POLICY STATEMENT Organizational Principles to Guide and Define the Child Health Care System and/or Improve the Health of all Children

William T. Shearer, MD, PhD, FAAP,a​ Bertram H. Lubin, MD, FAAP,b​ Mitchell S. Cairo, MD, FAAP,c​ LuigiCord D. Notarangelo, Blood MD,​d SECTION ONBanking HEMATOLOGY/ONCOLOGY, SECTIONfor ON Potential ALLERGY AND IMMUNOLOGY Future Transplantation This policy statement is intended to provide information to guide abstract pediatricians, obstetricians, and other medical specialists and health care providers in responding to parents’ questions about cord blood donation and banking as well as the types (public versus private) and quality of cord blood banks. Cord blood is an excellent source of stem cells for hematopoietic stem cell transplantation in children with some aDepartment of Pediatrics and Pathology and Immunology, College of Medicine, Baylor University and Section of Immunology, Allergy, and fatal diseases. Cord blood transplantation offers another method of Rheumatology, Texas Children’s Hospital, Houston, Texas; bChildren’s Health, University of California, San Francisco and Benioff Children’s definitive therapy for infants, children, and adults with certain hematologic Hospital, San Francisco, California; cDepartment of Pediatrics, malignancies, hemoglobinopathies, severe forms of T-lymphocyte and other Medicine, Pathology, Microbiology and Immunology, and Cell Biology and Anatomy, Maria Fareri Children’s Hospital and New York Medical immunodeficiencies, and metabolic diseases. The development of universal College, Valhalla, New York; and dLaboratory of Host Defenses, National screening for severe immunodeficiency assay in a growing number of states Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland is likely to increase the number of cord blood transplants. Both public and All of the authors shared responsibility for writing and editing the private cord blood banks worldwide hold hundreds of thousands of cord document and reviewing and responding to questions and comments blood units designated for the treatment of fatal or debilitating illnesses. The from reviewers and the Board of Directors. procurement, characterization, and cryopreservation of cord blood is free This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have for families who choose public banking. However, the family cost for private filed conflict of interest statements with the American Academy banking is significant and not covered by insurance, and the unit may never of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of be used. Quality-assessment reviews by several national and international Pediatrics has neither solicited nor accepted any commercial accrediting bodies show private cord blood banks to be underused for involvement in the development of the content of this publication. treatment, less regulated for quality control, and more expensive for the Policy statements from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and family than public cord blood banks. There is an unquestionable need to external reviewers. However, policy statements from the American Academy of Pediatrics may not reflect the views of the liaisons or the study the use of cord blood banking to make new and important alternative organizations or government agencies that they represent. means of reconstituting the hematopoietic blood system in patients The guidance in this statement does not indicate an exclusive course with malignancies and blood disorders and possibly regenerating tissue of treatment or serve as a standard of medical care. Variations, taking systems in the future. Recommendations regarding appropriate ethical into account individual circumstances, may be appropriate. and operational standards (including informed consent policies, financial All policy statements from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, disclosures, and conflict-of-interest policies) are provided for physicians, revised, or retired at or before that time. institutions, and organizations that operate or have a relationship with DOI: https://​doi.​org/​10.​1542/​peds.​2017-​2695 cord blood banking programs. The information on all aspects of cord blood banking gathered in this policy statement will facilitate parental choice for To cite: Shearer WT, Lubin BH, Cairo MS, et alAAP SECTION public or private cord blood banking. ON HEMATOLOGY/ONCOLOGY, AAP SECTION ON ALLERGY AND IMMUNOLOGY. Cord Blood Banking for Potential Future Transplantation. Pediatrics. 2017;140(5):e20172695

