REVIEW Impact of ethnicity on human umbilical cord blood banking: a systematic review Celine Akyurekli,1,2 Joshua Y.S. Chan,1 Heidi Elmoazzen,4 Jason Tay,1,3 and David S. Allan1,2,4

BACKGROUND: How ethnicity impacts characteristics of umbilical cord blood collected by cord blood banks remains unclear. STUDY DESIGN AND METHODS: After a systematic search, we identified 11 studies for analysis that reported on various variables of collected cord blood units. RESULTS: Non-Caucasian ethnicity of the cord blood donor was associated with a higher risk of failing to meet banking criteria, lower cord blood volume, reduced total nucleated cell count, fewer CD34+ cells, and reduced colony-forming units. CONCLUSIONS: Non-Caucasian ethnicity is associated with reductions in hematopoietic measures of collected cord blood units. Public banking efforts will have to balance issues related to building ethnic diversity within the bank and maintaining the characteristics of banked units that remain desirable by transplant centers.

ABBREVIATION: TNC = total nucleated cell. From the 1Blood and Marrow Transplant Program, Department of Medicine, University of Ottawa; 2Regenerative Medicine and 3 Clinical Epidemiology Programs, Ottawa Hospital Research Institute; and 4National Public Cord Blood Bank, Canadian Blood Services, Ottawa, Ontario, Canada. Address reprint requests to: David S. Allan, MD, FRCPC, Ottawa Hospital Research Institute, 501 Smyth Road, Box 704, Ottawa, Ontario, Canada K1H 8L6; e-mail: [email protected]. Funding support for students (CA, JYSC) was provided through an undergraduate summer research award of the National Science and Engineering Research Council (Canada) and The Ottawa Hospital Foundation. DSA receives salary support from a New Investigator Award from Canadian Institutes of Health Research. DSA and JT are supported in part by the Department of Medicine, University of Ottawa. Received for publication November 22, 2013; revision received January 9, 2014, and accepted January 13, 2014. doi: 10.1111/trf.12630 © 2014 AABB TRANSFUSION **;**:**-**.

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ematopoietic progenitor cell transplantation can be a lifesaving treatment for patients with a wide range of malignant and nonmalignant blood disorders. With declining fertility rates in recent decades, fewer patients will have HLA-matched siblings, and we anticipate an increasing reliance on finding alternative sources of cells from unrelated donor registries and umbilical cord blood banks.1 Registries of unrelated donors require strategic recruiting to ensure proportional representation of ethnic diversity, while cord blood banking may represent an ideal strategy to embrace the evolving ethic diversity in any given jurisdiction.2,3 The search for appropriately matched donors is increasingly difficult for patients of mixed ethnicity and for patients with ethnic backgrounds that are less well represented in worldwide registries of unrelated donors and these patients often cannot proceed with transplant.4 Many umbilical cord blood banks, in particular, have targeted various minority ethnic groups in an effort to enrich the diversity of the inventory that reflects the perceived needs of the bank. It remains unknown, however, to what extent strategic efforts to capture particular ethnic groups in umbilical cord blood bank inventories are associated with changes in the quality of banked units. The issue of ethnic diversity in cord blood banks may be especially relevant in countries with diverse immigration patterns over recent decades, such as Canada.5 Importantly, the requirements for HLA compatibility in cord blood transplantation are less stringent than with marrow or peripheral blood progenitor cells (PBPCs),6 thus allowing cord blood to be considered as a suitable alternative to finding appropriately matched stem cell graft for patients of certain ethnic backgrounds and for patients with rare HLA haplotypes. Previous studies have yielded conflicting insights on the impact of ethnicity on transplant outcomes and on the quality of units stored in public cord blood banks. Successful strategies that increase the ethnic diversity of cord blood units stored in banking establishments should ultimately translate into increased numbers of patients undergoing transplant and improved outcomes for patients within these ethnic groups. In this study, we performed a systematic review of the literature to summarize the role of ethnicity on the Volume **, ** **

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quality of collected cord blood units. Ultimately, our goal is to use current evidence to guide the development of strategies that aim to increase the ethnic diversity of the inventory in cord blood banks that will improve transplant outcomes for these patients.

MATERIALS AND METHODS Systematic search strategy Studies eligible for inclusion in our analysis had to meet the following criteria: 1) recruited human participants from at least two distinct ethnic populations, 2) compared outcomes between ethnic groups, and 3) reported clinical outcomes and/or clinical characteristics of cord blood hematopoietic progenitor cell transplantation and/or characteristics of collected and/or banked cord blood units. All review articles and editorials were excluded. MEDLINE and EMBASE databases were searched from 1946 to July 31, 2012. The electronic search strategy used in MEDLINE is presented in Table 1. Further, reference lists of relevant studies were searched manually and local experts were consulted to identify any additional studies. Studies that reported only clinical outcomes after transplantation but that did not provide information related to the cord blood unit were excluded.

