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ADC-FNN Online First, published on February 10, 2014 as 10.1136/archdischild-2013-304878 Review
Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis Deepak Louis,1 Kiran More,2 Sapna Oberoi,3 Prakesh S Shah1,4,5 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ archdischild-2013-304878). 1
Division of Neonatology, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada 2 Division of Neonatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada 3 Division of Pediatric Hematooncology, The Hospital for Sick Children, Toronto, Ontario, Canada 4 Departments of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada 5 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada Correspondence to Dr Prakesh S Shah, Department of Paediatrics, Mount Sinai Hospital, 775A-600 University Ave, Toronto, Ontario, Canada M5G 1X5; [email protected] Received 17 July 2013 Revised 14 January 2014 Accepted 19 January 2014
ABSTRACT Background Intravenous immunoglobulin (IVIg) is used in neonates with isoimmune haemolytic disease to prevent exchange transfusion (ET). However, studies supporting IVIg had methodological issues. Objective To update the systematic review of efficacy and safety of IVIg in neonates with isoimmune haemolytic disease. Methods MEDLINE, Embase databases and Cochrane Central Register of Controlled Trials (Cochrane Library) were searched (from inception to May 2013) for randomised or quasi-randomised controlled trials comparing IVIg with placebo/controls in neonates with isoimmune haemolytic disease without any language restriction. Three investigators assessed methodological quality of included trials. Meta-analyses were performed using random effect model and risk ratio (RR)/risk difference (RD) and mean difference with 95% CI calculated. Main results Twelve studies were included, ten trials (n=463) of Rh isoimmunisation and five trials (n=350) of ABO isoimmunisation (three studies had both population). Significant variations in risk of bias precluded an overall meta-analysis of Rh isoimmunisation. Studies with high risk of bias showed that IVIg reduced the rate of ET in Rh isoimmunisation (RR 0.23, 95% CI 0.13 to 0.40), whereas studies with low risk of bias that also used prophylactic phototherapy did not show statistically significant difference (RR 0.82, 95% CI 0.53 to 1.26). For ABO isoimmunisation, only studies with high risk of bias were available and metaanalysis revealed efficacy of IVIg in reducing ET (RR 0.31, 95% CI 0.18 to 0.55). Conclusions Efficacy of IVIg is not conclusive in Rh haemolytic disease of newborn with studies with low risk of bias indicating no benefit and studies with high risk of bias suggesting benefit. Role of IVIg in ABO disease is not clear as studies that showed a benefit had high risk of bias.
INTRODUCTION
To cite: Louis D, More K, Oberoi S, et al. Arch Dis Child Fetal Neonatal Ed Published Online First: [please include Day Month Year] doi:10.1136/ archdischild-2013-304878
Isoimmune haemolytic disease of fetus and newborn (HDFN) is characterised by breakdown of fetal and newborn red blood cells (RBCs) due to transplacentally derived maternal antibodies. These maternal antibodies might be naturally occurring or may arise following previous sensitisation.1 Haemolytic disease presents with anaemia and hydrops in fetuses or with anaemia and jaundice in neonates. Rhesus (Rh) and ABO isoimmunisation remain the two most important aetiologies of HDFN. The most dreaded complication of isoimmunisation is acute bilirubin encephalopathy, and
the main goal of management is to prevent this complication. Conventional treatment for isoimmunisation includes phototherapy and exchange transfusion (ET). Phototherapy is a relatively benign therapy; however, ET is not an innocuous procedure and is associated with mortality as well as morbidities such as catheter-related complications, thrombocytopenia and infections.2–5 Recently, intravenous immunoglobulin (IVIg) has emerged as a therapeutic modality in neonates with HDFN.6 It acts by blocking Fc receptors on macrophages thereby reducing the breakdown of antibody-coated RBCs and also enhancing the clearance of maternal antibodies.7 Few randomised controlled trials (RCT) have shown its efficacy in decreasing the need for ET, but they had moderate to high risk of bias and a majority of them were conducted prior to the current era of high-intensity phototherapy.8–13 IVIg is a blood product derived from healthy human donors, and the side effects include transfusion reactions, possibility of transmitting infectious diseases,14 a reported association with necrotising enterocolitis15–19 and can cause acute renal failure secondary to haemolysis.20 Previous meta-analyses, despite supporting the use of IVIg, emphasised the need for larger studies to confirm its benefits in HDFN.21–23 Recent RCTs of IVIg in neonatal Rh disease cast doubt on its efficacy as there was no difference in the rates of ET.24 25 It was argued that the efficacy for IVIg in the face of prophylactic and aggressive phototherapy in cases with antenatal diagnosis or suspicion is questionable. Thus, in this updated meta-analysis, we aimed to systematically review the efficacy and safety of IVIg in Rh and ABO haemolytic disease in newborn.
