Nonimmune Hydrops Fetalis.

Nonimmune hydrops fetalis (NIHF) poses a significant challenge in perinatal care due to its high mortality rates and diverse etiologies. This comprehensive review examines the pathophysiology, etiology, antenatal diagnosis and management, postnatal care, and outcomes of NIHF. NIHF arises from numerous underlying pathologies, including genetic disorders, cardiovascular causes, and fetal infections, with advances in diagnostic techniques improving identification rates. Management strategies include termination of pregnancy for severe cases and fetal therapy for selected treatable etiologies, and neonatal care involves assessing and treating fluid collections and identifying underlying causes. Prognosis depends on factors such as gestational age at diagnosis and the extent of resuscitation needed, with challenges remaining in improving outcomes for affected infants.

Etiology and perinatal outcomes between early and late-onset nonimmune hydrops fetalis.

OBJECTIVE: We aimed to compare the etiology and perinatal outcomes of non-immune hydrops fetalis diagnosed early- and late-onset at our hospital. METHODS: The records of the patients who applied to our department were reviewed, and we reached 42 non-immune hydrops fetalis cases retrospectively and examined the medical records. Hydrops diagnosis week, birth week, accompanying anomalies, and perinatal outcomes were compared as ≤12 weeks (early-onset) and >12 weeks (late-onset). RESULTS: The prevalence of non-immune hydrops fetalis was 0.05%, and the median week of diagnosis for hydrops was 18 weeks. Consanguinity (16.7%) was found in seven pregnancies, and the other seven patients (16.7%) had a history of hydrops in previous pregnancies. Anomalies of the skeletal system, central nervous system, and gastrointestinal tract accounted for 66.7% of ≤12 weeks in non-immune hydrops fetalis cases. Cardiac abnormalities were more common (26.7%) in patients at > 12 weeks (p=0.078). A statistically significant difference was found between the distribution of week of birth and week of diagnosis (p=0.029). Notably, 66.7% of patients diagnosed before week 12 and 23.3% of patients diagnosed after week 12 delivered their babies before week 24. Spontaneous intrauterine death occurred before week 12 in 45.5% (n=5) of non-immune hydrops fetalis and after week 12 in 39.1% (n=9) of non-immune hydrops fetalis. Notably, 69.2% (n=9) of the patients who had prenatal invasive testing resulted in normal karyotype. CONCLUSION: In this study, most of the fetuses diagnosed with early-onset non-immune hydrops fetalis were born in the first 24 weeks. Additionally, live birth rates and cardiac anomalies were observed to be higher in late-onset non-immune hydrops fetalis.

Glucose-6-phosphate dehydrogenase deficiency as a cause for nonimmune hydrops fetalis and severe fetal anemia: A systematic review.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive disorder that predisposes individuals to hemolysis due to an inborn error of metabolism. We performed a systematic literature review to evaluate G6PD deficiency as a possible etiology of nonimmune hydrops fetalis (NIHF) and severe fetal anemia. METHODS: PubMed, OVID Medline, Scopus, and clinicaltrials.gov were queried from inception until 31 April 2023 for all published cases of NIHF and severe fetal anemia caused by G6PD deficiency. Keywords included "fetal edema," "hydrops fetalis," "glucose 6 phosphate dehydrogenase deficiency," and "fetal anemia." Cases with workup presuming G6PD deficiency as an etiology for NIHF and severe fetal anemia were included. PRISMA guidelines were followed. RESULTS: Five cases of G6PD-related NIHF and one case of severe fetal anemia were identified. Four fetuses (4/6, 66.7%) were male and two fetuses (2/6, 33.3%) were female. Mean gestational age at diagnosis of NIHF/anemia and delivery was 32.2 ± 4.9 and 35.7 ± 2.4 weeks, respectively. Four cases (66.7%) required a cordocentesis for fetal transfusion, and two cases (33.3%) received blood transfusions immediately following delivery. Among the four multigravida cases, two (50%) noted previous pregnancies complicated by neonatal anemia. When reported, the maternal cases included two G6PD deficiency carrier patients and two G6PD-deficient patients. Exposures to substances known to cause G6PD deficiency-related hemolysis occurred in 3/6 (50%) cases. CONCLUSION: Six cases of NIHF/severe fetal anemia were associated with G6PD deficiency. While G6PD deficiency is an X-linked recessive condition, female fetuses can be affected. Fetal G6PD deficiency testing can be considered if parental history indicates, particularly if the standard workup for NIHF is negative.

