A Decline in the Frequency of Neonatal Exchange Transfusions and Its Effect on
                  Exchange-Related Morbidit...

A Decline in the Frequency of Neonatal Exchange
Transfusions and Its Effect on Exchange-Related
Morbidity and ...
E    XCHANGE TRANSFUSION (ECT) was introduced in the
      late 1940s to decrease the mortality of hemolytic
disease of th...
directly related to the ECT and occurred within 7 days
after the exchange.

Statistical Analysis
SPSS 13.0 (SPSS Inc, Chi...
TABLE 1 Demographic Data and Age at Exchange Transfusion
The 1994 AAP guidelines recommend that all infants          quency ventilation, dialysis, and extracorporeal mem-
17. Peterec SM. Management of neonatal Rh disease. Clin Perinatol.             in haemolytic disease of the newborn. Arch ...
A Decline in the Frequency of Neonatal Exchange Transfusions and Its Effect on
                  Exchange-Related Morbidit...
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A Decline In The Frequency Of Neonatal Exchange Transfusions And Its Effect On Exchange Related Morbidity And Mortality

  1. 1. A Decline in the Frequency of Neonatal Exchange Transfusions and Its Effect on Exchange-Related Morbidity and Mortality Laurie A. Steiner, Matthew J. Bizzarro, Richard A. Ehrenkranz and Patrick G. Gallagher Pediatrics 2007;120;27-32 DOI: 10.1542/peds.2006-2910 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/120/1/27 PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2007 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from www.pediatrics.org by on July 9, 2009
  2. 2. ARTICLE A Decline in the Frequency of Neonatal Exchange Transfusions and Its Effect on Exchange-Related Morbidity and Mortality Laurie A. Steiner, MD, Matthew J. Bizzarro, MD, Richard A. Ehrenkranz, MD, Patrick G. Gallagher, MD Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut The authors have indicated they have no financial relationships relevant to this article to disclose. ABSTRACT OBJECTIVE. Our goal was to identify trends in patient demographics and indications for and complications related to neonatal exchange transfusion over a 21-year www.pediatrics.org/cgi/doi/10.1542/ period in a single institution using a uniform protocol for performing the proce- peds.2006-2910 dure. doi:10.1542/peds.2006-2910 METHODS. A retrospective chart review of 107 patients who underwent 141 single- or Key Words exchange transfusion, hyperbilirubinemia, double-volume exchange transfusions from 1986 –2006 was performed. Patients complication, neonate were stratified into 2 groups, 1986 –1995 and 1996 –2006, on the basis of changes Abbreviations in clinical practice influenced by American Academy of Pediatrics management ECT— exchange transfusion guidelines for hyperbilirubinemia. HDN— hemolytic disease of the newborn AAP—American Academy of Pediatrics NBSCU—newborn special care unit RESULTS. There was a marked decline in the frequency of exchange transfusions per YNHH—Yale New Haven Hospital 1000 newborn special care unit admissions over the 21-year study period. Patient IVIg—intravenous immunoglobulin demographics and indications for exchange transfusion were similar between NEC—necrotizing enterocolitis groups. A significantly higher proportion of patients in the second time period Accepted for publication Feb 16, 2007 Address correspondence to Patrick G. received intravenous immunoglobulin before exchange transfusion. There was a Gallagher, MD, Department of Pediatrics, Yale higher proportion of patients in the 1996 –2006 group with a serious underlying University School of Medicine, 333 Cedar St, PO Box 208064, New Haven, CT 06520-8064. condition at the time of exchange transfusion. During that same time period, a E-mail: patrick.gallagher@yale.edu lower proportion of patients experienced an adverse event related to the exchange PEDIATRICS (ISSN Numbers: Print, 0031-4005; transfusion. Although a similar percentage of patients in both groups experienced Online, 1098-4275). Copyright © 2007 by the American Academy of Pediatrics hypocalcemia and thrombocytopenia after exchange transfusion, patients treated from 1996 –2006 were significantly more likely to receive calcium replacement or platelet transfusion. No deaths were related to exchange transfusion in either time period. CONCLUSIONS. Improvements in prenatal and postnatal care have led to a sharp decline in the number of exchange transfusions performed. This decline has not led to an increase in complications despite relative inexperience with the procedure. PEDIATRICS Volume 120, Number 1, July 2007 27 Downloaded from www.pediatrics.org by on July 9, 2009
