unit at St George's University Hospital, London, UK, between 2000 and 2018. All fetuses had detailed anomaly and cardiac ultrasound scans, karyotyping and infection screening. Prenatal diagnostic and therapeutic intervention, gestational age at diagnosis and delivery, as well as pregnancy outcome, were recorded. Regression analysis was used to test for potential association between possible risk factors and perinatal mortality.
RESULTS
We included 273 fetuses with NIFH. The etiology of the condition varied significantly in the three trimesters. Excluding 30 women who declined invasive testing, the cause of NIFH was defined as unknown in 62 of the remaining 243 cases (25.5%). Chromosomal aneuploidy was the most common cause of NIFH in the first trimester. It continued to be a significant etiologic factor in the second trimester, along with congenital infection. In the third trimester, the most common etiology was cardiovascular abnormality. Among the 152 (55.7%) women continuing the pregnancy, 48 (31.6%) underwent fetal intervention, including the insertion of pleuroamniotic shunts, fetal blood transfusion and thoracentesis. Fetal intervention was associated significantly with lower perinatal mortality (odds ratio (OR), 0.30 (95% CI, 0.14-0.61); P < 0.001); this association remained significant after excluding cases with a diagnosis of anemia or infection (OR, 0.29 (95% CI, 0.13-0.66); P = 0.003). In 104 fetuses not undergoing active fetal intervention, the gestational age at diagnosis was the only parameter that was significantly associated with the risk of perinatal mortality (OR, 0.92 (95% CI, 0.85-0.99); P = 0.035), while the affected body cavity and polyhydramnios were not (P > 0.05).
CONCLUSIONS
An earlier gestational age at diagnosis of NIFH was associated with an increased risk of aneuploidy and worse pregnancy outcome, including a higher risk of perinatal loss. Fetal therapy was associated significantly with lower perinatal mortality. © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Adult; England; Female; Gestational Age; Humans; Hydrops Fetalis; Pregnancy; Pregnancy Outcome; Pregnancy Trimesters; Prenatal Diagnosis; Regression Analysis; Risk Factors; Young Adult
PubMed: 32196790
DOI: 10.1002/uog.22019 -
Blood Mar 2017Hemoglobin (Hb) Bart's hydrops fetalis syndrome (BHFS) resulting from α-thalassemia is considered a universally fatal disorder. However, over the last 3 decades,... (Review)
Review
Hemoglobin (Hb) Bart's hydrops fetalis syndrome (BHFS) resulting from α-thalassemia is considered a universally fatal disorder. However, over the last 3 decades, improvements in intrauterine interventions and perinatal intensive care have resulted in increasing numbers of BHFS survivors. We have initiated an international registry containing information on 69 patients, of which 31 are previously unpublished. In this perspective, we analyze the available clinical information to document the natural history of BHFS. In the future, once we have accrued sufficient cases, we aim to build on this study and provide information to allow counseling of at-risk couples. To date, 39 patients have survived beyond the age of 5 years, 18 of whom are now older than 10 years. Based on the available cases, we find evidence to suggest that intrauterine therapy provides benefits during the perinatal and neonatal period; however, it may not provide additional benefits to long-term growth and neurodevelopmental outcomes. Growth retardation is a major adverse long-term outcome among BHFS patients with ∼40% being severely affected in terms of weight and ∼50% in terms of height. There is also an increased risk of neurodevelopmental delay as we find 20% (11/55) of BHFS survivors suffer from a serious delay of ≥6 months. Most patients in the registry require lifelong transfusion and often have associated congenital abnormalities and comorbidities. This perspective is a first step in gathering information to allow provision of informed counseling on the predicted outcomes of affected babies.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Hemoglobins, Abnormal; Humans; Hydrops Fetalis; Infant; Infant, Newborn; Male; Registries; Survivors; Young Adult; alpha-Thalassemia
PubMed: 28057638
DOI: 10.1182/blood-2016-08-697110 -
Molecular Genetics & Genomic Medicine Jan 2024Acid ceramidase (ACDase) deficiency is an ultrarare autosomal recessive lysosomal disorder caused by pathogenic N-acylsphingosine amidohydrolase (ASAH1) variants. It...
BACKGROUND
Acid ceramidase (ACDase) deficiency is an ultrarare autosomal recessive lysosomal disorder caused by pathogenic N-acylsphingosine amidohydrolase (ASAH1) variants. It presents with either Farber disease (FD) or spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME).
OBJECTIVE
The study aims to identify a novel splice site variant in a hydrops fetus that causes ASAH1-related disorder, aid genetic counseling, and accurate prenatal diagnosis.
METHODS
We report a case of hydrops fetalis with a novel homozygous mutation in ASAH1 inherited from non-consanguineous parents. We performed copy number variation sequencing (CNV-Seq) and whole exome sequencing (WES) on the fetus and family, respectively. Minigene splicing analyses were conducted to confirm the pathogenic variants.
RESULTS
WES data revealed a splice site variant of the ASAH1 (c.458-2A>T), which was predicted to affect RNA splicing. Minigene splicing analyses found that the c.458-2A>T variant abolished the canonical splicing of intron 6, thereby activating two cryptic splicing products (c.456_458ins56bp and c.458_503del).
CONCLUSIONS
Overall, we identified a novel splice site variant in the mutational spectrum of ASAH1 and its aberrant effect on splicing. These findings highlight the importance of ultrasonic manifestation and family history of fetal hydrops during ASAH1-related disorders and could also aid genetic counseling and accurate prenatal diagnosis. To the best of our knowledge, this is the shortest-lived account of ASAH1-related disorders in utero with severe hydrops fetalis.
