SOGC Clinical Practice Guideline| Volume 40, ISSUE 8, P1077-1090, August 2018

No. 363-Investigation and Management of Non-immune Fetal Hydrops



      To describe the current investigation and management of non-immune fetal hydrops with a focus on treatable or recurring etiologies.


      To provide better counselling and management in cases of prenatally diagnosed non-immune hydrops.


      Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2017 using key words (non-immune hydrops fetalis, fetal hydrops, fetal therapy, fetal metabolism). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, observational studies, and significant case reports. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to September 2017. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinicalpractice guideline collections, clinical trial registries, and national and international medical specialty societies.

      Benefits, Harms, and Costs

      These guidelines educate readers about the causes of non-immune fetal hydrops and its prenatal counselling and management. It also provides a standardized approach to non-immune fetal hydrops, emphasizing the search for prenatally treatable conditions and recurrent genetic etiologies.


      The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care.


      • 1.
        All patients with fetal hydrops should be referred promptly to a tertiary care centre for evaluation. Some conditions amenable to prenatal treatment represent a therapeutic emergency after 18 weeks, allowing prolongation of pregnancy with improved fetal/neonatal outcomes (II-2A).
      • 2.
        Fetal chromosome analysis through array comparative genomic hybridization (microarray) molecular testing should be offered where available in all cases of non-immune fetal hydrops (II-2A).
      • 3.
        Imaging studies should include comprehensive obstetrical ultrasound (including arterial and venous fetal Doppler) and fetal echocardiography (II-2A).
      • 4.
        Investigation for maternal–fetal infections and alpha-thalassemia in women at risk because of their ethnicity should be performed in all cases of unexplained fetal hydrops (II-2A).
      • 5.
        To evaluate the risk of fetal anemia, Doppler measurement of the middle cerebral artery peak systolic velocity should be performed in all hydropic fetuses after 16 weeks of gestation. In case of suspected fetal anemia, fetal blood sampling and intrauterine transfusion should be offered rapidly (II-2A).
      • 6.
        All cases of unexplained fetal hydrops should be referred to a medical genetics service where available. Detailed postnatal evaluation by a medical geneticist should be performed on all cases of newborns with unexplained non-immune hydrops (II-2A).
      • 7.
        Autopsy is strongly recommended for all cases of fetal or neonatal death for which no diagnosis is reached prenatally (II-2A).

