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A Diagnostic Flow Chart for Non-Immune Hydrops Fetalis

Carlo Bellini,1* Raoul C.M. Hennekam,2 and Eugenio Bonioli1
1 2

Department of Pediatrics, University of Genoa, Gaslini Institute, Genova, Italy

Institute of Child Health, Great Ormond Street Hospital for Children, University College London, London, UK and Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Received 21 October 2008; Accepted 30 October 2008

Hydrops fetalis is a condition characterized by abnormal accumulation of uid in two o more fetal compartment. It can include the presence of ascites, pleural effusion, pericardial effusion, and skin edema and it can also be associated with polyhydramnios and placental edema. In the accompanying paper we have reviewed the etiology of nonimmune hydrops fetalis extensively, and have described a wide range of associated anomalies [Bellini et al., in press]. Despite extensive pre- and postnatal investigations, including postmortem pathological examination of the fetus, we found that no denite cause can be found in 17% of cases of nonimmune hydrops. Based on the results of our review, we present here a ow-chart aimed to provide guidance in diagnosing the cause of nonimmune hydrops, both if detected prenatally and postnatally (Fig. 1). We hope that the diagnostic ow chart will facilitate the diagnostic process. Despite progress in diagnostics and therapeutic possibilities the mortality in nonimmune hydrops fetalis remains extremely high [Abrams et al., 2007]. Individual perinatal and neonatal centers will usually encounter only a limited number of patients which will prevent reliable comparisons of sufciently high numbers of results, both with respect to diagnoses and management strategies. Multicenter, collaborative studies will be a prerequisite for such studies. Further classications of patients according to diagnoses, increased insight in pathophysiologic mechanisms, and studies of results of diagnostic and therapeutic strategies, will ultimately lead to the best possible cure.

How to Cite this Article:

Bellini C, Hennekam RCM, Bonioli E. 2009. A diagnostic ow chart for non-immune hydrops fetalis. Am J Med Genet Part A 149A:852853.

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 (in press). Ergaz Z, Ornoy A. 2006. Parvovirus B19 in pregnancy. Reprod Toxicol 21:421435. Hall J, Allanson J, Gripp K, Slavotinek A. 2007. Handbook of physical measurement, 2nd edition. Berlin-Heidelberg, Germany: Springer Verlag. Kooper AJ, Janssens PM, de Groot AN, Liebrand-van Sambeek ML, van den Berg CJ, Tan-Sindhunata GB, van den Berg PP, Bijlsma EK, Smits AP, Wevers RA. 2006. Lysosomal storage diseases in non-immune hydrops fetalis pregnancies. Clin Chim Acta 371:176182. van Spronsen FJ, Molendijk H, Erwich JJ, Smit G. 2003. Inherited metabolic diseases and pregnancy: Consequences for mother and child. Ned Tijdschr Geneeskd 147:235240. Wainwright HC. 2006. My approach to performing a perinatal or neonatal autopsy. J Clin Pathol 59:673680.

Abrams ME, Meredith KS, Kinnard P, Clark RH. 2007. Hydrops fetalis: A retrospective review of cases reported to a large national database and identication of risk factors associated with death. Pediatrics 120:8489. Ayed K, Gorgi Y, Sfar I, Khrouf M. 2004. Congenital heart block associated with maternal anti SSA/SSB antibodies: A report of four cases. Pathol Biol (Paris) 52:138147. *Correspondence to: Carlo Bellini, M.D., Ph.D., Department of Pediatrics, University of Genoa, Gaslini Institute, Largo G. Gaslini 5, 16147 Genoa, Italy. E-mail: Published online 30 March 2009 in Wiley InterScience ( DOI 10.1002/ajmg.a.32677

