Fetal Anemia of Unknown Cause – A Diagnostic Challenge

 

 Buy Article Permissions and Reprints

Zusammenfassung

Ziel: Ursachenverteilung und Befunde bei transfusionspflichtigen fetalen Anämien unter Berücksichtigung seltener Erkrankungen. Material und Methoden: Retrospektive Auswertung der intrauterinen Erythrozytentransfusionen an zwei Zentren für Pränatale Medizin in 9 Jahren (2002 – 2010). Ergebnisse: Bei 82 Feten wurden 356 intrauterine Erythrozytentransfusionen durchgeführt. Die Ursache fetaler Anämien in unserem Kollektiv waren immunologischer Genese (32), Parvovirus Infektionen (23), feto-fetales Transfusionssyndrom (9), Steißbeinteratom (2) und Cytomegalie-Virus-Infektion (1). Von den 15 fetalen Anämien, deren Ursache pränatal ungeklärt blieb, konnte bei 6 Kindern die Diagnose postnatal gestellt werden (Blackfan-Diamond-Anämie [n = 1], Elliptozytose [n = 1], neonatale Hämochromatose [n = 1], Mukopolysaccharidose Typ VII [n = 1], diffuse neonatale Hämangiomatose [n = 1], Kaposiformes Hämangioendotheliom [n = 1]). In 4 Fällen sprachen Befunde und Verlauf für eine chronische fetomaternale Transfusion. In 5 Fällen blieb die Ursache der fetalen Anämie ungeklärt. Schlussfolgerung: In der großen Mehrzahl der Fälle mit fetalen Anämien lässt sich deren Ursache durch Antikörper-Suchtest und detaillierte sonografische Untersuchung diagnostizieren. Für die verbleibenden Fälle ist es erforderlich, bereits vor der ersten Bluttransfusion umfassende diagnostische Maßnahmen aus dem Fetalblut und maternalen Blut durchzuführen, um die Ursache der Anämie nachweisen zu können.

Abstract

Purpose: To assess the spectrum of underlying diseases in cases of fetal anemia in which the cause was unknown at the time of first and second transfusion or thereafter. Materials and Methods: All patients who underwent intrauterine transfusion were identified in the perinatal databases of two tertiary referral centers for prenatal medicine and treatment between 2002 and June 2010. Results: 82 fetuses received intrauterine transfusion in the study period. A total of 356 transfusions were performed in these patients. The causes of fetal anemia in our cohort were alloimmunization (32), parvovirus infection (23), feto-fetal transfusion syndrome (9), sacrococcygeal teratoma (2) and cytomegalovirus infection (1). In the remaining 15 cases, the cause of fetal anemia was unknown at the time of first and second transfusion, and could only be ascertained in the further course of pregnancy, in the postnatal period or was ultimately left in doubt. In all cases markedly elevated peak systolic velocities in the middle cerebral artery accurately predicted fetal anemia. The final diagnosis in these cases was fetomaternal hemorrhage (4), Blackfan-Diamond anemia (1), diffuse neonatal hemangiomatosis with chorangioma (1), kaposi-like hemangioendothelioma (1), elliptocytosis (1), neonatal hemochromatosis (1), mucopolysaccharidosis type VII (1) and in 5 cases the cause of fetal anemia remained unexplained. The latter 5 cases had an uneventful postnatal course and did not require further transfusions in infancy. Conclusion: In cases of fetal anemia with negative indirect Coombs test and TORCH serology, rare causes of anemia have to be considered. Fetal studies should therefore include reticulocyte count, parameters of hemolysis, peripheral blood smear and fetal liver function tests. Maternal studies should involve a search for fetal red cells using flow cytometry rather than Kleihauer-Betke test.