      Key Words


      AF (amniotic fluid), CBC (complete blood count), CMV (cytomegalovirus), DNA (deoxyribonucleic acid), ELISA (enzyme-linked immunosorbent assay), FISH (fluorescent in situ hybridization), GA (gestational age), Hb (hemoglobin), HbH (hemoglobin H), HIV (human immunodeficiency virus), IgG (immunoglobulin G), IgM (immunoglobulin M), MCA (middle cerebral artery), MPS (mucopolysaccharidosis), NIHF (non-immune hydrops fetalis), QF-PCR (quantitative fluorescent polymerase chain reaction), RT-PCR (real-time polymerase chain reaction), SOGC (Society of Obstetricians and Gynaecologists of Canada), TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex), UA (umbilical artery)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Obstetrics and Gynaecology Canada
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Machin G.A.
        Hydrops revisited: literature review of 1414 cases published in the 1980s.
        Am J Med Genet. 1989; 34: 366-390
        • Machin G.A.
        Hydrops, cystic hygroma, hydrothorax, pericardial effusion and fetal ascites.
        in: Gilbert-Barness E. Potter's pathology of the fetus and infant. Mosby, St-Louis1997
        • Fung Kee Fung K.
        • Eason E.
        • Crane J.
        • et al.
        Prevention of Rh alloimmunization. SOGC clinical practice guidelines, no. 133, September 2003.
        J Obstet Gynaecol Can. 2003; 25
        • Mari G.
        • Deter R.L.
        • Carpenter R.L.
        • et al.
        Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses.
        N Engl J Med. 2000; 342: 9-14
        • Hansen T.
        Non immune hydrops fetalis.
        in: Rudolph A. Kamei R. Overby K. Rudolph's pediatrics. 21st ed. McGraw-Hill, 2003
        • Ismail K.M.
        • Martin W.L.
        • Ghosh S.
        • et al.
        Etiology and outcome of hydrops fetalis.
        J Matern Fetal Med. 2001; 10: 175-181
        • Milunsky A.
        Genetic disorders of the fetus: diagnosis, prevention and treatment.
        5th ed. John Hopkins University Press, Baltimore2004
        • Kharrat R.
        • Yamamoto M.
        • Roume J.
        • et al.
        Karyotype and outcome of fetuses diagnosed with cystic hygroma in the first trimester in relation to nuchal translucency thickness.
        Prenat Diagn. 2006; 26: 369-372
        • Molina F.S.
        • Avgidou K.
        • Kagan K.O.
        • et al.
        Cystic hygromas, nuchal edema, and nuchal translucency at 11–14 weeks of gestation.
        Obstet Gynecol. 2006; 107: 678-683
        • Desilets V.
        • Oligny L.L.
        • et al.
        • Genetics Committee of the Society of Obstetricians and Gynaecology Canada
        Fetal and perinatal autopsy in prenatally diagnosed fetal abnormalities with normal karyotype.
        J Obstet Gynaecol Can. 2011; 33: 1047-1057
        • Gagnon A.
        • Wilson R.D.
        • Allen V.M.
        • et al.
        Evaluation of prenatally diagnosed structural congenital anomalies.
        J Obstet Gynaecol Can. 2009; 31 (82–9): 875-881
        • Chitayat D.
        • Langlois S.
        • Wilson R.D.
        • et al.
        Prenatal screening for fetal aneuploidy in singleton pregnancies.
        J Obstet Gynaecol Can. 2011; 33: 736-750
        • Audibert F.
        • De Bie I.
        • Johnson J.A.
        • et al.
        No. 348-Joint SOGC-CCMG guideline: update on prenatal screening for fetal aneuploidy, fetal anomalies, and adverse pregnancy outcomes.
        J Obstet Gynaecol Can. 2017; 39: 805-817
        • Morin L.
        • Lim K.
        Ultrasound in twin pregnancies.
        J Obstet Gynaecol Can. 2011; 33: 643-656
        • Senat M.V.
        • Deprest J.
        • Boulvain M.
        • et al.
        Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome.
        N Engl J Med. 2004; 351: 136-144
        • Yamamoto M.
        • Ville Y.
        Twin-to-twin transfusion syndrome: management options and outcomes.
        Clin Obstet Gynecol. 2005; 48: 973-980
        • Chalouhi G.E.
        • Stirnemann J.J.
        • Salomon L.J.
        • et al.
        Specific complications of monochorionic twin pregnancies: twin-twin transfusion syndrome and twin reversed arterial perfusion sequence.
        Semin Fetal Neonatal Med. 2010; 15: 349-356
        • Audibert F.
        • Gagnon A.
        • et al.
        • Genetics Committee of the Society of Obstetricians and Gynaecology Canada
