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Exchange transfusion in neonatal hyperbilirubinemia: A single Centre experience from Northern India
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Original article
Exchange transfusion in neonatal hyperbilirubinemia: A single Centre experience from Northern India Brinda Kakkar⁎,1, Soma Agrawal, Mohit Chowdhry, P.J. Muthukumaravel, Raj Nath Makroo, Uday K. Thakur Department of Transfusion Medicine and Immunology, Indraprastha Apollo Hospitals, New Delhi, 110076, India
A R T I C LE I N FO
A B S T R A C T
Keywords: Exchange transfusion Hyperbilirubinemia Reconstituted blood Blood group incompatibility Neonate
Objective: To determine the indication, efficacy and adverse events related to exchange transfusion (ET) with reconstituted blood (RB) in neonatal hyperbilirubinemia (NNH). Methods: Blood bank records of neonates who underwent double volume ET for NNH from January 2013 to July 2018 were retrospectively reviewed. Demographic details, cause of NNH, details of ET and ET related adverse events were recorded. Results: A total of 23 ET (average: 1.64/neonate) were performed in 14 neonates (9 males; 5 females) with a mean age of 9.8 ± 7.6 days. Ten (71.4%) neonates underwent 1 session of ET, while 4 (28.6%) underwent repeated sessions (average: 3.25/neonate). A total of 5912 ml of RB was transfused (average: 422 ml/neonate). A statistically significant reduction was noted in total serum bilirubin (TSB) level post-ET (p < 0.001) with overall TSB reduction/procedure being 46%. Of the 14 neonates with NNH, 11 (78.6%) had Rh haemolytic disease of foetus and new-born (HDFN), 2 (14.3%) had ABO HDFN and 1 (7.1%) had hyperbilirubinemia due to prematurity. Of the 11 neonates with Rh HDFN, only 5 underwent intrauterine transfusion (average: 1.8/neonate). Post-ET, top-up transfusions were noted in 8 (57.1%) neonates with packed red blood cell and/or platelet concentrate. ET related adverse were noted in 5 (21.7%) procedures only. Conclusion: Rh HDFN was the most common cause of NNH in our study population.Exchange transfusion is a safe treatment modality for treating NNH, as it results in the rapid elimination of serum bilirubin, thus, lowering the risk of kernicterus in these patients.
1. Introduction Neonatal hyperbilirubinemia (NNH) presenting within the first 24 h of life is considered a serious complication, thus, early identification and prompt management are necessary to prevent serious neurological complications like kernicterus [1,2]. The various risk factors for the development of NNH are blood group incompatibility (ABO and/or Rh), glucose-6-phosphate dehydrogenase (G6PD) deficiency, gestational age of 35–36 weeks, previous sibling on phototherapy, cephalohematoma and inadequate breastfeeding along with excessive weight loss [3]. The treatment options available for the prevention of kernicterus are intensive phototherapy and exchange transfusion (ET) [4]. Exchange transfusion is considered an important treatment modality for treating NNH, as it results in the rapid elimination of serum bilirubin especially in those infants/neonates who are at high risk of developing bilirubin
encephalopathy [3]. The aim of our study was to determine the indication, efficacy and adverse events related to ET with reconstituted blood (RB) in NNH. 2. Materials and methods This retrospective study was conducted in the Department of Transfusion Medicine in a tertiary care hospital from January 2013 to July 2018. Neonates who underwent ET with RB for NNH during the study period were included. Neonates with NNH were started on phototherapy or ET as per the nomogram given in the American Academy of Paediatrics (AAP) guidelines [5]. The neonates who did not respond to phototherapy and presented with increasing bilirubin levels to more than 5 mg/dl or with clinical features of bilirubin encephalopathy received ET. As per hospital policy, all neonates underwent a standard
⁎
Corresponding author at: Department of Transfusion Medicine, Institute of Liver and Biliary Sciences, New Delhi, 110070, India. E-mail address: [email protected] (B. Kakkar). 1 Current affiliation – Senior Resident, Institute of Liver and Biliary Sciences, New Delhi 110070, India. https://doi.org/10.1016/j.transci.2019.09.008 Received 30 June 2019; Received in revised form 30 August 2019; Accepted 27 September 2019 1473-0502/ © 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Brinda Kakkar, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.09.008
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
B. Kakkar, et al.
double volume ET over one hour. ET was performed using manual push and pull method and umbilical vein as a single access. RB for ET was prepared using three log leukoreduced, irradiated, less than 5 days old, group O Rh D negative packed red blood cell (PRBC) mixed with group AB fresh frozen plasma (FFP). Intravenous immunoglobulin (IVIG) was given prophylactically after the first session of ET to reduce the need for future sessions of ET. However, owing to the costs and no standard protocol for use of IVIG at our institute, it was used in accordance of the clinicians’ discretion. The data collected from the departmental records included demographic details (age, gender, birth weight, pre-term/term), cause of NNH, blood group of neonate and mother, details of ET (volume of RB, number of procedures, post ET transfusion of blood/blood components (if any), intra-uterine transfusion (if any), pre and post procedure total serum bilirubin (TSB), haemoglobin (Hb), haematocrit (HCT), serum calcium and total platelet count (TPC)], ET related adverse events and average length of stay (ALOS).