  3. 3. E XCHANGE TRANSFUSION (ECT) was introduced in the late 1940s to decrease the mortality of hemolytic disease of the newborn (HDN) and to prevent ker- therapy and intravenous immunoglobulin (IVIg), and ECT-related complications. Patients were divided into 2 groups, 1986 –1995 and nicterus in surviving patients.1 ECT was subsequently 1996 –2006, based on the AAP guidelines for the man- applied to neonatal hyperbilirubinemia from a variety of agement of hyperbilirubinemia published in October causes and quickly became one of the most commonly 1994 and implemented in the NBSCU at Yale in late performed neonatal procedures. 1995. Before this time, the threshold for ECT at YNHH, In 1968 and 1971, Lucey2,3 accurately predicted that with or without evidence of hemolysis, was a total se- prenatal interventions, particularly the development of rum bilirubin of 20 mg/dL for term infants, with thresh- Rh-immunoglobulin, coupled with advances in postna- old levels decreasing based on birth weight.17 Beginning tal care such as phototherapy, would lead to a dramatic in late 1995 and continuing to the present time, the decline in the number of ECTs performed. Maisels4, in a threshold for ECT at YNHH was raised to 25 mg/dL for review that combined data from 3 centers over 40 years, term infants 48 hours old without evidence of hemo- observed a decline in the frequency of ECT and predicted lysis, but remained at 20 mg/dL for those with hemoly- that it would lead to increased complications because of sis. Asymptomatic term infants were also provided the inexperience with the procedure. More recent advances, opportunity to respond to intensive phototherapy before such as use of intrauterine transfusions and improve- an ECT was initiated, and all infants were strictly mon- ments in diagnostic ultrasound,5–8 have likely accelerated itored for hyperbilirubinemia as per the AAP guide- this decline in the frequency of ECT.9,10 lines.15 Since the introduction of ECT, the level of bilirubin at A detailed, step-by-step protocol, provided in the which to initiate this procedure has been a controversial YNHH NBSCU procedure manual, was used for ECT. issue. Based on experience with HDN,11 a bilirubin level This technique, as described by Edwards and Fletcher,18 of 20 mg/dL was used by many centers, including Yale, did not change over the 21-year study period. but some questioned whether it was appropriate to ap- ply this cutoff to patients with nonhemolytic hyperbil- Indications and Comorbidities irubinemia.12 This debate intensified in the late 1980s The indications for ECT were hyperbilirubinemia or and early 1990s, when several reports demonstrated that anemia. Hyperbilirubinemia was further classified by eti- term infants with nonhemolytic jaundice were not as ology (Rh disease, ABO incompatibility, idiopathic hy- susceptible to kernicterus as infants with HDN.13,14 perbilirubinemia, and other hematologic diagnoses). Pa- In 1994, the American Academy of Pediatrics (AAP) tients were considered to have a significant preexisting published its first guidelines on the treatment of hyper- comorbidity if they were treated with blood pressure bilirubinemia.15 These guidelines increased the bilirubin support and/or mechanical ventilation, if they had a threshold for initiating ECT in term infants without he- major congenital anomaly, or if they had any of the molysis and allowed for a trial of intensive phototherapy following diagnoses: respiratory distress syndrome, in- before an ECT was initiated. In addition, these guidelines traventricular hemorrhage (all grades as defined by Pa- encouraged prenatal testing of maternal ABO and Rh pile et al19), necrotizing enterocolitis (NEC; modified types and recommended increased monitoring for hy- Bell’s criteria at