Nonimmune Hydrops Fetalis in the Liveborn: Series of 32 Autopsies

Nonimmune hydrops fetalis (NIHF) or generalized soft tissue edema and cavity effusions may be due to cardiovascular diseases, congenital infections, genitourinary malformations, thoracic masses, placental conditions, chromosomal abnormalities, and idiopathic. We report 32 cases of NIHF from among 429 neonates who underwent autopsies (incidence 7.45%). Sixteen cases (50%) had cardiovascular disease; all were due to low output cardiac failure; 7 had structural congenital heart disease. Three of the children with congenital heart disease also had chromosomal abnormalities: 2 had trisomy 18 and 1 had Noonan syndrome. Among myocardial conditions were five subjects with cardiomyopathies (1 of each of the following types): oncocytic, dilated, endocardial fibroelastosis, cardiac glycogenosis, and carnitine deficiency; 3 had myocarditis, and 1 had cardiac rhabdomyomas. Congenital infections were due to cytomegalovirus in 3 cases, bacteria in 2, and parvovirus in 1. The mechanism of NIHF in these cases might be a combination of decreased myocardial contractility due to myocarditis and fetal anemia. Genitourinary diseases were present in 5 newborns: Two had congenital nephrotic syndrome, 1 had VACTER association, 1 had prune-belly syndrome, and 1 had urogenital sinus malformation. Intrathoracic lesions were found in 2 babies (pulmonary sequestration and diaphragmatic hernia). One twin died of volume overload due to twin transfusion syndrome. Only 2 newborns were classified as idiopathic. Our study shows that cardiovascular diseases that lead to heart failure or impaired venous return are more common in the liveborn (50%), whereas congenital infections are more common in the stillborn with NIHF.     

非免疫性胎儿水肿新生儿的临床特征及预后分析

目的 分析非免疫性胎儿水肿（NIHF）新生儿的临床特征、病因及转归情况。方法 回顾性分析23例NIHF新生儿的临床资料及转归。结果 23例NIHF患儿中,早产儿18例（78%）,足月儿5例（22%）;出生窒息12例（52%）,其中重度窒息6例。NIHF病因包括双胎输血综合征（TTTS）8例（35%）,心血管畸形3例（13%）,微小病毒B19感染3例（13%）,先天性乳糜胸2例（9%）,Turner综合征1例（4%）,柯萨奇病毒感染1例（4%）,病因不明5例（22%）。临床治愈13例（57%）,死亡10例,新生儿期病死率为43%。死亡组中早产儿、新生儿窒息、5分钟Apgar评分<8分及心力衰竭比例（分别为100%、100%、60%、60%）明显高于存活组（分别为62%、15%、8%、8%）（P < 0.05）。结论 NIHF新生儿易发生出生窒息;胎龄越小、窒息程度越重、合并心力衰竭者新生儿期死亡风险越大。TTTS中受血儿是NIHF的主要病因。     

Osteochondral junction lesions in stillborn fetuses and their relationship to autopsy diagnoses

BACKGROUND: In the perinatal period, microscopic abnormalities of the costochondral junction in fetuses were described but little is known about the perinatal intercurrences that were associated with them. AIMS: The aim of this study was to correlate the findings of the osteochondral junction (OCJ) of stillborn with the autopsy findings. STUDY DESIGN: We studied 50 longitudinal sections of OCJ of the 5th and 6th ribs collected from stillborn fetuses, after decalcification and staining with Hematoxilyn and Eosin (HE). The gestational age ranged between 22 and 41 weeks. RESULTS: The incidence of abnormal OCJ in the ribs was 62%. Intrauterine growth restriction was associated most often with banding. In 12% of our cases, we found one pattern of OCJ alteration that did not fit into the previous described categories. This pattern was the presence of a bone in the middle of the cartilage column associated with disorganization of the OCJ. The other pattern that has rarely been mentioned in the literature, we called "bizarre" and all the fetuses were less than 37 weeks of gestational age. The incidence of the "bizarre" or the "funny bone" patterns was less frequent than the other patterns of OCJ alteration, although they seem to be associated with the cases that had the most severe placental abnormalities (massive perivillous fibrinoid, decreased placenta blood flow) or congenital malformations (complex congenital heart defect, hydrocolpos). CONCLUSION: In conclusion, OCJ alterations were more commonly associated with congenital malformation or placental abnormalities. Histologic examination of the OCJ is an easy and reproducible method of determining in utero growth disturbance even before there is a lag in fetal growth and is an important component of the perinatal autopsy.     

