301
Journal of Neonatal-Perinatal Medicine 7 (2014) 301–304 DOI 10.3233/NPM-14814026 IOS Press
Case Report
Successful treatment of neonatal hemochromatosis as gestational alloimmune liver disease with intravenous immunoglobulin C. Jimenez-Riveraa,b,∗ , A. Guptab , J. Feberovab,c , J.A. de Nanassyb,d and M.P. Bolanda,b a Division
of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada b University of Ottawa, Ottawa, ON, Canada c Division of Neonatology, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada d Department of Pathology, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
Received 21 March 2014 Revised 5 August 2014 Accepted 12 September 2014
Abstract. Neonatal hemochromatosis (NH) is a rare, often fatal disorder characterized by liver failure and hepatic and extrahepatic iron overload. Clinical manifestations can occur in utero or immediately after birth. Evidence suggests that most cases are due to a gestational disease with transplacental transfer of maternal IgG antibodies targeting the fetal liver resulting in immune injury. The alloimmune target is believed to be a fetal hepatocyte cell surface antigen, with subsequent complement activation resulting in severe loss of hepatocytes and fetal iron overload. This cascade of events leads to acute liver failure and neonatal death. With gestational alloimmune liver disease (GALD) being the mechanism of liver injury in most cases of NH, a new paradigm of treatment with intravenous immunoglobulin (IVIG) and exchange transfusion has been successfully used. We describe an extremely ill newborn with NH successfully treated with three doses of IVIG. Keywords: Liver failure, gestational alloimmune liver disease, neonatal hemochromatosis, intravenous immonoglobulin
1. Introduction Neonatal hemochromatosis (NH) is a rare, often fatal disorder characterized by liver failure and hepatic ∗ Corresponding author: Dr. Carolina Jimenez-Rivera, Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Eastern Ontario, 401 Smyth Rd., K1H 8L1 Ottawa, ON, Canada. Tel.: +1 613 737 7600/Ext: 3367; Fax: +1 613 7384854; E-mail: [email protected].
and extrahepatic iron overload. Clinical manifestations can occur in utero or immediately after birth [1]. Evidence suggests that most cases are due to a gestational disease with transplacental transfer of maternal IgG antibodies targeting the fetal liver resulting in immune injury. The alloimmune target is believed to be a fetal hepatocyte cell surface antigen, with subsequent complement activation resulting in severe loss of hepatocytes and fetal iron overload. This cascade
1934-5798/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
302
C. Jimenez-Rivera et al. / IVIG treatment of neonatal hemochromatosis
of events leads to acute liver failure and neonatal death [2]. With gestational alloimmune liver disease (GALD) being the mechanism of liver injury in most cases of NH, a new paradigm of treatment with intravenous immunoglobulin (IVIG) and exchange transfusion has been successfully used [3]. We describe an extremely ill newborn with NH successfully treated with three doses of IVIG. 2. Case description A male Caucasian baby was born at 36+6 weeks gestational age to a 44-year-old G3 T2 healthy mother. Ultrasound was normal at week 20 of gestation. The baby was delivered by emergency caesarean section due to pre-eclampsia and fetal distress. He was born hydropic with a birth weight of 4845 g and required extensive resuscitation including endotracheal intubation, 15 minutes of chest compressions and 3 doses of Epinephrine. Due to inability to achieve adequate ventilation and oxygenation, bilateral chest tubes were inserted at 2 hours of life to treat pleural effusions. Subsequent acute care included high frequency oscillation, management of persistent pulmonary hypertension with Nitric Oxide, inotropes, blood products and fluid support with glucose and electrolytes. Initial blood work revealed elevated transaminases with marked synthetic dysfunction; ALT was 653 IU/L,
AST was 1996 IU/L, albumin 21 g/L and INR 4.9. Ferritin was >10,500 g/L (Normal range 6.5– 196 g/L) (Table 1). His alpha-feto protein was normal at 15,054 g/L. Abdominal ultrasound demonstrated coarse heterogeneous hepatic parenchyma and severe ascites, which was treated with peritoneal drainage and albumin infusions. Multiple doses of vitamin K and fresh-frozen plasma were given. Investigations for infectious causes such as herpes viruses, viral hepatitis, parvovirus, toxoplasma and blood and urine cultures were all negative. Metabolic disorders including galactosemia, organic acidemia, mucoplysaccharidosis and disorders of bilirubin metabolism amongst others were negative. Given the severity of the clinical condition, NH was suspected and he was treated with three doses of IVIG 1 g/kg (of estimated dry weight 3 kg) at 3, 6 and 17 days of life. Exchange transfusion was considered prior to the first dose however not pursued due to the baby’s Table 1 Biochemical parameters DOL 1 DOL 3 Week 1 Week 2 Week 4 AST (IU/L) ALT (IU/L) Albumin (g/L) Conjugated bilirubin (mol/L) INR
1993 653 21 5
595 219 27 39
47 37 23 47
54 33 16 1
58 43 24 ND
3.5
4.4
1.25
1.1
1.0
DOL: day of life, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ND: none detected, INR: international normalized ratio.