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 140, number 5, November 2017:e20172695 From the American Academy of Pediatrics Introduction TABLE 1 Diseases Treated by Umbilical Cord Blood Transplant by Using Either of hematopoietic stem cells to meet Sibling or Unrelated Donors the increased use of cord blood in Malignant Diseases Nonmalignant Diseases Hematopoietic stem cells have the older children and adults, as was Acute lymphocytic Fanconi anemia potential to reconstitute any blood seen in 1 limited– study (which leukemia cell type and rescue children with requires3,15​ confirmation17 in a larger Acute myelocytic Idiopathic aplastic malignancies and other types of life- study). ‍ ‍ The implementation leukemia anemia threatening diseases. The need for of universal newborn screening by Juvenile chronic Thalassemia myelogenous cord blood transplantation to treat using dried blood on filter paper and leukemia malignancies, hemoglobinopathies, the T-lymphocyte receptor excision Chronic Sickle cell anemia primary immunodeficiencies, and circle assay in more than 3000000 myelogeneous leukemia metabolic diseases1 within the newborn infants permitted the last decade has prompted the recognition of the true incidence of Neuroblastoma Amegakaryocytic thrombocytopenia American Academy of Pediatrics SCID requiring HSCT; it was found to “ Myelodysplastic Kostman syndrome (AAP) to revise its 2007 policy be nearly double (ie, 1 in 58000 live ” 18 syndrome statement Cord Blood Banking for2 births) previous estimates. This Blackfan-Diamond Potential Future Transplantation. ‍ new development has prompted the syndrome This revised policy statement search for a more convenient method Severe combined immunodeficiency of HSCT, a method that applies to the reviews the new applications for X-linked transplantation of the hematopoietic use of cord blood. However, other lymphoproliferative cells contained in cord blood sources of hematopoietic stem cells syndrome taken from the placenta of normal (eg, haploidentical parent donors) Wiskott-Aldrich newborn infants, blood that was may prove useful for patients syndrome 19,20​ Hurler syndrome previously discarded because of a with infections. ‍ Perhaps the 3 Hunter syndrome lack of need for it. By 2013, more most immediate challenge is that Gunther disease than 30 000 hematopoietic stem of educating medical personnel, Osteopetrosis cell transplants (HSCTs) have been parents, and the public about the Globoid cell performed by using cord blood as increasing need and uses of cord leukodystrophy 4,5​ Adrenoleukodystrophy blood banking. the source of stem cells worldwide. Lesch-Nyhan syndrome The disease distributions were In the following sections, several Adapted from Cairo MS, Rocha V, Gluckman E, Hale 57% for malignancies, 32.5% for important features of public G, Wagner J. Alternative allogenic donor sources for hemoglobinopathies, 6% for severe versus private cord blood banking transplantation for childhood diseases: unrelated cord combined immunodeficiency disease blood and haploidentical family donors [published are compared: (1) purpose; (2) correction appears in Biol Blood Marrow Transplant. (SCID) or related T-lymphocyte quality control and accreditation; 2008;14(11):1317–1318]. Biol Blood Marrow Transplant. 2008;14(1, suppl 1):44 53. Copyright 2008 American disorders,6, and7​ 1.5% for other (3) cost and use of banked cord – © Society for Blood and Marrow Transplantation. disorders ‍ (Table 1). Approximately blood; (4) education of medical 800000 cord blood units are being personnel, expectant parents, and stored in public cord blood banks, the public; (5) summary; and (6) and more than 5000000 cord ’ recommendations. A review of these need to be aware that should their blood units are stored in private 8 components will enable parents and child develop leukemia, the child s cord blood banks. The trajectory medical personnel to make informed of increase in the number of cord stored cord blood already contains decisions on public or private cord premalignant cells and cannot, blood units being transplanted in blood banking for patients. patients older than 16 years has therefore, be used to treat21, the22​ child Public Versus Private Cord Blood (autologous transplant). ‍ In that progressively increased over the past Banking: Purpose and Opinions decade (Fig 1). Clinical outcomes of case, the cord blood from an unrelated both malignant and nonmalignant Purpose child (an allogeneic transplant) disorders are beginning to emerge is needed. When there is a known in the literature, and it is certain that genetic defect in a family, there can HLA barriers can be breached more The primary goal of this policy be a need for directed cord blood that easily with cord blood transplants statement is to help physicians could be stored in a cord blood bank compared with– nonmatched address the question of the value location (usually at a major medical marrow or peripheral blood HSCT of cord blood banking in public or institute) at which HLA typing could 9 15 ’ 2 transplants. ‍‍ Stem cell quantity private cord blood banks. Parents be performed before transplant. New limitations in cord blood may be who save their children s cord developments in early clinical trial addressed by laboratory expansion blood in private cord blood banks research for regenerative purposes Downloaded from www.aappublications.org/news by guest on September 29, 2021 2 FROM THE AMERICAN ACADEMY OF PEDIATRICS 26 World Marrow2 Donor Association,​ the AAP,​ the American Congress27 of Obstetricians and Gynecologists,​

and the American Society for Blood8 and Marrow Transplantation.