Fetal case of congenital cystic adenomatoid malformation of the lung: fetal therapy and a review of the published reports in Japan

We herein report a case of type I congenital cystic adenomatoid malformation of the lung (CCAML) with non-immune hydrops fetalis (NIHF), a mediastinal shift and polyhydramnios diagnosed at 24 weeks' gestation by ultrasonography. The fetus was treated with a cyst-amniotic shunt at 29 weeks' gestation. Following a postnatal whole resection of the right lung, postpneumonectomy syndrome appeared and, as a result, the infant died 13 months after delivery due to respiratory failure. Only 19 cases demonstrating CCAML associated with NIHF have been reported previously in Japan. Four cases showed a spontaneous resolution of NIHF, while 5 cases with type I CCAML, which all underwent fetal intervention, demonstrated an excellent outcome.     

Intrauterine treatment on non-immune hydrops fetalis.

In 51 cases with non-immunologic hydrops fetalis (NIHF), perinatal management was performed based on our protocol. Twenty-two cases were treated by albumin and/or packed red cell (PRC) injection into the fetal abdominal cavity, and 9 cases by transplacental digitalization. Among the cases treated by albumin and/or PRC injection, 6 of 8 cases without pleural effusion recovered in utero, and all 6 cases are alive. However, of 14 cases with pleural effusion, none recovered in utero, and only one case is alive. Of 9 cases treated by transplacental digitalization, 2 cases recovered in utero, and only one case is alive. All fetuses with congenital heart anomaly died. This evidence indicates that albumin and/or PRC injection into the fetal abdominal cavity is an effective procedure for in utero treatment of NIHF without pleural effusion, but suggests that in NIHF resulting from either congenital heart anomaly and/or heart failure, the survival rate may not be increased by transplacental digitalization.     

Evaluation and prognosis of fetal arrhythmia]

From January 1986 to August 1990, a fetal arrhythmia was diagnosed in 97 pregnant women referred to our unit. Atrial or ventricular extrasystoles were the most frequent rhythm disturbance encountered (71%). They were always well tolerated and all disappeared during the perinatal period. Tachycardia was found in 16 fetuses; 6 had a supraventricular reentrant tachycardia, 6 an atrial chaotic tachycardia, 1 an ectopic atrial tachycardia and the remaining 3 an atrial flutter. A congenital heart malformation was present in 4 fetuses. The arrhythmia induced hydrops fetalis in 25% of cases. One hydropic fetus died in utero and another needed premature delivery. Bradycardia was diagnosed in 12 cases, 3 had benign atrial blocked extrasystoles, 3 others sinus bradycardia due to fetal distress and 6 atrio-ventricular block. Atrio-ventricular block was associated with congenital malformation in 4 cases (66%). All these fetuses were hydropic and died. The 2 fetuses without cardiac malformation tolerated well their bradycardia during fetal life. Fetal arrhythmia is not rare, but in most cases is benign. Sustained tachycardia requires prompt treatment, because when hydrops fetalis appears the prognosis is worse. The major prognostic factor for atrio-ventricular block is the association with a cardiac malformation.     

Nonimmunologic hydrops fetalis--a review of 31 cases

Non-immunologic hydrops fetalis-a review of 31 cases: 31 Patients with non-immunologic hydrops fetalis (NIHF) seen between 1984 and 1987 are described. 13 infants survived. The infants with major congenital malformations and connatal infections died. In 8 of the patients who died a cause for NIHF could not be identified. 10 of the survivors presented chylous ascites and/or chylothorax without major congenital anomalies. 2 infants had fetal tachyarrhythmia and 1 patient showed severe anemia due to fetomaternal hemorrhage.     

Genetic Study on the Etiology of Congenital Heart Diseases

The etiology of congenital heart disease was studied in 1,076 patients who were diagnosed in our outpatient clinic from September 1, 198 1 to February 29, 1984. In these patients, 9(0.8%) had single gene disorders and 63(5.9%) had chromosomal aberrations, of which 55(87.7%) were Down syndrome. The number of patients who had congenital heart diseases due to environmental insult was 2(0.2%), and those with a malformation syndrome of unknown etiology were 6(0.6%). The etiology of congenital heart diseases in the remaining 996 patients (92.6%) was not clarified. In these cases, the rates of consanguinity of parents, and paternal and maternal grandparents, the ages of the parents when the patients were born, and the number of minor anomalies, were compared with those in normal controls. The complications of major anomalies were also investigated. Further, the recurrence risks in patients' siblings were also calculated.     