Study selection Titles and abstracts of studies identified in the systematic search were screened by two investigators (CA and JYSC) for relevance after removing duplicates. Subsequently, rel-

TABLE 1. Database: Ovid MEDLINE in-process and other nonindexed citations and Ovid MEDLINE (1946 to present) search strategy 1 2 3 4 5 6 7 8 9

Fetal Blood/ (23,777) (fetal blood or cord blood).tw. (21,724) uc blood.tw. (48) 1 or 2 or 3 (33,484) Blood Donors/or (donor$ or donation$).mp. (227,715) Blood Banks/or blood bank$.tw. (8,895) 5 or 6 (233,046) 4 and 7 (2,725) Cord Blood Stem Cell Transplantation/or cord blood transplantation.tw. (2,190) 10 cord blood bank$.tw. (433) 11 (ucb adj [bank$ or transplantation$]).tw. (174) 12 (ucbb or ucbt).tw. (184) 13 or/9-12 (2,526) 14 8 or 13 (4,000) 15 Minority Groups/ (9,191) 16 exp Ethnic Groups/ (98,159) 17 (minorit$ or racial or ethnic or ethnicity).tw. (105,691) 18 (african american$ or hispanic$ or asian$).tw. (79,390) 19 (non-european$ or non-caucasian$).tw. (1,612) 20 native american$.tw. (3,077) 21 or/15-20 (218,073) 22 14 and 21 (115) MEDLINE search strategy

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evant articles were retrieved for more complete assessment of eligibility criteria and for data extraction, which was conducted independently by two investigators (CA and JYSC). All discrepancies were resolved by a third investigator (DSA) to confirm the final list of studies for data extraction. Using standardized study extraction forms, relevant data were extracted from the identified published manuscripts. All data extraction was performed in duplicate by two investigators (CA and JYSC).

Summary measures and synthesis of results The number of studies that described the impact of ethnicity on particular outcomes was tabulated. Where data were available from primary studies, we sought to summarize the effects of ethnicity on outcomes by relative risks and 95% confidence intervals using a random-effects model, presenting the results in a Forest plot. In the absence of available raw data, we qualitatively classified studies as “positive” if there is a significant difference in reported outcome(s) or a significant correlation with an outcome in one ethnic group compared with another.

RESULTS A total of 403 published articles were identified in our literature search of electronic databases and from experts’ files. After duplicates were removed, relevance was screened for, and our eligibility criteria were applied, a total of 54 studies underwent comprehensive review and data extraction. Forty-three studies were excluded for the following reasons: reviews lacked primary data, studies did not provide data related to cord blood characteristics, reports lacked a comparator group, duplicate publications, or data analysis not based on ethnicity. In total, we identified 11 studies. A summary of the study selection process is provided in Fig. 1.

Study demographics Among the 11 studies addressing the impact of ethnicity on cord blood collection and banking, eight were performed in the United States and were reported by public cord blood banking establishments.7-14 The studies performed in Taiwan and the United Kingdom were conducted by public cord blood banks15,16 while one study, performed in Canada, was conducted by a private banking establishment.17

Studies Of the 11 studies reporting on the impact of ethnicity on variables of collected cord blood units, four reported on the success rate of adding the collected unit to the inventory (storage rate), nine studies reported on total volume collected, nine studies reported on the total