Topics: Female; Pregnancy; Humans; Muscular Atrophy, Spinal; DNA Copy Number Variations; Hydrops Fetalis; Mutation; Introns; Acid Ceramidase
PubMed: 37962265
DOI: 10.1002/mgg3.2317 -
Journal of Cardiothoracic Surgery Oct 2022Congenital chylothorax (CC) is an uncommon congenital disease. The objective of this study was to analyze the clinical features, treatment, and outcome of infants with...
OBJECTIVE
Congenital chylothorax (CC) is an uncommon congenital disease. The objective of this study was to analyze the clinical features, treatment, and outcome of infants with CC in a Chinese tertiary medical center.
METHODS
CC was defined as a non-traumatic pleural effusion with ≥ 80% lymphocytes detected before birth or within 28 days after birth. Clinical data were collected in CC infants discharged from June 2017 to March 2021.
RESULTS
A total of 24 CC infants were discharged during the study period, accounting for 67% of congenital pleural effusions. The median gestational age at birth was 36 weeks (range 29-41 weeks) and the birth weight was 3025 g (range 1850-4250 g). Twenty-one infants were diagnosed antenatally. The median gestational age at the time of diagnosis was 30 weeks (range 24-36 weeks). Nine infants presented with hydrops fetalis; 18 were bilateral. Prenatal interventions were performed in 13 fetuses. Nine infants (38%) had birth asphyxia. Compared with the infants without hydrops fetalis, the infants with CC and hydrops fetalis had lower Apgar scores at 1 and 5 min (P < 0.05) and a lower gestational age at birth (P < 0.05). Postnatally, 17 infants required continuous pleural drainage for 10 days (range 2-30 days). Analysis of the pleural effusion showed a higher cell count, lymphocyte fraction, and protein content after enteral feeding (P < 0.05). Fifteen infants required mechanical ventilation; 9 did not require any respiratory support. Ten infants received a delayed feeding strategy and 17 received a medium-chain triglyceride (MCT) formula. Only 1 infant received octreotide therapy. Twenty-one infants survived and 3 died. The main cause of death was pulmonary dysplasia. The duration of hospital stay in survivors was 21.5 days (range 10-43) days. For infants with CC and hydrops fetalis, prenatal therapy shortened the duration of pleural drainage and the length of hospital stay (P < 0.05).
CONCLUSION
CC is the most common cause of congenital pleural effusions. The poor prognosis is mainly associated with prematurity, hydrops fetalis, and pulmonary dysplasia. Prenatal intervention may improve the outcome of infants with hydrops fetalis.
Topics: Infant, Newborn; Infant; Pregnancy; Female; Humans; Chylothorax; Hydrops Fetalis; Pleural Effusion; China
PubMed: 36303149
DOI: 10.1186/s13019-022-02009-z -
BMC Pregnancy and Childbirth Sep 2021Mirror syndrome (MS) is a rare obstetric disorder complicated with high maternal morbidity and fetal mortality. MS is often misdiagnosed or underdiagnosed due to the low...
BACKGROUND
Mirror syndrome (MS) is a rare obstetric disorder complicated with high maternal morbidity and fetal mortality. MS is often misdiagnosed or underdiagnosed due to the low incidence and lack of awareness of its diverse features. This study aimed to summarise the etiology, clinical characteristics, and risk factors of MS among mothers with fetal hydrops.
METHODS
This retrospective case-control study included 37 pregnant women with fetal hydrops in the second and third trimesters from 58,428 deliveries performed at the Third Affiliated Hospital of Sun Yat-Sen University between January 2012 and December 2020. Cases were categorized as MS and non-MS according to the presence or absence of maternal mirroring symptoms. Binary logistic regression was performed for analysis.
RESULTS
Fourteen women developed MS with an overall incidence of 0.024% (14/58,428) and 37.8% (14/37) in the fetal hydrops cases. Among the 11 MS cases with known associated etiologies, seven had alpha thalassemia major. Onset of fetal hydrops was later (27.8 vs. 23.0 weeks) and the rate of placental thickening was higher (85.7% vs. 34.8%) in the MS group than in the non-MS group (P < 0.05). Regarding maternal characteristics, the MS group had higher maternal morbidity (85.7% vs. 8.7%), more weight gain (9.0 vs. 5.5 kg), higher rates of hypertension (35.7 vs. 0%) and proteinuria (64.3% vs. 4.3%), and lower levels of hemoglobin (88 vs. 105 g/L) and serum albumin (25.8 vs. 35.0 g/L) than the non-MS group (P < 0.05). Logistic regression analysis showed that onset of fetal hydrops at ≥24 weeks and placental thickening were associated with the risk of MS among fetal hydrops cases (OR 15.83, 95% CI 1.56-160.10 and OR 8.63, 95% CI 1.29-57.72, respectively).
CONCLUSIONS
MS is relatively common among fetal hydrops cases in the late second and third trimesters, and alpha thalassemia major is the main etiology for fetal hydrops and also MS in this population. Complicated with high maternal morbidity, the key maternal features of MS include more weight gain, hemodilution, and hypertension. Among those with fetal hydrops, the onset time of ≥24 weeks and placental thickening are risk factors for MS.
Topics: Case-Control Studies; China; Edema; Female; Hemodilution; Humans; Hydrops Fetalis; Hypertension; Placenta Diseases; Pregnancy; Pregnancy Complications; Prognosis; Retrospective Studies; Risk Factors; Syndrome; Weight Gain; alpha-Thalassemia
PubMed: 34583666
DOI: 10.1186/s12884-021-04143-3