Possible role of WT1 in a human fetus with evolving bronchial atresia, pulmonary malformation and renal agenesis

The association of peripheral bronchial atresia and congenital pulmonary airway malformation (CPAM) has recently been recognised, but the pathology of the lesions evolving together has not been described. We present autopsy findings in a 20 week fetus showing areas of peripheral bronchial destruction and airway malformation consistent with developing CPAM in the right lung supporting a causal relationship between these lesions. This fetus also had congenital heart defect, bilateral renal agenesis and syndactyly. We identified another fetus from our autopsy files, with bilateral renal agenesis, similar right sided pulmonary malformation and cardiac defects. Similar bilateral renal agenesis and defects of the heart and lungs are found in wt1(-/-) mice and we have investigated the expression of WT1 in these fetuses. We hypothesise that the cardiac, liver, renal and possibly lung lesions in these two cases may arise due to mesenchymal defects consequent to WT1 misexpression and discuss evidence for this from the scientific literature. We used immunoperoxidase stains to analyse WT1 expression in autopsy hepatic tissue in both fetuses. We also investigated the expression of α-smooth muscle actin (α-SMA), a marker of activated hepatic stellate cells/myofibroblasts, and desmin in hepatic mesenchyme and compare these findings with control fetuses, without congenital malformations. We found reduced WT1 expression in hepatic mesothelium in both fetuses with malformations. There was also increased expression of α-SMA in liver perisinusoidal cells, as seen in the wt1(-/-) mouse model. We therefore propose that abnormality of WT1 signalling may be an underlying factor, as WT1 is expressed in coelomic lining cells from which mesenchyme is derived in many organs.     

Ebstein anomaly as a rare cause of a non-immunological fetal hydrops: prenatal diagnosis using Doppler echocardiography

The Ebstein's malformation occurs in 0.5% of patients with congenital heart disease. The prenatal diagnosis of such a malformation in the 33rd week of pregnancy is reported. The fetal echocardiography was performed owing to a severe nonimmune hydrops fetalis. The typical distal displacement of the annular attachment of the tricuspid valve leaflets could be viewed in the apical four-chamber view. The application of the pulsed Doppler ultrasound enables the analysis of the cardial haemodynamics and thus the assessment of the severity and prognosis of the diagnosed malformation. In our case the prognosis was interdisciplinary estimated as being very poor (severe cardiac lesion with congestive heart failure already in utero); In the following days intrauterine death occurred. The autopsy confirmed all the prenatal findings.     

TISSUE IRON STORAGE PATTERNS IN FETAL HYDROPS ASSOCIATED WITH CONGESTIVE HEART FAILURE

To learn whether fetal congestive heart failure causes a characteristic tissue iron storage pattern, we selected 15 neonatal autopsy cases of hydrops fetalis in which both the clinical and gross autopsy findings suggested intrauterine congestive heart failure. The latter appeared to be due to functional causes in 10 (3 nonhemolytic anemia, 4 cardiac dysrhythmia, 3 dilated cardiomyopathy) and was associated with cardiac malformation in 5. We graded the amount of hepatocellular siderosis, reticuloendothelial siderosis, and renal tubular siderosis in Perls-stained microscopic sections of liver, spleen, and kidney and compared the iron storage pattern with that in 15 normally developed neonatal autopsy controls (4 preterm, 11 term) and a further 7 with hemolytic anemia (5 alpha-thalassemia, 2 parvovirus B19 infection). Liver cell siderosis was absent in the three cases with nonhemolytic anemia. It was increased in 11 of the remaining 12 cases, as in hemolytic anemia controls. Among the five cardiac malformation cases, three had proximal renal tubular siderosis (as in hemolytic anemia controls) attributed to turbulent blood flow through the heart. Among the five, hydrops appeared to be due to prenatal closure of the foramen ovale in one and to prenatal constriction of the ductus arteriosus in another. In one of the five, and despite complex malformation of the heart, hydrops appeared to be due to complete heart block. We concluded that, although clinical information and morphologic assessment of the heart were basic to identifying a cardiac cause of fetal hydrops, histologic assessment of the pattern of iron storage helped confirm the pathologic diagnosis. Analysis of the pathologic findings led to a scheme for categorizing cardiogenic fetal hydrops.     