References

• 1 Macafee C A, Fortune D W, Beischer N A. Non-immunological hydrops fetalis.  J Obstet Gynaecol Br Commonw. 1970;  77 226-237
  Google Scholar
• 2 Sohan K, Carroll S G, De La Fuente S et al. Analysis of outcome in hydrops fetalis in relation to gestational age at diagnosis, cause and treatment.  Acta Obstet Gynecol Scand. 2001;  80 726-730
  Google Scholar
• 3 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
  Google Scholar
• 4 Van der Schoot C E, Soussan A A, Koelewijn J et al. Non-invasive antenatal RHD typing.  Transfus Clin Biol. 2006;  13 53-57
  Google Scholar
• 5 Anandakumar C, Biswas A, Wong Y C et al. Management of non-immune hydrops: 8 years’ experience.  Ultrasound Obstet Gynecol. 1996;  8 196-200
  Google Scholar
• 6 Kamp I L, Klumper F J, Meerman R H et al. Treatment of fetal anemia due to red-cell alloimmunization with intrauterine transfusions in the Netherlands, 1988 – 1999.  Acta Obstet Gynecol Scand. 2004;  83 731-737
  Google Scholar
• 7 Thorp J A, Cohen G R, Yeast J D et al. Nonimmune hydrops caused by massive fetomaternal hemorrhage and treated by intravascular transfusion.  Am J Perinatol. 1992;  9 22-24
  Google Scholar
• 8 Montgomery L D, Belfort M A, Adam van K. Massive fetomaternal hemorrhage treated with serial combined intravascular and intraperitoneal fetal transfusions.  Am J Obstet Gynecol. 1995;  173 234-235
  Google Scholar
• 9 Rubod C, Houfflin V, Belot F et al. Successful in utero treatment of chronic and massive fetomaternal hemorrhage with fetal hydrops.  Fetal Diagn Ther. 2006;  21 410-413
  Google Scholar
• 10 Votino C, Mirlesse V, Gourand L et al. Successful treatment of a severe second trimester fetomaternal hemorrhage by repeated fetal intravascular transfusions.  Fetal Diagn Ther. 2008;  24 503-505
  Google Scholar
• 11 Siemer J, Wendler A, Schild R L et al. Massive fetomaternal hemorrhage and severe anemia in the newborn – two case reports.  Ultraschall in Med. 2010;  31 192-194
  Google Scholar
• 12 Friszer S, Cortey A, Pierre F et al. Using middle cerebral artery peak systolic velocity to time in utero transfusions in fetomaternal hemorrhage.  Obstet Gynecol. 2010;  115 1036-1038
  Google Scholar
• 13 Kleihauer E, Braun H, Betke K. Demonstration of fetal hemoglobin in erythrocytes of a blood smear.  Klin Wochenschr. 1957;  35 637-638
  Google Scholar
• 14 Radel D J, Penz C S, Dietz A B et al. A combined flow cytometry-based method for fetomaternal hemorrhage and maternal D.  Transfusion. 2008;  48 1886-1891
  Google Scholar
• 15 Fernandes B J, Dadelszen von P, Fazal I et al. Flow cytometric assessment of feto-maternal hemorrhage; a comparison with Betke-Kleihauer.  Prenat Diagn. 2007;  27 641-643
  Google Scholar
• 16 Wylie B J, D’Alton M E. Fetomaternal hemorrhage.  Obstet Gynecol. 2010;  115 1039-1051
  Google Scholar
• 17 Rivers A, Slayton W B. Congenital cytopenias and bone marrow failure syndromes.  Semin Perinatol. 2009;  33 20-28
  Google Scholar
• 18 Visser G H, Desmedt M C, Meijboom E J. Altered fetal cardiac flow patterns in pure red cell anaemia (the Blackfan-Diamond syndrome).  Prenat Diagn. 1988;  8 525-529
  Google Scholar
• 19 McLennan A C, Chitty L S, Rissik J et al. Prenatal diagnosis of Blackfan-Diamond syndrome: case report and review of the literature.  Prenat Diagn. 1996;  16 349-353
  Google Scholar
• 20 Van Hook J W, Gill P, Cyr D et al. Diamond-Blackfan anemia as an unusual cause of nonimmune hydrops fetalis: a case report.  J Reprod Med. 1995;  40 850-854
  Google Scholar
• 21 Du J, Gao S, Zhao Y. Clinical analysis of the absent and/or reverse end diastolic velocity of fetal umbilical artery.  Zhonghua Fu Chan Ke Za Zhi. 1999;  34 594-596
  Google Scholar
• 22 Saladi S M, Chattopadhyay T, Adiotomre P N. Nomimmune hydrops fetalis due to Diamond-Blackfan anemia.  Indian Pediatr. 2004;  41 187-188