Table 1 Patient Demographics. Characteristic Age (mean ± S.D.) Male : Female (number; %) Corrected Gestational age at the time of ET (mean ± S.D.) Term: Preterm Birth weight (mean ± S.D.) Race (ethnicity) Caesarean section Breastfeeding IUT for Rh HDFN Positive DCT Indication for ET Rh HDFN
ABO HDFN Hyperbilirubinemia due to prematurity Management of NNH Intensive phototherapy ET IVIg Adverse events post-ET Thrombocytopenia Hypocalcaemia Apnoea Post-ET top-up transfusions PRBC only PC only PRBC and PC ALOS (mean, range,)
3. Statistical analysis Descriptive statistics are presented as mean ± standard deviation or median with an inter-quartile range for continuous data, frequency, and percentage for categorical data. Paired t-test was used for comparing continuous data with a normal distribution and Wilcoxon signed ranked test for skewed data. A p-value of less than 0.05 was considered statistically significant. Statistical analysis was performed using IBM SPSS version 22 (SPSS Inc., Chicago, IL, USA). 4. Results A total of 17 neonates who did not respond to phototherapy alone, underwent ET during the study period. Three neonates were excluded due to incomplete records. Thus, a total of 14 neonates (9 males, 64.3%; 5 females, 35.7%) with a mean age of 9.8 ± 7.6 days were included in the analysis who underwent a total of 23 ETs. The average number of ET performed per neonate was 1.64 (range: 1–5). Around 71.4% (n = 10) neonates underwent single session of ET, while 28.6% (n = 4) underwent repeated sessions (average: 3.25/neonate). A total of 5912 ml of RB was transfused with an average of 422 ml/neonate. Table 1 summarizes the demographics of the neonates included in the study. Table 2 summarizes the changes in the laboratory parameters noted pre- and post-ET. A statistically significant reduction was noted in TSB levels post-ET (p < 0.001) and the overall reduction in TSB/procedure was 46%. The TSB levels at the time of discharge was 7.6 ± 3.4 mg/dL. Nine (64.3%) neonates received intravenous immunoglobulin (dose: 1 gm/kg) in addition to ET. All patients were discharged in a clinically stable condition after a declining trend was noted in TSB.
9.8 ± 7.6 days 9, 64.3% : 4, 37.5% 35.4 ± 1.5 weeks 5:9 2.55 ± 0.43 kg Asian (Indian) 10 (71.4%) 11 (78.6%) 5 (average IUT: 1.8/neonate) 11 (78.6%) 78.6%; 11 (6 anti-D; 3 anti-D and anti-C; 1 anti-D, anti-C, and anti-G; 1 anti-D, anti-C and anti-Fyb) 14.3%; 2 (neonate blood group: AB, B; mother’s blood group: O) 1, 7.1%
14 (100%) 14 (100%) 9 (64.3%) 5/23 ET sessions (21.7%) 2 2 1 8/14 neonates (57.1%) 6 (42.9%) 1 (7.1%) 1 (7.1%) 10.5 ± 6.7 days
[S.D. – standard deviation; IUT – intra-uterine transfusion; DCT – direct Coomb's test; HDFN – haemolytic disease of foetus and new-born; NNH – neonatal hyperbilirubinemia; ET – exchange transfusion; IVIg – intravenous immunoglobulin; PRBC- packed red blood cell; PC – platelet concentrate; TSB – total serum bilirubin; ALOS – average length of stay]. Table 2 Changes in laboratory parameters pre- and post-ET (mean ± standard deviation). Laboratory parameters
Pre-ET
Post-ET
p-value
Hb (g/dL; n = 14) HCT (%; n = 9) TPC (/μL; n = 9) TSB (mg/dL; n = 14) Serum calcium (mg/dL; n = 14)
11.3 ± 3.2 34.7 ± 10.7 237.1 ± 157.4 16.5 ± 6.5 8.2 ± 1.1
12.6 ± 2.4 39.2 ± 6.8 85.2 ± 49.2 9.2 ± 3.6 8.4 ± 1.0
0.17 0.52 0.02 < 0.001 0.81
[Hb – haemoglobin; HCT – haematocrit; TPC – total platelet count; TSB – total serum bilirubin].