Embryopathy and diabetic fetopathy in a premature stillborn infant. Case report and review of the disease picture

The diabetic embryopathy syndrome comprises a number of developmental anomalies among fetuses of diabetic mothers. Fetopathia diabetica, on the other hand, is characterized by typical, hormonal, and metabolic dysfunctions and their morphological sequelae in fetuses and offsprings of diabetic mothers. We observed the combination of both these conditions in an immature stillborn fetus. The 34 year-old diabetic mother, who had been treated by insulin since age 16, was first seen at 27 weeks of gestation. Sonography revealed severe congenital malformations of the fetus, and a late abortion was induced. The stillborn female revealed the typical congenital malformations of the diabetic embryopathy syndrome, such as abnormalities of face and skull, skeletal malformations of the thorax, spine, and lower extremities, and malformations of the heart, great vessels and the genitourinary system. We, too, found the characteristic features of fetopathia diabetica, i.e. obesity, macrosomia, increased weight and size of the internal organs, polynesia and macronesia of the pancreas, increased extramedullary hematopoiesis and cellular depletion of lymphoid tissues. A review of the literature revealed various hypotheses about the etiology and pathogenesis of both conditions.     

Fetal cystic hygroma and Turner's syndrome

Large nuchal cystic hygromas were observed in five second-trimester aborted fetuses at autopsy. Two female fetuses with generalized edema were karyotyped as 45,X. One of these was the twin of a 46,XX normal female sibling. The association of generalized edema with large nuchal cystic hygromas was seen only in these two fetuses and represents strong phenotypic evidence of Turner's syndrome. However, the absence of hydrops was not a reliable indicator of normal karyotype. One fetus without generalized edema was karyotyped as 47,XY, +21, inv(9). The remaining cases had normal karyotypes. Placental histology was not useful in discriminating monosomy X from other conditions, but placental tissue culture was important in obtaining a cytogenetic diagnosis. Karyotyping is recommended in all cases of fetal cystic hygroma.     

Non-immunologic hydrops fetalis--report of 14 cases and literature review

With the advent of prenatal diagnosis and the feasibility of intrauterine treatment, non-immune hydrops fetalis (NHIF) is gaining increasing importance. 14 patients are reported 10 of whom having been diagnosed prenatally. 13 were born prematurely severe asphyxia being a frequent occurrence. 7 out of 14 infants survived. In 5 cases no definite etiology could be established. In 7 patients NHIF was attributable to cardiovascular diseases, predominantly associated with brady- or tachycardia. A survey of the literature reveals that etiology remains unidentified in about 40%. For the rest fetal, maternal or placental diseases are the primary causes. The abundance of underlying diseases are operative via three pathophysiological pathways: hemodynamic disturbances, decreased oncotic pressure and increased capillary permeability. By ultrasound examination, NHIF can be detected prenatally permitting intrauterine treatment in selected cases. In combination with improved postnatal management, this might contribute to a better outcome of NIHF which is still associated with a high mortality rate. Meticulous diagnostic work-up facilitates genetic counseling and the pursuit of prenatal diagnosis in subsequent pregnancies.     

Correlation of Prenatal Ultrasound Diagnosis and Pathologic Findings in Fetal Anomalies

This retrospective study compared the prenatal ultrasound (US) diagnosis with autopsy findings in 61 intact fetuses following induced abortion and 36 fragmented fetuses from dilatation and evacuation (D&E). In intact fetuses, complete agreement between US diagnosis and autopsy findings was achieved in 65.6% of cases in the central nervous system (CNS) and 47.5% in other somatic organ systems (SOS). There were major differences between US and autopsy findings involving the CNS in 6.5% of cases and SOS in 27.9%. Correlation was better for evaluation of renal anomalies (complete agreement in 63.6% of 11 suspected cases, 2 false-positive and no false-negative cases) than congenital heart disease (complete agreement in 27.3% of 11 suspected cases, 5 false-positive and 3 false-negative cases). In D&E specimens, a prenatal diagnosis of neural tube defect (NTD) was confirmed in 90% of cases. However, due to fragmentation of fetal parts, the US diagnosis in the CNS could not be confirmed totally (69.4%) or partially (2.8%) in fetuses with chromosomal abnormalities (ChA) or multiple congenital anomalies (MCA). Nonetheless, the US diagnosis of SOS was confirmed in six cases on D&E, including Meckel-Gruber syndrome, cystic hygroma, renal agenesis with contralateral renal dysplasia, cardiac defect, fetal hydrops, and tracheal atresia. Our results show that a thorough autopsy of an intact fetus after abortion is necessary to confirm prenatal diagnosis and allow proper management and counseling. The pathologic examination of D&E specimens can reliably confirm the US diagnosis of NTD, but it is very limited in identifying other fetal anomalies. Received January 6, 1998; accepted May 25, 1998.     

