Hydrops fetalis caused by a complex congenital heart defect with concurrent hypoplasia of pulmonary blood vessels and lungs visualized by micro-CT in a French Bulldog.

BACKGROUND: Hydrops fetalis (HF) is fluid accumulation in fetus body cavities and subcutaneous tissue. The condition has been described in various farm and companion animal species, including dogs. Most of cases result from a heart defect. Exact nature of this defect is rarely clarified. CASE PRESENTATION: A newborn, male French bulldog puppy with severe HF underwent a full anatomopathological examination to diagnose the primary cause of HF. Based on the anatomopathological examination, fetal ultrasound, and micro-computed tomography, transposition of the great arteries with hypoplasia of the ascending aorta, aortic arch interruption, ostium secundum atrial septal defect, severe tricuspid valve dysplasia, as well as hypoplasia of pulmonary vessels and lungs were diagnosed. CONCLUSIONS: This is the first report of HF caused by severe, complex congenital heart defects with concurrent pulmonary vessel and lung hypoplasia.

Novel premature termination codon in the FOXP3 gene as the cause of familial hydrops fetalis in males.

A 19-year-old, G1P0, pregnant person was referred at 20w2d gestation for evaluation due to non-immune hydrops fetalis (NIHF), which was confirmed at the time of evaluation. Amniocentesis was performed at 20 w4d, and FISH, karyotype, chromosomal microarray, and exome sequencing (ES) were ordered. Trio ES identified a novel hemizygous c.142 C > T (p.Arg48*; maternally inherited) variant in the FOXP3 gene, resulting in a premature termination codon and establishing the diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Intrauterine fetal demise (IUFD) was diagnosed at 21w3d. CVS was performed at 12w1d in a subsequent pregnancy (male fetus) and the known familial variant was identified. NIHF was identified at 18w1d. Ultrasound at 19w2d revealed IUFD. This is the first report of this variant in a diagnosis of IPEX syndrome, presenting with NIHF and male fetal demise. Genotype-phenotype correlations are not available in many cases of IPEX syndrome, as the same genotype can be present with variable severity in different individuals. Given the near identical presentations in this family, we anticipate a more severe phenotype with this variant. We propose a novel variant resulting in an early premature termination codon as an explanation for the severe presentation of IPEX syndrome in two successive fetuses in this family.

Biallelic truncating TTN variants in M-band encoding exons cause a fetal lethal titinopathy.

To report two novel TTN variants associated with fetal recessive titinopathy, thereby broadening the range of TTN variants that can lead to titinopathy. Clinical information on the fetus and parents was gathered, and genomic DNAs were extracted from the fetal tissue and family members' peripheral blood samples. Exome sequencing on fetal DNA was performed and following bioinformatics analysis, the suspected pathogenic variants were confirmed through Sanger sequencing. Prenatal ultrasound performed at 29 weeks of gestation revealed hydrops fetalis, decreased fetal movements, multiple joint contractures and polyhydramnios. Intrauterine fetal death was noted in the third trimester. Exome sequencing revealed compound heterozygous variants in the TTN gene: a paternally inherited allele c.101227C>T (p.Arg33743Ter) and a maternally inherited c.104254C>T (p.Gln34752Ter) allele. These variants have not been previously reported and are evaluated to be likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. We report a fetus with hydrops fetalis and arthrogryposis multiplex congenita associated with a compound heterozygote in the TTN gene. Our report broadens the clinical and genetic spectrum associated with the TTN-related conditions.

SAM domain variants of EPHB4 associated with aberrant signaling are linked to lymphatic-related fetal hydrops and facial dysmorphology.

Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation-Arteriovenous Malformation syndrome 2 and lymphatic-related (non-immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine-kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development.

Multidisciplinary management of a large microcystic congenital pulmonary airway malformation: case report and literature review.

INTRODUCTION: Congenital pulmonary airway malformations (CPAMs) are rare sporadic lesions frequently associated with poor fetal prognosis. Type 3 CPAMs are characterized by small hyperechogenic cysts (<5 mm). Hydrops often develops secondarily, and the fetal survival rate is approximately 5% in this setting. CASE PRESENTATION: We present a case of a large type 3 CPAM complicated by fetal hydrops. The lesion was detected at 19 gestational weeks (GW) and confirmed by fetal MRI at 29 GW. At 22 GW, a course of maternal steroids was given as a possible treatment of type 3 CPAM. Peritoneal-amniotic shunt was placed twice to reduce fetal ascites, with unsatisfactory results. Similarly, polyhydramnios was relieved by two amnioreductions, but redeveloped soon after. A baby girl was delivered spontaneously at 33 GW and received a two-stage partial lobectomy in the first three months of life. Desaturations necessitated challenging invasive oscillatory ventilation between stages. Her outcome is unexpectedly positive and she may expect a good quality of life. She now approaches one year of age, with near-to-normal growth and developmental milestones. DISCUSSION: Type 3 CPAMs complicated by fetal hydrops are associated with high perinatal mortality. While open fetal surgery remains a viable option in select specialist centers, antenatal interventions are typically ineffective. The survival of this infant can be attributed to prenatal management and early postnatal surgical intervention. The lack of guidelines for ventilation in this setting was a significant challenge for neonatal intensivists. Multidisciplinary vigilance and collaboration with frequent specialist follow ups were the key to success for both mother and child.