5. Discussion
observed that mothers of neonates undergoing ET due to Rh HDFN were managed elsewhere in the primary health care centres lacking access to RHIG and therefore were alloimmunized and hence referred to our centre for further management. Besides anti-D, the other commonly encountered maternal alloantibodies in our study population were antiC, anti-G and anti-Fyb. HDFN due to maternal alloimmunization against Rh and Duffy antigens have been reported in the literature [11,12]. Majority of ABO HDFN cases present with mild to moderate hyperbilirubinemia that can be managed with phototherapy only, however; rarely these patients might present with severe hyperbilirubinemia requiring ET and has been reported more frequently when there is OeA/ O-B incompatibility between maternal and neonatal blood groups [13–15], while in our study OeB and OeAB incompatibility was noted between maternal and neonatal blood groups. Exchange transfusion helps in the removal of incompatible red cells, bilirubin, and maternal antibodies. A standard double volume ET
This retrospective observational study reveals that Rh HDFN followed by ABO HDFN were the most cause of NNH in our study population requiring ET, which is in agreement with the published literature [4,6–8]. The various other causes of severe hyperbilirubinemia requiring ET are hereditary spherocytosis, urinary tract infections, HDFN due to non-anti-D antibodies, hemoglobinopathies, hypothyroidism, enzyme deficiencies (pyruvate kinase), subdural hematoma and adrenal gland haemorrhage [4,7]. In developing countries such as India, HDFN due to Rh incompatibility is still commonly encountered as compared to the developed world where routine prophylaxis with Rh immunoglobulin (RhIG) has resulted in ABO incompatibility to be the most common cause of HDFN [9]. Another major issue in the developing countries are inadequate antenatal care and inability to afford RhIG, thus, resulting in more Rh isoimmunization [10]. Administration of prophylactic RhIG is a routine practice at our institute, however, we 2
3
Yes Rh incompatibility 14 Present study (2019)
23
614 Yu et al18 (2017)
Not mentioned
60 64 Singh et al3 (2015) Ballot et al19 (2016)
Not mentioned 67
Yes
No No
7% (hypocalcaemia, thrombocytopenia, hyperglycaemia, metabolic acidosis, hypomagnesemia, hyponatremia, hypokalemia, apnoea, NEC) 21.7% (hypocalcaemia, thrombocytopenia, apnoea)
No No No No
No – 398 Bujandric et al7 (2015)
468
Rh and ABO incompatibility ABO incompatibility Rh and ABO incompatibility ABO incompatibility
% not mentioned (hypercalcaemia) 7.8% (apnoea, thrombocytopenia, hypoglycaemia)
No Yes 86 73
ABO incompatibility
107
ABO incompatibility
17.8% (thrombocytopenia, hypocalcaemia, hypoglycaemia, apnoea, anaemia, bradycardia, petechial rash due to thrombocytopenia, bacteremia, death) No complications or death reported
No
No No No No No No Not mentioned No
% not mentioned (hypocalcaemia) 74% (thrombocytopenia, hypocalcaemia, metabolic acidosis) Not mentioned 32% (apnoea, hypocalcaemia, hypoglycaemia, hyponatremia, hypernatremia) 19.6% (thrombocytopenia, hypocalcaemia) ABO incompatibility Rh incompatibility Rh incompatibility ABO incompatibility Not mentioned 66 25 Not mentioned
Total number of ET sessions
[ET – exchange transfusion; IVIg – intravenous immunoglobulin; NEC – necrotising enterocolitis].
None.
92
Declaration of Competing Interest
Gharehbaghi et al6 (2010) Bulbul et al4 (2011)
None.
52 55 25 50
Source of funding
Jain et al17 (1997) Patra et al22 (2004) Sharma et al20 (2007) Behjati et al21 (2009)
All authors contributed equally towards data analysis and preparation of the manuscript.
Total number of patients undergoing ET
Authors contribution
Author (year)
Table 3 Comparison of the findings of present study with published literature.