Fig. 1. Liver biopsy. Needle biopsy of liver at 6 weeks of life. PAS, 100X. Extensive fibrosis with scattered groups of hepatocytes and sinusoidal fibrosis (right lower and mid-portion) and focal early bridging fibrosis (left upper).
C. Jimenez-Rivera et al. / IVIG treatment of neonatal hemochromatosis
303
Fig. 2. Iron stain, liver biopsy. Needle biopsy of liver at 6 weeks of life. Iron, 200X. Stainable iron in periportal hepatocytes but not in Kupffer cells.
critical condition and inotrope dependency. Ferritin decreased to 308 g/L; his liver function and overall condition improved one week after the first dose of IVIG. Transaminases and INR normalized 2 weeks after the first dose. Buccal mucosal biopsy (minor salivary glands) at 11 days of age did not reveal iron deposits. Abdominal MRI at 37 days of age failed to show iron deposits in the liver or other organs. Percutaneous liver biopsy at 6 weeks of life revealed extensive fibrosis and slight stainable iron in hepatocytes (Figs. 1 and 2). Additional complications included left diaphragm paralysis. Respiratory support was gradually weaned over 2 months. Karyotype demonstrated a mosaic for trisomy 21. The infant was discharged home at 3 months of age in stable condition on G-tube feeds due to poor oral intake. Liver function at 5 and 7-month follow up has been normal and the G-tube was eventually removed. The patient made significant progress nutritionally and developmentally without evidence of obvious neurological complications. 3. Discussion NH is a severe multiorgan disease manifested as liver failure and it is often fatal without liver transplantation. The outcome with the traditional chelation and antioxidant therapy is very poor and survivors often require liver transplantation in the first 3 months of life. However, the prognosis with medical therapy has improved in recent years as researchers have elucidated that the
mechanism of liver damage is most likely related to an alloimmune process [4]. Reports of infants treated with exchange transfusion and IVIG indicate that survival without liver transplantation improved tremendously [3]. The reasoning behind this therapeutic option comes from clinical experience in treating other alloimmune and/or autoimmune disorders such as thrombocytopenia and lupus; exchange transfusion is used for removal of existing IgG and IVIG is used to block IgG action and interfere with complement activation. Clinical features of NH include hypoglycemia, marked coagulopathy, hypoalbuminemia with edema (+/– ascites), and oliguria [2]. Serum ferritin and ␣-fetoprotein levels are usually elevated [5]. The diagnosis can be challenging as these neonates are quite ill and invasive tests are often deferred. Demonstration of siderosis by imaging, specifically by MRI may help confirm the diagnosis [6]. Identification of stainable iron in extrahepatic tissue can also be helpful as previously reported [7]. A French retrospective review on autopsies of fetuses and neonates diagnosed with NH described that extrahepatic stainable iron was more frequently seen in the thyroid gland than in the pancreas and only one of five cases had positive iron in the minor salivary glands [8]. In our case, we were unable to demonstrate siderosis on extrahepatic tissue either by MRI or by salivary gland biopsy. We speculate this could be related to the fact that these investigations took place after the child was given IVIG and improved clinically.