least stage 2a20), or sepsis (defined as a perbilirubinemia in all infants.15 These interventions had positive blood culture and/or signs and symptoms con- the potential to cause a further decline in the number of sistent with sepsis treated with antibiotics for 7 days). patients requiring ECT.16 We hypothesized that changes in prenatal and post- ECT-Related Complications natal care have altered the patient population undergo- ECT-related complications were defined as any compli- ing ECT, the indication for exchange, and the incidence cation, not present before the ECT, which occurred of ECT-related morbidity and mortality. To examine this, within 7 days after the exchange. They were defined we performed a longitudinal, 21-year review of ECT at a as follows: severe thrombocytopenia, platelet count single center. 50 000/mm3; hypocalcemia, serum calcium 8.0 mg/dL or plasma ionized calcium 3.5 mg/dL; seizures, PATIENTS AND METHODS clinical evidence of seizure-like activity treated with an- Infants who required single- or double-volume ECT and tiseizure medication; bradycardia, heart rate 100 beats had long-term admissions ( 24 hours) in the newborn per minute; apnea, cessation of respirations for 20 special care unit (NBSCU) at Yale New Haven Hospital seconds; catheter malfunction, central venous or arterial (YNHH) from January 1, 1986, through December 31, catheter thrombosis or rupture; hyperkalemia, serum 2006, were included. Neonates who received partial ECT potassium 6.5 meq/dL associated with electrocardio- for polycythemia or anemia were excluded. Data collec- gram changes; NEC, modified Bell’s criteria at least stage tion included patient demographics, comorbidities, indi- 2a20 diagnosed after the ECT; and ECT-related mortality, cation for exchange transfusion, treatment with photo- ECT-related mortality was defined as any death that was 28 STEINER et al Downloaded from www.pediatrics.org by on July 9, 2009
  4. 4. directly related to the ECT and occurred within 7 days after the exchange. Statistical Analysis SPSS 13.0 (SPSS Inc, Chicago, IL) and GraphPad Prism 3.0 (GraphPad Software, Inc, San Diego, CA) were used for data analyses. Continuous data were compared by using the Student’s t comparison of means. Dichoto- mous data were compared by using a Pearson’s 2 anal- ysis or Fisher’s exact test when at least 1 cell contained a value 5. Trends were analyzed by using linear regres- sion analysis. To incorporate both inborn and outborn neonates into this analysis of trends, the number of ECTs was evaluated per 1000 NBSCU admissions. In evaluat- ing inborn neonates separately, the number of ECTs was evaluated per 1000 live births. A P value of .05 was considered statistically significant. This study was approved by the institutional review board of the Yale University School of Medicine. RESULTS From January 1, 1986, to December 31, 2006, there were 98 901 live births at YNHH and 16 389 long-term admissions, inborn and outborn, to the NBSCU. One hundred seven infants underwent 141 ECTs from 1986 – 2006. Two patients in each time period received a single- volume ECT, with the remaining patients receiving a double-volume or near– double-volume exchange. Over FIGURE 1 the entire study period, there was a statistically signifi- Exchange transfusions at YNHH. A, Exchange transfusions in inborn neonates per 1000 cant decline in the number of ECTs performed per 1000 live births at YNHH: 1986 –2006 (r2 0.30; P .010). B, Exchange transfusions in inborn live births in inborn neonates (r2 0.30; P .010; Fig and outborn neonates per 1000 NBSCU admissions at YNHH: 1986 –2006 (r2 0.49; P .001). 