• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jmlaJournal informationSubscribeSubmissions on the Publisher web siteCurrent issue of JMLA in PMCAlso see BMLA journal in PMC
J Med Libr Assoc. Jul 2008; 96(3): 183–188.
PMCID: PMC2479049

Addressing Hemolysis in an Infant Due to Mother–Infant ABO Blood Incompatibility

Sandra Martin, MLS, Assistant Director, Rebecca N. Jerome, MLIS, MPH, Assistant Director, Adjunct Instructor, Marcia I. Epelbaum, MA, Assistant Director, Annette M. Williams, MLS, Associate Director, and William Walsh, MD, Chief of Nurseries

Introduction

This issue of the Journal of the Medical Library Association (JMLA) honors the life of and contributions to medical librarianship of Estelle Brodman, PhD. Dr. Brodman's interests in medical bibliography, automation, international collaboration, education, the history of medicine, and the profession were far reaching, and her ideas reflected innovation and a strong desire to grow the profession and skills of medical librarians [1, 2]. Since that time, medical librarianship has continued to evolve, realizing many of the ideas Dr. Brodman and others advocated. For example, the availability of medical databases and widespread use of computers in libraries have improved library processes and the ability to quickly locate information. With her strong advocacy of lifelong learning, Dr. Brodman also serves as an important role model as a librarian/educator, and she would likely have been pleased to see the profession's emphasis on continuing education and research [3, 4].

As McClure noted in her discussion of Dr. Brodman as a historian, Dr. Brodman found that the study of history “often illuminates the meaning of the present and indicates logical possibilities for the future” [5]. The history of the development of neonatal critical care, like that of medical librarianship, has doubtless been influenced and evolved by pioneering thinkers. One such thinker and contemporary of Dr. Brodman, Mildred T. Stahlman, MD, was also a leader in education, practice, and research in her chosen field, neonatal critical care medicine. In 1961, Dr. Stahlman, known as the pioneer of modern neonatal intensive care, led a National Institutes of Health research project to explore the physiological aspects of the developing fetus and changes that occur at birth [6, 7]. At a critical point in her research, Dr. Stahlman made the groundbreaking decision to adapt a scaled-down respirator, a breathing machine originally developed for polio patients, to assist breathing in an infant born with severe hyaline membrane disease, a lung disease seen in premature infants whose lungs have not yet fully developed. The infant, who previously faced certain death, was able to survive with this first-ever respiratory therapy that gave a viable treatment option for preterm babies with underdeveloped lungs [6, 8]. This groundbreaking research led Dr. Stahlman to develop the first modern neonatal intensive care unit (NICU) at Vanderbilt University Medical Center [6].

Today, NICUs have become an essential part of health care in the United States for critically ill infants and their families, providing constant observation and care for these babies. Premature babies, infants born earlier than thirty-seven weeks gestation (the typical threshold for defining normal gestation) [9], represent a high percentage of those cared for by a NICU. These babies often have a variety of developmental issues requiring intensive treatment. Given the constantly evolving state of clinical research, NICU teams frequently encounter information needs requiring consultation of the medical literature.

The Case

You are a librarian collaborating with the clinical team in your hospital's NICU, who round at the bedside of a thirty-six-week gestation infant girl. Although the baby was premature, the diagnosis that prompted her admission to the NICU was ABO incompatibility, a condition that can appear in both premature and full-term babies and part of a broader family of conditions that includes Rh incompatibility [10].

The human ABO system includes four blood groups: A, B, AB, and O [10]. Blood cells of individuals with type A or B blood have small molecules on their surfaces called antigens. The human body generates antibodies against whichever blood group antigens it does not have [11]. Humans with group A generate anti-B antibodies; those with group B generate anti-A antibodies; AB individuals have both antigens so they do not produce anti-A or anti-B antibodies; and individuals with type O blood do not have these surface antigens, so they create antibodies against both A and B [11, 12].