European countries have advocated for the adoption of strict guidelines regarding public collection and use of cord– blood

for transplant in the case28 39 of life- threatening illnesses. ‍ ‍ The most expressive opinion of these position statements is from the Italian Committee for the Proper Use of Umbilical Cord Blood to the Chairman of the Health Commission FIGURE 1 Umbilical cord blood transplant by age (based on unpublished data from the Center for International of the European Parliament, which Blood and Marrow Transplant Research [CIBMTR] and reproduced with permission). Shown are the noted (1) the total absence of latest data available. a Numbers for 2012–2013 are lower because of a reporting lag. scientifically valid data proving that the therapeutic use of autologous cord blood stored for preventive purposes is appropriate, effective, may affect cord blood banking in the Other professional groups that and risk free; (2) the for-profit future. Some examples of these trials favor public cord blood bank nature of the private collection and of cord blood transplants are those for donations over private cord blood storage of umbilical cord blood; Alzheimer disease, autism spectrum banking include the International and (3) the contrast between this disorder, diabetes, cerebral palsy, Federation of Gynecology and ’ type of storage of cord blood and hypoxic ischemic encephalopathy, Obstetrics and the United both the general interest and the systemic lupus erythematosus,4,​5,23​ and Kingdom s Royal College of 8 principle of altruistic donations and systemic sclerosis. ‍ However, no Obstetricians and Gynecologists. 24 solidarity repeatedly affirmed40 by breakthrough in therapy has yet been Petrini has addressed the critical the European Parliament. Canada realized. issue of the ethics of private cord Worldwide Opinion on Public Versus and Australia, although favoring blood banking versus public cord Private Cord Blood Banking the promotion of public cord blood blood banking. Most professional banking, nevertheless advocate organizations support donation to for a cooperative relationship public institutions. An exception between public41,42​ and private cord Since the publication of the previous to the preference of public cord blood banks. Some attempts blood banking would be in AAP policy2 statement on cord blood have been made to merge the banking,​ several other professional instances when a family member concepts of public and private cord societies have issued similar is identified as having a disease ’ blood banking by holding private statements. The American Society for that can be cured by cord blood cord blood banks to the same Blood and Marrow Transplantation s transplantation. In those instances, level of excellence and regulation view is that donation of cord blood the use of family-directed cord of laboratory experiments and to the public is preferable because blood banks (normally located storage facilities as public cord the use of cord blood stored in within universities or, in some blood banks in preparation43 for private cord blood banks for therapy cases, nested in private cord blood allogeneic transplantation. One rarely occurs3 (ie, 1 in several banks) may be preferred.24 The such hybrid cord blood bank has 1000). The American Society for review by Petrini lists all of the been evaluated and was found to Blood and Marrow Transplantation European and US professional be of less benefit to patients than acknowledges that private donation organizations that strongly either public or private44 cord blood may be used for family members with advocate for donation to and use banks separately. The authors nonmalignant conditions if there is of cord blood in public institutions: concluded that continued emphasis good HLA matching between a donor the Society of Obstetricians25 and should be placed44 on public cord and recipient. Gynecologists of Canada,​ the blood banking. Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 140, number 5, November 2017 3 Quality Control and Accreditation of Cord Blood Banks https://​parentsguidecordblood.​ ​ surveyed were somewhat familiar org/​en/​public-​banking). These with the 2007 AAP policy regarding