Most common indication for ET
ET related Adverse events (%; type)
Need for transfusion post-ET
IVIg administration in addition to ET
results reduction of incompatible red blood cells by 85% followed by a 25–45% reduction in maternal antibodies and bilirubin [16]. The average number of ET/neonate was 1.64 with only four neonates requiring multiple sessions of ET (average 3.25/neonate). All these four neonates presented with Rh HDFN as a result of maternal alloimmunization against Rh antigens such as anti-D, anti-C, anti-G, and Duffy antigen. In our study, a statistically significant reduction in serum bilirubin levels was noted post-procedure (p < 0.001) with an overall reduction in bilirubin levels/procedure being 46%, which is similar to the findings published by other authors [3,6,17–19]. We also observed that the mean hemoglobin and hematocrit post-ET were higher as compared to pre-ET, however, the change was not statistically significant. Similar results have been reported by Gharehbaghi et al. [6] and Sharma et al. [20]. The probable reason could be adequate mixing of RB during the procedure and the adjustment of the hematocrit of RB to 50 ± 5%. Hypocalcaemia is seen due to the use of citrated blood as it chelates calcium, [3,6,7,21,22] thus, it is recommended that calcium gluconate should be administered after every 100 ml of blood removed to avoid hypocalcaemia related adverse events. It has been noted that neonates tend to have low serum calcium levels after birth [23], thus, they are at risk of developing hypocalcaemia more commonly post-ET due to the use of citrated blood. We observed hypocalcaemia (8.7%) as one of the most commonly encountered complication post-ET in our patients. Thrombocytopenia (8.7%) was also encountered which required platelet transfusion post-ET (neonate 1 TPC 25,000/μL; neonate 2 TPC 34,000/μL). It is known that RB is deficient in platelets, thus, thrombocytopenia is a commonly seen adverse event post-ET [6,7,21,22]. Platelet transfusion is only indicated if infants present with significant thrombocytopenia that is platelet count < 50,000/μL or is actively bleeding [6]. Apart from these two complications, one of our neonates had apnoea post-procedure which was managed appropriately with no sequelae. Similar findings have been reported in the published literature [6,7,21,22]. Table 3 compares the findings of the present study with published literature. It has been reported that administration of intravenous immunoglobulin (IVIg) in Rh HDFN patients has led to reduced requirements for phototherapy, ET and shortened hospital stay [10,24,25]. It is also effective in reducing the need for multiple ET sessions especially when administered after the first session of ET [25]. We observed that nine (64.3%) neonates with Rh HDFN received IVIg (dose: 1 gm/kg) in addition to ET, thus, reducing the need for further ET sessions except in one neonate who underwent a total of five session despite receiving IVIg. Among these nine neonates, four received intrauterine transfusion (IUT). Aggressive antenatal management of the babies with hydrops fetalis with IUT leads to a decrease in the need for ET after birth [10]. Though in the current era, a steady decline has been noted in ET procedures being performed, it is still considered a safe and effective adjunct therapy for treating NNH, as it results in a rapid reduction in bilirubin levels, thus, lowering the risk of development of serious neurological sequelae such as kernicterus in these patients.
No
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References [14]
[1] Irshad M, Mohammad A, Hussain M, et al. Prevalence of rhesus type and ABO incompatibility in jaundiced neonates. Journal of Postgraduate Medical Institute (Peshawar - Pakistan). 2011;25(3):233–9. [2] Girish N, Santosh S, Keshavamurthy SR. Evolving trends: hyperbilirubinemia among newborns delivered to Rh-negative mothers in Southern India. J Clin Diagn Res 2013;7(11):2508–10. [3] Singh M, Singh M, Tiwari S. Effect of exchange transfusion in bilirubin and calcium level in Neonatal Hyperbilirubinemia. Int J Med Res Rev. 2015;3(7):733–7. [4] Bulbul A, Okan F, Kabakoglu Unsur E, Nuhoglu A. Adverse events associated with exchange transfusion and etiology of severe hyperbilirubinemia in near-term and term newborns. Turk J Med Sci 2011;41(1):93–100. [5] American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114(1):297–316. [6] Gharehbaghi MM, Hosseinpour SS. Exchange transfusion in neonatal hyperbilirubinemia: a comparison between citrated whole blood and reconstituted blood. Singapore Med J 2010;51(8):641–4. [7] Bujandric N, Grujic J. Exchange transfusion for severe neonatal hyperbilirubinemia: 17 years’ experience from Vojvodina, Serbia. Indian J Hematol Blood Transfus 2016;32(2):208–14. [8] Mammen KC. Experience with exchange transfusions in the neonates. Indian Pediatr 1967;4(11):413–7. [9] Basu S, Kaur R, Kaur G. Hemolytic disease of the fetus and newborn: current trends and perspectives. Asian J Transfus Sci 2011;5(1):3–7. [10] Girish G, Chawla D, Agarwal R, Paul VK, Deorari AK. Efficacy of two dose regimes of intravenous immunoglobulin in Rh hemolytic disease of newborn – a randomised controlled trial. Indian Pediatr 2008;45:653–9. [11] Makroo RN, Kaul A, Bhatia A, Agrawal S, Singh C, Karna P. Anti-G antibody in alloimmunized pregnant women: report of two cases. Asian J Transfus Sci 2015;9(2):210–2. [12] Lenkiewicz B, Zupanska B. Significance of alloantibodies other than anti-D hemolytic disease of the fetus and newborn (HDF/N). Ginekol Pol 2003;74(1):48–54. [13] Jain A, Malhotra S, Marwaha N, Kumar P, Sharma RR. Severe ABO hemolytic