ETHNICITY IN CORD BLOOD BANKING

be associated with reductions in indicators of hematopoietic potency in collected cord blood units, including the overall success rate of banking collected units and various measures of stem cell 403 studies identified during initial search and progenitor content and/or func104 excluded due to tion. Taken together, more work is duplication needed to understand determinants 299 studies reviewed by title and abstract of reduced hematopoietic potency of screen umbilical cord blood units from non245 unrelated to topic Caucasian cord blood donors. and excluded The impact of non-Caucasian eth54 studies reviewed nicity on hematopoietic potency of collected cord blood units should be 43 studies excluded: considered in light of previous studies that did not find reduced hematopoietic • 1 review progenitor number from marrow collec• 29 lacked hematopoietic potency data tions or mobilized PBPCs in relation to • 9 lacked comparator group non-Caucasian ethnicity.18,19 In recent • 3 repeat publications • 1 analysis not based on ethnicity studies investigating characteristics of allogeneic PBPCs after granulocyte– colony-stimulating factor mobilization, 11 studies included in review levels of CD34(+) cells and neutrophil counts were independent of donor Fig. 1. Outline of study selection process. ethnicity18 or were reduced in grafts from Caucasian donors.19 It is possible, however, that responses to colony-stimulating factors nucleated cell (TNC) count, nine studies provided data on used in the mobilization of hematopoietic progenitors is CD34+ cell yield, and nine studies reported on the total different between ethnic groups and these differences are colony-forming units (CFUs). Only three studies reported not present in steady state marrow or peripheral blood. on all five outcomes related to variables of the collected Likewise, it is possible that factors produced during labor unit, while four studies reported on four outcomes, two have differential effects on levels of hematopoietic prostudies reported on three outcomes, one study reported genitors mobilized in umbilical cord blood between on two outcomes, and one study reported on just one ethnic groups. Additional factors specific to umbilical outcome. Non-Caucasian ethnicity (reported as African cord blood may be important contributing factors in American, Asian, or non-Caucasian) compared with Cauunderstanding the particular role of ethnicity on characcasian was associated with reduced storage rates in all teristics of umbilical cord blood collections, including four studies reporting on this outcome,7,8,12,13 reduced total obstetric and neonatal factors. Previous studies have volume in three of nine studies,10-12 lower TNC count in reported reduced birthweight in non-Caucasian newfive of nine studies,7,10,12-14 fewer CD34+ cells in four of borns compared with Caucasians and birthweight has nine studies,8-10,12 and reduced CFUs in three of nine been correlated with the volume and TNC counts in studies12,14,17 (see Table 2). One study, however, did report umbilical cord blood units.20 Moreover, both African on the significance of paternal non-Caucasian ethnicity as being significantly associated with reduced volume and American and Asian mothers were observed to have lower CD34 count in collected units.10 No study reported shorter labor, on average, than Caucasian mothers.21 Both superiority of non-Caucasian ethnicity on any of the varishorter labor and low birthweight are associated with ables of collected units. The absence of sufficient raw smaller cord blood volumes,11,22,23 and low cord blood data with regard to the ethnic groups in the published volume has been correlated with reduced TNC and CD34+ manuscripts precludes formal meta-analysis of outcome levels.24 With regard to specific non-Caucasian ethnicities measures. associated with reductions in hematopoietic potency of collected cord blood units, African Americans are most commonly represented in the published studies. Whether DISCUSSION specific factors associated with this population are present in other ethnic groups in other jurisdictions Our study provides important new insight regarding the and the impact on variables of hematopoietic function potential impact of ethnicity on cord blood banking. In require additional study. particular, we observed that non-Caucasian ethnicity may 388 records identified through database searching

15 additional records identified through reviews and experts

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Ethnicities studied Caucasian (276) vs. AA (276) AA (200), Caucasian (1209), Asian (16), Hispanic (59), other (154) White (3631), AA (1253), Asian (987), Hispanic (1841), other (1018) Caucasian (5015), AA (1254), Hispanic (940), Asian (313), Native American (78), other (235) Caucasian (810) vs. non-C (108) Caucasian (3103), AA (1064), Hispanic (680) Caucasian, AA, Asian, Hispanic, other Caucasian (39), non-Caucasian (30) Caucasian (3473), AA (2582), Hispanic (2404), Asian (356), other (89) Asian (1949), AA (22), Hispanic (117), Caucasian (1888), other (39) Taiwan: Hoklo (1367), Hakka (163), Mainlander (149) ↔§ ↓Non-C† ↓AA† ↔ ↔ ↔

↔ ↓Non-C†|| ↔ ↔ ↓AA, Asian† ↓AA† ↔

↓AA, Asian†

↓AA†



↓Non-C†

TNC ↓AA† ↓AA†‡



Volume

Storage rate ↓AA† ↓AA†





↓Non-C†|| ↔ ↓Non-C†

↓AA†

↓AA†

CD34 ↔ ↔



↓Non-C† ↔ ↔ ↓Non-C†



↓AA†

CFU ↔ ↔

Taiwan

Canada

US US US UK US

US

US

Country US US

Public

Private

Public Public Public Public Public

Public

Public

Private or public Public Public

* The arrow indicates the direction of change in a variable and the associated ethnic group (AA =African-American; non-C = non-Caucasian). A horizontal arrow (↔) indicates no significant impact of ethnicity on characteristics described. A blank cell indicates that the variable was not reported. If ethnicity influenced outcome in univariate but not multivariable analysis, ↔ was assigned. If no multivariable analysis performed, results of univariate analysis guided arrow assignment. † A difference in measures of hematopoietic potency was reported. ‡ Percentage of excluded units if TNC threshold increased from 80 × 107 to 100 × 107 cells in a retrospective analysis. § Marked center variation with some significant differences at individual collection sites yet overall no significant impact of ethnicity on TNC counts. || Paternal ethnicity was significantly associated with the cord blood unit variables described.