2009 Wiley-Liss, Inc.




FIG. 1. Diagnostic ow chart for prenatal and postnatal hydrops fetalis. (1) Maternal history. Consider: collagen-vascular diseases, organ transplant, blunt abdominal
trauma, coagulopathies, sexually transmitted disorders, thyroid disorders, diabetes mellitus, viral infections, teratogenics through occupation, pets or place of living, and jaundice in other family member. Consider maternal medication use: indomethacin, sodium diclofenac, or potentially teratogenic drugs during pregnancy; prior administration of blood product; risks of illicit drug use. Determine ethnicity, and chances for hemoglobinopathies in the population from which parents originate. Exclude immune hydrops. Check history of previous pregnancies: jaundice in previous child, twin-to-twin tranfusion syndrome (TTTS) (see point 4), genetic disorders in earlier fetuses and children, chromosomal abnormalities, inborn errors of metabolism (see point 12), congenital malformations, cardiac defects, fetal death, polydramnios, TORCHES-CLAP (see point 14) [Ergaz and Ornoy, 2006]. (2) Maternal blood and invasive testing Blood cell count, blood grouping and Rh, Hb electrophoresis, Kleihauer-Betke test, erythrocytic enzymes (include at least G6PD, pyruvate kinase, and glucose phosphate isomerase), TORCHES-CLAP, serum alphafetoprotein, maternal anti-SSA/SSB antibodies [Ayed et al., 2004], karyotype, DNA storage, inborn errors of metabolism, total body scan, and MRI. (3) Autopsy. The value of autopsy can not be overestimated [Wainwright, 2006]. If consent to autopsy is refused, a total body MRI may be a non-invasive and acceptable alternative for the family involved. (4) TTTS. Twin-to-twin transfusion syndrome, including acardiac parasitic twin. (5) Fetal measurements. Length, weight and skull circumference are obligatory. Foot length can be used to determine gestational age [Hall et al., 2007]. Other useful measurements can be inner canthal distance, outer canthal distances, philtrum length, and ear length. In severe hydrops some of the obtained values may be unreliable. (6) Photograhic documentation. A full body picture, facial pictures in two directions, and pictures of any other structure that seems abnormal can be an important tool in diagnosis. Digital photographs are advisable as such pictures can be more easily used in consultations. (7) Total body X-ray scan. A total body radiograph in two directions is useful, and will allow diagnosis of most skeletal dysplasias and dysostoses. Detailed views of the hands and feet should be made if the suspicion of a skeletal dysplasia or dysostosis is high. (8) Skin for broblast culturing. A skin specimen (diameter 35 mm) should be collected and placed in culture medium. If culture media are unavailable, the skin specimen can be placed in sterile saline for a short time only. Do not allow specimen to freeze. It is our experience ear cartilage is usually the tissue that remains the longest viable. If there is intrauterine demise and delivery will be induced using prostaglandins it is advisable to obtain amnion cells before induction of the delivery, as growth of broblasts is usually very poor after prostaglandins. (9) Frozen tissue storage. Include specimen from muscle, heart, brain, liver, intestine, kidney, peripheral nerve, bone marrow, conjunctiva, amniocytes, and placenta. The specimens should be frozen as soon as possible at 70 C if available, or otherwise at 20 C. Tissue specimens should be stored in a non-xed way and not treated with a preservative. (10) Fluid storages. Parental informed consent. Include plasma, blood, urine, visceral effusion, bile, cerebrospinal uid. Use lter paper for adjunctive storage; the specimen should be allowed to dry. Post-mortem blood specimen collection is possible during many hours after demise by intracardiac puncture. Urine may be obtained by swabbing the bladder. Bile collection is obtained by direct gallbladder puncture. Cerebrospinal uid collection is obtained by anterior fontanel puncture. (11) Immunohistochemical studies. Routine staining on ve microtome sections, using as monoclonal antibodies at least a CD 31 antibody, a CD 34 antibody, a Smooth muscle actin antibody, and Podoplanin (D2-40) is advisable. Inclusion of specimens from the nuchal region is useful. (12) Inborn errors of metabolism testing. Consider lysosomal storage diseases: lysosomal enzyme and molecular analysis in cultured amniocytes or cell line from trophoblast [van Spronsen et al., 2003; Kooper et al., 2006]. Hydrops fetalis has been described in Gaucher disease, type II, Morquio disease, Hurler syndrome, Sly syndrome, Farber disease, GM1 gangliosidosis, I-cell disease, Niemann-Pick disease type A and type C, Infantile Sialic Acid Storage disorder, alpha-neuroaminidase deciency, multiple sulfatase deciency, and Wolman disease. Consider also non-lysosomal diseases, including Glycogenosis type IV, long-chain hydroxy-acyl CoA dehydrogenase deciency, CDG type1a, CDG type I/IX, hypothyroidism, Carnitine deciency, and Smith-LemliOpitz syndrome. (13) Fetal blood testng. Consider: fetal karyotype, fetal complete blood count, hemoglobin electrophoresis, TORCHES-CLAP, fetal albumin, and inborn errors of metabolism. (14) TORCHES-CLAP. TOxoplasma gondii; Rubella virus; Cytomegalovirus; Herpes simplex virus; Enterovirus; Syphilis; Chickenpox [varicella-zoster] virus; Lyme disease [borrelia burgdoferi]; Aids; Parvovirus B19.