304
C. Jimenez-Rivera et al. / IVIG treatment of neonatal hemochromatosis
Preventing this condition by identifying at risk pregnancies of previously affected siblings seems to be the current practice. Antenatal IVIG is given to pregnant women starting at 14 weeks gestation [2] or at 18 weeks on a weekly basis until the end of gestation with excellent outcomes. Some of the side effects of IVIG previously reported include fever, hypotension, hypoglycemia and necrotizing enterocolitis amongst others and should be monitored closely [9, 10]. Neonatal hemochromatosis has been previously described in children with trisomy 21 and should be suspected as a cause of liver dysfunction in this clinical setting [11, 12]; in addition, transient myeloproliferative disorder seen in neonates with trisomy 21, could present with hepatic involvement [13, 14], however our case had no features of such condition. This case exemplifies successful therapy with IVIG in a neonate with severe hydrops and multiorgan failure in the presence of elevated serum ferritin highly suspicious for NH. The infant was too ill for exchange transfusion or liver transplantation. Intensive care and supportive therapy were crucial in treating this patient; however IVIG appeared to halt the inflammatory cascade developed by an intrauterine alloimmune process and likely prevented death.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Financial disclosure statement The authors have no conflicts of interest to disclose. This work was not funded by any agency.
[12]
[13]
References [1]
[2]
Whitington PF. Gestational alloimmune liver disease and neonatal hemochromatosis. Semin Liver Dis 2012;32(4): 325-32. Lopriore E, Mearin ML, Oepkes D, Devlieger R, Whitington PF. Neonatal hemochromatosis: Management, outcome, and prevention. Prenat Diagn 2013;33(13):1221-5.
[14]
Babor F, Hadzik B, Stannigel H, Mayatepek E, Hoehn T. Successful management of neonatal hemochromatosis by exchange transfusion and immunoglobulin: A case report. J Perinatol 2013;33(1):83-5. Bonilla S, Prozialeck JD, Malladi P, Pan X, Yu S, MelinAldana H, et al. Neonatal iron overload and tissue siderosis due to gestational alloimmune liver disease. J Hepatol 2012;56(6):1351-5. Rodrigues F, Kallas M, Nash R, Cheeseman P, D’Antiga L, Rela M, et al. Neonatal hemochromatosis–medical treatment vs. transplantation: The king’s experience. Liver Transpl 2005;11(11):1417-24. Udell IW, Barshes NR, Voloyiannis T, Lee TC, Karpen SJ, Carter BA, et al. Neonatal hemochromatosis: Radiographical and histological signs. Liver Transpl 2005;11(8):998-1000. Magliocca KR, Lewis EL, Bhattacharyya I, Cohen DM, Dixon LR. Labial salivary gland biopsy in the investigation of neonatal hemochromatosis. J Oral Maxillofac Surg 2011;69(10):2592-4. Collardeau-Frachon S, Heissat S, Bouvier R, Fabre M, Baruteau J, Broue P, et al. French retrospective multicentric study of neonatal hemochromatosis: Importance of autopsy and autoimmune maternal manifestations. Pediatr Dev Pathol 2012;15(6):450-70. Corvaglia L, Legnani E, Galletti S, Arcuri S, Aceti A, Faldella G. Intravenous immunoglobulin to treat neonatal alloimmune haemolytic disease. J Matern Fetal Neonatal Med 2012;25(12):2782-5. Figueras-Aloy J, Rodriguez-Miguelez JM, Iriondo-Sanz M, Salvia-Roiges MD, Botet-Mussons F, Carbonell-Estrany X. Intravenous immunoglobulin and necrotizing enterocolitis in newborns with hemolytic disease. Pediatrics 2010;125(1):139-44. Cheung PC, Ng WF, Chan AK. Neonatal haemochromatosis associated with Down syndrome. J Paediatr Child Health 1995;31(3):249-52. Neil E, Cortez J, Joshi A, Bawle EV, Poulik J, Zilberman M, et al. Hepatic failure, neonatal hemochromatosis and portopulmonary hypertension in a newborn with trisomy 21–a case report. Ital J Pediatr 2010;36-38. Anuk D, Tarcan A, Alioglu B, Avci Z, Haberal N, Ozyurek E, et al. Hydrops fetalis in a neonate with down syndrome, transient myeloproliferative disorder and hepatic fibrosis. Fetal Pediatr Pathol 2007;26(5-6):223-8. Miyauchi J, Ito Y, Kawano T, Tsunematsu Y, Shimizu K. Unusual diffuse liver fibrosis accompanying transient myeloproliferative disorder in Down’s syndrome: A report of four autopsy cases and proposal of a hypothesis. Blood 1992;80(6):1521-7.