Dilatative fetal cardiomyopathy followed by a mirror syndrome.

Mirror syndrome (Ballantyne syndrome) is a rare condition characterized by maternal edema, which often affects the lungs. It mirrors the image of fetal and placental edema; therefore, it is also called triple edema. We present the case of a 37-year-old secundigravida, referred to our clinic at 26 weeks of a pregnancy complicated by fetal dilatative restrictive cardiomyopathy and hydrops, placentomegaly, new-onset dyspnea, and maternal calf edema. Due to worsening mirror syndrome, preterm labor was induced. Labor was complicated, with soft tissue dystocia, stillbirth, and postpartum hemorrhage. The first pregnancy was also complicated by fetal right ventricular noncompaction dilatative cardiomyopathy. A eutrophic male child was born vaginally at term and died due to deterioration of the cardiac disease in the third year of life. Next-generation sequencing panel for pediatric cardiology was performed in the deceased child and parents. Two gene variants were recorded: MYOM1: c.770_771delCA (p.Thr257fs) and TPM1: c.814G>A (p.Glu272Lys). Both variants were classified as variants of uncertain significance. This case emphasizes the importance of antenatal counseling, the timing of labor induction, appropriate management of possible complications such as postpartum hemorrhage and soft tissue dystocia, and the interpretation of placental biomarkers in the context of mirror syndrome. Finally, it contributes to understanding the clinical significance of the MYOM1 and TPM1 gene variants.

Spontaneous regression of fetal pleural effusion in pregnancy complicated with Herpes simplex infection: Clinical presentation and literature review.

Fetal primary hydrothorax is a rare congenital anomaly with an estimated incidence of 1:10,000-15,000 pregnancies, with an unpredictable clinical course, ranging from spontaneous resolution to fetal death. A case of unilateral fetal pleural effusion was diagnosed at 35th week of gestation during a routine ultrasonographic fetal assessment in an uncomplicated pregnancy. A large echogenic collection of fluid was revealed in the right pleural cavity, together with atelectasis of the right lung, as well as displacement of heart and mediastinal structures to the left side of thorax. The patient was also diagnosed with polyhydramnios and there was a disproportion of heart ventricles volume. No other fetal structural abnormalities were detected and there were no symptoms of edema. Fetal biometrics was consistent with the gestational age. In echocardiography, fetal heart was structurally and functionally normal. Screening tests for congenital infections of the fetus were negative. Autoimmune fetal hydrops was excluded after laboratory tests. There was no parents' consent for the analysis of the karyotype. The patient presented clinical symptoms and was diagnosed with Herpes simplex virus infection and was treated with oral acyclovir. Serial fetal ultrasound exams showed gradual decrease in pleural fluid volume up to complete resolution in 38th week of pregnancy. Pregnancy was ended in the 38th week of gestation with a cesarean delivery of a healthy neonate. It is yet to be determined if there is a direct association between Herpes simplex virus infection in pregnancy and the risk of fetal pleural effusion. The incidence of fetal pleural effusion is low and the neonatal outcome difficult to be predicted. The optimum management of fetal pleural effusion should be subject to further studies to determine the best clinical practice.

Challenges of managing anomalous mitral arcade with severe mitral regurgitation and hydrops fetalis in infants.

Anomalous mitral arcade (MA) is a rare congenital anomaly. We report a case of MA in a newborn who presented with hydrops fetalis due to severe mitral regurgitation. After birth, he developed severe respiratory failure, congestive heart failure and airway obstruction because an enlarged left atrium from severe mitral regurgitation compressed the distal left main bronchus. There is limited experience in surgical management of this condition in Thailand, and the patient's mitral valve was too small for replacement. Therefore, he was treated with medication to control heart failure and supported with positive pressure ventilation to promote growth. We have followed the patient until the current time of writing this report at the age of 2 years, and his outcome is favourable regarding heart failure symptoms, airway obstruction, growth and development. This case describes a challenging experience in the non-surgical management of MA with severe regurgitation, which presented at birth.

Epidemic of parvovirus B19 and disease severity in pregnant people, Denmark, January to March 2024.

We report an epidemic of parvovirus B19 infections in Denmark during the first quarter of 2024, with a peak incidence 3.5 times higher than during the most recent epidemic in 2017. In total, 20.1% (130/648) of laboratory-confirmed cases were pregnant. Severe adverse outcomes were observed among 12.3% (16/130) of pregnant people and included foetal anaemia, foetal hydrops and miscarriage. Parvovirus B19 infection is not systematically monitored, but a national laboratory-based surveillance system is currently being established in Denmark.