        Prenatal screening for and diagnosis of aneuploidy in twin pregnancies.
        J Obstet Gynaecol Can. 2011; 33: 754-767
        • Bellini C.
        • Hennekam R.C.
        • Bonioli E.
        A diagnostic flow chart for non-immune hydrops fetalis.
        Am J Med Genet A. 2009; 149A: 852-853
        • McCoy M.C.
        • Katz V.L.
        • Gould N.
        • et al.
        Non-immune hydrops after 20 weeks' gestation: review of 10 years' experience with suggestions for management.
        Obstet Gynecol. 1995; 85: 578-582
        • Santo S.
        • Mansour S.
        • Thilaganathan B.
        • et al.
        Prenatal diagnosis of non-immune hydrops fetalis: what do we tell the parents?.
        Prenat Diagn. 2011; 31: 186-195
        • Bellini C.
        • Donarini G.
        • Paladini D.
        • et al.
        Etiology of non-immune hydrops fetalis: an update.
        Am J Med Genet A. 2015; 167A: 1082-1088
        • Derderian S.C.
        • Jeanty C.
        • Fleck S.R.
        • et al.
        The many faces of hydrops.
        J Pediatr Surg. 2015; 50 (discussion 4): 50-54
        • Braun T.
        • Brauer M.
        • Fuchs I.
        • et al.
        Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome.
        Fetal Diagn Ther. 2010; 27: 191-203
        • Jauniaux E.
        • Van Maldergem L.
        • De Munter C.
        • et al.
        Nonimmune hydrops fetalis associated with genetic abnormalities.
        Obstet Gynecol. 1990; 75: 568-572
        • Has R.
        Non-immune hydrops fetalis in the first trimester: a review of 30 cases.
        Clin Exp Obstet Gynecol. 2001; 28: 187-190
        • Wapner R.J.
        • Driscoll D.A.
        • Simpson J.L.
        Integration of microarray technology into prenatal diagnosis: counselling issues generated during the NICHD clinical trial.
        Prenat Diagn. 2012; 32: 396-400
        • Klein J.B.
        • Baker C.J.
        • Remington J.S.
        • et al.
        Current concepts of infections of the fetus and newborn infant.
        in: Remington J.S. Klein J.O. Wilson C.B. Baker C.J. Infectious diseases of the fetus and newborn infant. Elsevier Saunders, Philadelphia2006
        • Knilans T.K.
        Cardiac abnormalities associated with hydrops fetalis.
        Semin Perinatol. 1995; 19: 483-492
        • de Jong E.P.
        • Walther F.J.
        • Kroes A.C.
        • et al.
        Parvovirus B19 infection in pregnancy: new insights and management.
        Prenat Diagn. 2011; 31: 419-425
        • Crino J.P.
        Ultrasound and fetal diagnosis of perinatal infection.
        Clin Obstet Gynecol. 1999; 42 (quiz 174–5): 71-80
        • Liao C.
        • Xie X.M.
        • Li D.Z.
        Two cases of homozygous alpha0-thalassemia diagnosed prenatally in pregnancies at risk for beta-thalassemia in China.
        Ultrasound Obstet Gynecol. 2007; 29: 474-475
        • Negishi H.
        • Yamada H.
        • Okuyama K.
        • et al.
        Outcome of non-immune hydrops fetalis and a fetus with hydrothorax and/or ascites: with some trials of intrauterine treatment.
        J Perinat Med. 1997; 25: 71-77
        • Yong P.J.
        • Von Dadelszen P.
        • Carpara D.
        • et al.
        Prediction of pediatric outcome after prenatal diagnosis and expectant antenatal management of congenital cystic adenomatoid malformation.
        Fetal Diagn Ther. 2012; 31: 94-102
        • Isaacs Jr, H.
        Fetal hydrops associated with tumors.
        Am J Perinatol. 2008; 25: 43-68
        • Norton M.E.
        Nonimmune hydrops fetalis.
        Semin Perinatol. 1994; 18: 321-332
        • Kooper A.J.
        • Janssens P.M.
        • de Groot A.N.
        • et al.
        Lysosomal storage diseases in non-immune hydrops fetalis pregnancies.
        Clin Chim Acta. 2006; 371: 176-182
        • Gort L.
        • Granell M.R.
        • Fernandez G.
        • et al.
        Fast protocol for the diagnosis of lysosomal diseases in nonimmune hydrops fetalis.
        Prenat Diagn. 2012; 32: 1139-1142
        • L'Hermine-Coulomb A.
        • Beuzen F.
        • Bouvier R.
        • et al.
        Fetal type IV glycogen storage disease: clinical, enzymatic, and genetic data of a pure muscular form with variable and early antenatal manifestations in the same family.
        Am J Med Genet A. 2005; 139A: 118-122
        • Venkat-Raman N.
        • Sebire N.J.