Copyright of Journal of Neonatal -- Perinatal Medicine is the property of IOS Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Journal of Neonatal-Perinatal Medicine 7 (2014) 301–304 DOI 10.3233/NPM-14814026 IOS Press
Case Report
Successful treatment of neonatal hemochromatosis as gestational alloimmune liver disease with intravenous immunoglobulin C. Jimenez-Riveraa,b,∗ , A. Guptab , J. Feberovab,c , J.A. de Nanassyb,d and M.P. Bolanda,b a Division
of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada b University of Ottawa, Ottawa, ON, Canada c Division of Neonatology, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada d Department of Pathology, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
Received 21 March 2014 Revised 5 August 2014 Accepted 12 September 2014
Abstract. Neonatal hemochromatosis (NH) is a rare, often fatal disorder characterized by liver failure and hepatic and extrahepatic iron overload. Clinical manifestations can occur in utero or immediately after birth. Evidence suggests that most cases are due to a gestational disease with transplacental transfer of maternal IgG antibodies targeting the fetal liver resulting in immune injury. The alloimmune target is believed to be a fetal hepatocyte cell surface antigen, with subsequent complement activation resulting in severe loss of hepatocytes and fetal iron overload. This cascade of events leads to acute liver failure and neonatal death. With gestational alloimmune liver disease (GALD) being the mechanism of liver injury in most cases of NH, a new paradigm of treatment with intravenous immunoglobulin (IVIG) and exchange transfusion has been successfully used. We describe an extremely ill newborn with NH successfully treated with three doses of IVIG. Keywords: Liver failure, gestational alloimmune liver disease, neonatal hemochromatosis, intravenous immonoglobulin
1. Introduction Neonatal hemochromatosis (NH) is a rare, often fatal disorder characterized by liver failure and hepatic ∗ Corresponding author: Dr. Carolina Jimenez-Rivera, Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Eastern Ontario, 401 Smyth Rd., K1H 8L1 Ottawa, ON, Canada. Tel.: +1 613 737 7600/Ext: 3367; Fax: +1 613 7384854; E-mail: [email protected].
and extrahepatic iron overload. Clinical manifestations can occur in utero or immediately after birth [1]. Evidence suggests that most cases are due to a gestational disease with transplacental transfer of maternal IgG antibodies targeting the fetal liver resulting in immune injury. The alloimmune target is believed to be a fetal hepatocyte cell surface antigen, with subsequent complement activation resulting in severe loss of hepatocytes and fetal iron overload. This cascade
1934-5798/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
302
C. Jimenez-Rivera et al. / IVIG treatment of neonatal hemochromatosis
of events leads to acute liver failure and neonatal death [2]. With gestational alloimmune liver disease (GALD) being the mechanism of liver injury in most cases of NH, a new paradigm of treatment with intravenous immunoglobulin (IVIG) and exchange transfusion has been successfully used [3]. We describe an extremely ill newborn with NH successfully treated with three doses of IVIG. 2. Case description A male Caucasian baby was born at 36+6 weeks gestational age to a 44-year-old G3 T2 healthy mother. Ultrasound was normal at week 20 of gestation. The baby was delivered by emergency caesarean section due to pre-eclampsia and fetal distress. He was born hydropic with a birth weight of 4845 g and required extensive resuscitation including endotracheal intubation, 15 minutes of chest compressions and 3 doses of Epinephrine. Due to inability to achieve adequate ventilation and oxygenation, bilateral chest tubes were inserted at 2 hours of life to treat pleural effusions. Subsequent acute care included high frequency oscillation, management of persistent pulmonary hypertension with Nitric Oxide, inotropes, blood products and fluid support with glucose and electrolytes. Initial blood work revealed elevated transaminases with marked synthetic dysfunction; ALT was 653 IU/L,
AST was 1996 IU/L, albumin 21 g/L and INR 4.9. Ferritin was >10,500 g/L (Normal range 6.5– 196 g/L) (Table 1). His alpha-feto protein was normal at 15,054 g/L. Abdominal ultrasound demonstrated coarse heterogeneous hepatic parenchyma and severe ascites, which was treated with peritoneal drainage and albumin infusions. Multiple doses of vitamin K and fresh-frozen plasma were given. Investigations for infectious causes such as herpes viruses, viral hepatitis, parvovirus, toxoplasma and blood and urine cultures were all negative. Metabolic disorders including galactosemia, organic acidemia, mucoplysaccharidosis and disorders of bilirubin metabolism amongst others were negative. Given the severity of the clinical condition, NH was suspected and he was treated with three doses of IVIG 1 g/kg (of estimated dry weight 3 kg) at 3, 6 and 17 days of life. Exchange transfusion was considered prior to the first dose however not pursued due to the baby’s Table 1 Biochemical parameters DOL 1 DOL 3 Week 1 Week 2 Week 4 AST (IU/L) ALT (IU/L) Albumin (g/L) Conjugated bilirubin (mol/L) INR
1993 653 21 5
595 219 27 39
47 37 23 47
54 33 16 1
58 43 24 ND
3.5
4.4
1.25
1.1
1.0
DOL: day of life, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ND: none detected, INR: international normalized ratio.