If the mother's blood type does not match the fetal blood type (in the current case, this baby is type B and her mother is type O), then the mother's immune system may create antibodies against the fetus's blood type, which then can travel back across the placenta to the fetus [13, 14]. After the baby is born, some of the baby's red blood cells (RBCs) may be coated with the maternal antibodies, leading to destruction of some of the RBCs (hemolysis, also referred to as hemolytic disease of the newborn) by the baby's immune system. The first signs of this kind of hemolysis often include jaundice and high bilirubin levels in the baby's blood (hyperbilirubinemia) [1517]. Clinicians aggressively treat these symptoms in infants affected by ABO incompatibility, because hyperbilirubinemia can cause serious adverse effects for the baby if left untreated. Such adverse events include kernicterus (brain damage due to high bilirubin), cerebral palsy, or deafness [15]. ABO incompatibility occurs in approximately 15% of all pregnancies, but hemolytic disease of the newborn develops in only 4%. This condition is also more common and often more severe in infants of African descent [10].

At birth, this baby's bilirubin is markedly high at 12 milligrams per deciliter (mg/dL) (normal range 0.3–1.9 mg/dL [18]. Her face and abdomen have become yellow in appearance, indicative of jaundice, and phototherapy (light therapy that aids the baby's body in removing excess bilirubin from the blood [19] and hydration have already been started to treat her jaundice. It is now day of life 2, and her bilirubin level continues to rise (now, 16 mg/dL) despite the interventions. During morning rounds, the team's discussion focuses on the next treatment steps to pursue. The clinical team discusses whether an exchange transfusion (a process by which the infant's blood would be removed and replaced with fresh donor blood or plasma [20] is necessary now or whether there might be another, less-invasive option to try first. Because exchange transfusion is very traumatic for preterm infants and is associated with numerous and potentially life-threatening complications [20], the team feels it is imperative to consider less intrusive treatments if available and effective. One physician notes that she has seen literature about intravenous immunoglobulin (IVIG) therapy to treat this type of hemolysis. The team asks you to investigate this therapeutic option immediately to support the development of this baby's treatment plan. Figure 1 provides additional commentary from the attending physician (Walsh) on the significance of this question for the practice of neonatal critical care medicine.

Figure 1
Clinician comments

The Clinical Question

Is IVIG a safe and effective alternative to exchange transfusion in a premature infant with hemolysis and hyperbilirubinemia secondary to ABO incompatibility, who has failed phototherapy?

Understanding The Medical Concepts

In addition to the concepts defined above, it also may be useful to look closer at the human body's immune response and the involvement of immunoglobulin G (IgG, also known as gammaglobulin) to better understand why the team is considering this agent as a treatment option.

Antibodies, also known as immunoglobulins, are one kind of protein found in the blood. These immunoglobulins function as a key part of the body's immune defense system. IgG is one of the most important parts of the immune response: it coats foreign cells so that other cells defending the body are better able to find and destroy the foreign cells [22]. To make IgG available for therapeutic use, donor blood plasma is pooled and purified and then administered to patients intravenously [22]. In the setting of hemolysis due to ABO incompatibility, researchers postulate that IVIG may block the maternal antibodies circulating in the baby's bloodstream from destroying the baby's RBCs, halting the progression of hemolytic anemia [16]. Thus, administration of IVIG may help the baby's body counteract the potential adverse effects of any blood group–related antibodies acquired from the mother during gestation.

Exploring The Literature

After building your knowledge on the topic, you may find it helpful to use the evidence-based format—patient, population, or problem; intervention or exposure; comparison; outcome (PICO)—to develop and organize your search strategy [23] (Table 1). Basing your strategy on this framework, your search in PubMed may look something like this:

Table 1
Potential terms for searching PubMed

(hyperbilirubinemia[mh] OR erythroblastosis, fetal[mh] OR anemia, hemolytic[mh]) AND immunoglobulins, intravenous[mh] AND infant, newborn[mh]

You try adding in terms for the ABO incompatibility portion of the question from Table 1, but you notice that doing so seems to screen out quite a bit of material, leading you to suspect that you may be risking omitting relevant information, and you return to the broader search strategy. Because this strategy retrieves approximately seventy articles, further limiting seems unnecessary. In considering this retrieval set, you exclude articles in which titles and abstracts indicate topics irrelevant to the case, such as those focusing on other blood incompatibilities that are fairly different from the ABO incompatibility illustrated by the current case (e.g., Rh hemolytic disease), conditions like parvovirus infection, or intrauterine diagnosis and therapy for the fetus.

After this process of elimination, you have a pool of six articles that report original patient data on IVIG treatment of hyperbilirubinemia due to ABO incompatibility [17,24 28], two relevant systematic reviews [29, 30], and one recent general review article [31]. Now you are ready to evaluate the quality of the evidence these citations provide by assessing the strength of this primary research on the topic.