Fetal cardiac teratoma and pericardiocentesis: A case report.

Fetal pericardial teratomas are rare. They present with pericardial effusion and hydrops. The definitive management is postnatal resection of the tumor. The exact antenatal management is not known due to its rarity. We present a case of fetal pericardial teratoma with pericardial tamponade. Pericardiocentesis performed at 31 weeks significantly relieved the venous compression, leading to resolution of hydrops and prolonging the gestational age for the definitive management.

Congenital metastatic neuroblastoma with placental involvement as a rare cause of non-immune fetal hydrops.

Non-immune hydrops fetalis represents the end-stage status of a variety of diseases, including metastatic tumors. We report a case of non-immune hydrops fetalis associated with multiple disseminated echogenic nodular lesions detected by ultrasound and confirmed by magnetic resonance. Cordocentesis demonstrated anemia and thrombopenia. Differential diagnosis included histiocytosis X, acute leukemia or metastatic disease. A stillbirth was diagnosed at week 25 + 6. The autopsy revealed hydrops fetalis, a right adrenal gland mass, multiple disseminated nodules histologically composed of small round blue cells positive for synaptophysin, and placental involvement, concordant findings with congenital undifferentiated neuroblastoma Stage M. No chromosomal abnormalities were associated, nor amplification abnormalities in MYCN and ALK genes. Metastatic neuroblastoma should be considered in the differential diagnosis of non-immune hydrops fetalis associated with multiple nodular lesions.

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.

Parvovirus B19 in Pregnancy.

Importance: Although the risk of parvovirus B19 infection during pregnancy and subsequent risk of adverse fetal outcome are low, understanding management practices is essential for proper treatment of fetuses with nonimmune hydrops fetalis. In addition, continued investigation into delivery management, breastfeeding recommendations, and congenital abnormalities associated with pregnancies complicated by parvovirus B19 infection is needed. Objective: This review describes the risks associated with parvovirus B19 infection during pregnancy and the management strategies for fetuses with vertically transmitted infections. Evidence Acquisition: Original articles were obtained from literature search in PubMed, Medline, and OVID; pertinent articles were reviewed. Results: Parvovirus B19 is a viral infection associated with negative pregnancy outcomes. Up to 50% of people of reproductive age are susceptible to the virus. The incidence of B19 in pregnancy is between 0.61% and 1.24%, and, overall, there is 30% risk of vertical transmission when infection is acquired during pregnancy. Although most pregnancies progress without negative outcomes, viral infection of the fetus may result in severe anemia, congestive heart failure, and hydrops fetalis. In addition, vertical transmission carries a 5% to 10% chance of fetal loss. In pregnancies affected by fetal B19 infection, Doppler examination of the middle cerebral artery peak systolic velocity should be initiated to surveil for fetal anemia. In the case of severe fetal anemia, standard fetal therapy involves an intrauterine transfusion of red blood cells with the goal of raising hematocrit levels to approximately 40% to 50% of total blood volume. One transfusion is usually sufficient, although continued surveillance may indicate the need for subsequent transfusions. There are fewer epidemiologic data concerning neonatal risks of congenital parvovirus, although case reports have shown that fetuses with severe anemia in utero may have persistent anemia, thrombocytopenia, and edema in the neonatal period. Conclusions and Relevance: Parvovirus B19 is a common virus; seropositivity in the geriatric population reportedly reaches 85%. Within the pregnant population, up to 50% of patients have not previously been exposed to the virus and consequently lack protective immunity. Concern for parvovirus B19 infection in pregnancy largely surrounds the consequences of vertical transmission of the virus to the fetus. Should vertical transmission occur, the overall risk of fetal loss is between 5% and 10%. Thus, understanding the incidence, risks, and management strategies of pregnancies complicated by parvovirus B19 is essential to optimizing care and outcomes. Further, there is currently a gap in evidence regarding delivery management, breastfeeding recommendations, and the risks of congenital abnormalities in pregnancies complicated by parvovirus B19. Additional investigations into optimal delivery management, feeding plans, and recommended neonatal surveillance are needed in this cohort of patients.

Hydrops and congenital diaphragmatic hernia: reported incidence and postnatal outcomes. Analysis of the congenital diaphragmatic hernia study group registry.