banks have sufficient capacity for cord blood banking55 1 year after its those requesting a donation of cord publication. This lack of awareness As noted in2 the 2007 AAP policy statement,​ the emphasis on quality blood. However, an area of concern represents an opportunity to provide is the relatively limited number of more education to physicians control and accreditation of cord45 blood banks is extremely important. Several banked cord blood units that are HLA regarding the policy statement and programs have such guidelines for matched to patients belonging to information regarding cord blood accreditation, including NetCord and ethnic and/or minority patients who banking. Using a survey tool with need a cord blood transplant. More women in the third trimester of the Foundation for the Accreditation46 of ’ individuals from these groups need pregnancy or postpartum, Bhandari Cellular Therapy (FACT),​ FACT and47 56 the Joint Accreditation Committee,​ to store their infants cord blood et al was able to show that the main in cord blood banks. Education for reason women refuse donating the and the American48 Association of Blood Banks. For example, their ethnic and/or minority members of cord blood of their infants was a lack recommendations address the society is important to allow public of information about the procedure collection and storage of cord blood cord blood banks to build their and its outcome. Therefore, it is and prescribe the following: (1) cord inventory to increase specific, HLA- important that physicians become blood receptacles, (2) time processing, compatible cord blood sets to serve familiar with the advantages and (3) standard freezing and storage Ctheost needs of all people. disadvantages of public versus conditions, (4) segments of cord blood private cord blood banking to for testing and confirmation of identity, serve as a trusted resource to their (5) extra cells for potential extra testing, patients. Educational opportunities There are no placement or (6) rapid testing for infectious– agents, on cord blood banking should be maintenance fees for public cord enhanced by educational seminars and (7) long-term storage36,40​ of48 cord blood units in liquid nitrogen. ‍ ‍ These blood banks. For private cord blood at national meetings and through standards are critical for the safety of banks, a placement fee of $1350 to electronic means of communication. the prospective recipient and essential $2300 and an annual maintenance The public has access to information to physicians selecting products for use fee of $10054 to $175 is required of through a variety of sources. in HSCT. Only approximately 25% to Ufamiliesse . Physicians can play a critical role in 40% of collected umbilical cord blood directing families to reliable sources units satisfy these criteria for storage in of information on this topic. For a public bank; in contrast, most private 54 example, additional information – Ballen et al reported the results of ’ banks store the product regardless of about cord blood banking is available 49,50​ 51 51 53 59 private cord blood banks surveyed cell count. ‍ Sun et al and others ‍ through the Parent s Guide to for case reports of family cord blood have compared the differences in Cord Blood Foundation (https://​ units released for clinical use and quality between privately and publicly parentsguidecordblood.​ ​org/​en/​ compared these results to the World banked cord blood. The authors of public-​banking) and Be The Match Marrow Donor Association data on these studies concluded that publicly (https://​bethematch.​org/About-​ ​us/​). public cord blood storage and release stored cord blood was of a higher In addition, physicians have the for clinical use. quality because private cord blood opportunity to discuss key issues, including: banks are not subject to the same These authors reported that 30-fold Key Educational Points to Share With regulatory oversight and– have lesser- more cord blood units stored in Parents quality stored cord blood51 53 units with public cord blood banks have been decreased viability. ‍‍ released for clinical purposes as Access, Cost, and Use of Banked compared with those released54 from When expectant parents are present Cord Blood private cord blood banks. during a medical office visit for Education: Medical Personnel, their child or are establishing a ’ Access: Number of Cord Blood Banks Expectant Parents, and the Public relationship with the obstetrician or in North America Need for Education About Cord Blood pediatrician before the child s birth, Banking that physician and other health care providers may use that time as an •opportunity• to address the following: As of 2017, there are 28 public cord blood banks in North America (the In an AAP periodic survey of The rationale for public and private United States, Canada, and Mexico; fellows, only 18% of pediatricians cord blood banking. Public cord Downloaded from www.aappublications.org/news by guest on September 29, 2021 4 FROM THE AMERICAN ACADEMY OF PEDIATRICS •• blood banking serves the entire Informed consent and the such as bone marrow and peripheral

