Etiology of non-immune hydrops fetalis: An update.

Hydrops fetalis is an excessive fluid accumulation within the fetal extra vascular compartments and body cavities. Non-immune hydrops fetalis (NIHF), due to causes other than Rh alloimmunization, is the cause in >85% of all affected individuals. Herein we present an update of our earlier systematic literature review [Bellini et al., 2009] using all publications between 2007 and 2013. We excluded most of the initial 31,783 papers by using strict selection criteria, thus resulting in 24 relevant NIHF publications describing 1,338 individuals with NIHF. We subdivided the affected individuals into 14 classification groups based on the cause of NIHF (percentage of the total group): Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal (9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), Inborn Errors of Metabolism (1.3%), Infections (7.0%), Thoracic (2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic Tumors (0.7%), TTTF-Placental (4.1%), Gastrointestinal (1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss the results of the review. There may be some shifts in the percentages of etiological categories as compared to the previous review, but the small numbers within each category make drawing firm conclusions hazardous. We highlight the need for multi-center series of NIHF cases collected and classified using the same schemes in diagnostic work-ups to allow for comparisons of larger numbers of cases.

Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1.

Autosomal dominant dehydrated hereditary stomatocytosis (DHSt) usually presents as a compensated hemolytic anemia with macrocytosis and abnormally shaped red blood cells (RBCs). DHSt is part of a pleiotropic syndrome that may also exhibit pseudohyperkalemia and perinatal edema. We identified PIEZO1 as the disease gene for pleiotropic DHSt in a large kindred by exome sequencing analysis within the previously mapped 16q23-q24 interval. In 26 affected individuals among 7 multigenerational DHSt families with the pleiotropic syndrome, 11 heterozygous PIEZO1 missense mutations cosegregated with disease. PIEZO1 is expressed in the plasma membranes of RBCs and its messenger RNA, and protein levels increase during in vitro erythroid differentiation of CD34(+) cells. PIEZO1 is also expressed in liver and bone marrow during human and mouse development. We suggest for the first time a correlation between a PIEZO1 mutation and perinatal edema. DHSt patient red cells with the R2456H mutation exhibit increased ion-channel activity. Functional studies of PIEZO1 mutant R2488Q expressed in Xenopus oocytes demonstrated changes in ion-channel activity consistent with the altered cation content of DHSt patient red cells. Our findings provide direct evidence that R2456H and R2488Q mutations in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells.

Immunohistochemistry in non-immune hydrops fetalis: a single center experience in 79 fetuses.

The objective of our study was to evaluate the usefulness of immunohistochemical (IHC) staining techniques in the etiological diagnosis of non-immune hydrops fetalis (NIHF). The records of all 1,098 autopsies performed between January 1987 and May 2008, by the Division of Fetal Pathology of the University of Genoa, were reviewed and all 79 fetuses diagnosed with NIHF were re-evaluated. Additional IHC staining using antibodies that specifically stain blood and lymph vessels (CD31, CD34, smooth muscle actin antibody, D2-40) were performed. Results were compared to results from the literature. Our results showed that in 67/79 cases, evaluation by standard autopsy protocol led to an etiologic diagnosis. Furthermore, we were able to identify the pathogenetic mechanisms that eventually caused NIHF in 42/79 cases. Adding IHC staining to all evaluations identified the pathogenetic mechanism in a further 17 cases (total 59/79 cases). Lymphatic dysplasia was diagnosed by standard autopsy protocol in 1/79 (1.3%), while adding IHC staining resulted in 18/79 (22.8%) cases being diagnosed (P = 0.0001). The present rate of 22.8% of lymphatic dysplasia in non-immune hydrops fetalis is significantly higher than reported in the literature (36/818 or 4.4%; P = 0.01). In conclusion, specific IHC staining techniques aimed at detecting lymphatic dysplasia are needed and should be mandatory in autopsies of fetuses with non-immune hydrops fetalis.