1A) and per 1000 NBSCU admission in those both in- born and outborn (r2 0.49; P .001; Fig 1B). Demographic data were similar between the 2 groups, with Rh disease in the first group and in 64% of patients with no statistically significant differences in gestational with Rh disease in the second group. age, birth weight, race, gender, or age at ECT (Table 1). A smaller proportion of patients in the 1996 –2006 The rate of phototherapy before exchange did not differ group experienced an ECT-related complication (Table significantly between groups. Neonates in the 1996 – 3). This result was not statistically significant, possibly 2006 group were significantly more likely to receive IVIg because of the small sample size. We observed a high before ECT (P .016; Table 1). rate of thrombocytopenia and hypocalcemia after ECT in There were no statistically significant differences in both the 1986 –1995 and the 1996 –2006 groups, com- the indications for ECT when comparing the 1986 –1995 parable to previous studies.21,22 Despite similar rates of and 1996 –2006 groups (Table 2). The most common thrombocytopenia and hypocalcemia, patients treated indication for ECT was hyperbilirubinemia, which was from 1996 –2006 were significantly more likely to be further subdivided into ABO incompatibility, Rh disease, transfused platelets or to be given intravenous calcium idiopathic hyperbilirubinemia, and other hematologic (Table 4). The retrospective nature of this study and the diagnoses. Other diagnoses included glucose-6-phos- small sample size make it difficult to determine the cau- phate dehydrogenase deficiency, pyruvate kinase defi- sality of these observations. The higher proportion of ciency, fibrosarcoma with large vascular compartment, preexisting comorbidities in the neonates undergoing hemolytic anemia because of Gram-negative sepsis, con- ECT from 1996 to 2006 may have resulted in more genital acute myelogenous leukemia, -thalassemia, he- aggressive management or, alternatively, the difference reditary pyropoikilocytosis, and hereditary spherocyto- might stem from unidentified changes in our clinical sis. The most common cause of hyperbilirubinemia practice over the last 2 decades. requiring ECT was Rh disease. Antibodies to non–D Rh A total of 5 deaths occurred within 7 days of the ECT, antigens were common, occurring in 40% of patients none of which were related to the ECT. PEDIATRICS Volume 120, Number 1, July 2007 29 Downloaded from www.pediatrics.org by on July 9, 2009
  5. 5. TABLE 1 Demographic Data and Age at Exchange Transfusion Total 1986–1995 1996–2006 Pa (N 107) (N 71) (N 36) Gestational age, mean SD, wk 35.3 4.7 35.7 4.8 34.6 4.5 .257 Birth weight, mean SD, g 2511.1 983.8 2469.4 956.4 2593.1 1044.7 .541 Birth weight 1000 g, n (%) 12 (11) 7 (10) 5 (14) .747 Birth weigh 1500 g, n (%) 19 (18) 12 (17) 7 (19) .740 Male gender, n (%) 61 (57) 43 (61) 18 (50) .296 Race, n (%) Caucasian 63 (59) 43 (61) 20 (56) .617 Black 31 (29) 20 (28) 11 (31) .791 Hispanic 9 (8) 5 (7) 4 (11) .715 Asian 4 (4) 3 (4) 1 (3) .999 Transport, n (%) 34 (32) 23 (32) 11 (31) .841 Age at exchange, mean SD, d 3.6 3.1 3.4 2.9 4.0 3.6 .347 Phototherapy before ECT, n (%) 91 (85) 60 (85) 31 (89) .823 IVIg administration, n (%) 6 (17) 1 (1) 5 (14) .016 Intrauterine transfusions, n (%) 20 (19) 14 (20) 6 (17) .699 Comorbidities, n (%) 41 (38) 24 (34) 17 (47) .177 Mechanical ventilation 37 (35) 23 (32) 14 (39) .502 Blood pressure support 17 (16) 11 (15) 6 (17) .888 NEC 4 (4) 1 (1) 3 (8) .110 Hydrops fetalis 6 (6) 3 (4) 3 (8) .661 IVH 10 (9) 8 (11) 2 (6) .490 RDS 23 (21) 14 (20) 9 (25) .532 Sepsis 13 (12) 7 (10) 6 (17) .354 a Comparison of the 2 time periods. TABLE 2 Indication for ECT TABLE 4 Hypocalcemia and Thrombocytopenia in Patients Total 1986–1995 1996–2006 Pa Undergoing Exchange Transfusion (N 141), (N 96), (N 45), Total 1986–1995 1996–2006 Pa n (%) n (%) n (%) (N 141), (N 96), (N 45), Hyperbilirubinemia 120 (85) 79 (82) 41 (91) .211 n (%) n (%) n (%) Rh disease 58 (41) 41 (43) 17 (39) .578 Hypocalcemia 53 (38) 32 (33) 21 (47) .128 ABO incompatibility 39 (28) 28 (29) 11 (24) .560 Calcium replacement 24 (45)b 9 (28) 15 (71) .002 Idiopathic 28 (20) 17 (18) 11 (24) .351 Thrombocytopenia 53 (38) 36 (38) 17 (38) .999 Other 14 (10) 10 (10) 4 (9) .999 Platelet transfusion 26 (49)c 11 (31) 15 (88) .0001 Anemia 3 (2) 1 (1) 2 (4) .239 a Comparison of the 2 time periods. a Comparison of the 2 time periods. b Percentage with hypocalcemia who received calcium replacement. c Percentage with thrombocytopenia who received platelet transfusion. TABLE 3 Exchange Transfusion-Related Complications Excluding Thrombocytopenia and Hypocalcemia weight compared with those 1500 g. Infants 1500 g Total 1986–1995 1996–2006 Pa did not experience increased rates