world, whereas private cord blood decision time frame, financial blood stem cell transplants (ie, banking serves the needs of 1 disclosure, and conflict of >600 000), appreciation for •• family; interest. The optimal time to alternative features and advantages obtain informed consent and to of cord blood transplants, such as The value of public cord blood make a decision on which form the use of partially HLA-matched banking to society. The parents of of cord blood banking (public or donor stem cells over haploidentical children who suffer fatal congenital private) is at the first prenatal stem cells, has not been fully disease or fatal acquired disease visit when the obstetrician and/ evaluated. will be able to search the public or pediatrician or other medical cord blood banks throughout the External oversight of cord blood personnel can discuss the option United States and other countries banking systems is critical in ’ in an unhurried environment. as well for matching of cord blood monitoring the quality of the blood Parents should not be asked to stem cells with a patient s HLA product from collection to long- make a decision after labor has ••antigens; term storage. External agencies begun. Disclosure of any medical (such as FACT, which has developed Accreditation and regulatory personnel with conflicts of accreditation guidelines and oversight of public and private interest in cord blood collection monitors public cord blood banks) cord blood banking. Public cord should be made to the expectant serve as an important mechanism to blood banking is highly regulated family at this time. In addition, a ensure across-the-board conformity by oversight accrediting declaration of potential conflict of with the strict purity of product institutions, whereas private interest needs to be made to the due to or expected by patients in cord blood banking may not meet institution in which the collection need of cord blood transplants. It is the strict requirements of some of cord blood cells is to be important that similar mechanisms accreditation bodies. Parents made. ’ be implemented to monitor private who are intent on donating their Conclusions cord blood banks. child s cord blood to a private cord blood bank are encouraged Selection Criteria As of today, public and private to ask industry representatives cord blood banking systems serve for evidence of validation and different purposes. Private cord ’ accreditation, financial cost, The AAP policy statement on blood banks serve parents who failure of cord blood to achieve cord blood banking for future elect to store their children s cord successful engraftment, and transplantation has been revised blood for potential self-use later in backup electrical systems in case because of the rapidly expanding life, although to date, there is little of storage equipment need for cord blood for HSCT for evidence supporting use for this ••failure; patients with childhood malignancies, purpose. Private cord blood banks hemoglobinopathies, primary also store cord blood for use in Costs associated with public immunodeficiencies, metabolic families with an identified sibling and private cord blood banking. ’ disease, and other disorders. Because in need of a transplant or a genetic There is no cost to families of the evolving use of cord blood risk of producing a sibling with a donating their infants cord ’ transplants for new applications in transplantable disease. Public cord blood to public banks, whereas – medicine, there is an important need blood banks store donated blood families who place their infants to inform medical personnel, parents, for non self-use (allogeneic) by cord blood with a private cord – and the public alike about advances individuals in the general public. blood bank must pay a placement in therapeutic approaches for cellular On average, cord blood stored fee ($1350 $2300) as well as a – immune reconstitution. in private cord blood banks is smaller annual maintenance fee 54 (1) underused, (2) not subject to ••($100 $175) ; The number of cord blood strict regulatory oversight, (3) The probability of use of public transplants for primary expensive for the family, and (4) and private cord blood banking. immunodeficiency is expected and may be of lesser quality (in The use rate of previously banked to increase because SCID is number and quality of stem cells) cord blood stem cells is at least increasingly being added to than that stored in public cord 30-fold greater in public cord newborn screening programs in blood banks. In contrast, cord