Incidence, causes and pregnancy outcomes of hydrops fetalis at Srinagarind Hospital, 1996-2005: a 10-year review.

OBJECTIVE: To identify the incidence and determine causes and pregnancy outcomes of hydrops fetalis at Srinagarind Hospital. STUDY DESIGN: A retrospective descriptive study. SETTING: Department of Obstetrics and Gynecology, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University. MATERIAL AND METHOD: A retrospective medical record review of all pregnant women and newborns who were diagnosed with hydrops fetalis at all gestational ages and delivered at Srinagarind Hospital between 1996 and 2005. RESULTS: During the period of study, the incidence of hydrops fetalis was 1.80 per 1,000 total births (82 cases of 45,499 total births). Thirty-nine cases (47.56%) were idiopathic, 30 cases (36.58%) were Hb Bart's hydrops fetalis, and three (3.66%) cases were caused by congenital infection. The others 10 cases (12.19%) were achondrogenesis, Turner syndrome, twin-to-twin transfusion syndrome, severe anemia with unknown primary cause, cystic hygroma, multiple congenital anomalies, and Rh isoimmunization. The mortality rate of hydrops fetalis in the present series was 98.78%. One case, caused by Rh isoimmunization, survived. Maternal complications were 30 cases (36.59%) consisting of preeclampsia, preterm labor, disseminated intravascular coagulopathy, placenta previa, and postpartum hemorrhage. CONCLUSION: The incidence of hydrops fetalis was 1.80 per 1,000 total births. The common known cause was Hb Bart's hydrops fetalis. The mortality rate of hydrops fetalis in the present study was very high.

Hydrops fetalis: recent advances.

Hydrops fetalis is a morbid condition caused by a wide variety of fetal, placental, and maternal diseases. Mortality is high and depends on the gestational age at the time of occurrence and underlying etiology. Although the condition was described more than 300 years ago, recent advances in obstetric ultrasound, prenatal diagnostics have made it possible to differentiate various etiologies involved. It is also possible to treat some of these fetuses prenatally. In utero medical and surgical therapy is presently done in some centers. However, the majority of cases diagnosed remain untreatable. Early diagnosis of untreatable cases allows parents to make informed choices about subsequent management. Recent advances are covered in this review.

The pathologist and the hydropic placenta, fetus, or infant.

Many anatomic and histologic abnormalities, in large variety, are associated with fetal and placental edema. It is the pathologist's responsibility first, to identify these abnormalities, and second, to propose or to establish a mechanism by which a candidate abnormality might have led to development of edema. The first process, of documentation, is often assisted by antenatal studies that have identified a candidate lesion. However, the pathologist must bear in mind that the presence of one disorder does not exclude others. The second process, of elucidating the abnormal physiologic mechanisms by which edema developed, can prove elusive and may verge on investigative rather than diagnostic work. An outline for pathologic examination of the hydropic placenta or fetus is presented.

Antenatal classification of hydrops fetalis.

Among 12,572 pregnant women referred for ultrasound examination from 1985-1990, 76 fetuses had ultrasonographic findings of hydrops fetalis, ten immune and 66 nonimmune. Fetuses with cystic hygroma (20), heart defects or arrhythmias (13), or other congenital anomalies (15) accounted for the majority of the nonimmune cases. Antenatal chromosomal studies were available in 42 fetuses with nonimmune hydrops, of which 14 (34%) were abnormal with seven monosomes and six trisomies. Seventeen cases of hydrops (22%) were classified as idiopathic because they had no recognizable etiology. It is concluded that: 1) The ultrasonographic incidence of fetal hydrops in referral centers can be as high as one in 165 pregnancies; 2) most cases of fetal hydrops are of the nonimmune type, which can occur in a low-risk population and can be detected with early second-trimester ultrasound screening; and 3) the complexity of this condition and the high rate of chromosomal abnormalities require referral to a high-risk center for evaluation and pregnancy management.