By looking at the retrieved prospective studies [17, 2426], you immediately realize that your topic has not been heavily investigated, and, after reading the abstracts, you note that the studies do not include a large number of infants. Because the retrieval yields no clinical trials conducted in the United States, you consider trials performed in foreign centers, being alert to variations—such as genetic, socioeconomic, and cultural differences—that can affect results when extrapolating and applying to a US NICU population. Even though the centers and investigators represented by the trials are not well known for pediatric research, they form the core of available evidence on the topic.

In addition to these prospective studies, you find two small case studies, one including nine babies [27] and one with three babies [28]. Given the relatively small size of this literature, these two articles may merit a brief mention in your summarization of the literature, though their small size and retrospective nature present challenges to generalizability.

You examine the two systematic reviews more closely to evaluate their relevance and relative strengths and weaknesses. The systematic review completed by Alcock and Liley in 2002 [29] evaluates whether IVIG is effective in reducing the need for exchange transfusion in neonates with isoimmune hemolytic jaundice (“isoimmune,” also “alloimmune,” refers to the development of antibodies in an individual against antibodies from another individual in the same species [30], a broad group of diseases to which ABO incompatibility belongs). Their analysis of three studies meeting their inclusion criteria (one of these studies included ABO incompatibility) indicates that IVIG is associated with a significant reduction in the need for exchange transfusion in isoimmune hemolytic jaundice; however, the authors emphasize that variability and other methodological concerns regarding the included studies are likely associated with significant limitations to applicability and generalizability. The second systematic review by Gottstein and Cooke examines the same literature with slightly less stringent methodological criteria and time period and arrives at similar conclusions [31].

Examining the references of the general review by Murray and Roberts [32] reassures you that you have found the key items in this area. Also, in the section of the review covering high-dose IVIG, you note that the authors identify late anemia as a potential problem in patients treated with IVIG instead of exchange therapy, because the maternal antibodies remain in the blood after IVIG therapy but are largely removed during the exchange transfusion process. Armed with this knowledge, you can watch for comments on this side effect as you summarize the individual studies for the team.

A brief search of guidelines.gov uncovers a 2004 guideline from the American Academy of Pediatrics (AAP) on the management of hyperbilirubinemia in newborn infants of thirty-five or more weeks of gestation [21]. This guideline includes the following recommendation statement: “Intravenous [gamma]-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease,” which is followed by a comment on the limited data available to support this recommendation, in line with the paucity of studies you have identified in your literature search.

Summarizing The Literature

To provide the team with an overview of your findings, you prepare a concise statement that encapsulates the main points of the topic with pertinent observations on the quality and quantity of the available evidence. For this question, your overall summary (example in Figure 2) may include:

Figure 2
Sample statement describing the overall state of the literature
  • commentary on the methodological variation and relatively small amount of data available to address the question, with reference to the two systematic reviews [29, 30] and the AAP guidelines [21] affirming these issues
  • brief commentary on the included studies and case series to give the team an overall sense of the available evidence on efficacy and safety
  • a note indicating that IVIG has also been used to treat other conditions in neonates (e.g., Rh incompatibility) and that you can provide summary of this literature as well if the team is interested in exploring broader applicability of this intervention in the NICU

Following your overall evaluation on the topic, you briefly summarize each of the articles you selected, highlighting their relevance to the question. Table 2 provides example summaries, including:

Table 2
Detailed summaries of included articles
  • the design of each study
  • the number of patients and their conditions (as some of the studies included Rh incompatibility as well)
  • methods of each study, including dosage and administration schedule for IVIG and other treatment information (e.g., concurrent phototherapy)
  • study results, including the number of patients requiring exchange transfusion and other outcomes measured (e.g., hospital stay), and any adverse events

Concluding Remarks

Because of the detrimental effect of exchange transfusion on an infant recipient, finding a safe and effective alternative would not only be beneficial for the present patient, but potentially for many who follow. A less invasive therapy would prevent the trauma and possible complications endured by infants with hemolysis and their families.

Sackett's classic definition for evidence-based medicine as the “conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients” [33] notes the importance of both clinical expertise and the best-available evidence in determining the ideal pathway for patient care. This case serves as an example of augmenting clinical judgment with evidence, however limited, from the literature and underscores the value of each. The literature serves to confirm clinician assumptions regarding the utility of the therapy, while clinical judgment dictates a need to explore options to reduce potential adverse events for this child.