blood banks compared with54 that more and more states. Although this blood donated to public banks is of private cord blood banks ; number of cord blood transplants is more commonly used and heavily and small compared with total HSCTs, regulated. Thus, the cost and value Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 140, number 5, November 2017 5 of the maintenance of private cord 2. It is important that the concepts forms by the institutional review blood banks is not supported by of autologous and allogeneic use board are necessary; the evidence for use at the present of cord blood units be explained 5 5. The AAP advocates for regulatory time. to parents by physicians and Future Research agencies (eg, the Food and Drug medical staff to enable expectant Administration, the Federal Trade parents to make informed choices ’ Commission, and state equivalents regarding where they should of these federal agencies) to New developments in cord blood deposit their infant s cord blood ’ ’ have an active role in providing stem cell research may demonstrate and whether to restrict the blood oversight of the cord blood a need for the use of autologous or for the infant s or family s use program. It is important that all close-relative use of long-term cord or release it to the public for cord blood banking programs blood in a private banking system. A any child in need of stem cell comply with FACT or equivalent smaller but no less important need transplantation; for family-directed cord blood banks accreditation standards; and continues to be demonstrated for 3. Physicians need to convey 6. Physicians or other professionals families with known malignancies or accurate information about the who recruit pregnant women congenital diseases (eg, children with potential benefits and limitations and their families for for-profit severe primary immunodeficiencies of allogeneic and autologous cord placental cord blood stem and hemoglobinopathies). These blood banking and transplantation cell banking need to disclose special cord blood banks are to parents, including that any financial interest or other frequently located at university autologous cord blood would not potential conflict of interest they teaching hospitals. Private or be used as a stem cell source if the have relative to the procedure autologous cord blood banking may donor developed leukemia later to their patients. Similarly, be considered for experimental stem in life. It is important for parents professionals affiliated with cell regenerative research, in which to be aware that at this time, there institutions or organizations stem cell transplants are used to are no scientific data to support that promote for-profit placental attempt to restore nonfunctioning the claim that autologous cord blood stem cell banking need to or diseased nonhematologic tissue blood is a tissue source proven make annual financial-disclosure (eg, central nervous system or heart – to be of value for regenerative and potential-conflicts-of-interest muscle). However, local institutional medical purposes, although statements to an appropriate review board approved protocols researchers are examining this institutional review committee are necessary in addition to Food possibility; that possesses oversight and Drug Administration approval, if authority. applicable. Moreover, parents would – 4. It is expected that physicians AcknowledgmentS need to sign the institutional review and designated medical staff board approved informed consent obtain specific permission for document if private banking is used maintaining demographic medical We thank Ms Janice Hopkins and for this purpose. information and that the potential Ms Carolyn Jackson for their Recommendations risks of breaches of confidentiality assistance in preparing this policy be disclosed to parents. Specific Lstatement.ead Authors efforts need to be made to recruit 1. Public cord blood banking is the underserved ethnic minorities William T. Shearer, MD, PhD, FAAP preferred method of collecting, for cord blood donations to Bertram H. Lubin, MD, FAAP Mitchell S. Cairo, MD, FAAP processing, and using cord blood enlarge the public cord blood Luigi D. Notarangelo, MD cells for use in transplantation repositories and better serve in infants and children with fatal these patient populations. Before Section on Hematology/Oncology diseases, such as malignancies, the onset of active labor, written Executive Committee, 2015–2016 blood disorders, immune permission needs to be obtained deficiencies, and metabolic from parents to collect the cord Jeffrey Hord, MD, FAAP, Chairperson Gary Crouch, MD, FAAP disorders. There is a more limited blood for banking purposes. If the Gregory Hale, MD, FAAP role of private cord blood banking cord blood bank is conducting James Harper, MD, FAAP with families with a known fatal therapeutic human research Jeffrey Lipton, MD, FAAP illness that can be rescued by a involving cord blood, review Zora Rogers, MD, FAAP healthy cord blood transplant and approval of the recruitment within the family; strategies and parental consent Downloaded from www.aappublications.org/news by guest on September 29, 2021 6 FROM THE AMERICAN ACADEMY OF PEDIATRICS Eric Werner, MD, FAAP, Immediate Past Jennifer S. Kim, MD, FAAP Chairperson Michael Pistiner, MD, FAAP Abbreviations Julie Wang, MD, FAAP Staff Additional Contributors Suzanne Kirkwood, MS AAP: American Academy of Thomas A. Fleisher, MD, FAAP, past member Pediatrics Section on Allergy and Immunology Scott H. Sicherer, MD, FAAP, past member FACT: Foundation for the Executive Committee, 2015–2016 Paul V. Williams, MD, FAAP, liaison to the Accreditation of Cellular Elizabeth C. Matsui, MD, FAAP, Chairperson American Academy of Allergy, Asthma, and Stuart L. Abramson, MD, PhD, FAAP Immunology Therapy Chitra Dinakar, MD, FAAP HSCT: hematopoietic stem cell Anne-Marie Irani, MD, FAAP Staff transplant Todd A. Mahr, MD, Immediate Past Chairperson Debra Burrowes, MHA SCID: severe combined immuno- deficiency disease

Address correspondence to William T. Shearer, MD, PhD, FAAP. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Notarangelo is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; and Drs Shearer, Lubin, and Cairo have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: Dr Notarangelo has had a consulting relationship with Sigma-Tau; this relationship is not currently active; and Drs Shearer, Lubin, and Cairo have indicated they have no potential conflicts of interest to disclose.

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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2017/10/26/peds.2 017-2695 References This article cites 35 articles, 9 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2017/10/26/peds.2 017-2695#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Hematology/Oncology http://www.aappublications.org/cgi/collection/hematology:oncology_ sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

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