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disease of fetus and newborn requiring blood exchange transfusion. Asian J Transfus Sci 2018;12(2):176–9. Bhat YR, Kumar CG. Morbidity of ABO hemolytic disease in the newborn. Paediatr Int Child Health 2012;32(2):93–6. Matteocci A, De Rosa A, Buffone E, Pierelli L. Retrospective analysis of HDFN due to ABO incompatibility in a single institution over 6 years. Transfus Med 2018. https://doi.org/10.1111/tme.12512. [Epub ahead of print]. Solheim B, Gronn M. Hemolytic disease of the fetus and newborn. In: Simon TL, Snyder EL, Solheim BG, Stowell CP, Strauss RG, Petrides M, editors. Rossi’s principles of transfusion medicine. Bethesda: AABB Press; 2009. p. 418–25. Jain A, Puri D, Faridi MMA. Biochemical changes during exchange transfusion in hyperbilirubinemia in term newborn babies. Indian J Clin Biochem 1997;12(2):119–24. Yu C, Li H, Zhang Q, He H, Chen X, Hua Z. Report about term infants with severe hyperbilirubinemia undergoing exchange transfusion in Southwestern China during an 11 year period, from 2001 to 2011. PLoS One 2017;12(6):e0179550. Ballot DE, Rugamba G. Exchange transfusion for neonatal hyperbilirubinemia in Johannesburg, South Africa, from 2006 to 2011. Int Sch Res Notices 2016;2016. ID 1268149. Sharma DC, Rai S, Mehra A, Kaur MM, Sao S, Gaur A, et al. Study of 25 cases of exchange transfusion by reconstituted blood in hemolytic disease of newborn. Asian J Transfus Sci 2007;1(2):56–8. Sh Behjati, Sagheb S, Aryasepehr S, Yaghmai B. Adverse events associated with neonatal exchange transfusion for hyperbilirubinemia. Indian J Pediatr 2009;76(1):83–5. Patra K, Storfer-Isser A, Siner B, Moore J, Hack M. Adverse events associated with neonatal exchange transfusion in the 1990s. J Pediatr 2004;144(5):626–31. Jain A, Agarwal R, Jeeva Sankar M, Deorari A, et al. Hypocalcemia in the newborn. Indian J Pediatr 2010;77:1123–8. Aylin T, Berkan G. Role of IVIg in preventing exchange transfusions in Rh hemolytic disease. Indian Pediatr 2005;42:77–9. Aggarwal R, Seth R, Paul VK, Deorari AK. High dose intravenous immunoglobulin therapy in the treatment of Rhesus Hemolytic disease. J Tropical Ped 2002;48:116–7.
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Original article
Exchange transfusion in neonatal hyperbilirubinemia: A single Centre experience from Northern India Brinda Kakkar⁎,1, Soma Agrawal, Mohit Chowdhry, P.J. Muthukumaravel, Raj Nath Makroo, Uday K. Thakur Department of Transfusion Medicine and Immunology, Indraprastha Apollo Hospitals, New Delhi, 110076, India
A R T I C LE I N FO
A B S T R A C T
Keywords: Exchange transfusion Hyperbilirubinemia Reconstituted blood Blood group incompatibility Neonate
Objective: To determine the indication, efficacy and adverse events related to exchange transfusion (ET) with reconstituted blood (RB) in neonatal hyperbilirubinemia (NNH). Methods: Blood bank records of neonates who underwent double volume ET for NNH from January 2013 to July 2018 were retrospectively reviewed. Demographic details, cause of NNH, details of ET and ET related adverse events were recorded. Results: A total of 23 ET (average: 1.64/neonate) were performed in 14 neonates (9 males; 5 females) with a mean age of 9.8 ± 7.6 days. Ten (71.4%) neonates underwent 1 session of ET, while 4 (28.6%) underwent repeated sessions (average: 3.25/neonate). A total of 5912 ml of RB was transfused (average: 422 ml/neonate). A statistically significant reduction was noted in total serum bilirubin (TSB) level post-ET (p < 0.001) with overall TSB reduction/procedure being 46%. Of the 14 neonates with NNH, 11 (78.6%) had Rh haemolytic disease of foetus and new-born (HDFN), 2 (14.3%) had ABO HDFN and 1 (7.1%) had hyperbilirubinemia due to prematurity. Of the 11 neonates with Rh HDFN, only 5 underwent intrauterine transfusion (average: 1.8/neonate). Post-ET, top-up transfusions were noted in 8 (57.1%) neonates with packed red blood cell and/or platelet concentrate. ET related adverse were noted in 5 (21.7%) procedures only. Conclusion: Rh HDFN was the most common cause of NNH in our study population.Exchange transfusion is a safe treatment modality for treating NNH, as it results in the rapid elimination of serum bilirubin, thus, lowering the risk of kernicterus in these patients.