Ten years' experience in prenatal diagnosis of α-thalassemia in a municipal hospital and retrospective analysis of ultrasonic abnormalities.

OBJECTIVE: This study reviewed and analyzed the prenatal diagnosis experience of thalassemia in our center over the past decade and the abnormal ultrasonic characteristics of fetuses with hemoglobin (Hb) Bart's hydrops fetalis. METHODS: Pregnant women and their partners who tested positive for α0-thalassemia or were diagnosed with thalassemia intermedia (HbH diseases) underwent genetic counseling, and a prenatal diagnostic procedure for α-thalassemia was recommended. Ultrasonography was performed before prenatal diagnosis. RESULTS: Invasive prenatal α-thalassemia diagnosis and ultrasonography were performed in 1049 patients at risk for Hb Bart's hydrops fetalis syndrome at our hospital from 2012 to 2021. Chorionic villus sampling (CVS) was performed in 58 cases (5.5%), amniocentesis in 902 cases (86%), and cordocentesis in 89 cases (8.5%). Hb Bart's hydrops fetalis syndrome was diagnosed in 280 fetuses. The most common body cavity effusion was pericardial effusion, ascites, and fetal systemic edema. CONCLUSIONS: The extensive experience at our center shows that carrier screening, molecular diagnostics, genetic counseling, and prenatal diagnosis are effective measures to prevent Hb Bart's hydrops fetalis syndrome. The ultrasonographic abnormalities in fetuses with Hb Bart's hydrops are mainly caused by an increase in cardiac output, which leads to the body cavity effusion from various organs.

First-trimester septated cystic hygroma, marked non-immune fetal hydrops, 45,X and coarctation of the aorta with neonatal survival.

Marked first-trimester nonimmue hydrops fetalis and 45,X with neonatal survival.

Isolated non-immune hydrops fetalis: an observational study on complete spontaneous resolution, perinatal outcome, and long-term follow-up.

PURPOSE: The aim of our study was to investigate spontaneous resolution and postnatal outcome in non-immune hydrops fetalis (NIHF). We specifically studied NIHF cases that occurred without any other anomalies in the prenatal diagnostic workup, defined as isolated NIHF (iNIHF). METHODS: To identify iNIHF we retrospectively classified prenatal findings of 700 NIHF singletons, diagnosed in our prenatal referral center between 1997 and 2016. We studied the occurrence of prenatal resolution in iNIHF and linked it to the perinatal outcome. We obtained long-term outcome by contacting the parents, children, and the pediatricians and listed all functional and structural anomalies and temporary logopedic, psychosocial and motoric impairments. RESULTS: Among 70 iNIHF cases, 54 (77.1%) resolved completely prenatally. The baby-take-home rate was 98.1% in these cases. In contrast, the baby-take-home rate in the subgroup without complete resolution was 25.0%. We achieved pediatric long-term outcome in 27 of 57 survivors (47.4%) of iNIHF with a mean follow-up period of 10.9 years. Among these 27 children, fetal hydrops had completely resolved prenatally in 26 cases and had regressed to a mild effusion in one case. In the pediatric development, two children had significant functional impairment and two children showed recurrent skin edema. CONCLUSION: Complete spontaneous resolution was the most common intrauterine course of iNIHF in our collective. Completely resolved iNIHF had a favorable perinatal outcome in our study. Our data on the long-term outcomes are consistent with the assumption of an increased rate of functional impairments. TRIAL REGISTRY: Internal study number of Heinrich-Heine-University, Duesseldorf: 6177R. Date of registration: December 2017.

Intrauterine transfusion of a hydropic fetus with anemia due to a giant chorioangioma: A case report.

