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.

Etiology of non-immune hydrops fetalis: An update.

Background
Lysosomal storage disorders (LSD) are a rare cause of non immunological hydrops fetalis (NIHF) and congenital ascites. The reported incidence is about 1%. The incidence of idiopathic NIHF is estimated to be about 18%.

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Lysosomal storage disorder in non-immunological hydrops fetalis (NIHF) - more common than assumed? Report of four cases with transient NIHF and a review of the literature

We report the first case of nonimmune hydrops fetalis (NIHF) associated with a recessive, in-frame deletion of V205 in the G protein–coupled receptor, Calcitonin Receptor-Like Receptor (hCALCRL). Homozygosity results in fetal demise from hydrops fetalis, while heterozygosity in females is associated with spontaneous miscarriage and subfertility. Using molecular dynamic modeling and in vitro biochemical assays, we show that the hCLR(V205del) mutant results in misfolding of the first extracellular loop, reducing association with its requisite receptor chaperone, receptor activity modifying protein (RAMP), translocation to the plasma membrane and signaling. Using three independent genetic mouse models we establish that the adrenomedullin–CLR–RAMP2 axis is both necessary and sufficient for driving lymphatic vascular proliferation. Genetic ablation of either lymphatic endothelial Calcrl or nonendothelial Ramp2 leads to severe NIHF with embryonic demise and placental pathologies, similar to that observed in humans. Our results highlight a novel candidate gene for human congenital NIHF and provide structure–function insights of this signaling axis for human physiology.

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hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia.

Objective To investigate the clinical characteristics of fetal hydrops and to find the antenatal ultrasound findings predictive of adverse perinatal outcome. Methods This is a retrospective study of 42 women with fetal hydrops who delivered in a tertiary-referral center from 2005 to 2013. Fetal hydrops was defined as the presence of fluid collection in ≥2 body cavities: ascites, pleural effusion, pericardial effusion, and skin edema. Predictor variables recorded included: maternal characteristics, gestational age at diagnosis, ultrasound findings, and identifiable causes. Primary outcome variables analyzed were fetal death and neonatal death. Results The mean gestational age at diagnosis was 29.3±5.4 weeks (range, 18 to 39 weeks). The most common identifiable causes were cardiac abnormality (10), followed by syndrome (4), aneuploidy (3), congenital infection (3), twin-to-twin transfusion syndrome (3), non-cardiac anormaly (2), chorioangioma (2), inborn errors of metabolism (1), and immune hydrops by anti-E antibody isoimmunization (1). Thirteen cases had no definite identifiable causes. Three women elected termination of pregnancy. Fetal death occurred in 4 cases. Among the 35 live-born babies, only 16 survived (54.0% neonatal mortality rate). Fetal death and neonatal mortality rate was not significantly associated with Doppler velocimetry indices or location of fluid collection, but increasing numbers of fluid collection site was significantly associated with a higher risk of neonatal death. Conclusion The incidence of fetal hydrops in our retrospective study was 24.4 per 10,000 deliveries and the perinatal mortality rate was 61.9% (26/42). The number of fluid collection sites was the significant antenatal risk factor to predict neonatal death.

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Clinical characteristics and perinatal outcome of fetal hydrops.

Maternal illness, infection, or disease may require medication during pregnancy, which presents the challenge of balancing the benefits and risks associated with fetal drug exposure In cases of certain fetal disorders, however, the opposite situation arises: the need to weigh the benefits of fetal drug therapy against the risks of maternal side effects Fetal arrhythmias, lung maturation, hematological or endocrinological disorders, and other conditions may warrant drug delivery to the fetus This chapter presents advantages and disadvantages of several strategies for fetal drug delivery, such as direct fetal injection An overview of human placental transport functions is provided as it relates to fetal therapy following maternal drug administration Potential applications of gene therapy, stem cell transplantation, and nanomedicine are highlighted and special considerations concerning fetal pharmacokinetics and ethics are discussed

Fetal Drug Therapy

Nonimmune hydrops fetalis (NIHF) is a condition in which excess fluid has accumulated in the fetal interstitial spaces as a result of one or more nonimmune factors. A plethora of maternal, placental, and fetal disease processes have been associated with NIHF. Knowledge of the various etiologies of NIHF and how the disease process affects fluid homeostasis is important for planning patient care and counseling families of patients diagnosed with nonimmune hydrops fetalis. This article discusses the mechanisms governing fluid distribution in the extracellular spaces, examines the various etiologies associated with NIHF, and describes the pathogenesis of NIHF for each etiologic category.

Andrea L Randenberg

Papers

Nonimmune hydrops fetalis part I: etiology and pathophysiology.