of thrombocytopenia, (N 141), (N 96), (N 45), hypocalcemia, calcium replacement, or platelet transfu- n (%) n (%) n (%) sion (data not shown). The small sample size of this Catheter malfunction 4 (3) 2 (2) 2 (4) .592 premature cohort (n 19) made it difficult to draw any Seizures 3 (2) 3 (3) 0 (0) .551 valid conclusions from the analyses. NEC 2 (1) 2 (2) 0 (0) .562 Apnea 1 (1) 1 (1) 0 (0) .999 Bradycardia 5 (4) 4 (4) 1 (2) .673 DISCUSSION Hyperkalemia 1 (1) 1 (1) 0 (0) .999 These data demonstrate a dramatic decline in the fre- Any complication 16 (11) 13 (14) 3 (7) .270 quency of ECT at YNHH over 2 decades, representing the a Comparison of the 2 time periods. longest single-center, longitudinal documentation of trends in ECT. This decline is likely multifactorial with contributions from advances in both prenatal and post- Authors of previous reports have hypothesized that natal care, such as middle cerebral artery Doppler studies premature infants are more susceptible to complications to noninvasively follow fetal anemia,7,8 and IVIg treat- from ECT.21,22 We observed no significant differences in ment for patients with hemolysis.23 In addition, adoption either time period in the frequency of ECT-related com- of the 1994 AAP guidelines may have contributed to this plications or their treatment in neonates 1500 g birth decline.15 30 STEINER et al Downloaded from www.pediatrics.org by on July 9, 2009
  6. 6. The 1994 AAP guidelines recommend that all infants quency ventilation, dialysis, and extracorporeal mem- jaundiced in the first 24 hours of life receive a total brane oxygenation than with ECT, a standardized pro- serum bilirubin and all infants be assessed for jaundice tocol for performing ECT may be an important tool for by a health care provider at 2 to 3 days of life. These decreasing the number of adverse, procedure-related guidelines also recommend prenatal testing of maternal events. Inclusion of ECT in neonatal education will also ABO and Rh types, prenatal screening for unusual ma- help minimize ECT-related morbidity and mortality, ternal antibodies, and screening of the cord blood if the even as the frequency of ECT continues to decline. mother was Rh negative or if the mother’s ABO type was unknown. The heightened monitoring of all infants for ACKNOWLEDGMENT hyperbilirubinemia may have contributed to early de- This work was supported, in part, by National Institute of tection and treatment of infants with significant jaundice Child Health and Human Development grant T32 (hemolytic and nonhemolytic) and, therefore, caused a HD07094 (to Dr Steiner). decline in the number of ECT necessary. The declining rate of ECT has led to speculation that inexperience with the procedure would result in in- REFERENCES creased rates of ECT-associated morbidity and mortali- 1. Diamond LK, Allen FH Jr, Thomas WO Jr. Erythroblastosis ty.4,21–22 Historically, morbidity and mortality associated fetalis: VII. Treatment with exchange transfusion. N Engl J Med. with ECT steadily declined from the 1950s through the 1951;244:39 – 49 2. Lucey JF. Changing concepts regarding exchange transfusion 1970s, a period of time when the procedure was com- and neonatal jaundice. 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  8. 8. A Decline in the Frequency of Neonatal Exchange Transfusions and Its Effect on Exchange-Related Morbidity and Mortality Laurie A. Steiner, Matthew J. Bizzarro, Richard A. Ehrenkranz and Patrick G. Gallagher Pediatrics 2007;120;27-32 DOI: 10.1542/peds.2006-2910 Updated Information including high-resolution figures, can be found at: & Services http://www.pediatrics.org/cgi/content/full/120/1/27 References This article cites 24 articles, 9 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/120/1/27#BIBL Citations This article has been cited by 3 HighWire-hosted articles: http://www.pediatrics.org/cgi/content/full/120/1/27#otherarticles Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Premature & Newborn http://www.pediatrics.org/cgi/collection/premature_and_newbor n Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Reprints Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml Downloaded from www.pediatrics.org by on July 9, 2009