OBJECTIVE: Congenital Diaphragmatic Hernia (CDH) associated with hydrops is rare. The aim of this study was to describe the incidence of this combination of anomalies and the postnatal outcomes from a large database for CDH. STUDY DESIGN: Data from the multicenter, multinational database on infants with prenatally diagnosed CDH (CDHSG Registry) born from 2015 to 2021 were analyzed. RESULTS: A total of 3985 patients were entered in the registry during the study period, 3156 were prenatally diagnosed and 88 were reported to have associated fluid in at least 1 compartment, representing 2.8% of all prenatally diagnosed CDH cases in the registry. The overall survival to discharge for CDH patients with hydrops was 43%. The hydropic CDH group had lower birth weight and gestational age at birth, and increased incidence of right-sided CDH (55%), and rate of non-repair (45%). However, the survival rate for hydropic infants with CDH undergoing surgical repair was 80%. Other associated anomalies were more common in hydropic CDH (50% vs 37%, p = 0.001). CONCLUSION: Hydropic CDH is rare, only 2.8% of all prenatally diagnosed cases, and more commonly occurring in right-sided CDH. Survival rates are low, with higher rates of non-repair. However, decision-making regarding goals of care and an aggressive surgical approach in selected cases may result in survival rates comparable to non-hydropic cases.

Echocardiographic assessment of cardiovascular physiology of preterm miniature piglets supported with a pumped artificial placenta system.

OBJECTIVES: We evaluated fetal cardiovascular physiology and mode of cardiac failure in premature miniature piglets on a pumped artificial placenta (AP) circuit. METHODS: Fetal pigs were cannulated via the umbilical vessels and transitioned to an AP circuit composed of a centrifugal pump and neonatal oxygenator and maintained in a fluid-filled biobag. Echocardiographic studies were conducted to measure ventricular function, umbilical blood flow, and fluid status. In utero scans were used as control data. RESULTS: AP fetuses (n = 13; 102±4d gestational age [term 115d]; 616 ± 139 g [g]; survival 46.4 ± 46.8 h) were tachycardic and hypertensive with initially supraphysiologic circuit flows. Increased myocardial wall thickness was observed. Signs of fetal hydrops were present in all piglets. Global longitudinal strain (GLS) measurements increased in the left ventricle (LV) after transition to the circuit. Right ventricle (RV) and LV strain rate decreased early during AP support compared with in utero measurements but recovered toward the end of the experiment. Fetuses supported for >24 h had similar RV GLS to in utero controls and significantly higher GLS compared to piglets surviving only up to 24 h. CONCLUSIONS: Fetuses on a pump-supported AP circuit experienced an increase in afterload, and redistribution of blood flow between the AP and systemic circulations, associated with elevated end-diastolic filling pressures. This resulted in heart failure and hydrops. These preterm fetuses were unable to tolerate the hemodynamic changes associated with connection to the current AP circuit. To better mimic the physiology of the native placenta and preserve normal fetal cardiovascular physiology, further optimization of the circuit will be required.

Maternal "mirror" syndrome: Evaluating the benefits of fetal therapy.

OBJECTIVE: To evaluate maternal and perinatal outcomes following fetal intervention in the context of maternal "mirror" syndrome. STUDY DESIGN: A multicenter retrospective study of all cases of fetal hydrops complicated by maternal "mirror" syndrome and treated by any form of fetal therapy between 1995 and 2022. Medical records and ultrasound images of all cases were reviewed. "Mirror" syndrome was defined as fetal hydrops and/or placentomegaly associated with the maternal development of pronounced edema, with or without pre-eclampsia. Fetal hydrops was defined as the presence of abnormal fluid collections in ≥2 body cavities. RESULTS: Twenty-one pregnancies met the inclusion criteria. Causes of fetal hydrops and/or placentomegaly included fetal lung lesions (n = 9), twin-twin transfusion syndrome (n = 6), severe fetal anemia (n = 4), and others (n = 2). Mean gestational age at "mirror" presentation was 27.0 ± 3.8 weeks. Maternal "mirror" syndrome was identified following fetal therapeutic intervention in 14 cases (66.6%). "Mirror" symptoms resolved or significantly improved before delivery in 8 (38.1%) cases with a mean interval from fetal intervention to maternal recovery of 13.1 days (range 4-35). Three women needed to be delivered because of worsening "mirror" syndrome. Of the 21 pregnancies treated (27 fetuses), there were 15 (55.5%) livebirths, 7 (25.9%) neonatal deaths and 5 (18.5%) intra-uterine deaths. CONCLUSION: Following successful treatment and resolution of fetal hydrops, maternal "mirror" syndrome can improve or sometimes completely resolve before delivery. Furthermore, the recognition that "mirror" syndrome may arise only after fetal intervention necessitates hightened patient maternal surveillance in cases of fetal hydrops.