1. Introduction Neonatal hyperbilirubinemia (NNH) presenting within the first 24 h of life is considered a serious complication, thus, early identification and prompt management are necessary to prevent serious neurological complications like kernicterus [1,2]. The various risk factors for the development of NNH are blood group incompatibility (ABO and/or Rh), glucose-6-phosphate dehydrogenase (G6PD) deficiency, gestational age of 35–36 weeks, previous sibling on phototherapy, cephalohematoma and inadequate breastfeeding along with excessive weight loss [3]. The treatment options available for the prevention of kernicterus are intensive phototherapy and exchange transfusion (ET) [4]. Exchange transfusion is considered an important treatment modality for treating NNH, as it results in the rapid elimination of serum bilirubin especially in those infants/neonates who are at high risk of developing bilirubin
encephalopathy [3]. The aim of our study was to determine the indication, efficacy and adverse events related to ET with reconstituted blood (RB) in NNH. 2. Materials and methods This retrospective study was conducted in the Department of Transfusion Medicine in a tertiary care hospital from January 2013 to July 2018. Neonates who underwent ET with RB for NNH during the study period were included. Neonates with NNH were started on phototherapy or ET as per the nomogram given in the American Academy of Paediatrics (AAP) guidelines [5]. The neonates who did not respond to phototherapy and presented with increasing bilirubin levels to more than 5 mg/dl or with clinical features of bilirubin encephalopathy received ET. As per hospital policy, all neonates underwent a standard
⁎
Corresponding author at: Department of Transfusion Medicine, Institute of Liver and Biliary Sciences, New Delhi, 110070, India. E-mail address: [email protected] (B. Kakkar). 1 Current affiliation – Senior Resident, Institute of Liver and Biliary Sciences, New Delhi 110070, India. https://doi.org/10.1016/j.transci.2019.09.008 Received 30 June 2019; Received in revised form 30 August 2019; Accepted 27 September 2019 1473-0502/ © 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Brinda Kakkar, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.09.008
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
B. Kakkar, et al.
double volume ET over one hour. ET was performed using manual push and pull method and umbilical vein as a single access. RB for ET was prepared using three log leukoreduced, irradiated, less than 5 days old, group O Rh D negative packed red blood cell (PRBC) mixed with group AB fresh frozen plasma (FFP). Intravenous immunoglobulin (IVIG) was given prophylactically after the first session of ET to reduce the need for future sessions of ET. However, owing to the costs and no standard protocol for use of IVIG at our institute, it was used in accordance of the clinicians’ discretion. The data collected from the departmental records included demographic details (age, gender, birth weight, pre-term/term), cause of NNH, blood group of neonate and mother, details of ET (volume of RB, number of procedures, post ET transfusion of blood/blood components (if any), intra-uterine transfusion (if any), pre and post procedure total serum bilirubin (TSB), haemoglobin (Hb), haematocrit (HCT), serum calcium and total platelet count (TPC)], ET related adverse events and average length of stay (ALOS).
Table 1 Patient Demographics. Characteristic Age (mean ± S.D.) Male : Female (number; %) Corrected Gestational age at the time of ET (mean ± S.D.) Term: Preterm Birth weight (mean ± S.D.) Race (ethnicity) Caesarean section Breastfeeding IUT for Rh HDFN Positive DCT Indication for ET Rh HDFN
ABO HDFN Hyperbilirubinemia due to prematurity Management of NNH Intensive phototherapy ET IVIg Adverse events post-ET Thrombocytopenia Hypocalcaemia Apnoea Post-ET top-up transfusions PRBC only PC only PRBC and PC ALOS (mean, range,)
3. Statistical analysis Descriptive statistics are presented as mean ± standard deviation or median with an inter-quartile range for continuous data, frequency, and percentage for categorical data. Paired t-test was used for comparing continuous data with a normal distribution and Wilcoxon signed ranked test for skewed data. A p-value of less than 0.05 was considered statistically significant. Statistical analysis was performed using IBM SPSS version 22 (SPSS Inc., Chicago, IL, USA). 4. Results A total of 17 neonates who did not respond to phototherapy alone, underwent ET during the study period. Three neonates were excluded due to incomplete records. Thus, a total of 14 neonates (9 males, 64.3%; 5 females, 35.7%) with a mean age of 9.8 ± 7.6 days were included in the analysis who underwent a total of 23 ETs. The average number of ET performed per neonate was 1.64 (range: 1–5). Around 71.4% (n = 10) neonates underwent single session of ET, while 28.6% (n = 4) underwent repeated sessions (average: 3.25/neonate). A total of 5912 ml of RB was transfused with an average of 422 ml/neonate. Table 1 summarizes the demographics of the neonates included in the study. Table 2 summarizes the changes in the laboratory parameters noted pre- and post-ET. A statistically significant reduction was noted in TSB levels post-ET (p < 0.001) and the overall reduction in TSB/procedure was 46%. The TSB levels at the time of discharge was 7.6 ± 3.4 mg/dL. Nine (64.3%) neonates received intravenous immunoglobulin (dose: 1 gm/kg) in addition to ET. All patients were discharged in a clinically stable condition after a declining trend was noted in TSB.