        • Murphy K.W.
        Recurrent fetal hydrops due to mucopolysaccharidoses type VII.
        Fetal Diagn Ther. 2006; 21: 250-254
        • Carvalho S.
        • Martins M.
        • Fortuna A.
        • et al.
        Galactosialidosis presenting as nonimmune fetal hydrops: a case report.
        Prenat Diagn. 2009; 29: 895-896
      1. Saudubray J. van den Burgh G. Walter J.H. Inborn metabolic diseases: diagnosis and treatment. Springer-Verlag, Berlin2007
        • Valayannopoulos V.
        • Verhoeven N.M.
        • Mention K.
        • et al.
        Transaldolase deficiency: a new cause of hydrops fetalis and neonatal multi-organ disease.
        J Pediatr. 2006; 149: 713-717
        • Burin M.G.
        • Scholz A.P.
        • Gus R.
        • et al.
        Investigation of lysosomal storage diseases in nonimmune hydrops fetalis.
        Prenat Diagn. 2004; 24: 653-657
        • Stone D.L.
        • Sidransky E.
        Hydrops fetalis: lysosomal storage disorders in extremis.
        Adv Pediatr. 1999; 46: 409-440
        • Sheth J.
        • Mistri M.
        • Shah K.
        • et al.
        Lysosomal storage disorders in Nonimmune Hydrops Fetalis (NIHF): an Indian experience.
        JIMD Rep. 2017; 35: 47-52
        • Whybra C.
        • Mengel E.
        • Russo A.
        • et al.
        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.
        Orphanet J Rare Dis. 2012; 7: 86
        • Huhta J.C.
        Guidelines for the evaluation of heart failure in the fetus with or without hydrops.
        Pediatr Cardiol. 2004; 25: 274-286
        • Hernandez-Andrade E.
        • Scheier M.
        • Dezerega V.
        • et al.
        Fetal middle cerebral artery peak systolic velocity in the investigation of non-immune hydrops.
        Ultrasound Obstet Gynecol. 2004; 23: 442-445
        • Mari G.
        Middle cerebral artery peak systolic velocity for the diagnosis of fetal anemia: the untold story.
        Ultrasound Obstet Gynecol. 2005; 25: 323-330
        • Cosmi E.
        • Dessole S.
        • Uras L.
        • et al.
        Middle cerebral artery peak systolic and ductus venosus velocity waveforms in the hydropic fetus.
        J Ultrasound Med. 2005; 24: 209-213
        • Hofstaetter C.
        • Hansmann M.
        • Eik-Nes S.H.
        • et al.
        A cardiovascular profile score in the surveillance of fetal hydrops.
        J Matern Fetal Neonatal Med. 2006; 19: 407-413
        • Pajkrt E.
        • Weisz B.
        • Firth H.V.
        • et al.
        Fetal cardiac anomalies and genetic syndromes.
        Prenat Diagn. 2004; 24: 1104-1115
        • Eliasson H.
        • Sonesson S.E.
        • Sharland G.
        • et al.
        Isolated atrioventricular block in the fetus: a retrospective, multinational, multicenter study of 175 patients.
        Circulation. 2011; 124: 1919-1926
        • Fouron J.C.
        Fetal arrhythmias: the Saint-Justine hospital experience.
        Prenat Diagn. 2004; 24: 1068-1080
        • Berg C.
        • Geipel A.
        • Kohl T.
        • et al.
        Atrioventricular block detected in fetal life: associated anomalies and potential prognostic markers.
        Ultrasound Obstet Gynecol. 2005; 26: 4-15
        • Mendelson E.
        • Aboudy Y.
        • Smetana Z.
        • et al.
        Laboratory assessment and diagnosis of congenital viral infections: Rubella, cytomegalovirus (CMV), varicella-zoster virus (VZV), herpes simplex virus (HSV), parvovirus B19 and human immunodeficiency virus (HIV).
        Reprod Toxicol. 2006; 21: 350-382
        • Abdel-Fattah S.A.
        • Bhat A.
        • Illanes S.
        • et al.
        TORCH test for fetal medicine indications: only CMV is necessary in the United Kingdom.
        Prenat Diagn. 2005; 25: 1028-1031
        • Enders M.
        • Weidner A.
        • Zoellner I.
        • et al.
        Fetal morbidity and mortality after acute human parvovirus B19 infection in pregnancy: prospective evaluation of 1018 cases.
        Prenat Diagn. 2004; 24: 513-518
        • Enders M.
        • Schalasta G.
        • Baisch C.
        • et al.
        Human parvovirus B19 infection during pregnancy–value of modern molecular and serological diagnostics.
        J Clin Virol. 2006; 35: 400-406
        • Crane J.
        • Mundle W.
        • Boucoiran I.
        • et al.
        Parvovirus B19 infection in pregnancy.