MATERIALS AND METHODS Study questions 1. What is the efficacy and safety of IVIg in neonates with Rh incompatibility? 2. What is the efficacy and safety of IVIg in neonates with ABO incompatibility? Standard methods were used for performing this systematic review and PRISMA guidelines were used for reporting.26
Study selection RCTs and quasi-RCTs were included in this review. Case–control, cohort studies, case reports, case series, letters to editors, editorials, review articles and commentaries were excluded, but were read to identify other potential studies. Duplicate reports not providing additional information were excluded.
Louis D, etArticle al. Arch Disauthor Child Fetal(or Neonatal 2014;0:F1–F7. doi:10.1136/archdischild-2013-304878 F1 Copyright theirEdemployer) 2014. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
Downloaded from fn.bmj.com on May 6, 2014 - Published by group.bmj.com
Review Search strategy We searched MEDLINE (1948–May 2013), Embase (1980–May 2013), and Cochrane Central Register of Controlled Trials (May 2013 Issue of the Cochrane Library) for published studies with the help of an experienced librarian. Search was performed by using database-specific terms without any language restrictions (see online supplementary appendix 1). The reference lists of identified studies were also searched to identify further eligible studies.
Criteria for study selection Type of participants Term and preterm neonates with the diagnosis of isoimmune haemolytic disease secondary to Rh or ABO incompatibility were included. Neonates who had additional minor group incompatibility in addition to Rh or ABO incompatibility were included. Neonates who had isolated minor group incompatibility were not included. Studies including both Rh and ABO incompatibility, but not providing results on these conditions separately were excluded.
Type of intervention IVIg given as prophylaxis or treatment in any dose versus placebo or no intervention were included. The intervention must have been used for the purpose of prevention or treatment of Rh or ABO incompatibility. The use of IVIg for other reasons was not included.
Outcomes Primary outcome was the need for ET after the intervention. Secondary outcomes included number of ETs per infant, peak serum bilirubin level (micromoles per litre), duration of phototherapy (days), duration of hospitalisation (days), need for top-up blood transfusions, neonatal mortality and adverse reactions requiring cessation of therapy. Studies reporting any of these outcomes were included. Subgroup analyses were planned according to the following factors: 1. Prophylactic IVIg versus placebo/controls ( prophylactic IVIg is the use of IVIg in the first few hours of age in neonates with antenatal or immediate postnatal diagnosis of Rh or ABO haemolytic disease before they develop significant hyperbilirubinemia) 2. Gestational age (≥37 weeks and
ADC-FNN Online First, published on February 10, 2014 as 10.1136/archdischild-2013-304878 Review
Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis Deepak Louis,1 Kiran More,2 Sapna Oberoi,3 Prakesh S Shah1,4,5 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ archdischild-2013-304878). 1
Division of Neonatology, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada 2 Division of Neonatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada 3 Division of Pediatric Hematooncology, The Hospital for Sick Children, Toronto, Ontario, Canada 4 Departments of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada 5 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada Correspondence to Dr Prakesh S Shah, Department of Paediatrics, Mount Sinai Hospital, 775A-600 University Ave, Toronto, Ontario, Canada M5G 1X5; [email protected] Received 17 July 2013 Revised 14 January 2014 Accepted 19 January 2014
ABSTRACT Background Intravenous immunoglobulin (IVIg) is used in neonates with isoimmune haemolytic disease to prevent exchange transfusion (ET). However, studies supporting IVIg had methodological issues. Objective To update the systematic review of efficacy and safety of IVIg in neonates with isoimmune haemolytic disease. Methods MEDLINE, Embase databases and Cochrane Central Register of Controlled Trials (Cochrane Library) were searched (from inception to May 2013) for randomised or quasi-randomised controlled trials comparing IVIg with placebo/controls in neonates with isoimmune haemolytic disease without any language restriction. Three investigators assessed methodological quality of included trials. Meta-analyses were performed using random effect model and risk ratio (RR)/risk difference (RD) and mean difference with 95% CI calculated. Main results Twelve studies were included, ten trials (n=463) of Rh isoimmunisation and five trials (n=350) of ABO isoimmunisation (three studies had both population). Significant variations in risk of bias precluded an overall meta-analysis of Rh isoimmunisation. Studies with high risk of bias showed that IVIg reduced the rate of ET in Rh isoimmunisation (RR 0.23, 95% CI 0.13 to 0.40), whereas studies with low risk of bias that also used prophylactic phototherapy did not show statistically significant difference (RR 0.82, 95% CI 0.53 to 1.26). For ABO isoimmunisation, only studies with high risk of bias were available and metaanalysis revealed efficacy of IVIg in reducing ET (RR 0.31, 95% CI 0.18 to 0.55). Conclusions Efficacy of IVIg is not conclusive in Rh haemolytic disease of newborn with studies with low risk of bias indicating no benefit and studies with high risk of bias suggesting benefit. Role of IVIg in ABO disease is not clear as studies that showed a benefit had high risk of bias.