The role of fetal therapy in the management of mirror syndrome: a narrative review.

OBJECTIVES: Mirror syndrome (MS) is a condition characterized by the presence of maternal, fetal, and placental edema and is reversible through delivery or pregnancy termination. As fetal hydrops itself may be amenable to treatment, we sought to determine outcomes for MS primarily managed by fetal therapy through a narrative review of the literature and cases managed at our fetal center. STUDY DESIGN: PubMed, Embase, Web of Science, Scopus, and Google Scholar databases were searched through January 2024 using key words: mirror syndrome, Ballantyne's syndrome, fetal hydrops, maternal hydrops, pseudotoxemia, triple edema, maternal recovery, fetal therapy, and resolution. Manuscripts describing primary management by fetal therapy that included maternal and fetal outcomes were identified. Clinical details of MS patients managed with fetal therapy at our center were also included for descriptive analysis. RESULTS: 16 of 517 manuscripts (3.1%) described fetal therapy as the primary intended treatment in 17 patients. 3 patients managed at our center were included in the analysis. Among 20 patients undergoing primary fetal therapy for management of mirror syndrome, median gestational age of presentation was 24 weeks and 5 days gestation; predominant clinical findings were maternal edema (15/20), proteinuria (10/20), pulmonary edema (8/20), and hypertension (8/20); the primary laboratory abnormalities were anemia (8/20) and elevated creatinine or transaminases (5/20). Condition-specific fetal therapies led to resolution of hydrops in 17 (85%) cases and MS in 19 (95%) cases. The median time to hydrops resolution was 7.5 days and to resolution of mirror syndrome was 10 days. Fetal therapy prolonged pregnancy by a median of 10 weeks with a median gestational age of 35 weeks and 5 days at delivery. All women delivered for indications other than mirror syndrome and 19/20 fetuses survived. CONCLUSION: In appropriately selected cases, MS often resolves after fetal therapy of hydrops allowing for safe pregnancy prolongation with good maternal and infant outcomes.

Prenatal Management and Perinatal Outcome in a Large Series of Hydrops Fetalis.

INTRODUCTION: Nonimmune hydrops fetalis (NIHF) is the most frequent etiology of hydrops fetalis (HF), accounting for around 95% of cases. It associates high perinatal mortality and morbidity rates. The aim of the study was, first, to investigate etiology, prenatal management, and perinatal outcome in a large single-center series of HF; second, to identify prenatal prognostic factors with impact on perinatal outcome. MATERIALS AND METHODS: Observational retrospective study of 80 HF diagnosed or referred to a single tertiary center between 2012 and 2021. Clinical characteristics, etiology, prenatal management, and perinatal outcome were recorded. Adverse perinatal outcome was defined as intrauterine fetal death (IUFD), early neonatal death (first 7 days of life) and late neonatal death (between 7 and 28 days). RESULTS: Seventy-six of the 80 cases (95%) were NIHF, main etiology being genetic disorders (28/76; 36.8%). A total of 26 women (32.5%) opted for termination of pregnancy, all of them in the NIHF group. IUFD occurred in 24 of 54 patients (44.4%) who decided to continue the pregnancy. Intrauterine treatment was performed in 29 cases (53.7%). There were 30 newborns (55.6%). Adverse perinatal outcome rate was 53.7% (29/54), significantly higher in those diagnosed <20 weeks of gestation (82.4% < 20 weeks vs. 40.5% ≥ 20 weeks; p = 0.004). Survival rate was higher when fetal therapy was performed compared to the expectantly managed group (58.6% vs. 32%; p = 0.05). Intrauterine blood transfusion and thoraco-amniotic shunt were the procedures that achieved the highest survival rates (88.9% and 100%, respectively, p = 0.003). CONCLUSION: NIHF represented 95% of HF with genetic disorders as the main etiology. Most of them were diagnosed before 20 weeks of gestation, with worse prognosis than cases detected later in gestation. Rates of TOP, IUFD, and early neonatal death were higher in NIHF. Intrauterine therapy, when indicated, improved the perinatal outcome.