        J Obstet Gynaecol Can. 2014; 36: 1107-1116
        • Yinon Y.
        • Farine D.
        • Yudin M.H.
        • et al.
        Cytomegalovirus infection in pregnancy.
        J Obstet Gynaecol Can. 2010; 32: 348-354
        • Yinon Y.
        • Farine D.
        • Yudin M.H.
        Screening, diagnosis, and management of cytomegalovirus infection in pregnancy.
        Obstet Gynecol Surv. 2010; 65: 736-743
        • Lazzarotto T.
        • Gabrielli L.
        • Foschini M.P.
        • et al.
        Congenital cytomegalovirus infection in twin pregnancies: viral load in the amniotic fluid and pregnancy outcome.
        Pediatrics. 2003; 112: e153-e157
        • Harger J.H.
        • Ernest J.M.
        • Thurnau G.R.
        • et al.
        Frequency of congenital varicella syndrome in a prospective cohort of 347 pregnant women.
        Obstet Gynecol. 2002; 100: 260-265
        • Mouly F.
        • Mirlesse V.
        • Meritet J.F.
        • et al.
        Prenatal diagnosis of fetal varicella-zoster virus infection with polymerase chain reaction of amniotic fluid in 107 cases.
        Am J Obstet Gynecol. 1997; 177: 894-898
        • Bachmaier N.
        • Fusch C.
        • Stenger R.D.
        • et al.
        Nonimmune hydrops fetalis due to enterovirus infection.
        Eur J Obstet Gynecol Reprod Biol. 2009; 142: 83-84
        • Langlois S.
        • Ford J.C.
        • Chitayat D.
        • et al.
        Carrier screening for thalassemia and hemoglobinopathies in Canada.
        J Obstet Gynaecol Can. 2008; 30: 950-971
        • Dwinnell S.J.
        • Coad S.
        • Butler B.
        • et al.
        In Utero diagnosis and management of a fetus with homozygous alpha-Thalassemia in the second trimester: a case report and literature review.
        J Pediatr Hematol Oncol. 2011; 33: e358-e360
        • Ramsay S.L.
        • Maire I.
        • Bindloss C.
        • et al.
        Determination of oligosaccharides and glycolipids in amniotic fluid by electrospray ionisation tandem mass spectrometry: in utero indicators of lysosomal storage diseases.
        Mol Genet Metab. 2004; 83: 231-238
        • Edwards M.
        • McKenzie F.
        • O'Callaghan S.
        • et al.
        Prenatal diagnosis of congenital disorder of glycosylation type Ia (CDG-Ia) by cordocentesis and transferrin isoelectric focussing of serum of a 27-week fetus with non-immune hydrops.
        Prenat Diagn. 2006; 26: 985-988
        • Acar A.
        • Balci O.
        • Gezginc K.
        • et al.
        Evaluation of the results of cordocentesis.
        Taiwan J Obstet Gynecol. 2007; 46: 405-409
        • Gedikbasi A.
        • Oztarhan K.
        • Gunenc Z.
        • et al.
        Preeclampsia due to fetal non-immune hydrops: mirror syndrome and review of literature.
        Hypertens Pregnancy. 2011; 30: 322-330
        • Kelly T.
        • Mathers A.
        Early presentation and spontaneous resolution of hydrops fetalis, secondary to parvovirus B19 infection.
        J Obstet Gynaecol. 1998; 18: 190-191
        • Iskaros J.
        • Jauniaux E.
        • Rodeck C.
        Outcome of nonimmune hydrops fetalis diagnosed during the first half of pregnancy.
        Obstet Gynecol. 1997; 90: 321-325
        • Ayida G.A.
        • Soothill P.W.
        • Rodeck C.H.
        Survival in non-immune hydrops fetalis without malformation or chromosomal abnormalities after invasive treatment.
        Fetal Diagn Ther. 1995; 10: 101-105
        • Abrams M.E.
        • Meredith K.S.
        • Kinnard P.
        • et al.
        Hydrops fetalis: a retrospective review of cases reported to a large national database and identification of risk factors associated with death.
        Pediatrics. 2007; 120: 84-89
        • Huang B.R.
        • Liao C.C.
        • Huang W.H.
        • et al.
        Prognostic factors of spontaneous intracerebral haemorrhage in haemodialysis patients and predictors of 30-day mortality.
        Intern Med J. 2008; 38: 568-574
        • Breur J.M.
        • Gooskens R.H.
        • Kapusta L.
        • et al.
        Neurological outcome in isolated congenital heart block and hydrops fetalis.
        Fetal Diagn Ther. 2007; 22: 457-461
        • Rodriguez M.M.
        • Bruce J.H.
        • Jimenez X.F.
        • et al.
        Nonimmune hydrops fetalis in the liveborn: series of 32 autopsies.
        Pediatr Dev Pathol. 2005; 8: 369-378