  Google Scholar
• 23 Dhermy D, Feo C, Garbarz M et al. Prenatal diagnosis of hereditary elliptocytosis with molecular defect of spectrin.  Prenat Diagn. 1987;  7 471-483
  Google Scholar
• 24 Zarkowsky H S. Heat-induced erythrocyte fragmentation in neonatal elliptocytosis.  Br J Haematol. 1979;  41 515-518
  Google Scholar
• 25 Lux S E, Wolfe L C. Inherited disorders of the red cell membrane skeleton.  Pediatr Clin North Am. 1980;  27 463-486
  Google Scholar
• 26 Whitington P F, Hibbard J U. High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis.  Lancet. 2004;  364 1690-1698
  Google Scholar
• 27 Keller M, Scholl-Buergi S, Sergi C et al. An unusual case of intrauterine symptomatic neonatal liver failure.  Klin Padiatr. 2008;  220 32-36
  Google Scholar
• 28 Kassem E, Dolfin T, Litmanowitz I et al. Familial perinatal hemochromatosis: a disease that causes recurrent non-immune hydrops.  J Perinat Med. 1999;  27 122-127
  Google Scholar
• 29 Colletti R B, Clemmons J J. Familial neonatal hemochromatosis with survival.  J Pediatr Gastroenterol Nutr. 1988;  7 39-45
  Google Scholar
• 30 Vervoort R, Islam M R, Sly W S et al. Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII.  Am J Hum Genet. 1996;  58 457-471
  Google Scholar
• 31 Stone D L, Sidransky E. Hydrops fetalis: lysosomal storage disorders in extremis.  Adv Pediatr. 1999;  46 409-440
  Google Scholar
• 32 Cheng Y, Verp M S, Knutel T et al. Mucopolysaccharidosis type VII as a cause of recurrent non-immune hydrops fetalis.  J Perinat Med. 2003;  31 535-537
  Google Scholar
• 33 Venkat-Raman N, Sebire N J, Murphy K W. Recurrent fetal hydrops due to mucopolysaccharidoses type VII.  Fetal Diagn Ther. 2006;  21 250-254
  Google Scholar
• 34 Geipel A, Berg C, Germer U et al. Mucopolysaccharidosis VII (Sly disease) as a cause of increased nuchal translucency and non-immune fetal hydrops: study of a family and technical approach to prenatal diagnosis in early and late pregnancy.  Prenat Diagn. 2002;  22 493-495
  Google Scholar
• 35 Martinez A E, Robinson M J, Alexis J B. Kaposiform hemangioendothelioma associated with nonimmune fetal hydrops.  Arch Pathol Lab Med. 2004;  128 678-681
  Google Scholar
• 36 Walsh M A, Carcao M, Pope E et al. Kaposiform hemangioendothelioma presenting antenatally with a pericardial effusion.  J Pediatr Hematol Oncol. 2008;  30 761-763
  Google Scholar
• 37 Wu T J, Teng R J. Diffuse neonatal haemangiomatosis with intra-uterine haemorrhage and hydrops fetalis: a case report.  Eur J Pediatr. 1994;  153 759-761
  Google Scholar
• 38 Gembruch U, Baschat A A, Gloeckner-Hoffmann K et al. Prenatal diagnosis and management of fetuses with liver hemangiomata.  Ultrasound Obstet Gynecol. 2002;  19 454-460
  Google Scholar
• 39 Sheu B C, Shyu M K, Lin Y F et al. Prenatal diagnosis and corticosteroid treatment of diffuse neonatal hemangiomatosis: case report.  J Ultrasound Med. 1994;  13 495-499
  Google Scholar
• 40 Goodman P, Dominguez R, Castillo M. Diffuse neonatal hemangiomatosis: imaging findings in two patients.  Comput Med Imaging Graph. 1992;  16 117-120
  Google Scholar
• 41 Kamil D, Geipel A, Heep A et al. Prenatal diagnosis and therapy of upper extremity vascular malformation causing high cardiac output and Kasabach-Merritt sequence: a report of two cases.  Ultrasound Obstet Gynecol. 2006;  27 217-219
  Google Scholar
• 42 Moise Jr K J. The usefulness of middle cerebral artery Doppler assessment in the treatment of the fetus at risk for anemia.  Am J Obstet Gynecol. 2008;  198 161, e1-e4
  Google Scholar

Dr. Charlotte Amann

Gynecology and Obstetrics, University Bonn

Sigmund-Freud-Straße 25

53105 Bonn

Germany

Phone:  ++ 49/2 28/28 71 54 49

Fax:  ++ 49/2 28/28 71 54 46

Email: charlotte.amann@ukb.uni-bonn.de