Shlebak et al.16

Jan et al.15

George et al.10 Page et al.14 Cairo et al.9 Yang et al.17 Jones et al.11

Ballen et al.8

Kurtzburg et al.12

Ref Wofford et al.7 Unold et al.13

TABLE 2. Impact of ethnicity on characteristics of cord blood units collected and/or banked*

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ETHNICITY IN CORD BLOOD BANKING

Our study has limitations that are worth mentioning. In many of the studies identified, the number of participants enrolled were quite small, or the proportion of participants from ethnic minority groups was much smaller than the proportion of Caucasian subjects. Characteristics of collected cord blood units within these ethnic groups, therefore, may not accurately reflect these variables within the entire population of patients or donors of that ethnicity. Indeed, many of the subjects were enrolled in the United States and results may be skewed compared with similar ethnic groups from different countries. Moreover, despite our extensive search strategy, only a small number of papers met the inclusion criteria and only a few of these reported on the same outcomes or could be combined. In some cases, ethnicity was presented as part of a larger data set and data were not presented in a way that allowed us to pool the results with other studies. This decreased our ability to draw clear conclusions as data from several studies could not be pooled. In summary, our report highlights the apparent influence of ethnicity on cord blood banking. Understanding genetic and sociodemographic factors that underlie the influence of ethnicity may help banking and transplant establishments address potential hurdles that could allow improved success of cord blood–based therapy. ACKNOWLEDGMENT We acknowledge the assistance of Risa Schorr from the library at

5. Kobayashi KM, Prus SG. Examining the gender, ethnicity, and age dimensions of the healthy immigrant effect: factors in the development of equitable health policy. Int J Equity Health 2012;11:8. 6. Rubinstein P, Carrier C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 1998;339:1565-77. 7. Wofford J, Kemp J, Regan D, et al. Ethnically mismatched cord blood transplants in African Americans: the Saint Louis Cord Blood Bank experience. Cytotherapy 2007;9: 660-6. 8. Ballen KK, Kutzberg J, Lane TA, et al. Racial diversity with high nucleated cell counts and CD34 counts achieved in a national network of cord blood banks. Biol Blood Marrow Transplant 2004;10:269-75. 9. Cairo MS, Wagner EL, Fraser J, et al. Characterization of banked umbilical cord blood hematopoietic progenitor cells and lymphocyte subsets and correlation with ethnicity, birth weight, sex and type of delivery: a Cord Blood Transplantation (COBLT) Study report. Transfusion 2005; 45:856-66. 10. George TJ, Sugrue MW, George SN, et al. Factors associated with parameters of engraftment potential of umbilical cord blood. Transfusion 2006;46:1803-12. 11. Jones J, Stevens CE, Rubinstein P, et al. Obsteric predictors of placental/umbilical cord blood volume for transplantation. Am J Obstet Gynecol 2003;188:503-9. 12. Kurtzberg J, Cairo MS, Fraser JK, et al. Results of the Cord Blood Transplantation (COBLT) Study unrelated donor banking program. Transfusion 2005;45:842-55.

The Ottawa Hospital. CONFLICT OF INTEREST DSA is a medical consultant with the National Public Cord Blood Bank at Canadian Blood Services (CBS) and HE is employed as the Director of the National Public Cord Blood Bank at CBS. The remaining authors have no conflicts of interest to disclose.

13. Unold KM, Hertel L, Lambert A, et al. The impact of increasing the pre-processing total nucleated cell count banking threshold on racial and ethnic diversity in cord blood banking. Transfusion 2011;51:279A-80A. 14. Page KM, Betz-Stablein B, Mendizabal AM, et al. What

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19. Vasu S, Leitman SF, Tisdale JF, et al. Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population. Blood 2008;112:2092-100. 20. Wen SH, Zhao WL, Lin PY, et al. Associations among birth weight, placental weight, gestational period and product quality indicators of umbilical cord blood units. Transfus Apher Sci 2012;46:39-45. 21. Chilvers G, Szydlo R, Regan F. Feto-maternal haemorrhage does not account for blood volume obtained from Black and Asian versus Caucasoid donors. Br J Haematol 2009; 148:948-63.

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Impact of ethnicity on human umbilical cord blood banking: a systematic review.

How ethnicity impacts characteristics of umbilical cord blood collected by cord blood banks remains unclear...
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