At the authors' institution when this question was originally asked in 2003, this practice of evidence-based medicine resulted in the NICU team's decision to treat this patient with IVIG, successfully restoring her bilirubin level to normal. Subsequently, this therapy was adopted as part of the NICU's protocol for hyperbilirubinemia with ABO incompatibility and is now frequently employed in babies whose bilirubin continues to increase despite phototherapy. Thus, the integration of evidence from the literature with the expertise of the clinical team, including the librarian as a key member, led to an exciting and important advancement for infant care in the NICU.

Contributor Information

Sandra Martin, Eskind Biomedical Library ; ude.tlibrednav@nitram.idnas.

Rebecca N. Jerome, Eskind Biomedical Library and Department of Biomedical Informatics ; ude.tlibrednav@emorej.acceber.

Marcia I. Epelbaum, ude.tlibrednav@muablepe.aicram.

Annette M. Williams, Eskind Biomedical Library ; ude.tlibrednav@smailliw.ettenna.

William Walsh, Neonatal Intensive Care Unit, Division of Pediatrics, Vanderbilt University Medical Center, Nashville, TN ; ude.tlibrednav@hslaw.mailliw.

References

1. Brodman E. The development of medical bibliography. Baltimore, MD: Medical Library Association; 1954.
2. Messerle J. Celebrating individual heroes: the continuing relevance of Estelle Brodman [editorial] J Med Libr Assoc. 2008 Jul;96(3):181–2. [PMC free article] [PubMed]
3. Medical Library Association. Professional competencies: MLA's educational policy statement [Internet] Chicago, IL: The Association; 2006 [cited 15 Feb 2008]. < http://www.mlanet.org/education/policy/>.
4. Medical Library Association. The research imperative: the research policy statement policy statement of the Medical Library Association [Internet] Chicago, IL: The Association; 2007 [cited 15 Feb 2008]. < http://www.mlanet.org/research/policy/policy-02.html>.
5. McClure L.W. Introduction: personal recollections of the contributions of Estelle Brodman: an enduring legacy for health sciences librarianship. J Med Libr Assoc. 2008 Jul;96(3):239–41. [PMC free article] [PubMed]
6. Monroe Carell, Jr. Children's Hospital at Vanderbilt, Division of Neonatology. History [Internet] Nashville, TN: Vanderbilt University Medical Center; 2006 [rev. 23 Oct 2006; cited 8 Feb 2008]. < http://www.vanderbiltchildrens.com/interior.phpmid209>.
7. Meet local legend: Mildred Stahlman, M.D. [Internet] Bethesda, MD: National Institutes of Health [cited 5 Feb 2008]; < http://www.nlm.nih.gov/locallegends/Biographies/Stahlman_Mildred.html>.
8. Stahlman M. Respiratory regulation in the newborn. Ann N Y Acad Sci. 1963 Jun 24;109:882–91. [PubMed]
9. MedlinePlus medical encyclopedia [Internet] Atlanta, GA: A.D.A.M; 2007 [rev. 19 Oct 2007; cited 8 Feb 2008]. Gestational age. < http://www.nlm.nih.gov/medlineplus/ency/article/002367.htm>.
10. Calhoun D.A. UpToDate [Internet] Waltham, MA: UpToDate; 2007. Postnatal diagnosis and management of alloimmune hemolytic disease of the newborn.
11. Cohen D.W. UpToDate [Internet] Waltham, MA: UpToDate; 2007. A primer of red blood cell antigens and antibodies.
12. MedlinePlus medical encyclopedia [Internet] Atlanta, GA: A.D.A.M; 2007 [rev. 13 Mar 2007; cited 5 Feb 2008]. ABO incompatibility. < http://www.nlm.nih.gov/medlineplus/ency/article/001306.htm>.
13. McGraw-Hill encyclopedia of science and technology [Internet] Columbus, OH: The McGraw-Hill Companies; 2005 [cited 8 Feb 2008]. Blood groups. < http://www.answers.com/topic/blood-groupcathealth>.
14. Cohen D.W. UpToDate [Internet] Waltham, MA: UpToDate; 2006. Hemolytic disease of the newborn: RBC alloantibodies in pregnancy and associated serologic issues.