Nonimmunologic hydrops fetalis: a clinicopathological study of 50 autopsy cases

Fifty cases of nonimmunologic hydrops fetalis found in Japanese infants are reported. Nonimmunologic hydrops fetalis is associated with various pathological conditions, twin transfusion syndrome including acardiac monsters, fetal heart diseases, congenital cystic adenomatoid malformation, pulmonary sequestration, pulmonary lymphangiectasia, intrauterine infections such as cytomegalovirus infection and neonatal hepatitis, congenital neuroblastoma, Kasabach-Merritt syndrome, cystic hygroma, and chromosomal aberrations. The mechanism of hydrops fetalis found in these conditions is discussed from various viewpoints. Despite a careful examination, no causative conditions were found in 14 cases. The placenta showed a proliferation of Hofbauer cells that were strongly positive for immunoreactive alpha 1-antichymotrypsin and there were other common findings such as edema of terminal villi and fibrin thrombi.     

Cardiac abnormalities and nonimmune hydrops fetalis: a coincidental, not causal, relationship

Few conditions associated with nonimmune hydrops fetalis have had a demonstrable causal relationship. Congenital heart disease is often said to be a cause of nonimmune hydrops fetalis and antenatal closure of the foramen ovale is the cardiac abnormality most frequently reported in association with hydrops. In order to examine the role of congenital heart disease in hydrops, and, in particular, that of antenatal closure of the foramen ovale, we reviewed all autopsy cases with hydrops fetalis over an 11 year period and compared cardiac anomalies with those of nonhydropic controls. The incidence of various congenital heart malformations was not significantly different among these groups, suggesting that factors in addition to cardiac anomalies must be considered in the pathogenesis of nonimmune hydrops fetalis.     

Cardiac Abnormalities and Nonimmune Hydrops Fetalis: a Coincidental, Not Causal, Relationship

Few conditions associated with nonimmune hydrops fetalis have had a demonstrable causal relationship. Congenital heart disease is often said to be a cause of nonimmune hydrops fetalis and antenatal closure of the foramen ovale is the cardiac abnormality most frequently reported in association with hydrops. In order to examine the role of congenital heart disease in hydrops, and, in particular, that of antenatal closure of the foramen ovale, we reviewed all autopsy cases with hydrops fetalis over an 11 year period and compared cardiac anomalies with those of nonhydropic controls. The incidence of various congenital heart malformations was not significantly different among these groups, suggesting that factors in addition to cardiac anomalies must be considered in the pathogenesis of nonimmune hydrops fetalis.     

Management of congenital lung lesions

The prenatal diagnostic hallmarks, natural history, and management of congenital cystic adenomatoid malformation of the lung and pulmonary sequestration are reviewed. Large lung tumors may disappear partially on serial prenatal sonography, suggesting that improvement can occur occasionally during fetal life. The fetus with a lung mass but without hydrops has an excellent chance for survival with maternal transport, planned delivery, and postnatal evaluation and surgery. The finding that fetuses with hydrops are at very high risk for fetal or neonatal death has led to successful fetal thoracoamniotic shunt placement or fetal surgical resection.     

单胎濒死儿发生的围生期危险因素分析

目的 探讨单胎濒死儿发生的围生期危险因素,为濒死儿综合诊治提供依据。 方法 该研究为病例对照研究。选取2006年1月—2015年12月在复旦大学附属妇产科医院出生的154例胎龄≥28周、1 min Apgar评分为0~1分的单胎新生儿为病例组（濒死组）,按1∶4比例随机选取616例同期出生的单胎非濒死儿（1 min Apgar评分>1分）为对照组,采用单因素分析和多因素logistic回归分析评估濒死儿发生的围生期危险因素。 结果 濒死组胎龄和出生体重均显著低于对照组（P<0.05）。濒死组胎儿水肿、脐带脱垂、羊水Ⅲ度污染、胎盘早剥、臀位、重度子痫前期、母亲产时全麻、产前胎心监护异常、产前胎动减少发生比例显著高于对照组（P<0.05）。多因素logistic回归分析显示母亲产时全麻（OR=34.520）、产前胎动减少（OR=28.168）、胎盘早剥（OR=15.641）、羊水Ⅲ度污染（OR=6.365）、产前胎心监护异常（OR=5.739）、臀位（OR=2.614）是濒死儿发生的危险因素（P<0.05）,胎龄较大（OR=0.686）是濒死儿发生的保护因素（P<0.05）。 结论 临床需对产前胎心监护异常、胎动减少、早产、胎盘早剥、臀位、羊水Ⅲ度污染、全麻手术的产妇引起重视,做好新生儿复苏准备,防范濒死儿的发生。