9.8 ± 7.6 days 9, 64.3% : 4, 37.5% 35.4 ± 1.5 weeks 5:9 2.55 ± 0.43 kg Asian (Indian) 10 (71.4%) 11 (78.6%) 5 (average IUT: 1.8/neonate) 11 (78.6%) 78.6%; 11 (6 anti-D; 3 anti-D and anti-C; 1 anti-D, anti-C, and anti-G; 1 anti-D, anti-C and anti-Fyb) 14.3%; 2 (neonate blood group: AB, B; mother’s blood group: O) 1, 7.1%
14 (100%) 14 (100%) 9 (64.3%) 5/23 ET sessions (21.7%) 2 2 1 8/14 neonates (57.1%) 6 (42.9%) 1 (7.1%) 1 (7.1%) 10.5 ± 6.7 days
[S.D. – standard deviation; IUT – intra-uterine transfusion; DCT – direct Coomb's test; HDFN – haemolytic disease of foetus and new-born; NNH – neonatal hyperbilirubinemia; ET – exchange transfusion; IVIg – intravenous immunoglobulin; PRBC- packed red blood cell; PC – platelet concentrate; TSB – total serum bilirubin; ALOS – average length of stay]. Table 2 Changes in laboratory parameters pre- and post-ET (mean ± standard deviation). Laboratory parameters
Pre-ET
Post-ET
p-value
Hb (g/dL; n = 14) HCT (%; n = 9) TPC (/μL; n = 9) TSB (mg/dL; n = 14) Serum calcium (mg/dL; n = 14)
11.3 ± 3.2 34.7 ± 10.7 237.1 ± 157.4 16.5 ± 6.5 8.2 ± 1.1
12.6 ± 2.4 39.2 ± 6.8 85.2 ± 49.2 9.2 ± 3.6 8.4 ± 1.0
0.17 0.52 0.02 < 0.001 0.81
[Hb – haemoglobin; HCT – haematocrit; TPC – total platelet count; TSB – total serum bilirubin].
5. Discussion
observed that mothers of neonates undergoing ET due to Rh HDFN were managed elsewhere in the primary health care centres lacking access to RHIG and therefore were alloimmunized and hence referred to our centre for further management. Besides anti-D, the other commonly encountered maternal alloantibodies in our study population were antiC, anti-G and anti-Fyb. HDFN due to maternal alloimmunization against Rh and Duffy antigens have been reported in the literature [11,12]. Majority of ABO HDFN cases present with mild to moderate hyperbilirubinemia that can be managed with phototherapy only, however; rarely these patients might present with severe hyperbilirubinemia requiring ET and has been reported more frequently when there is OeA/ O-B incompatibility between maternal and neonatal blood groups [13–15], while in our study OeB and OeAB incompatibility was noted between maternal and neonatal blood groups. Exchange transfusion helps in the removal of incompatible red cells, bilirubin, and maternal antibodies. A standard double volume ET
This retrospective observational study reveals that Rh HDFN followed by ABO HDFN were the most cause of NNH in our study population requiring ET, which is in agreement with the published literature [4,6–8]. The various other causes of severe hyperbilirubinemia requiring ET are hereditary spherocytosis, urinary tract infections, HDFN due to non-anti-D antibodies, hemoglobinopathies, hypothyroidism, enzyme deficiencies (pyruvate kinase), subdural hematoma and adrenal gland haemorrhage [4,7]. In developing countries such as India, HDFN due to Rh incompatibility is still commonly encountered as compared to the developed world where routine prophylaxis with Rh immunoglobulin (RhIG) has resulted in ABO incompatibility to be the most common cause of HDFN [9]. Another major issue in the developing countries are inadequate antenatal care and inability to afford RhIG, thus, resulting in more Rh isoimmunization [10]. Administration of prophylactic RhIG is a routine practice at our institute, however, we 2
3
Yes Rh incompatibility 14 Present study (2019)
23
614 Yu et al18 (2017)
Not mentioned
60 64 Singh et al3 (2015) Ballot et al19 (2016)
Not mentioned 67
Yes
No No
7% (hypocalcaemia, thrombocytopenia, hyperglycaemia, metabolic acidosis, hypomagnesemia, hyponatremia, hypokalemia, apnoea, NEC) 21.7% (hypocalcaemia, thrombocytopenia, apnoea)
No No No No
No – 398 Bujandric et al7 (2015)
468
Rh and ABO incompatibility ABO incompatibility Rh and ABO incompatibility ABO incompatibility
% not mentioned (hypercalcaemia) 7.8% (apnoea, thrombocytopenia, hypoglycaemia)
No Yes 86 73
ABO incompatibility
107
ABO incompatibility
17.8% (thrombocytopenia, hypocalcaemia, hypoglycaemia, apnoea, anaemia, bradycardia, petechial rash due to thrombocytopenia, bacteremia, death) No complications or death reported
No
No No No No No No Not mentioned No
% not mentioned (hypocalcaemia) 74% (thrombocytopenia, hypocalcaemia, metabolic acidosis) Not mentioned 32% (apnoea, hypocalcaemia, hypoglycaemia, hyponatremia, hypernatremia) 19.6% (thrombocytopenia, hypocalcaemia) ABO incompatibility Rh incompatibility Rh incompatibility ABO incompatibility Not mentioned 66 25 Not mentioned
Total number of ET sessions
[ET – exchange transfusion; IVIg – intravenous immunoglobulin; NEC – necrotising enterocolitis].