15. MedlinePlus medical encyclopedia [Internet] Atlanta, GA: A.D.A.M; 2007 [rev. 6 Sep 2007; cited 8 Feb 2008]. Newborn jaundice. < http://www.nlm.nih.gov/medlineplus/ency/article/001559.htm>.
16. Mundy C.A. Intravenous immunoglobulin in the management of hemolytic disease of the newborn. Neonatal Netw. 2005 Nov;24(6):17–24. [PubMed]
17. Hammerman C., Vreman H.J., Kaplan M., Stevenson D.K. Intravenous immune globulin in neonatal immune hemolytic disease: does it reduce hemolysis. Acta Paediatr. 1996 Nov;85(11):1351–3. [PubMed]
18. MedlinePlus medical encyclopedia [Internet] Atlanta, GA: A.D.A.M; 2007 [rev. 22 Jan 2007; cited 5 Feb 2008]. Bilirubin. < http://www.nlm.nih.gov/medlineplus/ency/article/003479.htm>.
19. MedlinePlus medical encyclopedia [Internet] Atlanta, GA: A.D.A.M; 2007 [rev. 19 Oct 2007; cited 8 Feb 2008]. Bili lights. < http://www.nlm.nih.gov/medlineplus/ency/article/002394.htm>.
20. MedlinePlus medical encyclopedia [Internet] Atlanta, GA: A.D.A.M; 2007 [rev. 19 Oct 2007; cited 5 Feb 2008]. Exchange transfusion. < http://www.nlm.nih.gov/medlineplus/ency/article/002923.htm>.
21. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul;114(1):297–316. [PubMed]
22. Primary immunodeficiency [Internet] Bethesda, MD: National Institute of Child Health and Human Development; 2006 [rev. 9 Aug 2006; cited 8 Feb 2008]. < http://www.nichd.nih.gov/publications/pubs/primary_immuno.cfm>.
23. Schardt C., Adams M.B., Owens T., Keitz S., Fontelo P. Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inform Decis Mak. 2007 Jun 15;7:16. [PMC free article] [PubMed]
24. Miqdad A.M., Abdelbasit O.B., Shaheed M.M., Seidahmed M.Z., Abomelha A.M., Arcala O.P. Intravenous immunoglobulin G (IVIG) therapy for significant hyperbilirubinemia in ABO hemolytic disease of the newborn. J Matern Fetal Neonatal Med. 2004 Sep;16(3):163–6. [PubMed]
25. Alpay F., Sarici S.U., Okutan V., Erdem G., Ozcan O., Gökcay E. High-dose intravenous immunoglobulin therapy in neonatal immune haemolytic jaundice. Acta Paediatr. 1999 Feb;88(2):216–9. [PubMed]
26. Tanyer G., Siklar Z., Dallar Y., Yildirmak Y., Tiraş U. Multiple dose IVIG treatment in neonatal immune hemolytic jaundice. J Trop Pediatr. 2001 Feb;47(1):50–3. [PubMed]
27. Ergaz Z., Arad I. Intravenous immunoglobulin therapy in neonatal immune hemolytic jaundice. J Perinat Med. 1993;21(3):183–7. [PubMed]
28. Sato K., Hara T., Kondo T., Iwao H., Honda S., Ueda K. High-dose intravenous gammaglobulin therapy for neonatal immune haemolytic jaundice due to blood group incompatibility. Acta Paediatr Scand. 1991 Feb;80(2):163–6. [PubMed]
29. Alcock G.S., Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev. 2002. art. no.: CD003313. DOI: 10.1002/14651858.CD003313. [PubMed]
30. Concise medical dictionary [Internet] Oxford, UK: Oxford University Press; 2007 [cited 8 Feb 2008]. Isoimmunization. < http://www.oxfordreference.com/views/ENTRY.htmlsubviewMainentryt60.e5219>.
31. Gottstein R., Cooke R.W. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed. 2003 Jan;88(1):F6–10. [PMC free article] [PubMed]
32. Murray N.A., Roberts I.A. Haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed. 2007 Mar;92(2):F83–8. [PMC free article] [PubMed]
33. Sackett D.L., Rosenberg W.M., Gray J.A., Haynes R.B., Richardson W.S. Evidence based medicine: what it is and what it isn't. BMJ. 1996 Jan 13;312(7023):71–2. [PMC free article] [PubMed]

Articles from Journal of the Medical Library Association : JMLA are provided here courtesy of Medical Library Association
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...