RESEARCH ARTICLE Etiology of Nonimmune Hydrops Fetalis: A Systematic Review Carlo Bellini, 1 * Raoul C.M. Hennekam, 2,3 Ezio Fulcheri, 4 Mariangela Rutigliani, 4 Guido Morcaldi, 5 Francesco Boccardo, 5 and Eugenio Bonioli 5 1 Neonatal Intensive Care Unit, Department of Pediatrics, Gaslini Institute, University of Genoa, Genova, Italy 2 Institute of Child Health, Great Ormond Street Hospital for Children, University College London, London, UK 3 Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 4 Department of Pathology and Surgery, S. Martino Hospital, University of Genoa, Genova, Italy 5 Department of Pediatrics, Gaslini Institute, University of Genoa, Genova, Italy Received 16 July 2008; Accepted 13 October 2008 Hydrops fetalis (HF) indicates excessive fluid accumulation within the fetal extravascular compartments and body cavities. HF is not a diagnosis in itself but a symptom, and the end-stage of a wide variety of disorders. In the era before routine immuni- zation of Rhesus (Rh) negative mothers, most cases of hydrops were due to erythroblastosis from Rh alloimmunization, but nowadays, nonimmune hydrops fetalis (NIHF) is more frequent, representing 76–87% of all described HF cases. We performed a systematic review of the pertinent literature based on the QUality Of Reporting Of Meta-analyses (QUOROM) recommendations, using a QUOROM flowchart and QUOROM checklist. At initial screening 33,345 articles were retrieved. The various inclusion and exclusion criteria aimed at obtaining data that were as unbiased yet as complete as possible decreased the numbers dramatically, and eventually a total of 225 relevant NIHF articles were identified, describing 6,361 individuals. We established 14 different diagnostic categories and provide the pathophysiologic background of each, if known. All 6,361 patients were subclassi- fied into one of the following diagnostic categories: Cardio- vascular (21.7%), hematologic (10.4%), chromosomal (13.4%), syndromic (4.4%), lymphatic dysplasia (5.7%), inborn errors of metabolism (1.1%), infections (6.7%), thoracic (6.0%), urinary tract malformations (2.3%), extra thoracic tumors (0.7%), TTTF-placental (5.6%), gastrointestinal (0.5%), miscellaneous (3.7%), and idiopathic (17.8%). Ó 2009 Wiley-Liss, Inc. Key words: hydrops fetalis; nonimmune hydrops fetalis; classifi- cation; etiology; pathophysiology; systematic review; flowchart INTRODUCTION Hydrops fetalis (HF) is an excessive fluid accumulation within the fetal extravascular compartments and body cavities, characterized by generalized skin thickness of >5 mm, placental enlargement, pericardial or pleural effusion, or ascites. HF is a nonspecific finding and the end-stage of a wide variety of disorders. In the past, before routine immunization of Rhesus (Rh)-negative mothers, most cases of hydrops were due to eryth- roblastosis from Rh alloimmunization. At present, nonimmune hydrops fetalis (NIHF) is more frequent, comprising 76–87% of all described HF case. NIHF has a multifactorial cause, consisting of fetal, placental, and maternal disorders. Although diagnosis and management has improved in recent years, NIHF is still associated with a high mortality rate [Abrams et al., 2007]. Increased knowledge and understanding of the underlying mechanisms may therefore be of great importance. The most widely used review on the etiology of hydrops dates back to 1989 [Machin, 1989]. Since then, many other articles have been published, though often reporting only on one single cause, on small series, or on biased series of patients, and data were sometimes contradictory. In this article we provide a systematic review of all available literature on NIHF in order to obtain a list of the causes of NIHF that is as complete and unbiased as possible and that allows us to estimate the relative frequencies of causes. We provide an NIHF pathophysiologic flowchart. *Correspondence to: Carlo Bellini, M.D., Ph.D., Neonatal Intensive Care Unit, Pediatrics Department, University of Genoa, Gaslini Institute, Largo G. Gaslini 5, 16147 Genoa, Italy. E-mail: carlobellini@ospedale-gaslini.ge.it Published online 30 March 2009 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.a.32655 How to Cite this Article: Bellini C, Hennekam RCM, Fulcheri E, Rutigliani M, Morcaldi G, Boccardo F, Bonioli E. 2009. Etiology of nonimmune hydrops fetalis: A systematic review. Am J Med Genet Part A 149A:844–851. Ó 2009 Wiley-Liss, Inc. 844