Giant chorioangiomas are a potentially life-threatening condition that may require intrauterine therapy. We describe a case of a large chorioangioma (>4cm) diagnosed at 30 weeks of gestation causing severe fetal anemia and hydrops. An intrauterine blood transfusion was performed at 31 weeks with reversal of the anemia and hydrops. The neonate was born at 37 weeks showing respiratory distress syndrome that required neonatal intensive care unit admission but was discharged at 30 days of life. Further evaluation at two months of age showed no signs of abnormal neurodevelopment. When timely indicated, intrauterine transfusion of a hydropic fetus with anemia due to a giant chorioangioma is a potentially life-saving therapy that shows good neurodevelopment of the surviving fetus.

[Prenatal diagnosis and prognostic factors analysis of fetal sacrococcygeal teratoma].

Objective: To investigate the prenatal diagnosis and prognostic factors of fetal sacrococcygeal teratoma (SCT). Methods: A retrospective analysis was performed on 41 pregnant women who were diagnosed with fetal SCT by prenatal ultrasound at the Women's Hospital, Zhejiang University School of Medicine from January 2014 to September 2021. The prenatal imaging features and pregnancy outcomes, including tumor volume to fetal weight ratio (TFR), proportion of solid tumor, tumor growth rate (TGR), fetal hydrops, placentomegaly and polyhydramnios were analyzed. Receiver operating characteristic (ROC) curve was used to determine the critical values of TFR and TGR for predicting adverse fetal outcomes. Results: (1) Among the 41 pregnant women with fetal SCT, the diagnostic gestational week of ultrasound was (24.2±2.9) weeks (range: 18-28 weeks). Among them, 1 case progressed to fetal hydrops and induced labor at 22 weeks of gestation, 1 case developed intrauterine death and induced labor at 29 weeks of gestation, and 39 pregnancies continued until delivery. Among the 39 cases of continued pregnancy, 1 case underwent cesarean section at 31 weeks of gestation due to malignant polyhydramnios and increased fetal cardiothoracic ratio in the third trimester, 1 case underwent cesarean section at 32 weeks of gestation due to fetal heart failure, and 1 case underwent cesarean section at 32 weeks of gestation due to fetal heart failure and hydrops. The other 36 cases underwent surgical resection of tumor within 3 weeks after birth with good prognosis. (2) TFR>0.12 before 28 weeks of gestation could predict poor fetal prognosis, with a sensitivity of 100.0%, a specificity of 86.1% and an area under curve (AUC) of 0.922 (P<0.01). Among the fetuses with TFR>0.12, 5/10 had poor prognosis, while the fetuses with TFR≤0.12 all had good prognosis (100%,31/31), and the difference between the two groups was statistically significant (P<0.001). (3) TGR>48 cm3/week could predict poor fetal prognosis with a sensitivity of 100.0%, a specificity of 78.3% and an AUC of 0.880 (P<0.05). (4) Among the 28 SCT fetuses delivered in our hospital, the incidence rate of poor fetal prognosis was 0 (0/20) in those with solid tumor component<50%, and 5/8 in those with solid tumor component ≥50%, and the difference between the two groups was statistically significant (P<0.01). The incidence rate of poor fetal prognosis was 2/2 in those with placentomegaly (all with fetal hydrops), and 12% (3/26) in those without placentomegaly. The risk of poor fetal prognosis was 8.67 times higher in those with placentomegaly than those without placentomegaly, and the difference between the two groups was statistically significant (P<0.05). The incidence rate of poor fetal prognosis in those with polyhydramnios was 3/7, and 10% (2/21) in those without polyhydramnios, but there was no statistically significant difference between the two groups (P>0.05). Conclusion: TFR combined with solid tumor morphology, TGR, and presence of placentomegaly could predict the adverse pregnancy outcomes of fetal SCT.

Treatment of Severe Fetal Ebstein's Anomaly with Prenatal Nonsteroidal Anti-Inflammatory Therapy.

INTRODUCTION: Prenatally diagnosed Ebstein's anomaly with tricuspid valve dysplasia (EA/TVD) is a rare and high-risk congenital heart malformation with limited effective treatments. We report a case of severe fetal EA with hydrops treated with modest doses of nonsteroidal anti-inflammatory drug (NSAID) therapy, resulting in reversal of hydrops and a favorable fetal outcome. CASE PRESENTATION: Fetal heart defects included an inferiorly displaced tricuspid valve, severe tricuspid regurgitation, significantly dilated right atrium, and hypoplastic pulmonary valve with moderate regurgitation resulting in a circular shunt across the ductus arteriosus. Maternal indomethacin therapy was initiated at 31+5 weeks gestation due to the development of fetal hydrops as demonstrated by the presence of a pericardial effusion and ascites. Indomethacin therapy resulted in the desired restriction of the ductus arteriosus and resolution of fetal hydrops. Maternal therapy was transitioned to ibuprofen and serial fetal echocardiograms ensured continued ductal restriction. Delivery occurred via cesarean at 36+3 weeks. The neonate did not require immediate cardiac surgical intervention and was discharged home with close follow-up. DISCUSSION/CONCLUSION: A lower dose of prenatal NSAID therapy effected successful ductal restriction and hemodynamic mitigation of the circular shunt, resulting in reversal of hydrops and avoidance of postnatal cardiac surgical intervention.