Fig. 1. Liver biopsy. Needle biopsy of liver at 6 weeks of life. PAS, 100X. Extensive fibrosis with scattered groups of hepatocytes and sinusoidal fibrosis (right lower and mid-portion) and focal early bridging fibrosis (left upper).
C. Jimenez-Rivera et al. / IVIG treatment of neonatal hemochromatosis
303
Fig. 2. Iron stain, liver biopsy. Needle biopsy of liver at 6 weeks of life. Iron, 200X. Stainable iron in periportal hepatocytes but not in Kupffer cells.
critical condition and inotrope dependency. Ferritin decreased to 308 g/L; his liver function and overall condition improved one week after the first dose of IVIG. Transaminases and INR normalized 2 weeks after the first dose. Buccal mucosal biopsy (minor salivary glands) at 11 days of age did not reveal iron deposits. Abdominal MRI at 37 days of age failed to show iron deposits in the liver or other organs. Percutaneous liver biopsy at 6 weeks of life revealed extensive fibrosis and slight stainable iron in hepatocytes (Figs. 1 and 2). Additional complications included left diaphragm paralysis. Respiratory support was gradually weaned over 2 months. Karyotype demonstrated a mosaic for trisomy 21. The infant was discharged home at 3 months of age in stable condition on G-tube feeds due to poor oral intake. Liver function at 5 and 7-month follow up has been normal and the G-tube was eventually removed. The patient made significant progress nutritionally and developmentally without evidence of obvious neurological complications. 3. Discussion NH is a severe multiorgan disease manifested as liver failure and it is often fatal without liver transplantation. The outcome with the traditional chelation and antioxidant therapy is very poor and survivors often require liver transplantation in the first 3 months of life. However, the prognosis with medical therapy has improved in recent years as researchers have elucidated that the
mechanism of liver damage is most likely related to an alloimmune process [4]. Reports of infants treated with exchange transfusion and IVIG indicate that survival without liver transplantation improved tremendously [3]. The reasoning behind this therapeutic option comes from clinical experience in treating other alloimmune and/or autoimmune disorders such as thrombocytopenia and lupus; exchange transfusion is used for removal of existing IgG and IVIG is used to block IgG action and interfere with complement activation. Clinical features of NH include hypoglycemia, marked coagulopathy, hypoalbuminemia with edema (+/– ascites), and oliguria [2]. Serum ferritin and ␣-fetoprotein levels are usually elevated [5]. The diagnosis can be challenging as these neonates are quite ill and invasive tests are often deferred. Demonstration of siderosis by imaging, specifically by MRI may help confirm the diagnosis [6]. Identification of stainable iron in extrahepatic tissue can also be helpful as previously reported [7]. A French retrospective review on autopsies of fetuses and neonates diagnosed with NH described that extrahepatic stainable iron was more frequently seen in the thyroid gland than in the pancreas and only one of five cases had positive iron in the minor salivary glands [8]. In our case, we were unable to demonstrate siderosis on extrahepatic tissue either by MRI or by salivary gland biopsy. We speculate this could be related to the fact that these investigations took place after the child was given IVIG and improved clinically.