INTRODUCTION
To cite: Louis D, More K, Oberoi S, et al. Arch Dis Child Fetal Neonatal Ed Published Online First: [please include Day Month Year] doi:10.1136/ archdischild-2013-304878
Isoimmune haemolytic disease of fetus and newborn (HDFN) is characterised by breakdown of fetal and newborn red blood cells (RBCs) due to transplacentally derived maternal antibodies. These maternal antibodies might be naturally occurring or may arise following previous sensitisation.1 Haemolytic disease presents with anaemia and hydrops in fetuses or with anaemia and jaundice in neonates. Rhesus (Rh) and ABO isoimmunisation remain the two most important aetiologies of HDFN. The most dreaded complication of isoimmunisation is acute bilirubin encephalopathy, and
the main goal of management is to prevent this complication. Conventional treatment for isoimmunisation includes phototherapy and exchange transfusion (ET). Phototherapy is a relatively benign therapy; however, ET is not an innocuous procedure and is associated with mortality as well as morbidities such as catheter-related complications, thrombocytopenia and infections.2–5 Recently, intravenous immunoglobulin (IVIg) has emerged as a therapeutic modality in neonates with HDFN.6 It acts by blocking Fc receptors on macrophages thereby reducing the breakdown of antibody-coated RBCs and also enhancing the clearance of maternal antibodies.7 Few randomised controlled trials (RCT) have shown its efficacy in decreasing the need for ET, but they had moderate to high risk of bias and a majority of them were conducted prior to the current era of high-intensity phototherapy.8–13 IVIg is a blood product derived from healthy human donors, and the side effects include transfusion reactions, possibility of transmitting infectious diseases,14 a reported association with necrotising enterocolitis15–19 and can cause acute renal failure secondary to haemolysis.20 Previous meta-analyses, despite supporting the use of IVIg, emphasised the need for larger studies to confirm its benefits in HDFN.21–23 Recent RCTs of IVIg in neonatal Rh disease cast doubt on its efficacy as there was no difference in the rates of ET.24 25 It was argued that the efficacy for IVIg in the face of prophylactic and aggressive phototherapy in cases with antenatal diagnosis or suspicion is questionable. Thus, in this updated meta-analysis, we aimed to systematically review the efficacy and safety of IVIg in Rh and ABO haemolytic disease in newborn.
MATERIALS AND METHODS Study questions 1. What is the efficacy and safety of IVIg in neonates with Rh incompatibility? 2. What is the efficacy and safety of IVIg in neonates with ABO incompatibility? Standard methods were used for performing this systematic review and PRISMA guidelines were used for reporting.26
Study selection RCTs and quasi-RCTs were included in this review. Case–control, cohort studies, case reports, case series, letters to editors, editorials, review articles and commentaries were excluded, but were read to identify other potential studies. Duplicate reports not providing additional information were excluded.
Louis D, etArticle al. Arch Disauthor Child Fetal(or Neonatal 2014;0:F1–F7. doi:10.1136/archdischild-2013-304878 F1 Copyright theirEdemployer) 2014. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
Downloaded from fn.bmj.com on May 6, 2014 - Published by group.bmj.com
Review Search strategy We searched MEDLINE (1948–May 2013), Embase (1980–May 2013), and Cochrane Central Register of Controlled Trials (May 2013 Issue of the Cochrane Library) for published studies with the help of an experienced librarian. Search was performed by using database-specific terms without any language restrictions (see online supplementary appendix 1). The reference lists of identified studies were also searched to identify further eligible studies.
Criteria for study selection Type of participants Term and preterm neonates with the diagnosis of isoimmune haemolytic disease secondary to Rh or ABO incompatibility were included. Neonates who had additional minor group incompatibility in addition to Rh or ABO incompatibility were included. Neonates who had isolated minor group incompatibility were not included. Studies including both Rh and ABO incompatibility, but not providing results on these conditions separately were excluded.
Type of intervention IVIg given as prophylaxis or treatment in any dose versus placebo or no intervention were included. The intervention must have been used for the purpose of prevention or treatment of Rh or ABO incompatibility. The use of IVIg for other reasons was not included.
Outcomes Primary outcome was the need for ET after the intervention. Secondary outcomes included number of ETs per infant, peak serum bilirubin level (micromoles per litre), duration of phototherapy (days), duration of hospitalisation (days), need for top-up blood transfusions, neonatal mortality and adverse reactions requiring cessation of therapy. Studies reporting any of these outcomes were included. Subgroup analyses were planned according to the following factors: 1. Prophylactic IVIg versus placebo/controls ( prophylactic IVIg is the use of IVIg in the first few hours of age in neonates with antenatal or immediate postnatal diagnosis of Rh or ABO haemolytic disease before they develop significant hyperbilirubinemia) 2. Gestational age (≥37 weeks and