Innovative Fetal Therapy for a Giant Congenital Pulmonary Airway Malformation with Hydrops.

INTRODUCTION: Congenital pulmonary airway malformations (CPAMs) complicated by hydrops portend significant morbidity and mortality, with fetal survival estimates less than 10%. CASE PRESENTATION: We report successful use of ultrasound-guided radiofrequency ablation at 21-week gestation in a hydropic fetus with CPAM, with subsequent resolution of hydrops. Thirty-two-week MRI noted persistent mediastinal shift, and US at 36 weeks and 5 days noted polyhydramnios. Maternal gestational hypertension prompted delivery at 37 weeks, with a cesarean section performed after a failed trial of labor. The infant required CPAP at 100% and weaned to 21%. Tachypnea persisted, and chest CT on day of life 2 demonstrated multiple large cysts in the right lower lobe with anterior pneumothorax. On day of life 3, she successfully underwent a thoracoscopic right lower lobectomy. Adhesions to the chest wall and rib abnormalities were noted. She was extubated to CPAP at the conclusion of the procedure. She was able to wean to 21% on POD2 and transitioned to oral feeds. Her chest tube was removed with resultant ex vacuo pneumothorax noted. She remained asymptomatic and was discharged home on room air POD11. Pathology confirmed a type 1 CPAM. CONCLUSION: In utero radiofrequency ablation may be an adjunct to the management of large CPAM.

20 years review of antenatal diagnosis of haemoglobin Bart's disease and treatment with intrauterine transfusion.

OBJECTIVE: To review prenatal diagnosis and outcome of alpha thalassaemia major through universal antenatal screening. METHOD: This was a retrospective study on ultrasound features, antenatal diagnosis, in-utero intervention and long term outcome of pregnancies at risk of Haemoglobin Bart's hydrops foetalis syndrome attending prenatal diagnosis from 2000 to 2019 at Tsan Yuk Hospital in Hong Kong. RESULTS: Among 390 foetuses from 373 at-risk pregnancies, 122 (31%) prenatal invasive procedures were performed and 65 affected foetuses were diagnosed antenatally. For foetuses with ultrasound features of anaemia, the diagnostic yield of BHFS was 73%. Cardiomegaly carried a positive predictive value of 65.2% while its absence had the highest negative predictive value (96.0%). Three women having affected foetuses continued pregnancy and received intrauterine transfusion beginning 20 weeks of gestation. All babies were born alive and non-hydropic. They were managed with regular transfusion and cured by haematopoietic stem cell transplantation. CONCLUSIONS: Absence of ultrasound features of anaemia had high negative predictive value for alpha thalassaemia major. Couple at risk of having affected foetus could be offered serial ultrasound surveillance. Invasive testing for pregnancies with features of foetal anaemia provided high diagnostic yield. Intrauterine transfusion corrected foetal anaemia and allowed long term transfusion free survival without significant neurological sequelae following postnatal transplant therapy.

Is fetal middle cerebral artery peak systolic velocity correlated with hemoglobin levels in cases of nonimmune fetal anemia?

OBJECTIVES: To establish whether a correlation exists between the fetal middle cerebral artery peak systolic velocity (MCA PSV) and fetal hemoglobin levels before intrauterine transfusion (IUT) in cases of severe fetal anemia. METHODS: This was a single-center, retrospective study of data from 49 fetuses treated with IUT for fetal anemia between 2003 and 2018. Severe fetal anemia was suspected when MCA PSV was or exceeded 1.55 multiples of the median. RESULTS: The causes of anemia were largely idiopathic, and the overall survival rate was 57%. MCA PSV and hemoglobin were correlated in all 34 fetuses with alloimmune fetal anemia, whereas the 15 fetuses with nonimmune causes showed no correlation. Of the 15 noncorrelated cases, twin pregnancy was most common, followed by idiopathic causes. All the twin pregnancies involved monochorionic twins. Fetal hydrops, especially ascites, was significantly associated with severe anemia. CONCLUSIONS: Fetal MCA PSV may not be a reliable independent factor for the diagnosis of severe fetal anemia in nonimmune cases, and the presence of associated hydrops implies that the fetus is more likely to have severe fetal anemia than in a fetus without hydrops.