None.
92
Declaration of Competing Interest
Gharehbaghi et al6 (2010) Bulbul et al4 (2011)
None.
52 55 25 50
Source of funding
Jain et al17 (1997) Patra et al22 (2004) Sharma et al20 (2007) Behjati et al21 (2009)
All authors contributed equally towards data analysis and preparation of the manuscript.
Total number of patients undergoing ET
Authors contribution
Author (year)
Table 3 Comparison of the findings of present study with published literature.
Most common indication for ET
ET related Adverse events (%; type)
Need for transfusion post-ET
IVIg administration in addition to ET
results reduction of incompatible red blood cells by 85% followed by a 25–45% reduction in maternal antibodies and bilirubin [16]. The average number of ET/neonate was 1.64 with only four neonates requiring multiple sessions of ET (average 3.25/neonate). All these four neonates presented with Rh HDFN as a result of maternal alloimmunization against Rh antigens such as anti-D, anti-C, anti-G, and Duffy antigen. In our study, a statistically significant reduction in serum bilirubin levels was noted post-procedure (p < 0.001) with an overall reduction in bilirubin levels/procedure being 46%, which is similar to the findings published by other authors [3,6,17–19]. We also observed that the mean hemoglobin and hematocrit post-ET were higher as compared to pre-ET, however, the change was not statistically significant. Similar results have been reported by Gharehbaghi et al. [6] and Sharma et al. [20]. The probable reason could be adequate mixing of RB during the procedure and the adjustment of the hematocrit of RB to 50 ± 5%. Hypocalcaemia is seen due to the use of citrated blood as it chelates calcium, [3,6,7,21,22] thus, it is recommended that calcium gluconate should be administered after every 100 ml of blood removed to avoid hypocalcaemia related adverse events. It has been noted that neonates tend to have low serum calcium levels after birth [23], thus, they are at risk of developing hypocalcaemia more commonly post-ET due to the use of citrated blood. We observed hypocalcaemia (8.7%) as one of the most commonly encountered complication post-ET in our patients. Thrombocytopenia (8.7%) was also encountered which required platelet transfusion post-ET (neonate 1 TPC 25,000/μL; neonate 2 TPC 34,000/μL). It is known that RB is deficient in platelets, thus, thrombocytopenia is a commonly seen adverse event post-ET [6,7,21,22]. Platelet transfusion is only indicated if infants present with significant thrombocytopenia that is platelet count < 50,000/μL or is actively bleeding [6]. Apart from these two complications, one of our neonates had apnoea post-procedure which was managed appropriately with no sequelae. Similar findings have been reported in the published literature [6,7,21,22]. Table 3 compares the findings of the present study with published literature. It has been reported that administration of intravenous immunoglobulin (IVIg) in Rh HDFN patients has led to reduced requirements for phototherapy, ET and shortened hospital stay [10,24,25]. It is also effective in reducing the need for multiple ET sessions especially when administered after the first session of ET [25]. We observed that nine (64.3%) neonates with Rh HDFN received IVIg (dose: 1 gm/kg) in addition to ET, thus, reducing the need for further ET sessions except in one neonate who underwent a total of five session despite receiving IVIg. Among these nine neonates, four received intrauterine transfusion (IUT). Aggressive antenatal management of the babies with hydrops fetalis with IUT leads to a decrease in the need for ET after birth [10]. Though in the current era, a steady decline has been noted in ET procedures being performed, it is still considered a safe and effective adjunct therapy for treating NNH, as it results in a rapid reduction in bilirubin levels, thus, lowering the risk of development of serious neurological sequelae such as kernicterus in these patients.
No
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
B. Kakkar, et al.
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
B. Kakkar, et al.
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