304
C. Jimenez-Rivera et al. / IVIG treatment of neonatal hemochromatosis
Preventing this condition by identifying at risk pregnancies of previously affected siblings seems to be the current practice. Antenatal IVIG is given to pregnant women starting at 14 weeks gestation [2] or at 18 weeks on a weekly basis until the end of gestation with excellent outcomes. Some of the side effects of IVIG previously reported include fever, hypotension, hypoglycemia and necrotizing enterocolitis amongst others and should be monitored closely [9, 10]. Neonatal hemochromatosis has been previously described in children with trisomy 21 and should be suspected as a cause of liver dysfunction in this clinical setting [11, 12]; in addition, transient myeloproliferative disorder seen in neonates with trisomy 21, could present with hepatic involvement [13, 14], however our case had no features of such condition. This case exemplifies successful therapy with IVIG in a neonate with severe hydrops and multiorgan failure in the presence of elevated serum ferritin highly suspicious for NH. The infant was too ill for exchange transfusion or liver transplantation. Intensive care and supportive therapy were crucial in treating this patient; however IVIG appeared to halt the inflammatory cascade developed by an intrauterine alloimmune process and likely prevented death.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Financial disclosure statement The authors have no conflicts of interest to disclose. This work was not funded by any agency.
[12]
[13]
References [1]
[2]
Whitington PF. Gestational alloimmune liver disease and neonatal hemochromatosis. Semin Liver Dis 2012;32(4): 325-32. Lopriore E, Mearin ML, Oepkes D, Devlieger R, Whitington PF. Neonatal hemochromatosis: Management, outcome, and prevention. Prenat Diagn 2013;33(13):1221-5.
[14]
Babor F, Hadzik B, Stannigel H, Mayatepek E, Hoehn T. Successful management of neonatal hemochromatosis by exchange transfusion and immunoglobulin: A case report. J Perinatol 2013;33(1):83-5. Bonilla S, Prozialeck JD, Malladi P, Pan X, Yu S, MelinAldana H, et al. Neonatal iron overload and tissue siderosis due to gestational alloimmune liver disease. J Hepatol 2012;56(6):1351-5. Rodrigues F, Kallas M, Nash R, Cheeseman P, D’Antiga L, Rela M, et al. Neonatal hemochromatosis–medical treatment vs. transplantation: The king’s experience. Liver Transpl 2005;11(11):1417-24. Udell IW, Barshes NR, Voloyiannis T, Lee TC, Karpen SJ, Carter BA, et al. Neonatal hemochromatosis: Radiographical and histological signs. Liver Transpl 2005;11(8):998-1000. Magliocca KR, Lewis EL, Bhattacharyya I, Cohen DM, Dixon LR. Labial salivary gland biopsy in the investigation of neonatal hemochromatosis. J Oral Maxillofac Surg 2011;69(10):2592-4. Collardeau-Frachon S, Heissat S, Bouvier R, Fabre M, Baruteau J, Broue P, et al. French retrospective multicentric study of neonatal hemochromatosis: Importance of autopsy and autoimmune maternal manifestations. Pediatr Dev Pathol 2012;15(6):450-70. Corvaglia L, Legnani E, Galletti S, Arcuri S, Aceti A, Faldella G. Intravenous immunoglobulin to treat neonatal alloimmune haemolytic disease. J Matern Fetal Neonatal Med 2012;25(12):2782-5. Figueras-Aloy J, Rodriguez-Miguelez JM, Iriondo-Sanz M, Salvia-Roiges MD, Botet-Mussons F, Carbonell-Estrany X. Intravenous immunoglobulin and necrotizing enterocolitis in newborns with hemolytic disease. Pediatrics 2010;125(1):139-44. Cheung PC, Ng WF, Chan AK. Neonatal haemochromatosis associated with Down syndrome. J Paediatr Child Health 1995;31(3):249-52. Neil E, Cortez J, Joshi A, Bawle EV, Poulik J, Zilberman M, et al. Hepatic failure, neonatal hemochromatosis and portopulmonary hypertension in a newborn with trisomy 21–a case report. Ital J Pediatr 2010;36-38. Anuk D, Tarcan A, Alioglu B, Avci Z, Haberal N, Ozyurek E, et al. Hydrops fetalis in a neonate with down syndrome, transient myeloproliferative disorder and hepatic fibrosis. Fetal Pediatr Pathol 2007;26(5-6):223-8. Miyauchi J, Ito Y, Kawano T, Tsunematsu Y, Shimizu K. Unusual diffuse liver fibrosis accompanying transient myeloproliferative disorder in Down’s syndrome: A report of four autopsy cases and proposal of a hypothesis. Blood 1992;80(6):1521-7.
Copyright of Journal of Neonatal -- Perinatal Medicine is the property of IOS Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
